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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TREXIMET safely and effectively. See full prescribing information for TREXIMET. TREXIMET (sumatriptan and naproxen sodium) tablets, for oral use Initial U.S. Approval: 2008 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.1) • TREXIMET is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2) ---------------------------RECENT MAJOR CHANGES --------------------------­ Warnings and Precautions (5.14) 11/2024 --------------------------- INDICATIONS AND USAGE---------------------------­ TREXIMET is a combination of sumatriptan, a serotonin (5-HT) 1b/1d receptor agonist (triptan), and naproxen sodium, a non-steroidal anti- inflammatory drug, indicated for the acute treatment of migraine with or without aura in adults and pediatric patients 12 years of age and older. (1) Limitations of Use: • Use only if a clear diagnosis of migraine headache has been established. (1) • Not indicated for the prophylactic therapy of migraine attacks. (1) • Not indicated for the treatment of cluster headache. (1) -----------------------DOSAGE AND ADMINISTRATION ----------------------­ Adults • Recommended dosage: 1 tablet of 85/500 mg. (2.1) • Maximum dosage in a 24-hour period: 2 tablets of 85/500 mg; separate doses by at least 2 hours. (2.1) Pediatric Patients 12 to 17 years of Age • Recommended dosage: 1 tablet of 10/60 mg. (2.2) • Maximum dosage in a 24-hour period: 1 tablet of 85/500 mg. Mild to Moderate Hepatic Impairment • Recommended dosage: 1 tablet of 10/60 mg. (2.3, 8.7) --------------------- DOSAGE FORMS AND STRENGTHS---------------------­ Tablets: 85 mg sumatriptan / 500 mg naproxen sodium (3) 10 mg sumatriptan / 60 mg naproxen sodium (3) ------------------------------ CONTRAINDICATIONS -----------------------------­ • History of coronary artery disease or coronary vasospasm. (4) • In the setting of CABG surgery. (4) • Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders. (4) • History of stroke, transient ischemic attack, or hemiplegic or basilar migraine. (4) • Peripheral vascular disease. (4) • Ischemic bowel disease. (4) • Uncontrolled hypertension. (4) • Recent (within 24 hours) use of another 5-HT1 agonist (e.g., another triptan) or of ergotamine-containing medication. (4) • Concurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor. (4) • History of asthma, urticaria, other allergic type reactions, rhinitis, or nasal polyps syndrome after taking aspirin or other NSAID/analgesic drugs. (4) • Known hypersensitivity to sumatriptan, naproxen, or any components of TREXIMET (angioedema and anaphylaxis seen). (4) • Severe hepatic impairment. (4) • Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure: Generally not associated with myocardial ischemia; evaluate for coronary artery disease in patients at high risk. (5.4) • Cerebrovascular Events: Discontinue TREXIMET if occurs. (5.5) • Other Vasospasm Reactions: Discontinue TREXIMET if non-coronary vasospastic reaction occurs. (5.6) • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.7) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.8) • Heart Failure and Edema: Avoid use of TREXIMET in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.9) • Medication Overuse Headache: Detoxification may be necessary. (5.10) • Serotonin Syndrome: Discontinue TREXIMET if occurs. (5.11) • Renal Toxicity and Hyperkalemia: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of TREXIMET in patients with advanced renal disease. (5.12) • Anaphylactic Reactions: TREXIMET should not be given to patients with the aspirin triad. Seek emergency help if an anaphylactic reaction occurs. (5.13) • Serious Skin Reactions: Discontinue TREXIMET at first sign of rash or other signs of hypersensitivity. (5.14) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically. (5.15) • Fetal Toxicity: Limit use of NSAIDs, including TREXIMET, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. (5.16, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. (5.17) • Exacerbation of Asthma Related to Aspirin Sensitivity: TREXIMET is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.18) ------------------------------ ADVERSE REACTIONS -----------------------------­ The most common adverse reactions (incidence ≥2%) were: • Adults: Dizziness, somnolence, nausea, chest discomfort/chest pain, neck/throat/jaw pain/tightness/pressure, paresthesia, dyspepsia, dry mouth. (6.1) • Pediatrics: Hot flush (i.e., hot flash[es]) and muscle tightness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Currax Pharmaceuticals LLC at 1-800-793-2145 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS------------------------------­ • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking TREXIMET with drugs that interfere with hemostasis. Concomitant use of TREXIMET and analgesic doses of aspirin is not generally recommended. (7.1) • ACE Inhibitors and ARBs: Concomitant use with TREXIMET in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. (7.1) • Diuretics: NSAIDs can reduce natriuretic effect of loop and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. (7.1) • Digoxin: Concomitant use with TREXIMET can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. (7.1) • Lithium: Increases lithium plasma levels. (7.1) • Methotrexate: Increases methotrexate plasma levels. (7.1) -----------------------USE IN SPECIFIC POPULATIONS-----------------------­ • Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of TREXIMET in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDA­ ------------------------ WARNINGS and PRECAUTIONS -----------------------­ approved Medication Guide. • Cardiovascular Thrombotic Events: Perform cardiac evaluation in patients Revised: 11/2024 with cardiovascular risk factors. (5.1) • Arrhythmias: Discontinue TREXIMET if occurs. (5.3) Reference ID: 5482765 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosage in Adults 2.2 Dosage in Pediatric Patients 12 to 17 years of age 2.3 Dosage in Patients with Hepatic Impairment 2.4 Administration Information 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Arrhythmias 5.4 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure 5.5 Cerebrovascular Events 5.6 Other Vasospasm Reactions 5.7 Hepatotoxicity 5.8 Hypertension 5.9 Heart Failure and Edema 5.10 Medication Overuse Headache 5.11 Serotonin Syndrome 5.12 Renal Toxicity and Hyperkalemia 5.13 Anaphylactic Reactions 5.14 Serious Skin Reactions 5.15 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.16 Fetal Toxicity 5.17 Hematologic Toxicity 5.18 Exacerbation of Asthma Related to Aspirin Sensitivity 5.19 Seizures 5.20 Masking of Inflamation and Fever 5.21 Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Clinically Significant Drug Interactions with TREXIMET 7.2 Drug/Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Adults 14.2 Pediatric Patients 12 to 17 Years of Age 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482765 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • TREXIMET is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE TREXIMET is indicated for the acute treatment of migraine with or without aura in adults and pediatric patients 12 years of age and older. Limitations of Use: • Use only if a clear diagnosis of migraine headache has been established. If a patient has no response to the first migraine attack treated with TREXIMET, reconsider the diagnosis of migraine before TREXIMET is administered to treat any subsequent attacks. • TREXIMET is not indicated for the prevention of migraine attacks. • Safety and effectiveness of TREXIMET have not been established for cluster headache. 2 DOSAGE AND ADMINISTRATION 2.1 Dosage in Adults The recommended dosage for adults is 1 tablet of TREXIMET 85/500 mg. TREXIMET 85/500 mg contains a dose of sumatriptan higher than the lowest effective dose. The choice of the dose of sumatriptan, and of the use of a fixed combination such as in TREXIMET 85/500 mg should be made on an individual basis, weighing the possible benefit of a higher dose of sumatriptan with the potential for a greater risk of adverse reactions. The maximum recommended dosage in a 24-hour period is 2 tablets, taken at least 2 hours apart. The safety of treating an average of more than 5 migraine headaches in adults in a 30-day period has not been established. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. 2.2 Dosage in Pediatric Patients 12 to 17 Years of Age The recommended dosage for pediatric patients 12 to 17 years of age is 1 tablet of TREXIMET 10/60 mg. The maximum recommended dosage in a 24-hour period is 1 tablet of TREXIMET 85/500 mg. The safety of treating an average of more than 2 migraine headaches in pediatric patients in a 30-day period has not been established. Reference ID: 5482765 Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. 2.3 Dosing in Patients with Hepatic Impairment TREXIMET is contraindicated in patients with severe hepatic impairment [see Contraindications (4), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. In patients with mild to moderate hepatic impairment, the recommended dosage in a 24-hour period is 1 tablet of TREXIMET 10/60 mg [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. 2.4 Administration Information TREXIMET may be administered with or without food. Tablets should not be split, crushed, or chewed. 3 DOSAGE FORMS AND STRENGTHS 10 mg sumatriptan/60 mg naproxen sodium, light-blue film-coated tablets, debossed on one side with “TREXIMET” and the other side with “10-60”. 85 mg sumatriptan/500 mg naproxen sodium, blue film-coated tablets, debossed on one side with “TREXIMET” 4 CONTRAINDICATIONS TREXIMET is contraindicated in the following patients: • Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal’s angina [see Warnings and Precautions (5.1)]. • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]. • Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions (5.3)]. • History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [see Warnings and Precautions (5.5)]. • Peripheral vascular disease [see Warnings and Precautions (5.6)]. • Ischemic bowel disease [see Warnings and Precautions (5.6)]. • Uncontrolled hypertension [see Warnings and Precautions (5.8)]. • Recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine1 (5-HT1) agonist [see Drug Interactions (7)]. • Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor [see Drug Interactions (7), Clinical Pharmacology (12.3)]. • History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.13, 5.14, 5.18)]. • Known hypersensitivity (e.g., anaphylactic reactions, angioedema, and serious skin reactions) to sumatriptan, naproxen, or any components of TREXIMET [see Warnings and Precautions (5.14)]. • Severe hepatic impairment [see Warnings and Precautions (5.7), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Reference ID: 5482765 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events The use of TREXIMET is contraindicated in patients with ischemic or vasospastic coronary artery disease (CAD) and in the setting of coronary artery bypass graft (CABG) surgery due to increased risk of serious cardiovascular events with sumatriptan and NSAIDS [see Contraindications (4)]. Cardiovascular Events with Sumatriptan There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of sumatriptan. Some of these reactions occurred in patients without known CAD. TREXIMET may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD. Cardiovascular Thrombotic Events with Nonsteroidal Anti-inflammatory Drugs Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Perform a cardiovascular evaluation in patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving TREXIMET. If there is evidence of CAD or Reference ID: 5482765 coronary artery vasospasm, TREXIMET is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of TREXIMET in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of TREXIMET. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of TREXIMET. Physicians and patients should remain alert for the development of cardiovascular events, even in the absence of previous cardiovascular symptoms. Patients should be informed about the signs and/or symptoms of serious cardiovascular events and the steps to take if they occur. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including naproxen, a component of TREXIMET, cause serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only 1 in 5 patients who develop a serious upper gastrointestinal adverse event on NSAID therapy is symptomatic. Upper gastrointestinal ulcers, gross bleeding, or perforation caused by NSAIDs appear to occur in approximately 1% of patients treated daily for 3 to 6 months and in about 2% to 4% of patients treated for 1 year. However, even short-term therapy is not without risk. Among 3,302 adult patients with migraine who received TREXIMET in controlled and uncontrolled clinical trials, 1 patient experienced a recurrence of gastric ulcer after taking 8 doses over 3 weeks, and 1 patient developed a gastric ulcer after treating an average of 8 attacks per month over 7 months. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing gastrointestinal bleeding compared with patients with neither of these risk factors. Other factors that increase the risk for gastrointestinal bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal gastrointestinal events occurred in elderly or debilitated patients, and therefore special care should be taken in treating this population. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For high risk patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue TREXIMET until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue TREXIMET if these disturbances occur. Reference ID: 5482765 TREXIMET is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. 5.4 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with sumatriptan and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of TREXIMET is contraindicated in patients with CAD and those with Prinzmetal’s variant angina. 5.5 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue TREXIMET if a cerebrovascular event occurs. Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, exclude other potentially serious neurological conditions. TREXIMET is contraindicated in patients with a history of stroke or TIA [see Contraindications (4)]. 5.6 Other Vasospasm Reactions Sumatriptan may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud′s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional TREXIMET. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established. 5.7 Hepatotoxicity Borderline elevations of 1 or more liver tests may occur in up to 15% of patients who take NSAIDs including naproxen, a component of TREXIMET. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Notable (3 times the upper limit of normal) elevations of SGPT (ALT) or SGOT (AST) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare, sometimes fatal cases of severe hepatic injury, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure have been reported with NSAIDs. TREXIMET is contraindicated in patients with severe hepatic impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with TREXIMET. TREXIMET should be discontinued if clinical signs and symptoms consistent with liver disease develop, if systemic manifestations occur (e.g., eosinophilia, rash), or if abnormal liver tests persist or worsen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flulike" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if Reference ID: 5482765 systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue TREXIMET immediately, and perform a clinical evaluation of the patient. 5.8 Hypertension Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including sumatriptan, a component of TREXIMET. This occurrence has included patients without a history of hypertension. NSAIDs, including naproxen, a component of TREXIMET, can also lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of cardiovascular events. Patients taking angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure in patients treated with TREXIMET. TREXIMET is contraindicated in patients with uncontrolled hypertension [see Contraindications (4)]. 5.9 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID- treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of TREXIMET in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If TREXIMET is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Since each TREXIMET 85/500 mg tablet contains approximately 60 mg of sodium and each TREXIMET 10/60 mg tablet contains approximately 20 mg of sodium, this should be considered in patients whose overall intake of sodium must be severely restricted. 5.10 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.11 Serotonin Syndrome Serotonin syndrome may occur with TREXIMET, particularly during coadministration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Contraindications (4) and Drug Interactions (7.1)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually Reference ID: 5482765 occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue TREXIMET if serotonin syndrome is suspected. 5.12 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and angiotensin-converting enzyme (ACE) inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. TREXIMET should be discontinued if clinical signs and symptoms consistent with renal disease develop or if systemic manifestations occur. TREXIMET is not recommended for use in patients with severe renal impairment (creatinine clearance [CrCl] <30 mL/min) unless the benefits are expected to outweigh the risk of worsening renal function [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. If TREXIMET is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Monitor renal function in patients with mild (CrCl = 60 to 89 mL/min) or moderate (CrCl = 30 to 59 mL/min) renal impairment, preexisting kidney disease, or dehydration. The renal effects of TREXIMET may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating TREXIMET. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of TREXIMET [see Drug Interactions (7)]. Avoid the use of TREXIMET in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If TREXIMET is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with the use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic­ hypoaldosteronism state. 5.13 Anaphylactic Reactions Anaphylactic reactions may occur in patients without known prior exposure to either component of TREXIMET. Such reactions can be life-threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens although anaphylactic reactions with naproxen have occurred in patient without known hypersensitivity to naproxen or to patients with aspirin sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.18)]. TREXIMET should not be given to patients with the aspirin triad. This symptom complex typically occurs in patients with asthma who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see Contraindications (4)]. TREXIMET is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan, naproxen, or any other component of TREXIMET. Naproxen has been associated with anaphylactic reactions in patients without known hypersensitivity to naproxen and Reference ID: 5482765 in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.18)]. Seek emergency help if an anaphylactic reaction occurs. 5.14 Serious Skin Reactions NSAID-containing products can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of TREXIMET at the first appearance of skin rash or any other sign of hypersensitivity. TREXIMET is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.15 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as TREXIMET. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue TREXIMET and evaluate the patient immediately. 5.16 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including TREXIMET, in pregnant women at about 30 weeks gestation and later. NSAIDs, including TREXIMET, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including TREXIMET, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit TREXIMET use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if TREXIMET treatment extends beyond 48 hours. Discontinue TREXIMET if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.17 Hematologic Toxicity Anemia has occurred in patients receiving NSAIDs. This may be due to fluid retention, occult or gross gastrointestinal blood loss, or an incompletely described effect upon erythropoiesis. If a patient treated with TREXIMET has signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including TREXIMET, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and Reference ID: 5482765 6 serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.18 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, TREXIMET is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma [see Contraindications (4)]. When TREXIMET is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.19 Seizures Seizures have been reported following administration of sumatriptan. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. TREXIMET should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold. 5.20 Masking of Inflammation and Fever The pharmacological activity of TREXIMET in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.21 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.7, 5.12)]. ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] • Arrhythmias [see Warnings and Precautions (5.3)] • Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure [see Warnings and Precautions (5.4)] • Cerebrovascular Events [see Warnings and Precautions (5.5)] • Other Vasospasm Reactions [see Warnings and Precautions (5.6)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Hypertension [see Warnings and Precautions (5.8)] • Heart Failure and Edema [see Warnings and Precautions (5.9)] • Medication Overuse Headache [see Warnings and Precautions (5.10)] • Serotonin Syndrome [see Warnings and Precautions (5.11)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.12)] • Anaphylactic Reactions [see Warnings and Precautions (5.13)] • Serious Skin Reactions [see Warnings and Precautions (5.14)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.15)] • Hematological Toxicity [see Warnings and Precautions (5.17)] Reference ID: 5482765 • Exacerbation Asthma Related to Aspirin Sensitivity [see Warnings and Precautions (5.18)] • Seizures [see Warnings and Precautions (5.19)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults The adverse reactions reported below are specific to the clinical trials with TREXIMET 85/500 mg. See also the full prescribing information for naproxen and sumatriptan products. Table 1 lists adverse reactions that occurred in 2 placebo-controlled clinical trials (Study 1 and 2) in adult patients who received 1 dose of study drug. Only adverse reactions that occurred at a frequency of 2% or more in any group treated with TREXIMET 85/500 mg and that occurred at a frequency greater than the placebo group are included in Table 1. Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials in Adult Patients with Migraine Adverse Reactions TREXIMET 85/500 mg % (n = 737) Placebo % (n = 752) Sumatriptan 85 mg % (n = 735) Naproxen Sodium 500 mg % (n = 732) Nervous system disorders Dizziness 4 2 2 2 Somnolence 3 2 2 2 Paresthesia 2 <1 2 <1 Gastrointestinal disorders Nausea 3 1 3 <1 Dyspepsia 2 1 2 1 Dry mouth 2 1 2 <1 Pain and other pressure sensations Chest discomfort/chest pain 3 <1 2 1 Neck/throat/jaw pain/tightness/pressure 3 1 3 1 The incidence of adverse reactions in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse reactions. Pediatric Patients 12 to 17 Years of Age In a placebo controlled clinical trial that evaluated pediatric patients 12 to 17 years of age who received 1 dose of TREXIMET 10/60 mg, 30/180 mg, or 85/500 mg, adverse reactions occurred in 13% of patients who received 10/60 mg, 9% of patients who received 30/180 mg, 13% who received 85/500 mg, and 8% who received placebo. No patients who received TREXIMET experienced adverse reactions leading to withdrawal from the trial. The incidence of adverse reactions in pediatric patients 12 to 17 years of age was comparable across all 3 doses compared with placebo. Table 2 lists adverse reactions that occurred in a placebo- Reference ID: 5482765 7 controlled trial in pediatric patients 12 to 17 years of age at a frequency of 2% or more with TREXIMET and were more frequent than the placebo group. Table 2. Adverse Reactions in a Placebo-Controlled Trial in Pediatric Patients 12 to 17 Years of Age with Migraine Adverse Reactions TREXIMET 10/60 mg % (n = 96) TREXIMET 30/180 mg % (n = 97) TREXIMET 85/500 mg % (n = 152) Placebo % (n = 145) Vascular Hot flush (i.e., hot flash[es]) 0 2 <1 0 Musculoskeletal Muscle tightness 0 0 2 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of NSAIDs, such as naproxen, which is a component of TREXIMET. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE) [see Warnings and Precautions (5.14)]. DRUG INTERACTIONS 7.1 Clinically Significant Drug Interactions with TREXIMET See Table 3 for clinically significant drug interactions with NSAIDs or Sumatriptan. Table 3. Clinically Significant Drug Interactions with Naproxen or Sumatriptan Ergot-Containing Drugs Clinical Impact: Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Intervention: Because these effects may be additive, coadministration of TREXIMET and ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) within 24 hours of each other is contraindicated. Monoamine Oxidase-A Inhibitors Clinical Impact: MAO-A inhibitors increase systemic exposure of orally administered sumatriptan by 7-fold. Intervention: The use of TREXIMET in patients receiving MAO-A inhibitors is contraindicated. Other 5-HT1 Agonists Clinical Impact: 5-HT1 agonist drugs can cause vasospastic effects. Intervention: Because these effects may be additive, coadministration of TREXIMET and other 5 HT1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. Reference ID: 5482765 Drugs That Interfere with Hemostasis Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case- control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of TREXIMET with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.17)]. Aspirin Clinical Impact: A pharmacodynamic (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen [see Clinical Pharmacology (12.2)]. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Intervention: Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics where appropriate. Concomitant use of TREXIMET and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.17)]. Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Clinical Impact: Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.11)]. Intervention: Discontinue TREXIMET if serotonin syndrome is suspected. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers Reference ID: 5482765 Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of TREXIMET and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained [see Warnings and Precautions (5.8)]. • During concomitant use of TREXIMET and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.8)]. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of TREXIMET with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.8, 5.12)]. Digoxin Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of TREXIMET and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of TREXIMET and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant administration of some NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of TREXIMET and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NSAIDs and cyclosporine may increase cyclosporine’s Reference ID: 5482765 nephrotoxicity. Intervention: During concomitant use of TREXIMET and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NSAIDs and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of TREXIMET and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half- lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Probenecid Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. The clinical significance of this is unknown. Intervention: Reduce the frequency of administration of Treximet when given concurrently with probenecid. 7.2 Drug/Laboratory Test Interactions Blood Tests Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined. Urine Tests The administration of naproxen sodium may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artificially altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Reference ID: 5482765 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including TREXIMET, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of TREXIMET use between about 20 and 30 weeks of gestation, and avoid TREXIMET use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including TREXIMET, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see Human Data). In animal studies, administration of sumatriptan and naproxen, alone or in combination, during pregnancy resulted in developmental toxicity (increased incidences of fetal malformations, embryofetal and pup mortality, decreased embryofetal growth) at clinically relevant doses (see Animal Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen sodium resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Several studies have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including TREXIMET, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment: Reference ID: 5482765 --- If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If TREXIMET treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue TREXIMET and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of naproxen tablets during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. The Sumatriptan/Naratriptan/Treximet (sumatriptan and naproxen sodium) Pregnancy Registry, a population-based international prospective study, collected data for sumatriptan from January 1996 to September 2012. The Registry included only 6 pregnancy exposures to TREXIMET, with no major birth defects reported. The Registry documented outcomes of 626 infants and fetuses exposed to sumatriptan during pregnancy (528 with earliest exposure during the first trimester, 78 during the second trimester, 16 during the third trimester, and 4 unknown). The occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to sumatriptan was 4.2% (20/478 [95% CI: 2.6% to 6.5%]) and during any trimester of exposure was 4.2% (24/576 [95% CI: 2.7% to 6.2%]). The sample size in this study had 80% power to detect at least a 1.73- to 1.91-fold increase in the rate of major malformations. The number of exposed pregnancy outcomes accumulated during the registry was insufficient to support definitive conclusions about overall malformation risk or to support making comparisons of the frequencies of specific birth defects. Of the 20 infants with reported birth defects after exposure to sumatriptan in the first trimester, 4 infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and 3 infants had pyloric stenosis. No other birth defect was reported for more than 2 infants in this group. In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not. Of the 2,257 births with first-trimester exposure to sumatriptan, 107 infants were born with malformations (relative risk 0.99 [95% CI: 0.91 to 1.21]). A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group. Of the 415 women who redeemed prescriptions for sumatriptan during the first trimester, 15 had infants with major congenital malformations (OR 1.16 [95% CI: 0.69 to 1.94]) while for the 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy, 20 had infants with major congenital malformations (OR 1.83 [95% CI: 1.17 to 2.88]), each compared with the population comparison group. Additional smaller observational studies evaluating use of sumatriptan during pregnancy have not suggested an increased risk of teratogenicity. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Reference ID: 5482765 Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Oral administration of sumatriptan alone to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day, or approximately 3 times the maximum recommended human dose (MRHD) of 170 mg/day on a mg/m2 basis. Oral administration of sumatriptan alone to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no- effect doses for developmental toxicity in rabbits were 15 (approximately 2 times the MRHD on a mg/m2 basis) and 0.75 mg/kg/day, respectively. Oral administration of sumatriptan combined with naproxen sodium (5/9, 25/45, or 50/90 mg/kg/day sumatriptan/naproxen sodium) or each drug alone (50/0, 0/90 mg/kg/day sumatriptan/naproxen sodium) to pregnant rabbits during the period of organogenesis resulted in increased total incidences of fetal abnormalities at all doses and increased incidences of specific malformations (cardiac interventricular septal defect in the 50/90 mg/kg/day group, fused caudal vertebrae in the 50/0 and 0/90 mg/kg/day groups) and variations (absent intermediate lobe of the lung, irregular ossification of the skull, incompletely ossified sternal centra) at the highest dose of sumatriptan and naproxen alone and in combination. A no-effect dose for developmental toxicity in rabbit was not established. The lowest effect dose of 5/9 mg/kg/day sumatriptan/naproxen sodium was associated with plasma exposures (AUC) to sumatriptan and naproxen that were less than those attained at the MRHD of 170 mg sumatriptan and 1000 mg naproxen sodium (two tablets of TREXIMET 85/500 mg in a 24-hour period). Oral administration of sumatriptan alone to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day, or approximately 3 times the MRHD on a mg/m2 basis. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day, or approximately 3 times the MRHD on a mg/m2 basis. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day, or approximately 6 times the MRHD on a mg/m2 basis. Reference ID: 5482765 In reproduction studies of naproxen in rats (20 mg/kg/day), rabbits (20 mg/kg/day, and mice (170 mg/kg/day, no evidence of impaired fertility or harm to the fetus was observed. The doses tested in rats, rabbits, and mice were less (≤0.8 times) the MRHD, based on body surface area (mg/m2) comparisons. 8.2 Lactation Risk Summary The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. Sumatriptan is excreted in human milk following subcutaneous administration (see Data). There is no information regarding sumatriptan concentrations in milk from lactating women following administration of sumatriptan tablets. There are no data on the effects of naproxen or sumatriptan on the breastfed infant or the effects of naproxen or sumatriptan on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TREXIMET and any potential adverse effects on the breastfed infant from TREXIMET or from the underlying maternal condition. Clinical Considerations Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan tablets. Data Following subcutaneous administration of a 6-mg dose of sumatriptan injection in 5 lactating volunteers, sumatriptan was present in milk. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including naproxen tablets, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including naproxen tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness of TREXIMET in pediatric patients under 12 years of age have not been established. The safety and efficacy of TREXIMET for the acute treatment of migraine in pediatric patients 12 to 17 years of age was established in a double-blind, placebo-controlled trial [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. TREXIMET is not recommended for use in elderly patients who have decreased renal function, higher risk for unrecognized CAD, and increases in blood pressure that may be more pronounced in the elderly [see Warnings and Precautions (5.1, 5.2, 5.3, 5.8, 5.12) and Clinical Pharmacology (12.3)]. Reference ID: 5482765 COOH I CH2 • I CH2 " cooH A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving TREXIMET [see Warnings and Precautions (5.1)]. 8.6 Renal Impairment TREXIMET is not recommended for use in patients with creatinine clearance less than 30 mL/min. Monitor the serum creatinine or creatinine clearance in patients with mild (CrCl = 60 to 89 mL/min) or moderate (CrCL = 30 to 59 mL/min) renal impairment, preexisting kidney disease, or dehydration [see Warnings and Precautions (5.12) and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment TREXIMET is contraindicated in patients with severe hepatic impairment. For patients with mild or moderate hepatic impairment, the TREXIMET dose should be reduced. [see Contraindications (4), Warnings and Precautions (5.7), and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Patients (N = 670) have received single oral doses of 140 to 300 mg of sumatriptan without significant adverse effects. Volunteers (N = 174) have received single oral doses of 140 to 400 mg without serious adverse events. Overdose of sumatriptan in animals has been fatal and has been heralded by convulsions, tremor, paralysis, inactivity, ptosis, erythema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, salivation, and lacrimation. Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting and epigastric pain. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2)]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222). 11 DESCRIPTION TREXIMET contains sumatriptan (as the succinate), a selective 5-hydroxytryptamine1 (5-HT1) receptor subtype agonist, and naproxen sodium, a member of the arylacetic acid group of NSAIDs. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: Reference ID: 5482765 COoN, 12 The empirical formula is C14H21N3O2S•C4H6O4, representing a molecular weight of 413.5. Sumatriptan succinate is a white to off- white powder that is readily soluble in water and in saline. Naproxen sodium is chemically designated as (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid, sodium salt, and it has the following structure: The empirical formula is C14H13NaO3, representing a molecular weight of 252.23. Naproxen sodium is a white-to-creamy white crystalline solid, freely soluble in water at neutral pH. Each TREXIMET 85/500 mg tablet for oral administration contains 119 mg of sumatriptan succinate equivalent to 85 mg of sumatriptan and 500 mg of naproxen sodium. Each tablet also contains the inactive ingredients croscarmellose sodium, dibasic calcium phosphate, FD&C Blue No. 2, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, sodium bicarbonate, talc, titanium dioxide, and triacetin. Each TREXIMET 10/60 mg tablet for oral administration contains 14 mg of sumatriptan succinate equivalent to 10 mg of sumatriptan and 60 mg of naproxen sodium. Each tablet also contains the inactive ingredients croscarmellose sodium, dibasic calcium phosphate, FD&C Blue No. 2, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, sodium bicarbonate, talc, and titanium dioxide. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action TREXIMET contains sumatriptan and naproxen. Sumatriptan binds with high affinity to cloned 5-HT1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of neuropeptide release. TREXIMET has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of TREXIMET, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate-release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B2 inhibition at Reference ID: 5482765 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%]. Following administration of naproxen 220 mg twice-daily with low-dose immediate–release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%] [see Drug Interactions (7.1)]. Blood Pressure In a randomized, double-blind, parallel group, active control trial, TREXIMET 85/500 mg administered intermittently over 6 months did not increase blood pressure in a normotensive adult population (n = 122). However, significant elevation in blood pressure has been reported with 5-HT1 agonists and NSAIDs in patients with and without a history of hypertension. 12.3 Pharmacokinetics Absorption and Bioavailability Sumatriptan, when given as TREXIMET 85/500 mg, has a mean Cmax similar to that of sumatriptan succinate 100 mg tablets alone. The median Tmax of sumatriptan, when given as TREXIMET 85/500 mg, was 1 hour (range: 0.3 to 4.0 hours), which is slightly different compared with sumatriptan succinate 100 mg tablets (median Tmax of 1.5 hours). Naproxen, when given as TREXIMET 85/500 mg, has a Cmax which is approximately 36% lower than naproxen sodium 550 mg tablets and a median Tmax of 5 hours (range: 0.3 to 12 hours), which is approximately 4 hours later than from naproxen sodium tablets 550 mg. AUC values for sumatriptan and for naproxen are similar for TREXIMET 85/500 mg compared with sumatriptan succinate 100 mg tablets or naproxen sodium 550 mg tablets, respectively. In a crossover trial in 16 subjects, the pharmacokinetics of both components administered as TREXIMET 85/500 mg were similar during a migraine attack and during a migraine-free period. Bioavailability of sumatriptan is approximately 15%, primarily due to presystemic (first-pass) metabolism and partly due to incomplete absorption. Naproxen is absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. Food had no significant effect on the bioavailability of sumatriptan or naproxen administered as TREXIMET, but slightly delayed the Tmax of sumatriptan by about 0.6 hour [see Dosage and Administration (2.3)]. Distribution Plasma protein binding is 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. The volume of distribution of sumatriptan is 2.7 L/kg. The volume of distribution of naproxen is 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin bound. At doses of naproxen greater than 500 mg/day, there is a less-than-proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css = 36.5, 49.2, and 56.4 mg/L with 500-; 1,000-; and 1,500-mg daily doses of naproxen, respectively). However, the concentration of unbound naproxen continues to increase proportionally to dose. Metabolism In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme. No significant effect was seen with an MAO-B inhibitor. Reference ID: 5482765 Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Elimination The elimination half-life of sumatriptan is approximately 2 hours. Radiolabeled 14C-sumatriptan administered orally is largely renally excreted (about 60%), with about 40% found in the feces. Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Three percent of the dose can be recovered as unchanged sumatriptan. The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%), or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans is approximately 19 hours. The corresponding half-lives of both metabolites and conjugates of naproxen are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. In patients with renal failure, metabolites may accumulate. Specific Populations Geriatrics The pharmacokinetics of TREXIMET in geriatric patients have not been studied. Elderly patients are more likely to have decreased hepatic function and decreased renal function [see Specific Populations (8.5)]. The pharmacokinetics of oral sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in patients with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction, which represents <1% of the total concentration, increased in the elderly (range of unbound trough naproxen from 0.12% to 0.19% in elderly subjects versus 0.05% to 0.075% in younger subjects). Pediatrics A pharmacokinetic study compared 3 doses of TREXIMET in pediatric patients 12 to 17 years of age (n=24) with adults (n=26). The AUC and Cmax of sumatriptan were 50-60% higher following a single dose of TREXIMET 10/60 mg in pediatric patients 12 to 17 years of age (n=7) compared with adult subjects (n=8), and were 6-26% higher following a single dose of TREXIMET 30/180 mg or 85/500 mg in pediatrics than adults. Naproxen pharmacokinetic parameters were similar between pediatrics and adults. Renal Impairment The effect of renal impairment on the pharmacokinetics of TREXIMET has not been studied. Since naproxen and its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment [see Warnings and Precautions (5.12), Use in Specific Populations (8.6)]. Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of TREXIMET has not been studied. In a study in patients with moderate hepatic impairment (n = 8) matched for sex, age, and weight with healthy subjects (n = 8), patients with hepatic impairment had an approximately 70% increase in AUC and Cmax of sumatriptan and a Tmax 40 minutes earlier compared to healthy subjects. The pharmacokinetics of sumatriptan in patients with severe hepatic impairment has not been studied. Reference ID: 5482765 13 Gender In a pooled analysis of 5 pharmacokinetic trials, there was no effect of gender on the systemic exposure of TREXIMET. Race The effect of race on the pharmacokinetics of TREXIMET has not been studied. The systemic clearance and Cmax of sumatriptan were similar in black (n = 34) and white (n = 38) healthy male subjects. Drug Interaction Studies Aspirin When naproxen was administered with aspirin (>1 gram/day), the protein binding of naproxen was reduced, although the clearance of free naproxen was not altered. See Table 3 for clinically significant drug interactions of naproxen, an NSAID, with aspirin [see Drug Interactions (7)]. Propranolol Propranolol 80 mg given twice daily had no significant effect on sumatriptan pharmacokinetics. See Table 3 for clinically significant drug interactions of propranolol, a beta-blocker, with TREXIMET [see Drug Interactions (7)]. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis The carcinogenic potential of TREXIMET has not been studied. In carcinogenicity studies in mouse and rat, sumatriptan was administered orally for 78 and 104 weeks, respectively, at doses up to 160 mg/kg/day. The highest doses tested are approximately 5 (mouse) and 9 (rat) times the maximum human daily dose (MHDD) of 170 mg sumatriptan on a mg/m2 basis (two tablets of TREXIMET 85/500 mg in a 24-hour period). The carcinogenic potential of naproxen was evaluated in a 2-year oral carcinogenicity study in rats at doses of 8, 16, and 24 mg/kg/day and in another 2-year oral carcinogenicity study in rats at a dose of 8 mg/kg/day. No evidence of tumorigenicity was found in either study. The highest dose tested is less than the MHDD (1000 mg) of naproxen, on a mg/m2 basis. Mutagenesis Sumatriptan and naproxen sodium tested alone and in combination were negative in an in vitro bacterial reverse mutation assay, and in an in vivo micronucleus assay in mice. The combination of sumatriptan and naproxen sodium was negative in an in vitro mouse lymphoma tk assay in the presence and absence of metabolic activation. However, in separate in vitro mouse lymphoma tk assays, naproxen sodium alone was reproducibly positive in the presence of metabolic activation. Naproxen sodium alone and in combination with sumatriptan was positive in an in vitro clastogenicity assay in mammalian cells in the presence and absence of metabolic activation. The clastogenic effect for the combination was reproducible within this assay and was greater than observed with naproxen sodium alone. Sumatriptan alone was negative in these assays. Chromosomal aberrations were not induced in peripheral blood lymphocytes following 7 days of twice-daily dosing with TREXIMET in human volunteers. Reference ID: 5482765 14 In previous studies, sumatriptan alone was negative in in vitro (bacterial reverse mutation [Ames], gene cell mutation in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays. Impairment of Fertility The effect of TREXIMET on fertility in animals has not been studied. When sumatriptan (5, 50, 500 mg/kg/day) was administered orally to male and female rats prior to and throughout the mating period, there was a drug-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day (less than the MHDD of 170 mg on a mg/m2 basis). It is not clear whether this finding was due to an effect on males or females or both. 13.2 Animal Toxicology and/or Pharmacology Corneal Opacities Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dosage tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60­ week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established. The lowest dose tested is less than the MHDD (170 mg) of sumatriptan on a mg/m2 basis. CLINICAL STUDIES 14.1 Adults The efficacy of TREXIMET in the acute treatment of migraine with or without aura in adults was demonstrated in 2 randomized, double-blind, multicenter, parallel-group trials utilizing placebo and each individual active component of TREXIMET 85/500 mg (sumatriptan and naproxen sodium) as comparison treatments (Study 1 and Study 2). Patients enrolled in these 2 trials were predominately female (87%) and white (88%), with a mean age of 40 years (range: 18 to 65 years). Patients were instructed to treat a migraine of moderate to severe pain with 1 tablet. No rescue medication was allowed within 2 hours postdose. Patients evaluated their headache pain 2 hours after taking 1 dose of study medication; headache relief was defined as a reduction in headache severity from moderate or severe pain to mild or no pain. Associated symptoms of nausea, photophobia, and phonophobia were also evaluated. Sustained pain free was defined as a reduction in headache severity from moderate or severe pain to no pain at 2 hours postdose without a return of mild, moderate, or severe pain and no use of rescue medication for 24 hours postdose. The results from Study 1 and 2 are summarized in Table 4. In both trials, the percentage of patients achieving headache pain relief 2 hours after treatment was significantly greater among patients receiving TREXIMET 85/500 mg (65% and 57%) compared with those who received placebo (28% and 29%). Further, the percentage of patients who remained pain free without use of other medications through 24 hours postdose was significantly greater among patients receiving a single dose of TREXIMET 85/500 mg (25% and 23%) compared with those who received placebo (8% and 7%) or either sumatriptan (16% and 14%) or naproxen sodium (10%) alone. Reference ID: 5482765 ga BO !! a! :;ro ~ iii fiO J!I .. ~ 50 ,ii '15 40 E ,ID .. ~ B! 20 10 0 D •♦ llEIEX IMEir fi!liOO mg • ,sumlitrlpmn,85 mg Nllpr.lXDl11JSDdlum1-~ mg + Ill B 1Jibo1 D.S 1.D 15 1JJ Hoon l'mi!Xlllm Table 4. Percentage of Adult Patients with 2-Hour Pain Relief and Sustained Pain Free Following Treatmenta TREXIMET 85/500 mg Sumatriptan 85 mg Naproxen Sodium 500 mg Placebo 2-Hour Pain Relief Study 1 65%b n = 364 55% n = 361 44% n = 356 28% n = 360 Study 2 57%b n = 362 50% n = 362 43% n = 364 29% n = 382 Sustained Pain Free (2-24 Hours) Study 1 25%c n = 364 16% n = 361 10% n = 356 8% n = 360 Study 2 23%c n = 362 14% n = 362 10% n = 364 7% n = 382 aP values provided only for prespecified comparisons. bP<0.05 versus placebo and sumatriptan. cP <0.01 versus placebo, sumatriptan, and naproxen sodium. The percentage of patients achieving initial headache pain relief within 2 hours following treatment with TREXIMET 85/500 mg is shown in Figure 1. Figure 1. Percentage of Adult Patients with Initial Headache Pain Relief within 2 Hours Compared with placebo, there was a decreased incidence of photophobia, phonophobia, and nausea 2 hours after the administration of TREXIMET 85/500 mg. The estimated probability of taking a rescue medication over the first 24 hours is shown in Figure 2. Reference ID: 5482765 100 C: 90 0 :.:: ... u 80 :a ... == 70 ... :::, u 60 en ... cc ... 50 en .e .:,,: 40 ~ - ~ 30 en - 20 u ... ::E" :::, 10 V) 0 0 2 4 6 Placebo Naproxen Sumatriptan TREXIMET 85/500 mg 8 10 12 14 16 18 20 22 24 Hours Postdose Figure 2. Estimated Probability of Adults Taking a Rescue Medication over the 24 Hours following the First Dosea a Kaplan-Meier plot based on data obtained in the 2 clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24 hours. Plot also includes patients who had no response to the initial dose. No rescue medication was allowed within 2 hours postdose. TREXIMET 85/500 mg was more effective than placebo regardless of the presence of aura; duration of headache prior to treatment; gender, age, or weight of the subject; or concomitant use of oral contraceptives or common migraine prophylactic drugs (e.g., beta-blockers, anti-epileptic drugs, tricyclic antidepressants). 14.2 Pediatric Patients 12 to 17 Years of Age The efficacy of TREXIMET in the acute treatment of migraine with or without aura in pediatric patients 12 to 17 years of age was demonstrated in a randomized, double-blind, multicenter, parallel-group, placebo-controlled, multicenter trial comparing 3 doses of TREXIMET and placebo (Study 3). Patients enrolled in this trial were mostly female (59%) and white (81%), with a mean age of 15 years. Patients were required to have at least a 6-month history of migraine attacks with or without aura usually lasting 3 hours or more when untreated. Following a single-blind, placebo run-in phase, placebo nonresponders were randomized to receive a single dose of either TREXIMET 10/60 mg, 30/180 mg, 85/500 mg, or placebo. Patients were instructed to treat a single migraine attack with headache pain of moderate to severe intensity. No rescue medication was allowed within 2 hours postdose. Patients evaluated their headache pain 2 hours after taking 1 dose of study medication. Two-hour pain free was defined as a reduction in headache severity from moderate or severe pain to no pain at 2 hours postdose. Results are summarized in Table 5. The percentage of patients who were pain free at 2 hours postdose was significantly greater among patients who received any of the 3 doses of TREXIMET compared with placebo. Table 5. Percentage of Pediatric Patients 12 to 17 Years of Age with 2-Hour Pain-Free Response Following Treatment in Study 3a Endpoint TREXIMET 10/60 mg (n = 96) TREXIMET 30/180 mg (n = 97) TREXIMET 85/500 mg (n = 152) Placebo (n = 145) 2-Hour Pain Free 29%b 27% b 24% b 10% Reference ID: 5482765 aP values provided only for prespecified comparisons. bP<0.01 versus placebo. The percentage of pediatric patients who remained pain free without use of other medications 2 through 24 hours postdose was significantly greater after administration of a single dose of TREXIMET 85/500 mg compared with placebo. A greater percentage of pediatric patients who received a single dose of 10/60 mg or 30/180 mg remained pain free 2 through 24 hours postdose compared with placebo. Compared with placebo, the incidence of photophobia and phonophobia was significantly decreased 2 hours after the administration of a single dose of 85/500 mg, whereas, the incidence of nausea was comparable. There was a decreased incidence of photophobia, phonophobia, and nausea 2 hours after single-dose administration of 10/60 mg or 30/180 mg compared with placebo. 16 HOW SUPPLIED/STORAGE AND HANDLING TREXIMET 85/500 mg contains 119 mg of sumatriptan succinate equivalent to 85 mg of sumatriptan and 500 mg of naproxen sodium and is supplied as blue film-coated tablets debossed on one side with TREXIMET in bottles of 9 tablets with desiccant (NDC 42847­ 850-09). TREXIMET 10/60 mg contains 14 mg of sumatriptan succinate equivalent to 10 mg of sumatriptan and 60 mg of naproxen sodium and is supplied as light-blue film-coated tablets debossed on one side with TREXIMET and the other side with 10-60 in bottles of 9 tablets with desiccant (NDC 42847-860-09). Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Do not repackage; dispense and store in original container with desiccant. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with TREXIMET and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events, Prinzmetal's Angina, Other Vasospasm-Related Events, Arrhythmias and Cerebrovascular Events Advise patients to be alert for the symptoms of cardiovascular thrombotic effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for signs and symptoms of chest pain, shortness of breath, weakness, irregular heartbeat, significant rise in blood pressure, weakness and slurring of speech, and should be advised to report any of these symptoms to their health care provider immediately. Apprise patients of the importance of this follow-up [see Warnings and Precautions (5.1, 5.3, 5.5, 5.6, 5.8)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Reference ID: 5482765 Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop TREXIMET and seek immediate medical therapy [see Warnings and Precautions (5.7)]. Anaphylactic Reactions Inform patients that anaphylactic reactions have occurred in patients receiving the components of TREXIMET. Such reactions can be life-threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help [see Contraindications (4), Warnings and Precautions (5.13)]. Serious Skin Reactions, including DRESS Inform patients that TREXIMET, like other NSAID-containing products, may increase the risk of serious skin side effects such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching and should ask for medical advice when observing any indicative signs or symptoms. Advise patients to stop taking TREXIMET immediately if they develop any type of rash or fever and contact their healthcare providers as soon as possible [see Warnings and Precautions (5.14, 5.15)]. Fetal Toxicity Inform pregnant women to avoid use of TREXIMET and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with TREXIMET is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.16), Use in Specific Populations (8.1)]. Lactation Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including TREXIMET, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.9)]. Concomitant Use with Other Triptans or Ergot Medications Inform patients that use of TREXIMET within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated [see Contraindications (4), Drug Interactions (7.1)]. Serotonin Syndrome Caution patients about the risk of serotonin syndrome with the use of TREXIMET or other triptans, particularly during concomitant use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.11), Drug Interactions (7.1)]. Reference ID: 5482765 CurraX,M pharmaceuticals LLC Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.10)]. Ability to Perform Complex Tasks Treatment with TREXIMET may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of TREXIMET [see Adverse Reactions (6.1)]. Asthma Advise patients with preexisting asthma to seek immediate medical attention if their asthma worsens after taking TREXIMET. Patients with a history of aspirin-sensitive asthma should not take TREXIMET [see Contraindications (4), Warnings and Precautions (5.18)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of TREXIMET with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with TREXIMET until they talk to their healthcare provider [see Drug Interactions (7)]. TREXIMET is a registered trademark of Currax™ Pharmaceuticals LLC. The other brands listed are trademarks of their respective owners and are not trademarks of Currax™ Pharmaceuticals LLC. The makers of these brands are not affiliated with and do not endorse Currax™ Pharmaceuticals LLC or its products. Distributed by Currax™ Pharmaceuticals LLC Brentwood, TN 37027 © 2024 Currax™ Pharmaceuticals LLC. All rights reserved. TRE-LC003.10 Reference ID: 5482765 MEDICATION GUIDE TREXIMET® [trex' i-met] Tablets (sumatriptan and naproxen sodium) Read this Medication Guide before you start taking TREXIMET and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment. What is the most important information I should know about TREXIMET? TREXIMET may increase your chance of a heart attack or stroke that can lead to death. TREXIMET contains 2 medicines: sumatriptan and naproxen sodium (a nonsteroidal anti-inflammatory drug [NSAID]). • This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take TREXIMET right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking TREXIMET after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. Stop taking TREXIMET and get emergency help right away if you have any of the following symptoms of a heart attack or stroke: • discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back • severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw • pain or discomfort in your arms, back, neck, jaw, or stomach • shortness of breath with or without chest discomfort • breaking out in a cold sweat • nausea or vomiting • feeling lightheaded • weakness in one part or on one side of your body • slurred speech TREXIMET is not for people with risk factors for heart disease unless a heart exam is done and shows no problem. You have a higher risk for heart disease if you: • have high blood pressure • have high cholesterol levels • smoke • are overweight • have diabetes • have a family history of heart disease TREXIMET can cause ulcers and bleeding in the stomach and intestines at any time during your treatment. Ulcers and bleeding can happen without warning symptoms and may cause death. Your chance of getting an ulcer or bleeding increases with: • past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs • the use of medicines called “corticosteroids,” “anticoagulants,” and • longer use antidepressant medicines called “SSRIs” or “SNRIs” • more frequent use • smoking • drinking alcohol • older age • having poor health • advanced liver disease • bleeding problems TREXIMET may cause serious allergic reactions or serious skin reactions that can be life-threatening. Stop taking TREXIMET and get emergency help right away if you develop: • sudden wheezing • swelling of your lips, tongue, throat or body • rash • fainting • problems breathing or swallowing • reddening of your skin with blisters or peeling • blisters or bleeding of your lips, eye lids, mouth, nose, or genitals TREXIMET should only be used exactly as prescribed, at the lowest dose possible for your treatment, and for the shortest time needed. TREXIMET already contains an NSAID (naproxen). Do not use TREXIMET with other medicines to lessen pain or fever or with other medicines for colds or sleeping problems without talking to your healthcare provider first, because they may contain an NSAID also. What is TREXIMET? TREXIMET is a prescription medicine that contains sumatriptan and naproxen sodium (an NSAID). TREXIMET is used to treat acute migraine headaches with or without aura in patients 12 years of age and older. Reference ID: 5482765 TREXIMET is not used to treat other types of headaches such as hemiplegic (that make you unable to move on one side of your body) or basilar (rare form of migraine with aura) migraines. TREXIMET is not used to prevent or decrease the number of migraine headaches you have. It is not known if TREXIMET is safe and effective to treat cluster headaches. Who should not take TREXIMET? Do not take TREXIMET if you have: • heart problems, history of heart problems, or right before or after heart bypass surgery • had a stroke, transient ischemic attack (TIAs), or problems with your blood circulation • hemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider. • narrowing of blood vessels to your legs and arms (peripheral vascular disease), stomach (ischemic bowel disease), or kidneys • uncontrolled high blood pressure • taken any medicines in the last 24 hours that are called 5-HT1 agonists that are triptans or contain ergotamine. Ask your healthcare provider for a list of these medicines if you are not sure. • taken an antidepressant medicine called a monoamine oxidase (MAO) inhibitor within the last 2 weeks. Ask your healthcare provider for a list if you are not sure. • had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine • an allergy to sumatriptan, naproxen, or any of the ingredients in TREXIMET. See “What are the ingredients in TREXIMET?” below for a complete list of ingredients. • liver problems What should I tell my healthcare provider before taking TREXIMET? Before you take TREXIMET, tell your healthcare provider about all of your medical conditions, including if you: • have high blood pressure • have asthma • have high cholesterol • have diabetes • smoke • are overweight • have heart problems or a family history of heart problems or stroke • have kidney problems • have liver problems • have had epilepsy or seizures • are not using effective birth control • are pregnant, think you might be pregnant, or are trying to become pregnant. Taking NSAIDs, including TREXIMET, at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breastfeed. The components of TREXIMET pass into your breast milk and may harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take TREXIMET. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TREXIMET and certain other medicines can affect each other, causing serious side effects. How should I take TREXIMET? • Certain people should take their first dose of TREXIMET in their healthcare provider’s office or in another medical setting. Ask your healthcare provider if you should take your first dose in a medical setting. • Take TREXIMET exactly as your healthcare provider tells you to take it. • Take TREXIMET tablets whole with water or other liquids. • TREXIMET can be taken with or without food. • If you do not get any relief after your first dose, do not take a second dose without first talking with your healthcare provider. • If your headache comes back or you only get some relief from your headache: • For adults: a second dose may be taken 2 hours after the first dose. Do not take more than 2 doses of TREXIMET 85/500 mg in a 24-hour period. • For children 12 to 17 years of age: it is not known if taking more than 1 dose of TREXIMET in 24 hours is safe and effective. Talk to your healthcare provider about what to do if your headache does not go away or comes back. • If you take too much TREXIMET, call your healthcare provider or go to the nearest hospital emergency room right away. • You should write down when you have headaches and when you take TREXIMET so you can talk with your healthcare provider about how TREXIMET is working for you. Reference ID: 5482765 What should I avoid while taking TREXIMET? TREXIMET can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not drive a car, use machinery, or do anything where you need to be alert. What are the possible side effects of TREXIMET? TREXIMET may cause serious side effects. See “What is the most important information I should know about TREXIMET?” These serious side effects include: • changes in color or sensation in your fingers and toes (Raynaud’s syndrome) • new or worse high blood pressure • heart failure from body swelling (fluid retention) • kidney problems including kidney failure • low red blood cells (anemia) • liver problems including liver failure • asthma attacks in people who have asthma • stomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include: • sudden or severe stomach pain • stomach pain after meals • weight loss • nausea or vomiting • constipation or diarrhea • bloody diarrhea • fever • problems with blood circulation to your legs and feet (peripheral vascular ischemia). Symptoms of peripheral vascular ischemia include: • cramping and pain in your legs or hips • feeling of heaviness or tightness in your leg muscles • burning or aching pain in your feet or toes while resting • numbness, tingling, or weakness in your legs • cold feeling or color changes in 1 or both legs or feet • medication overuse headaches. Some people who use too many TREXIMET tablets may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with TREXIMET. • serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in people using TREXIMET, especially if TREXIMET is used with antidepressant medicines called SSRIs or SNRIs. Stop taking TREXIMET and call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome: • changes in blood pressure • fast heartbeat • tight muscles • high body temperature • mental changes such as seeing things that are not there (hallucinations), • trouble walking agitation, or coma • seizures. Seizures have happened in people taking sumatriptan, one of the ingredients in TREXIMET, who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take TREXIMET. The most common side effects of TREXIMET include: • dizziness • feeling weak, drowsy, or tired • pain, discomfort, or stiffness in your neck, throat, jaw, or chest • nausea • tingling or numbness in your fingers or toes • heartburn • dry mouth • feeling hot • heartbeat problems • muscle tightness Stop TREXIMET and call your healthcare provider right away if you have any of the following symptoms: • nausea that seems out of proportion to your migraine • sudden or severe stomach pain • vomit blood • blood in your bowel movement or it is black and sticky like tar • yellow skin or eyes • unusual weight gain • more tired or weaker than usual • flu-like symptoms • itching • diarrhea • swelling of the arms, legs, hands, and feet • tenderness in your upper right side Tell your healthcare provider if you have any side effects that bother you or do not go away. These are not all of the side effects of TREXIMET. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Reference ID: 5482765 How should I store TREXIMET? Store TREXIMET at room temperature between 68°F to 77°F (20°C to 25°C). Keep TREXIMET and all medicines out of the reach of children. General information about the safe and effective use of TREXIMET Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TREXIMET for a condition for which it was not prescribed. Do not give TREXIMET to other people, even if they have the same problem you have. It may harm them. This Medication Guide summarizes the most important information about TREXIMET. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about TREXIMET that is written for healthcare professionals. For more information call 1-800-793-2145 or visit www.TREXIMET.com. What are the ingredients in TREXIMET? Active ingredients: sumatriptan succinate and naproxen sodium. Inactive ingredients in all strengths: croscarmellose sodium, dibasic calcium phosphate, FD&C Blue No. 2, magnesium stearate, microcrystalline cellulose, povidone, sodium bicarbonate, talc, and titanium dioxide. 85/500-mg tablets also contain: hypromellose and triacetin. 10/60-mg tablets also contain: polyethylene glycol and polyvinyl alcohol. TREXIMET is a registered trademark of Currax™ Pharmaceuticals LLC. The other brands listed are trademarks of their respective owners and are not trademarks of Currax™ Pharmaceuticals LLC. The makers of these brands are not affiliated with and do not endorse Currax™ Pharmaceuticals LLC or its products. TRE-LC006.08 Distributed by Currax™ Pharmaceuticals LLC; Brentwood, TN 37027 © 2024 Currax™ Pharmaceuticals LLC. All rights reserved. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 02/2024 Reference ID: 5482765
custom-source
2025-02-12T15:47:14.730912
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DAPTOMYCIN FOR INJECTION safely and effectively. See full prescribing information for DAPTOMYCIN FOR INJECTION. DAPTOMYCIN for injection, for intravenous use Initial U.S. Approval: 2003 ----------------------------INDICATIONS AND USAGE -------------------------- Daptomycin for Injection is a lipopeptide antibacterial indicated for the treatment of: • Complicated skin and skin structure infections (cSSSI) in adult and pediatric patients (1 to 17 years of age) (1.1) and, • Staphylococcus aureus bloodstream infections (bacteremia), in adult patients including those with right-sided infective endocarditis, (1.2) • Staphylococcus aureus bloodstream infections (bacteremia) in pediatric patients (1 to 17 years of age). (1.3) Limitations of Use: • Daptomycin for Injection is not indicated for the treatment of pneumonia. (1.4) • Daptomycin for Injection is not indicated for the treatment of left-sided infective endocarditis due to S. aureus. (1.4) • Daptomycin for Injection is not recommended in pediatric patients younger than one year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs. (1.4) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Daptomycin for Injection and other antibacterial drugs, Daptomycin for Injection should be used to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.5) --------------------- DOSAGE AND ADMINISTRATION ----------------------­ Adult Patients • Administer to adult patients intravenously, either by injection over a 2-minute period or by infusion over a 30-minute period. (2.1, 2.7) • Recommended dosage regimen for adult patients (2.2, 2.4, 2.6): Creatinine Clearance (CLCR) Dosage Regimen cSSSI For 7 to 14 days S. aureus Bacteremia For 2 to 6 weeks ≥30 mL/min 4 mg/kg once every 24 hours 6 mg/kg once every 24 hours <30 mL/min, including hemodialysis and CAPD 4 mg/kg once every 48 hours* 6 mg/kg once every 48 hours* * Administered following hemodialysis on hemodialysis days. Pediatric Patients • Unlike in adults, do NOT administer by injection over a two (2) minute period to pediatric patients. (2.1, 2.7) • Administer to pediatric patients intravenously by infusion over a 30- or 60­ minute period, based on age. (2.1, 2.7) • Recommended dosage regimen for pediatric patients (1 to 17 years of age) with cSSSI, based on age (2.3): Age Group Dosage* Duration of therapy 12 to 17 years 5 mg/kg once every 24 hours infused over 30 minutes Up to 14 days 7 to 11 years 7 mg/kg once every 24 hours infused over 30 minutes 2 to 6 years 9 mg/kg once every 24 hours infused over 60 minutes 1 to less than 2 years 10 mg/kg once every 24 hours infused over 60 minutes *Recommended dosage is for pediatric patients (1 to 17 years of age) with normal renal function. Dosage adjustment for pediatric patients with renal impairment has not been established. • Recommended dosage regimen for pediatric patients (1 to 17 years of age) with S. aureus bacteremia, based on age (2.5): Age Group Dosage* Duration of therapy 12 to 17 years 7 mg/kg once every 24 hours infused over 30 minutes Up to 42 days 7 to 11 years 9 mg/kg once every 24 hours infused over 30 minutes 2 to 6 years 12 mg/kg once every 24 hours infused over 60 minutes *Recommended dosage is for pediatric patients (1 to 17 years of age) with normal renal function. Dosage adjustment for pediatric patients with renal impairment has not been established. • There are other formulations of daptomycin that have differences concerning storage and reconstitution. Carefully follow the reconstitution and storage procedures in labeling. (2.7) • Do not use in conjunction with ReadyMED® elastomeric infusion pumps in adult and pediatric patients. (2.9) ----------------------DOSAGE FORMS AND STRENGTHS --------------------­ • For Injection: 350 mg of daptomycin as a lyophilized powder in single- dose vial for reconstitution (3) • For Injection: 500 mg of daptomycin as a lyophilized powder in a single- dose vial for reconstitution (3) ------------------------------- CONTRAINDICATIONS ---------------------------­ • Known hypersensitivity to daptomycin (4) ----------------------- WARNINGS AND PRECAUTIONS ----------------------­ • Anaphylaxis/hypersensitivity reactions (including life- threatening): Discontinue Daptomycin for Injection and treat signs/symptoms. (5.1) • Myopathy and rhabdomyolysis: Monitor CPK levels and follow muscle pain or weakness; if elevated CPK or myopathy occurs, consider discontinuation of Daptomycin for Injection. (5.2) • Eosinophilic pneumonia: Discontinue Daptomycin for Injection and consider treatment with systemic steroids. (5.3) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue daptomycin and institute appropriate treatment. (5.4) • Tubulointerstitial Nephritis (TIN): Discontinue Daptomycin for Injection and institute appropriate treatment. (5.5) • Peripheral neuropathy: Monitor for neuropathy and consider discontinuation. (5.6) • Potential nervous system and/or muscular system effects in pediatric patients younger than 12 months: Avoid use of Daptomycin for Injection in this age group. (5.7) • Clostridioides difficile–associated diarrhea: Evaluate patients if diarrhea occurs. (5.8) • Persisting or relapsing S. aureus bacteremia/endocarditis: Perform susceptibility testing and rule out sequestered foci of infection. (5.9) • Decreased efficacy was observed in adult patients with moderate baseline renal impairment. (5.10) ------------------------------- ADVERSE REACTIONS ----------------------------­ • Adult cSSSI Patients: The most common adverse reactions that occurred in ≥2% of adult cSSSI patients receiving daptomycin for injection 4 mg/kg were diarrhea, headache, dizziness, rash, abnormal liver function tests, elevated creatine phosphokinase (CPK), urinary tract infections, hypotension, and dyspnea. (6.1) • Pediatric cSSSI Patients: The most common adverse reactions that occurred in ≥2% of pediatric patients receiving daptomycin for injection were diarrhea, vomiting, abdominal pain, pruritus, pyrexia, elevated CPK, and headache. (6.1) • Adult S. aureus bacteremia/endocarditis Patients: The most common adverse reactions that occurred in ≥5% of S. aureus bacteremia/endocarditis patients receiving daptomycin for injection 6 mg/kg were sepsis, bacteremia, abdominal pain, chest pain, edema, pharyngolaryngeal pain, pruritus, increased sweating, insomnia, elevated CPK, and hypertension. (6.1) • Pediatric S. aureus bacteremia Patients: The most common adverse reactions that occurred in ≥5% of pediatric patients receiving daptomycin for injection were vomiting and elevated CPK. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact MAIA Pharmaceuticals, Inc. at 1-888-877-9064 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION. Revised: 11/2024 Reference ID: 5483234 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 5.8 Clostridioides difficile-Associated Diarrhea 1.1 Complicated Skin and Skin Structure Infections (cSSSI) 5.9 Persisting or Relapsing S. aureus Bacteremia/Endocarditis 1.2 Staphylococcus aureus Bloodstream Infections (Bacteremia) in 5.10 Decreased Efficacy in Patients with Moderate Baseline Renal Adult Patients, Including Those with Right-Sided Infective Impairment Endocarditis, Caused by Methicillin- Susceptible and Methicillin- 5.11 Increased International Normalized Ratio (INR)/Prolonged Resistant Isolates Prothrombin Time 1.3 Staphylococcus aureus Bloodstream Infections (Bacteremia) in 5.12 Development of Drug-Resistant Bacteria Pediatric Patients (1 to 17 Years of Age) 6 ADVERSE REACTIONS 1.4 Limitations of Use 6.1 Clinical Trials Experience 1.5 Usage 6.2 Postmarketing Experience 2 DOSAGE AND ADMINISTRATION 7 DRUG INTERACTIONS 2.1 Important Administration Duration Instructions 7.1 HMG-CoA Reductase Inhibitors 2.2 Dosage in Adults for cSSSI 7.2 Drug-Laboratory Test Interactions 2.3 Dosage in Pediatric Patients (1 to 17 Years of Age) for cSSSI 8 USE IN SPECIFIC POPULATIONS 2.4 Dosage in Adult Patients with Staphylococcus aureus Bloodstream 8.1 Pregnancy Infections (Bacteremia), Including Those with Right-Sided Infective 8.2 Lactation Endocarditis, Caused by Methicillin-Susceptible and Methicillin- 8.4 Pediatric Use Resistant Isolates 8.5 Geriatric Use 2.5 Dosage in Pediatric Patients (1 to 17 Years of Age) with 8.6 Patients with Renal Impairment Staphylococcus aureus Bloodstream Infections (Bacteremia) 10 OVERDOSAGE 2.6 Dosage in Patients with Renal Impairment 11 DESCRIPTION 2.7 Preparation and Administration of Daptomycin for Injection 12 CLINICAL PHARMACOLOGY 2.8 Compatible Intravenous Solution for Reconstitution and Dilution 12.1 Mechanism of Action 2.9 Incompatibilities 12.2 Pharmacodynamics 3 DOSAGE FORMS AND STRENGTHS 12.3 Pharmacokinetics 4 CONTRAINDICATIONS 12.4 Microbiology 5 WARNINGS AND PRECAUTIONS 13 NONCLINICAL TOXICOLOGY 5.1 Anaphylaxis/Hypersensitivity Reactions 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.2 Myopathy and Rhabdomyolysis 13.2 Animal Toxicology and/or Pharmacology 5.3 Eosinophilic Pneumonia 14 CLINICAL STUDIES 5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 14.1 Complicated Skin and Skin Structure Infections 5.5 Tubulointerstitial Nephritis (TIN) 14.2 S. aureus Bacteremia/Endocarditis 5.6 Peripheral Neuropathy 15 REFERENCES 5.7 Potential Nervous System and/or Muscular System Effects in 16 HOW SUPPLIED/STORAGE AND HANDLING Pediatric Patients Younger than 12 Months 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5483234 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Complicated Skin and Skin Structure Infections (cSSSI) Daptomycin for Injection is indicated for the treatment of adult and pediatric patients (1 to 17 years of age) with complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following Gram- positive bacteria: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only). 1.2 Staphylococcus aureus Bloodstream Infections (Bacteremia) in Adult Patients, Including Those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible and Methicillin-Resistant Isolates Daptomycin for Injection is indicated for the treatment of adult patients with Staphylococcus aureus bloodstream infections (bacteremia), including adult patients with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates. 1.3 Staphylococcus aureus Bloodstream Infections (Bacteremia) in Pediatric Patients (1 to 17 Years of Age) Daptomycin for Injection is indicated for the treatment of pediatric patients (1 to 17 years of age) with Staphylococcus aureus bloodstream infections (bacteremia) 1.4 Limitations of Use Daptomycin for Injection is not indicated for the treatment of pneumonia. Daptomycin for Injection is not indicated for the treatment of left-sided infective endocarditis due to S. aureus. The clinical trial of Daptomycin for Injection in adult patients with S. aureus bloodstream infections included limited data from patients with left-sided infective endocarditis; outcomes in these patients were poor [see Clinical Studies (14.2)]. Daptomycin for Injection has not been studied in patients with prosthetic valve endocarditis. Daptomycin for Injection is not recommended in pediatric patients younger than 1 year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs [see Warnings and Precautions (5.7) and Nonclinical Toxicology (13.2)]. 1.5 Usage Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to daptomycin. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Daptomycin for Injection and other antibacterial drugs, Daptomycin for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information is available, it should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Empiric therapy may be initiated while awaiting test results. 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Duration Instructions Adults Administer the appropriate volume of the reconstituted Daptomycin for Injection (concentration of 50 mg/mL) Reference ID: 5483234 to adult patients intravenously either by injection over a two (2) minute period or by intravenous infusion over a thirty (30) minute period [see Dosage and Administration (2.2, 2.4, 2.7)]. Pediatric Patients (1 to 17 Years of Age) Unlike in adults, do NOT administer Daptomycin for Injection by injection over a two (2) minute period to pediatric patients. • Pediatric Patients 7 to 17 years of Age: Administer Daptomycin for Injection intravenously by infusion over a 30-minute period [see Dosage and Administration (2.3, 2.5, 2.7)]. • Pediatric Patients 1 to 6 years of Age: Administer Daptomycin for Injection intravenously by infusion over a 60-minute period [see Dosage and Administration (2.3, 2.5, 2.7)]. 2.2 Dosage in Adults for cSSSI Administer Daptomycin for Injection 4 mg/kg to adult patients intravenously once every 24 hours for 7 to 14 days. 2.3 Dosage in Pediatric Patients (1 to 17 Years of Age) for cSSSI The recommended dosage regimens based on age for pediatric patients with cSSSI are shown in Table 1. Administer Daptomycin for Injection intravenously once every 24 hours for up to 14 days. Table 1: Recommended Dosage of Daptomycin for Injection in Pediatric Patients (1 to 17 Years of Age) with cSSSI, Based on Age Age Range Dosage Regimen* Duration of therapy 12 to 17 years 5 mg/kg once every 24 hours infused over 30 minutes Up to 14 days 7 to 11 years 7 mg/kg once every 24 hours infused over 30 minutes 2 to 6 years 9 mg/kg once every 24 hours infused over 60 minutes 1 to less than 2 years 10 mg/kg once every 24 hours infused over 60 minutes * Recommended dosage regimen is for pediatric patients (1 to 17 years of age) with normal renal function. Dosage adjustment for pediatric patients with renal impairment has not been established. 2.4 Dosage in Adult Patients with Staphylococcus aureus Bloodstream Infections (Bacteremia), Including Those with Right-Sided Infective Endocarditis, Caused by Methicillin-Susceptible and Methicillin-Resistant Isolates Administer Daptomycin for Injection 6 mg/kg to adult patients intravenously once every 24 hours for 2 to 6 weeks. There are limited safety data for the use of Daptomycin for Injection for more than 28 days of therapy. In the Phase 3 trial, there were a total of 14 adult patients who were treated with Daptomycin for Injection for more than 28 days. 2.5 Dosage in Pediatric Patients (1 to 17 Years of Age) with Staphylococcus aureus Bloodstream Infections (Bacteremia) The recommended dosage regimens based on age for pediatric patients with S. aureus bloodstream infections (bacteremia) are shown in Table 2. Administer Daptomycin for Injection intravenously in 0.9% sodium chloride injection once every 24 hours for up to 42 days. Reference ID: 5483234 Table 2: Recommended Dosage of Daptomycin for Injection in Pediatric Patients (1 to 17 Years of Age) with S. aureus Bacteremia, Based on Age Age Group Dosage* Duration of therapy 12 to 17 years 7 mg/kg once every 24 hours infused over 30 minutes Up to 42 days 7 to 11 years 9 mg/kg once every 24 hours infused over 30 minutes 1 to 6 years 12 mg/kg once every 24 hours infused over 60 minutes * Recommended dosage is for pediatric patients (1 to 17 years of age) with normal renal function. Dosage adjustment for pediatric patients with renal impairment has not been established. 2.6 Dosage in Patients with Renal Impairment Adult Patients: No dosage adjustment is required in adult patients with creatinine clearance (CLCR) greater than or equal to 30 mL/min. The recommended dosage regimen for Daptomycin for Injection in adult patients with CLCR less than 30 mL/min, including adult patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), is 4 mg/kg (cSSSI) or 6 mg/kg (S. aureus bloodstream infections) once every 48 hours (Table 3). When possible, Daptomycin for Injection should be administered following the completion of hemodialysis, on hemodialysis days [see Warnings and Precautions (5.2, 5.10), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. Table 3: Recommended Dosage of Daptomycin for Injection in Adult Patients Creatinine Clearance Dosage Regimen in Adults (CLCR) cSSSI S. aureus Bloodstream Infections Greater than or equal to 30 mL/min 4 mg/kg once every 24 hours 6 mg/kg once every 24 hours Less than 30 mL/min, including hemodialysis and CAPD 4 mg/kg once every 48 hours* 6 mg/kg once every 48 hours* * When possible, administer Daptomycin for Injection following the completion of hemodialysis, on hemodialysis days. Pediatric Patients: The dosage regimen for Daptomycin for Injection in pediatric patients with renal impairment has not been established. 2.7 Preparation and Administration of Daptomycin for Injection There are other formulations of daptomycin that have differences concerning reconstitution and storage. Carefully follow the reconstitution and storage procedures described in this labeling. Reconstitution of Daptomycin for Injection Vial Daptomycin for Injection must be reconstituted within the vial only with Sterile Water for Injection. Do NOT use saline based diluents for the reconstitution in the vial because this will result in a hyperosmotic solution that may result in injection site reactions if the reconstituted product is administered as an intravenous injection over a period of 2 minutes. Reconstitution Procedure Daptomycin for Injection is supplied in single-dose vials, each containing 350 mg or 500 mg daptomycin as a sterile, lyophilized powder. The contents of a Daptomycin for Injection vial should be reconstituted, using Reference ID: 5483234 aseptic technique, to 50 mg/mL as follows: 1. To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution. 2. Remove the polypropylene flip-off cap from the Daptomycin for Injection vial to expose the central portion of the rubber stopper. 3. Wipe the top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do not touch the rubber stopper or allow it to touch any other surface. 4. Slowly transfer 7 mL (for 350 mg/vial) or 10 mL (for 500 mg/vial) of the recommended reconstitution fluid through the center of the rubber stopper into the Daptomycin for Injection vial, pointing the transfer needle toward the wall of the vial. Use a beveled sterile transfer needle that is 21 gauge or smaller in diameter, pointing the transfer needle toward the wall of the vial. 5. Ensure that all of the Daptomycin for Injection powder is wetted by holding the vial upright by the cap and gently swirling in a circular motion or gently rotating from upright to horizontal orientation for a few minutes, as needed, to obtain a completely reconstituted solution. Administration Instructions Parenteral drug products should be inspected visually for particulate matter prior to administration. Slowly remove reconstituted liquid (50 mg daptomycin/mL) from the vial using a beveled sterile needle that is 21 gauge or smaller in diameter. Administer as an intravenous injection or infusion as described below: Adults Intravenous Injection over a period of 2 minutes • For intravenous (IV) injection over a period of 2 minutes in adult patients only: Administer the appropriate volume of the reconstituted Daptomycin for Injection (concentration of 50 mg/mL). Intravenous Infusion over a period of 30 minutes • For IV infusion over a period of 30 minutes in adult patients: The appropriate volume of the reconstituted Daptomycin for Injection (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into a 50 mL IV infusion bag containing 0.9% sodium chloride injection or Lactated Ringer’s Injection. Pediatric Patients (1 to 17 Years of Age) Intravenous Infusion over a period of 30 or 60 minutes • Unlike in Adults, do NOT administer Daptomycin for Injection by injection over a two (2) minute period to pediatric patients [see Dosage and Administration (2.1)]. • For Intravenous infusion over a period of 60 minutes in pediatric patients 1 to 6 years of age: The appropriate volume of the reconstituted Daptomycin for Injection (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into an intravenous infusion bag containing 25 mL of 0.9% sodium chloride injection or Lactated Ringer’s Injection. The infusion rate should be maintained at 0.42 mL/minute over the 60-minute period. • For Intravenous infusion over a period of 30 minutes in pediatric patients 7 to 17 years of age: The appropriate volume of the Daptomycin for Injection reconstituted in either Sterile Water for Injection or 0.9% sodium chloride injection (concentration of 50 mg/mL) should be further diluted, using aseptic technique, into a 50 mL IV infusion bag containing 0.9% sodium chloride injection or Lactated Ringer’s. The infusion rate should be maintained at 1.67 mL/minute over the 30-minute period. No preservative or bacteriostatic agent is present in this product. Aseptic technique must be used in the preparation of final IV solution. Table 4 below provides in-use storage conditions for reconstituted Daptomycin for Injection in acceptable intravenous diluents in the syringe, vial and intravenous bag (for reconstitution and dilution). Do not exceed the listed shelf-life of reconstituted and diluted solutions of Daptomycin for Injection. Discard unused portions of Daptomycin for Injection. Reference ID: 5483234 Table 4: In-Use Storage Conditions for Daptomycin for Injection Once Reconstituted with Sterile Water for Injection Container Diluent In-Use Shelf-Life Room Temperature (20°C–25°C, 68°F–77°F) Refrigerated (2°C–8°C, 36°F–46°F) Vial Sterile Water for Injection 18 Hours 5 Days Syringe* Sterile Water for Injection 18 Hours 10 Days Intravenous Bag Vial reconstituted with Sterile Water for Injection and immediately diluted with 0.9% sodium chloride injection 18 Hours 10 Days Vial reconstituted with Sterile Water for Injection and immediately diluted with Lactated Ringer’s injection. 18 Hours 2 Days * Polypropylene syringe with elastomeric plunger stopper. 2.8 Compatible Intravenous Solution for Reconstitution and Dilution Daptomycin for Injection is compatible with Sterile Water for Injection for reconstitution. [see Dosage and Administration (2.7)]. Reconstituted Daptomycin for Injection can be diluted with 0.9% sodium chloride injection or Lactated Ringer’s injection. 2.9 Incompatibilities Daptomycin for Injection is not compatible with dextrose-containing diluents. Daptomycin for Injection should not be used in conjunction with ReadyMED® elastomeric infusion pumps. Stability studies of Daptomycin for Injection solutions stored in ReadyMED® elastomeric infusion pumps identified an impurity (2-mercaptobenzothiazole) leaching from this pump system into the Daptomycin for Injection solution. Because only limited data are available on the compatibility of Daptomycin for Injection with other IV substances, additives and other medications should not be added to Daptomycin for Injection single-dose vials or infusion bags, or infused simultaneously with Daptomycin for Injection through the same IV line. If the same IV line is used for sequential infusion of different drugs, the line should be flushed with a compatible intravenous solution before and after infusion with Daptomycin for Injection. 3 DOSAGE FORMS AND STRENGTHS For Injection: 350 mg or 500 mg of daptomycin as a sterile, pale yellow to light brown lyophilized powder for reconstitution in a single-dose vial. 4 CONTRAINDICATIONS Daptomycin for Injection is contraindicated in patients with known hypersensitivity to daptomycin [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Anaphylaxis/Hypersensitivity Reactions Anaphylaxis/hypersensitivity reactions have been reported with the use of antibacterial agents, including daptomycin for injection, and may be life-threatening. If an allergic reaction to Daptomycin for Injection occurs, discontinue the drug and institute appropriate therapy [see Adverse Reactions (6.2)]. Reference ID: 5483234 5.2 Myopathy and Rhabdomyolysis Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal (ULN), has been reported with the use of daptomycin. Rhabdomyolysis, with or without acute renal failure, has been reported [see Adverse Reactions (6.2)]. Patients receiving Daptomycin for Injection should be monitored for the development of muscle pain or weakness, particularly of the distal extremities. In patients who receive Daptomycin for Injection, CPK levels should be monitored weekly, and more frequently in patients who received recent prior or concomitant therapy with an HMG-CoA reductase inhibitor or in whom elevations in CPK occur during treatment with Daptomycin for Injection. In adult patients with renal impairment, both renal function and CPK should be monitored more frequently than once weekly [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. In Phase 1 studies and Phase 2 clinical trials in adults, CPK elevations appeared to be more frequent when Daptomycin for Injection was dosed more than once daily. Therefore, Daptomycin for Injection should not be dosed more frequently than once a day. Daptomycin for Injection should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevations to levels >1,000 U/L (~5× ULN), and in patients without reported symptoms who have marked elevations in CPK, with levels >2,000 U/L (≥10× ULN). In addition, consideration should be given to suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, temporarily in patients receiving daptomycin [see Drug Interactions (7.1)]. 5.3 Eosinophilic Pneumonia Eosinophilic pneumonia has been reported in patients receiving daptomycin for injection [see Adverse Reactions (6.2)]. In reported cases associated with daptomycin for injection, patients developed fever, dyspnea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates or organizing pneumonia. In general, patients developed eosinophilic pneumonia 2 to 4 weeks after starting daptomycin for injection and improved when daptomycin for injection was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving Daptomycin for Injection should undergo prompt medical evaluation, and Daptomycin for Injection should be discontinued immediately. Treatment with systemic steroids is recommended. 5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) DRESS has been reported in post-marketing experience with daptomycin for injection [see Adverse Reactions (6.2)]. Patients who develop skin rash, fever, peripheral eosinophilia, and systemic organ (for example, hepatic, renal, pulmonary) impairment while receiving Daptomycin for Injection should undergo medical evaluation. If DRESS is suspected, discontinue Daptomycin for Injection promptly and institute appropriate treatment. 5.5 Tubulointerstitial Nephritis (TIN) TIN has been reported in post-marketing experience with daptomycin for injection [see Adverse Reactions (6.2)]. Patients who develop new or worsening renal impairment while receiving Daptomycin for Injection should undergo medical evaluation. If TIN is suspected, discontinue Daptomycin for Injection promptly and institute appropriate treatment. 5.6 Peripheral Neuropathy Cases of peripheral neuropathy have been reported during the daptomycin postmarketing experience [see Adverse Reactions (6.2)]. Therefore, physicians should be alert to signs and symptoms of peripheral Reference ID: 5483234 neuropathy in patients receiving daptomycin. Monitor for neuropathy and consider discontinuation. 5.7 Potential Nervous System and/or Muscular System Effects in Pediatric Patients Younger than 12 Months Avoid use of Daptomycin for Injection in pediatric patients younger than 12 months due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs with intravenous daptomycin [see Nonclinical Toxicology (13.2)]. 5.8 Clostridioides difficile-Associated Diarrhea Clostridioides difficile–associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including daptomycin for injection, and may range in severity from mild diarrhea to fatal colitis [see Adverse Reactions (6.2)]. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, since these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.9 Persisting or Relapsing S. aureus Bacteremia/Endocarditis Patients with persisting or relapsing S. aureus bacteremia/endocarditis or poor clinical response should have repeat blood cultures. If a blood culture is positive for S. aureus, minimum inhibitory concentration (MIC) susceptibility testing of the isolate should be performed using a standardized procedure, and diagnostic evaluation of the patient should be performed to rule out sequestered foci of infection. Appropriate surgical intervention (e.g., debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibacterial regimen may be required. Failure of treatment due to persisting or relapsing S. aureus bacteremia/endocarditis may be due to reduced daptomycin susceptibility (as evidenced by increasing MIC of the S. aureus isolate) [see Clinical Studies (14.2)]. 5.10 Efficacy in Patients with Moderate Baseline Renal Impairment Limited data are available from the two Phase 3 complicated skin and skin structure infection (cSSSI) trials regarding clinical efficacy of daptomycin for injection treatment in adult patients with creatinine clearance (CLCR) <50 mL/min; only 31/534 (6%) patients treated with daptomycin for injection in the intent-to-treat (ITT) population had a baseline CLCR <50 mL/min. Table 5 shows the number of adult patients by renal function and treatment group who were clinical successes in the Phase 3 cSSSI trials. Table 5: Clinical Success Rates by Renal Function and Treatment Group in Phase 3 cSSSI Trials in Adult Patients (Population: ITT) CLCR Success Rate n/N (%) Daptomycin for Injection 4 mg/kg every 24h Comparator 50-70 mL/min 25/38 (66%) 30/48 (63%) 30-<50 mL/min 7/15 (47%) 20/35 (57%) Reference ID: 5483234 In a subgroup analysis of the ITT population in the Phase 3 S. aureus bacteremia/endocarditis trial, clinical success rates, as determined by a treatment-blinded Adjudication Committee [see Clinical Studies (14.2)], in the daptomycin-treated adult patients were lower in patients with baseline CLCR <50 mL/min (see Table 6). A decrease of the magnitude shown in Table 6 was not observed in comparator-treated patients. Table 6: Adjudication Committee Clinical Success Rates at Test of Cure by Baseline Creatinine Clearance and Treatment Subgroup in the S. aureus Bacteremia/Endocarditis Trial in Adult Patients (Population: ITT) Baseline CLCR Success Rate n/N (%) Daptomycin for Injection 6 mg/kg every 24h Comparator Bacteremia Right-Sided Infective Endocarditis Bacteremia Right-Sided Infective Endocarditis >80 mL/min 30/50 (60%) 7/14 (50%) 19/42 (45%) 5/11 (46%) 50–80 mL/min 12/26 (46%) 1/4 (25%) 13/31 (42%) 1/2 (50%) 30–<50 mL/min 2/14 (14%) 0/1 (0%) 7/17 (41%) 1/1 (100%) Consider these data when selecting antibacterial therapy for use in adult patients with baseline moderate to severe renal impairment. 5.11 Increased International Normalized Ratio (INR)/Prolonged Prothrombin Time Clinically relevant plasma concentrations of daptomycin have been observed to cause a significant concentration-dependent false prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay [see Drug Interactions (7.2)]. 5.12 Development of Drug-Resistant Bacteria Prescribing Daptomycin for Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other sections: • Anaphylaxis/Hypersensitivity Reactions [see Warnings and Precautions (5.1)] • Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.2)] • Eosinophilic Pneumonia [see Warnings and Precautions (5.3)] • Drug Reaction with Eosinophilia and Systemic Symptoms [see Warnings and Precautions (5.4)] • Tubulointerstitial Nephritis [see Warnings and Precautions (5.5)] • Peripheral Neuropathy [see Warnings and Precautions (5.6)] • Increased International Normalized Ratio (INR)/Prolonged Prothrombin Time [see Warnings and Precautions (5.11) and Drug Interactions (7.2)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trial Experience in Adult Patients Clinical trials enrolled 1,864 adult patients treated with daptomycin for injection and 1,416 treated with comparator. Reference ID: 5483234 Complicated Skin and Skin Structure Infection Trials in Adults In Phase 3 complicated skin and skin structure infection (cSSSI) trials in adult patients, daptomycin for injection was discontinued in 15/534 (2.8%) patients due to an adverse reaction, while comparator was discontinued in 17/558 (3.0%) patients. The rates of the most common adverse reactions, organized by body system, observed in adult patients with cSSSI (receiving 4 mg/kg daptomycin for injection) are displayed in Table 7. Table 7: Incidence of Adverse Reactions that Occurred in ≥2% of Adult Patients in the Daptomycin for InjectionTreatment Group and ≥ the Comparator Treatment Group in Phase 3 cSSSI Trials Adverse Reaction Adult Patients (%) Daptomycin for Injection 4 mg/kg (N=534) Comparator* (N=558) Gastrointestinal disorders Diarrhea 5.2 4.3 Nervous system disorders Headache 5.4 5.4 Dizziness 2.2 2.0 Skin/subcutaneous disorders Rash 4.3 3.8 Diagnostic investigations Abnormal liver function tests 3.0 1.6 Elevated CPK 2.8 1.8 Infections Urinary tract infections 2.4 0.5 Vascular disorders Hypotension 2.4 1.4 Respiratory disorders Dyspnea 2.1 1.6 * Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g/day IV in divided doses). Drug-related adverse reactions (possibly or probably drug-related) that occurred in <1% of adult patients receiving daptomycin for injection in the cSSSI trials are as follows: Body as a Whole: fatigue, weakness, rigors, flushing, hypersensitivity Blood/Lymphatic System: leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased International Normalized Ratio (INR) Cardiovascular System: supraventricular arrhythmia Dermatologic System: eczema Digestive System: abdominal distension, stomatitis, jaundice, increased serum lactate dehydrogenase Metabolic/Nutritional System: hypomagnesemia, increased serum bicarbonate, electrolyte disturbance Musculoskeletal System: myalgia, muscle cramps, muscle weakness, arthralgia Nervous System: vertigo, mental status change, paresthesia Special Senses: taste disturbance, eye irritation S. aureus Bacteremia/Endocarditis Trial in Adults In the S. aureus bacteremia/endocarditis trial involving adult patients, daptomycin for injection was discontinued in 20/120 (16.7%) patients due to an adverse reaction, while comparator was discontinued in 21/116 (18.1%) patients. Reference ID: 5483234 Serious Gram-negative infections (including bloodstream infections) were reported in 10/120 (8.3%) daptomycin-treated patients and 0/115 comparator-treated patients. Comparator-treated patients received dual therapy that included initial gentamicin for 4 days. Infections were reported during treatment and during early and late follow-up. Gram-negative infections included cholangitis, alcoholic pancreatitis, sternal osteomyelitis/mediastinitis, bowel infarction, recurrent Crohn's disease, recurrent line sepsis, and recurrent urosepsis caused by a number of different Gram-negative bacteria. The rates of the most common adverse reactions, organized by System Organ Class (SOC), observed in adult patients with S. aureus bacteremia/endocarditis (receiving 6 mg/kg daptomycin for injection) are displayed in Table 8. Table 8: Incidence of Adverse Reactions that Occurred in ≥5% of Adult Patients in the Daptomycin for Injection Treatment Group and ≥ the Comparator Treatment Group in the S. aureus Bacteremia/Endocarditis Trial Adverse Reaction* Adult Patients n (%) Daptomycin for Injection 6 mg/kg (N=120) Comparator† (N=116) Infections and infestations Sepsis NOS 6 (5%) 3 (3%) Bacteremia 6 (5%) 0 (0%) Gastrointestinal disorders Abdominal pain NOS 7 (6%) 4 (3%) General disorders and administration site conditions Chest pain 8 (7%) 7 (6%) Edema NOS 8 (7%) 5 (4%) Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain 10 (8%) 2 (2%) Skin and subcutaneous tissue disorders Pruritus 7 (6%) 6 (5%) Sweating increased 6 (5%) 0 (0%) Psychiatric disorders Insomnia 11 (9%) 8 (7%) Investigations Blood creatine phosphokinase increased 8 (7%) 1 (1%) Vascular disorders Hypertension NOS 7 (6%) 3 (3%) * NOS, not otherwise specified. † Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 2 g IV q4h), each with initial low-dose gentamicin. The following reactions, not included above, were reported as possibly or probably drug-related in the daptomycin-treated group: Blood and Lymphatic System Disorders: eosinophilia, lymphadenopathy, thrombocythemia, thrombocytopenia Cardiac Disorders: atrial fibrillation, atrial flutter, cardiac arrest Ear and Labyrinth Disorders: tinnitus Eye Disorders: vision blurred Gastrointestinal Disorders: dry mouth, epigastric discomfort, gingival pain, hypoesthesia oral Reference ID: 5483234 Infections and Infestations: candidal infection NOS, vaginal candidiasis, fungemia, oral candidiasis, urinary tract infection fungal Investigations: blood phosphorous increased, blood alkaline phosphatase increased, INR increased, liver function test abnormal, alanine aminotransferase increased, aspartate aminotransferase increased, prothrombin time prolonged Metabolism and Nutrition Disorders: appetite decreased NOS Musculoskeletal and Connective Tissue Disorders: myalgia Nervous System Disorders: dyskinesia, paresthesia Psychiatric Disorders: hallucination NOS Renal and Urinary Disorders: proteinuria, renal impairment NOS Skin and Subcutaneous Tissue Disorders: pruritus generalized, rash vesicular Other Trials in Adults In Phase 3 trials of community-acquired pneumonia (CAP) in adult patients, the death rate and rates of serious cardiorespiratory adverse events were higher in daptomycin-treated patients than in comparator-treated patients. These differences were due to lack of therapeutic effectiveness of daptomycin in the treatment of CAP in patients experiencing these adverse events [see Indications and Usage (1.4)]. Laboratory Changes in Adults Complicated Skin and Skin Structure Infection Trials in Adults In Phase 3 cSSSI trials of adult patients receiving daptomycin at a dose of 4 mg/kg, elevations in CPK were reported as clinical adverse events in 15/534 (2.8%) daptomycin-treated patients, compared with 10/558 (1.8%) comparator-treated patients. Of the 534 patients treated with daptomycin, 1 (0.2%) had symptoms of muscle pain or weakness associated with CPK elevations to greater than 4 times the upper limit of normal (ULN). The symptoms resolved within 3 days and CPK returned to normal within 7 to 10 days after treatment was discontinued [see Warnings and Precautions (5.2)]. Table 9 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI adult trials. Table 9: Incidence of CPK Elevations from Baseline during Therapy in Either the Daptomycin for Injection Treatment Group or the Comparator Treatment Group in Phase 3 cSSSI Adult Trials Change in CPK All Adult Patients Adult Patients with Normal CPK at Baseline Daptomycin for Injection 4 mg/kg (N=430) Comparator* (N=459) Daptomycin for Injection 4 mg/kg (N=374) Comparator* (N=392) % n % n % n % n No Increase 90.7 390 91.1 418 91.2 341 91.1 357 Maximum Value >1× ULN† 9.3 40 8.9 41 8.8 33 8.9 35 >2× ULN 4.9 21 4.8 22 3.7 14 3.1 12 >4× ULN 1.4 6 1.5 7 1.1 4 1.0 4 >5× ULN 1.4 6 0.4 2 1.1 4 0.0 0 >10× ULN 0.5 2 0.2 1 0.2 1 0.0 0 Note: Elevations in CPK observed in adult patients treated with daptomycin or comparator were not clinically or statistically significantly different. * Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g/day IV in divided doses). † ULN (Upper Limit of Normal) is defined as 200 U/L. Reference ID: 5483234 S. aureus Bacteremia/Endocarditis Trial in Adults In the S. aureus bacteremia/endocarditis trial in adult patients, at a dose of 6 mg/kg, 11/120 (9.2%) daptomycin­ treated patients, including two patients with baseline CPK levels >500 U/L, had CPK elevations to levels >500 U/L, compared with 1/116 (0.9%) comparator-treated patients. Of the 11 daptomycin-treated patients, 4 had prior or concomitant treatment with an HMG-CoA reductase inhibitor. Three of these 11 daptomycin-treated patients discontinued therapy due to CPK elevation, while the one comparator-treated patient did not discontinue therapy [see Warnings and Precautions (5.2)]. Clinical Trial Experience in Pediatric Patients Complicated Skin and Skin Structure Infection Trial in Pediatric Patients The safety of daptomycin for injection was evaluated in one clinical trial (in cSSSI), which included 256 pediatric patients (1 to 17 years of age) treated with intravenous daptomycin for injection and 133 patients treated with comparator agents. Patients were given age-dependent doses once daily for a treatment period of up to 14 days (median treatment period was 3 days). The doses given by age group were as follows: 10mg/kg for 1 to < 2 years, 9 mg/kg for 2 to 6 years, 7mg/kg for 7 to 11 years and 5 mg/kg for 12 to 17 years of age [see Clinical Studies (14)]. Patients treated with daptomycin for injection were (51%) male, (49%) female and (46%) Caucasian and (32%) Asian. Adverse Reactions Leading to Discontinuation In the cSSSI study, daptomycin for injection was discontinued in 7/256 (2.7%) patients due to an adverse reaction, while comparator was discontinued in 7/133 (5.3%) patients. Most Common Adverse Reactions The rates of the most common adverse reactions, organized by body system, observed in these pediatric patients with cSSSI are displayed in Table 10. Table 10: Adverse Reactions that Occurred in ≥2% of Pediatric Patients in the Daptomycin for Injection Treatment-Arm and Greater Than or Equal to the Comparator Treatment-Arm in the cSSSI Pediatric Trial Adverse Reaction Daptomycin for Injection (N = 256) Comparator* (N = 133) n (%) n (%) Gastrointestinal disorders Diarrhea 18 (7.0) 7 (5.3) Vomiting 7 (2.7) 1 (0.8) Abdominal Pain 5 (2.0) 0 Skin and subcutaneous tissue disorders Pruritus 8 (3.1) 2 (1.5) General disorders and administration site conditions Pyrexia 10 (3.9) 4 (3.0) Investigations Blood CPK increased 14 (5.5) 7 (5.3) Nervous system disorders Headache 7 (2.7) 3 (2.3) *Comparators included intravenous therapy with either vancomycin, clindamycin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin) The safety profile in the clinical trial of cSSSI pediatric patients was similar to that observed in the cSSSI adult patients. Reference ID: 5483234 S. aureus Bacteremia Trial in Pediatric Patients The safety of daptomycin for injection was evaluated in one clinical trial (in S. aureus bacteremia), which treated 55 pediatric patients with intravenous daptomycin and 26 patients with comparator agents. Patients were given age-dependent doses once daily for a treatment period of up to 42 days (mean duration of IV treatment was 12 days). The doses by age group were as follows: 12 mg/kg for 1 to <6 years, 9 mg/kg for 7 to 11 years and 7 mg/kg for 12 to 17 years of age [see Clinical Studies (14)]. Patients treated with daptomycin were (69%) male and (31%) female. No patients 1 to <2 years of age were enrolled. Adverse Reactions Leading to Discontinuation In the bacteremia study, daptomycin for injection was discontinued in 3/55 (5.5%) patients due to an adverse reaction, while comparator was discontinued in 2/26 (7.7%) patients. Most Common Adverse Reactions The rates of the most common adverse reactions, organized by body system, observed in these pediatric patients with bacteremia are displayed in Table 11. Table 11: Incidence of Adverse Reactions that Occurred in ≥5% of Pediatric Patients in the Daptomycin for Injection Treatment- Arm and Greater Than or Equal to the Comparator Treatment-Arm in the Pediatric Bacteremia Trial Adverse Reaction Daptomycin for Injection (N = 55) Comparator* (N = 26) n (%) n (%) Gastrointestinal disorders Vomiting 6 (10.9) 2 (7.7) Investigations Blood CPK increased 4 (7.3) 0 *Comparators included intravenous therapy with either vancomycin, cefazolin, or an anti-staphylococcal semi-synthetic penicillin (nafcillin, oxacillin or cloxacillin) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of daptomycin for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: anemia, thrombocytopenia General and administration site conditions: pyrexia Immune System Disorders: anaphylaxis; hypersensitivity reactions, including angioedema, pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia [see Contraindications (4) and Warnings and Precautions (5.1)] Infections and Infestations: Clostridioides difficile–associated diarrhea [see Warnings and Precautions (5.8)] Laboratory Investigations: platelet count decreased; hyperkalemia Musculoskeletal Disorders: myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with daptomycin and HMG-CoA reductase inhibitors) [see Warnings and Precautions (5.2), Drug Interactions (7.1), and Clinical Pharmacology (12.3)] Respiratory, Thoracic, and Mediastinal Disorders: cough, eosinophilic pneumonia, organizing pneumonia [see Warnings and Precautions (5.3)] Reference ID: 5483234 Nervous System Disorders: peripheral neuropathy [see Warnings and Precautions (5.6)] Skin and Subcutaneous Tissue Disorders: serious skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), vesiculobullous rash (with or without mucous membrane involvement, including Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]), and acute generalized exanthematous pustulosis [see Warnings and Precautions (5.4)] Gastrointestinal Disorders: nausea, vomiting Renal and urinary disorders: acute kidney injury, renal insufficiency, renal failure, and tubulointerstitial nephritis (TIN) [see Warnings and Precautions (5.5)] Special Senses: visual disturbances 7 DRUG INTERACTIONS 7.1 HMG-CoA Reductase Inhibitors In healthy adult subjects, concomitant administration of daptomycin for injection and simvastatin had no effect on plasma trough concentrations of simvastatin, and there were no reports of skeletal myopathy [see Clinical Pharmacology (12.3)]. However, inhibitors of HMG-CoA reductase may cause myopathy, which is manifested as muscle pain or weakness associated with elevated levels of creatine phosphokinase (CPK). In the adult Phase 3 S. aureus bacteremia/endocarditis trial, some patients who received prior or concomitant treatment with an HMG-CoA reductase inhibitor developed elevated CPK [see Adverse Reactions (6.1)]. Experience with the coadministration of HMG-CoA reductase inhibitors and daptomycin in patients is limited; therefore, consideration should be given to suspending use of HMG-CoA reductase inhibitors temporarily in patients receiving Daptomycin for Injection. 7.2 Drug-Laboratory Test Interactions Clinically relevant plasma concentrations of daptomycin have been observed to cause a significant concentration-dependent false prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay. The possibility of an erroneously elevated PT/INR result due to interaction with a recombinant thromboplastin reagent may be minimized by drawing specimens for PT or INR testing near the time of trough plasma concentrations of daptomycin. However, sufficient daptomycin concentrations may be present at trough to cause interaction. If confronted with an abnormally high PT/INR result in a patient being treated with Daptomycin for Injection, it is recommended that clinicians: 1. Repeat the assessment of PT/INR, requesting that the specimen be drawn just prior to the next daptomycin dose (i.e., at trough concentration). If the PT/INR value obtained at trough remains substantially elevated above what would otherwise be expected, consider evaluating PT/INR utilizing an alternative method. 2. Evaluate for other causes of abnormally elevated PT/INR results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data on use of daptomycin for injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies performed in rats and rabbits daptomycin was administered intravenously during organogenesis at doses 2 and 4-times, respectively, the recommended 6 mg/kg human dose (on a body surface area basis). No evidence of adverse developmental outcomes was observed. Reference ID: 5483234 The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In pregnant rats, daptomycin was administered intravenously at doses of 5, 20, or 75 mg/kg/day during the gestation days 6 to 18. Maternal body weight gain was decreased at 75 mg/kg/day. No embryo/fetal effects were noted at the highest dose of 75 mg/kg/day, a dose approximately 2-fold higher than in humans at the recommended maximum dose of 6mg/kg (based on body surface area). In pregnant rabbits, daptomycin was administered intravenously at doses of 5, 20, or 75 mg/kg/day during the gestation days 6 to 15. Maternal body weight gain and food consumption were decreased at 75 mg/kg/day. No embryo/fetal effects were noted at the highest dose of 75 mg/kg/day, a dose approximately 4-fold higher than in humans at the maximum recommended dose of 6mg/kg (based on body surface area). In a combined fertility and pre/postnatal development study, daptomycin was administered intravenously to female rats at doses of 2, 25, 75 mg/kg/day from 14-days pre-mating through lactation/postpartum day 20). No effects on pre/postnatal development were observed up to the highest dose of 75 mg/kg/day, a dose approximately 2-fold higher than the maximum recommended human dose of 6 mg/kg (based on body surface area)1. 8.2 Lactation Risk Summary Limited published data report that daptomycin is present in human milk at infant doses of 0.1% of the maternal dose (see Data)2,3,4. There is no information on the effects of daptomycin on the breastfed infant or the effects of daptomycin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Daptomycin for Injection and any potential adverse effects on the breastfed infant from Daptomycin for Injection or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of daptomycin for injection in the treatment of cSSSI and S. aureus bloodstream infections (bacteremia) have been established in the age groups 1 to 17 years of age. Use of daptomycin for injection in these age groups is supported by evidence from adequate and well-controlled studies in adults, with additional data from pharmacokinetic studies in pediatric patients, and from safety, efficacy and PK studies in pediatric patients with cSSSI and S. aureus bloodstream infections [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2)]. Safety and effectiveness in pediatric patients below the age of one year have not been established. Avoid use of Daptomycin for Injection in pediatric patients younger than one year of age due to the risk of potential effects on muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) observed in neonatal dogs [see Warnings and Precautions (5.7) and Nonclinical Toxicology (13.2)]. Daptomycin for Injection is not indicated in pediatric patients with renal impairment because dosage has not been established in these patients. Daptomycin for Injection has not been studied in pediatric patients with other bacterial infections. 8.5 Geriatric Use Of the 534 adult patients treated with daptomycin for injection in Phase 3 controlled clinical trials of complicated skin and skin structure infections (cSSSI), 27% were 65 years of age or older and 12% were 75 Reference ID: 5483234 I CONH, 0 HO, ,LO O '----< ,. 0 CO,H -s™ r;:, H02C~~o ~o ~~NH, HN N 0 H 0 Ho2c f N H years of age or older. Of the 120 adult patients treated with daptomycin in the Phase 3 controlled clinical trial of S. aureus bacteremia/endocarditis, 25% were 65 years of age or older and 16% were 75 years of age or older. In Phase 3 adult clinical trials of cSSSI and S. aureus bacteremia/endocarditis, clinical success rates were lower in patients ≥65 years of age than in patients <65 years of age. In addition, treatment-emergent adverse events were more common in patients ≥65 years of age than in patients <65 years of age. The exposure of daptomycin was higher in healthy elderly subjects than in healthy young adult subjects. However, no adjustment of Daptomycin for Injection dosage is warranted for elderly patients with creatinine clearance (CLCR) ≥30 mL/min [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)]. 8.6 Patients with Renal Impairment Daptomycin is eliminated primarily by the kidneys; therefore, a modification of daptomycin dosage interval is recommended for adult patients with CLCR <30 mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). In adult patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently than once weekly [see Dosage and Administration (2.6), Warnings and Precautions (5.2, 5.10), and Clinical Pharmacology (12.3)]. The dosage regimen for Daptomycin for Injection in pediatric patients with renal impairment has not been established. 10 OVERDOSAGE In the event of overdosage, supportive care is advised with maintenance of glomerular filtration. Daptomycin is cleared slowly from the body by hemodialysis (approximately 15% of the administered dose is removed over 4 hours) and by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours). The use of high-flux dialysis membranes during 4 hours of hemodialysis may increase the percentage of dose removed compared with that removed by low-flux membranes. 11 DESCRIPTION Daptomycin for Injection contains daptomycin, a cyclic lipopeptide antibacterial agent derived from the fermentation of Streptomyces roseosporus. The chemical name is N-decanoyl-L-tryptophyl-D-asparaginyl- L-aspartyl-L-threonylglycyl-L-ornithyl-L- aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L­ glutamyl-3-anthraniloyl-L- alanine ε1-lactone. The empirical formula is C72H101N17O26; the molecular weight is 1620.67. The chemical structure is: Reference ID: 5483234 Daptomycin for Injection is supplied in a single-dose vial as a sterile, preservative-free, pale yellow to light brown lyophilized powder containing 350 mg or 500 mg of daptomycin for intravenous (IV) use following reconstitution with Sterile Water for Injection [see Dosage and Administration (2.7)]. Freshly reconstituted solutions of Daptomycin for Injection range in color from pale yellow to light brown. • Daptomycin for Injection 350 mg per vial, contains 350 mg daptomycin and 210 mg arginine hydrochloride. Hydrochloric acid and/or sodium hydroxide is used to adjust the pH. • Daptomycin for Injection 500 mg per vial contains 500 mg daptomycin, and 300 mg arginine hydrochloride. Hydrochloric acid and/or sodium hydroxide is used to adjust the pH. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Daptomycin is an antibacterial drug [see Clinical Pharmacology (12.4)]. 12.2 Pharmacodynamics Based on animal models of infection, the antimicrobial activity of daptomycin for injection appears to correlate with the AUC/MIC (area under the concentration-time curve/minimum inhibitory concentration) ratio for certain pathogens, including S. aureus. The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with daptomycin for injection. 12.3 Pharmacokinetics Daptomycin Administered over a 30-Minute Period in Adults The mean and standard deviation (SD) pharmacokinetic parameters of daptomycin at steady-state following intravenous (IV) administration of daptomycin for injection over a 30-minute period at 4 to 12 mg/kg every 24h to healthy young adults are summarized in Table 12. Table 12: Mean (SD) Daptomycin Pharmacokinetic Parameters in Healthy Adult Volunteers at Steady-State Dose*† (mg/kg) Pharmacokinetic Parameters‡ AUC0-24 (mcg∙h/mL) t1/2 (h) VSS (L/kg) CLT (mL/h/kg) Cmax (mcg/mL) 4 (N=6) 494 (75) 8.1 (1.0) 0.096 (0.009) 8.3 (1.3) 57.8 (3.0) 6 (N=6) 632 (78) 7.9 (1.0) 0.101 (0.007) 9.1 (1.5) 93.9 (6.0) 8 (N=6) 858 (213) 8.3 (2.2) 0.101 (0.013) 9.0 (3.0) 123.3 (16.0) 10 (N=9) 1039 (178) 7.9 (0.6) 0.098 (0.017) 8.8 (2.2) 141.1 (24.0) 12 (N=9) 1277 (253) 7.7 (1.1) 0.097 (0.018) 9.0 (2.8) 183.7 (25.0) * Daptomycin for injection was administered by IV infusion over a 30-minute period. † Doses of daptomycin for injection in excess of 6 mg/kg have not been approved. ‡ AUC0-24, area under the concentration-time curve from 0 to 24 hours; t1/2, elimination half-life; VSS, volume of distribution at steady-state; CLT, total plasma clearance; Cmax, maximum plasma concentration. Daptomycin pharmacokinetics were generally linear and time-independent at daptomycin doses of 4 to 12 mg/kg every 24h administered by IV infusion over a 30-minute period for up to 14 days. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following the administration of 4, 6, 8, 10, and 12 mg/kg every 24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9), and 13.7 (5.2) mcg/mL, respectively. Reference ID: 5483234 Daptomycin for Injection Administered over a 2-Minute Period in Adults Following IV administration of daptomycin for injection over a 2-minute period to healthy adult volunteers at doses of 4 mg/kg (N=8) and 6 mg/kg (N=12), the mean (SD) steady-state systemic exposure (AUC) values were 475 (71) and 701 (82) mcg∙h/mL, respectively. Values for maximum plasma concentration (Cmax) at the end of the 2-minute period could not be determined adequately in this study. However, using pharmacokinetic parameters from 14 healthy adult volunteers who received a single dose of daptomycin 6 mg/kg IV administered over a 30-minute period in a separate study, steady-state Cmax values were simulated for daptomycin 4 and 6 mg/kg IV administered over a 2-minute period. The simulated mean (SD) steady-state Cmax values were 77.7 (8.1) and 116.6 (12.2) mcg/mL, respectively. Distribution Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration- independent manner. The overall mean binding ranges from 90 to 93%. In clinical studies, mean serum protein binding in adult subjects with creatinine clearance (CLCR) ≥30 mL/min was comparable to that observed in healthy adult subjects with normal renal function. However, there was a trend toward decreasing serum protein binding among subjects with CLCR <30 mL/min (88%), including those receiving hemodialysis (86%) and continuous ambulatory peritoneal dialysis (CAPD) (84%). The protein binding of daptomycin in adult subjects with moderate hepatic impairment (Child-Pugh Class B) was similar to that in healthy adult subjects. The volume of distribution at steady-state (VSS) of daptomycin in healthy adult subjects was approximately 0.1 L/kg and was independent of dose. Metabolism In in vitro studies, daptomycin was not metabolized by human liver microsomes. In 5 healthy adults after infusion of radiolabeled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference between total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma on Day 1 following the administration of daptomycin at 6 mg/kg to adult subjects. Minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified. Excretion Daptomycin is excreted primarily by the kidneys. In a mass balance study of 5 healthy adult subjects using radiolabeled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations), and 5.7% of the administered dose was recovered from feces (collected for up to 9 days) based on total radioactivity. Specific Populations Patients with Renal Impairment Population-derived pharmacokinetic parameters were determined for infected adult patients (complicated skin and skin structure infections [cSSSI] and S. aureus bacteremia) and noninfected adult subjects with various degrees of renal function (Table 13). Total plasma clearance (CLT), elimination half-life (t1/2), and volume of distribution at steady-state (VSS) in patients with cSSSI were similar to those in patients with S. aureus bacteremia. Following administration of daptomycin for injection 4 mg/kg every 24h by IV infusion over a 30-minute period, the mean CLT was 9%, 22%, and 46% lower among subjects and patients with mild (CLCR 50–80 mL/min), moderate (CLCR 30–<50 mL/min), and severe (CLCR <30 mL/min) renal impairment, respectively, than in those with normal renal function (CLCR >80 mL/min). The mean steady-state systemic exposure (AUC), t1/2, and VSS increased with decreasing renal function, although the mean AUC for patients with CLCR 30–80 mL/min was not markedly different from the mean AUC for patients with normal renal function. The mean AUC for patients with CLCR <30 mL/min and for patients on dialysis (CAPD and Reference ID: 5483234 hemodialysis dosed post-dialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function. The mean Cmax ranged from 60 to 70 mcg/mL in patients with CLCR ≥30 mL/min, while the mean Cmax for patients with CLCR <30 mL/min ranged from 41 to 58 mcg/mL. After administration of daptomycin for injection 6 mg/kg every 24h by IV infusion over a 30-minute period, the mean Cmax ranged from 80 to 114 mcg/mL in patients with mild to moderate renal impairment and was similar to that of patients with normal renal function. Table 13: Mean (SD) Daptomycin Population Pharmacokinetic Parameters Following Infusion of Daptomycin for Injection 4 mg/kg or 6 mg/kg to Infected Adult Patients and Noninfected Adult Subjects with Various Degrees of Renal Function Renal Function Pharmacokinetic Parameters* t1/2† (h) 4 mg/kg Vss† (L/kg) 4 mg/kg CLT † (mL/h/kg) 4 mg/kg AUC0-∞† (mcg∙h/mL) 4 mg/kg AUCss‡ (mcg∙h/mL) 6 mg/kg Cmin,ss‡ (mcg/mL) 6 mg/kg Normal (CLCR >80 mL/min) 9.39 (4.74) N=165 0.13 (0.05) N=165 10.9 (4.0) N=165 417 (155) N=165 545 (296) N=62 6.9 (3.5) N=61 Mild Renal Impairment (CLCR 50–80 mL/min) 10.75 (8.36) N=64 0.12 (0.05) N=64 9.9 (4.0) N=64 466 (177) N=64 637 (215) N=29 12.4 (5.6) N=29 Moderate Renal Impairment (CLCR 30– <50 mL/min) 14.70 (10.50) N=24 0.15 (0.06) N=24 8.5 (3.4) N=24 560 (258) N=24 868 (349) N=15 19.0 (9.0) N=14 Severe Renal Impairment (CLCR <30 mL/min) 27.83 (14.85) N=8 0.20 (0.15) N=8 5.9 (3.9) N=8 925 (467) N=8 1050 (892) N=2 24.4 (21.4) N=2 Hemodialysis 30.51 (6.51) N=16 0.16 (0.04) N=16 3.9 (2.1) N=16 1193 (399) N=16 NA NA CAPD 27.56 (4.53) N=5 0.11 (0.02) N=5 2.9 (0.4) N=5 1409 (238) N=5 NA NA Note: daptomycin for injection was administered over a 30-minute period. * CLCR, creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; CAPD, continuous ambulatory peritoneal dialysis; AUC0-∞, area under the concentration-time curve extrapolated to infinity; AUCSS, area under the concentration-time curve calculated over the 24-hour dosing interval at steady-state; Cmin,SS, trough concentration at steady-state; NA, not applicable. † Parameters obtained following a single dose from patients with complicated skin and skin structure infections and healthy subjects. ‡ Parameters obtained at steady-state from patients with S. aureus bacteremia. Because renal excretion is the primary route of elimination, adjustment of Daptomycin for Injection dosage interval is necessary in adult patients with severe renal impairment (CLCR <30 mL/min) [see Dosage and Administration (2.6)]. Patients with Hepatic Impairment The pharmacokinetics of daptomycin were evaluated in 10 adult subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with those in healthy adult volunteers (N=9) matched for gender, age, and Reference ID: 5483234 weight. The pharmacokinetics of daptomycin were not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when Daptomycin for Injection is administered to patients with mild to moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh Class C) have not been evaluated. Gender No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when daptomycin is administered. Geriatric Patients The pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (≥75 years of age) and 11 healthy young adult controls (18 to 30 years of age). Following administration of a single 4 mg/kg dose of daptomycin for injection by IV infusion over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0-∞ was approximately 58% higher in elderly subjects than in healthy young adult subjects. There were no differences in Cmax [see Use in Specific Populations (8.5)]. Obese Patients The pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m2) and 6 extremely obese (BMI ≥40 kg/m2) adult subjects and controls matched for age, gender, and renal function. Following administration of daptomycin for injection by IV infusion over a 30-minute period as a single 4 mg/kg dose based on total body weight, the total plasma clearance of daptomycin normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects than in nonobese controls. The AUC0-∞ of daptomycin was approximately 30% higher in moderately obese subjects and 31% higher in extremely obese subjects than in nonobese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No adjustment of daptomycin dosage is warranted in obese patients. Pediatric Patients The pharmacokinetics of daptomycin in pediatric subjects was evaluated in 3 single-dose pharmacokinetic studies. In general, body weight-normalized total body clearance in pediatric patients was higher than in adults and increased with a decrease of age, whereas elimination half-life tends to decrease with a decrease of age. Body weight- normalized total body clearance and elimination half-life of daptomycin in children 2 to 6 years of age were similar at different doses. A study was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in pediatric patients (1 to 17 years old, inclusive) with cSSSI caused by Gram-positive pathogens. Patients were enrolled into 4 age groups [see Clinical Studies (14.1)], and intravenous daptomycin for injection doses of 5 to 10 mg/kg once daily were administered. Following administration of multiple doses, daptomycin exposure (AUCSS and Cmax,SS) was similar across different age groups after dose adjustment based on body weight and age (Table 14). Table 14: Mean (SD) Daptomycin Population Pharmacokinetic Parameters in cSSSI Pediatric Patients Age Pharmacokinetic Parameters Dose (mg/kg) Infusion Duration (min) AUCss (mcg∙h/mL) t1/2 (h) Vss (mL) CLT (mL/h/kg) Cmax,ss (mcg/mL) 12 to 17 years (N=6) 5 30 434 (67.9) 7.1 (0.9) 8200 (3250) 11.8 (2.15) 76.4 (6.75) Reference ID: 5483234 7 to 11 years (N=2) 7 30 543* 6.8* 4470* 13.2* 92.4* 2 to 6 years (N=7) 9 60 452 (93.1) 4.6 (0.8) 2750 (832) 20.8 (4.29) 90.3 (14.0) 1 to less than 2 years 10 60 462 (138) 4.8 (0.6) 1670 (446) 23.1 (5.43) 81.6 (20.7) (N=27) AUCss, area under the concentration-time curve at steady state; CLT, clearance normalized to body weight; Vss, volume of distribution at steady state; t½, terminal half-life * Mean is calculated from N=2 A study was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in pediatric patients with S. aureus bacteremia. Patients were enrolled into 3 age groups [see Clinical Studies (14.2)], and intravenous doses of 7 to 12 mg/kg once daily were administered. Following administration of multiple doses, daptomycin exposure (AUCSS and Cmax,SS) was similar across different age groups after dose adjustment based on body weight and age (Table 15). Table 15: Mean (SD) of Daptomycin Pharmacokinetics in Bacteremia Pediatric Patients Age Pharmacokinetic Parameters Dose (mg/kg) Infusion Duration (min) AUCss (mcg∙h/mL) t1/2 (h) Vss (mL) CLT (mL/h/kg) Cmax,ss (mcg/mL) 12 to 17 years (N=13) 7 30 656 (334) 7.5 (2.3) 6420 (1980) 12.4 (3.9) 104 (35.5) 7 to 11 years (N=19) 9 30 579 (116) 6.0 (0.8) 4510 (1470) 15.9 (2.8) 104 (14.5) 2 to 6 years (N=19) 12 60 620 (109) 5.1 (0.6) 2200 (570) 19.9 (3.4) 106 (12.8) AUCSS, area under the concentration-time curve at steady state; CLT, clearance normalized to body weight; VSS, volume of distribution at steady state; t1/2 terminal half-life No patients 1 to <2 years of age were enrolled in the study. Simulation using a population pharmacokinetic model demonstrated that the AUCSS of daptomycin in pediatric patients 1 to <2 years of age receiving 12 mg/kg once daily would be comparable to that in adult patients receiving 6 mg/kg once daily. Drug Interaction Studies In Vitro Studies In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the P450 system. Aztreonam In a study in which 15 healthy adult subjects received a single dose of daptomycin for injection 6 mg/kg IV and a combination dose of Daptomycin for Injection 6 mg/kg IV and aztreonam 1 g IV, administered over a 30­ minute period, the Cmax and AUC0-∞ of daptomycin were not significantly altered by aztreonam. Tobramycin In a study in which 6 healthy adult males received a single dose of daptomycin for injection 2 mg/kg IV, Reference ID: 5483234 tobramycin 1 mg/kg IV, and both in combination, administered over a 30-minute period, the mean Cmax and AUC0-∞ of daptomycin were 12.7% and 8.7% higher, respectively, when daptomycin was coadministered with tobramycin. The mean Cmax and AUC0-∞ of tobramycin were 10.7% and 6.6% lower, respectively, when tobramycin was coadministered with daptomycin. These differences were not statistically significant. The interaction between daptomycin and tobramycin with a clinical dose of daptomycin is unknown. Warfarin In 16 healthy adult subjects, administration of daptomycin for injection 6 mg/kg every 24h by IV infusion over a 30-minute period for 5 days, with coadministration of a single oral dose of warfarin (25 mg) on the 5th day, had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR (International Normalized Ratio). Simvastatin In 20 healthy adult subjects on a stable daily dose of simvastatin 40 mg, administration of daptomycin for injection 4 mg/kg every 24h by IV infusion over a 30-minute period for 14 days (N=10) had no effect on plasma trough concentrations of simvastatin and was not associated with a higher incidence of adverse events, including skeletal myopathy, than in subjects receiving placebo once daily (N=10) [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. Probenecid Concomitant administration of probenecid (500 mg 4 times daily) and a single dose of daptomycin for injection 4 mg/kg by IV infusion over a 30-minute period in adults did not significantly alter the Cmax or AUC0-∞ of daptomycin. 12.4 Microbiology Daptomycin belongs to the cyclic lipopeptide class of antibacterials. Daptomycin has clinical utility in the treatment of infections caused by aerobic, Gram-positive bacteria. The in vitro spectrum of activity of daptomycin encompasses most clinically relevant Gram-positive pathogenic bacteria. Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive bacteria in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. Daptomycin maintained bactericidal activity in vitro against stationary phase S. aureus in simulated endocardial vegetations. The clinical significance of this is not known. Mechanism of Action Daptomycin binds to bacterial cell membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death. Resistance The mechanism(s) of daptomycin resistance is not fully understood. Currently, there are no known transferable elements that confer resistance to daptomycin. Interactions with Other Antibacterials In vitro studies have investigated daptomycin interactions with other antibacterials. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, β-lactam antibacterials, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates). Complicated Skin and Skin Structure Infection (cSSSI) Trials in Adults The emergence of daptomycin non-susceptible isolates occurred in 2 infected patients across the set of Phase 2 and pivotal Phase 3 clinical trials of cSSSI in adult patients. In one case, a non-susceptible S. aureus was Reference ID: 5483234 isolated from a patient in a Phase 2 trial who received daptomycin at less than the protocol-specified dose for the initial 5 days of therapy. In the second case, a non-susceptible Enterococcus faecalis was isolated from a patient with an infected chronic decubitus ulcer who was enrolled in a salvage trial. S. aureus Bacteremia/Endocarditis and Other Post-Approval Trials in Adults In subsequent clinical trials in adult patients, non-susceptible isolates were recovered. S. aureus was isolated from a patient in a compassionate-use trial and from 7 patients in the S. aureus bacteremia/endocarditis trial [see Clinical Studies (14.2)]. An E. faecium was isolated from a patient in a vancomycin-resistant enterococci trial. Antimicrobial Activity Daptomycin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections [see Indications and Usage (1)]. Gram-Positive Bacteria Enterococcus faecalis (vancomycin-susceptible isolates only) Staphylococcus aureus (including methicillin-resistant isolates) Streptococcus agalactiae Streptococcus dysgalactiae subsp. equisimilis Streptococcus pyogenes The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for daptomycin against isolates of similar genus or organism group. However, the efficacy of daptomycin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Gram-Positive Bacteria Corynebacterium jeikeium Enterococcus faecalis (vancomycin-resistant isolates) Enterococcus faecium (including vancomycin-resistant isolates) Staphylococcus epidermidis (including methicillin-resistant isolates) Staphylococcus haemolyticus Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for daptomycin, please see: https://www.fda.gov/STIC 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies in animals have not been conducted to evaluate the carcinogenic potential of daptomycin for injection. However, neither mutagenic nor clastogenic potential was found in a battery of genotoxicity tests, including the Ames assay, a mammalian cell gene mutation assay, a test for chromosomal aberrations in Chinese hamster ovary cells, an in vivo micronucleus assay, an in vitro DNA repair assay, and an in vivo sister chromatid exchange assay in Chinese hamsters. Daptomycin did not affect the fertility or reproductive performance of male and female rats when administered intravenously at doses of 25, 75, or 150 mg/kg/day, which is approximately up to 9 times the estimated human exposure level based upon AUCs (or approximately up to 4 times the recommended human dose of 6 mg/kg based on body surface area comparison). Reference ID: 5483234 13.2 Animal Toxicology and/or Pharmacology Adult Animals In animals, daptomycin administration has been associated with effects on skeletal muscle. However, there were no changes in cardiac or smooth muscle. Skeletal muscle effects were characterized by microscopic degenerative/regenerative changes and variable elevations in creatine phosphokinase (CPK). No fibrosis or rhabdomyolysis was evident in repeat-dose studies up to the highest doses tested in rats (150 mg/kg/day) and dogs (100 mg/kg/day). The degree of skeletal myopathy showed no increase when treatment was extended from 1 month to up to 6 months. Severity was dose-dependent. All muscle effects, including microscopic changes, were fully reversible within 30 days following the cessation of dosing. In adult animals, effects on peripheral nerve (characterized by axonal degeneration and frequently accompanied by significant losses of pate lar reflex, gag reflex, and pain perception) were observed at daptomycin doses higher than those associated with skeletal myopathy. Deficits in the dogs' pate lar reflexes were seen within 2 weeks after the start of treatment at 40 mg/kg/day (9 times the human Cmax at the 6 mg/kg/day dose), with some clinical improvement noted within 2 weeks after the cessation of dosing. However, at 75 mg/kg/day for 1 month, 7 of 8 dogs failed to regain full pate lar reflex responses within a 3-month recovery period. In a separate study in dogs receiving doses of 75 and 100 mg/kg/day for 2 weeks, minimal residual histological changes were noted at 6 months after the cessation of dosing. However, recovery of peripheral nerve function was evident. Tissue distribution studies in rats showed that daptomycin is retained in the kidney but appears to penetrate the blood-brain barrier only minimally following single and multiple doses. Juvenile Animals Target organs of daptomycin-related effects in 7-week-old juvenile dogs were skeletal muscle and nerve, the same target organs as in adult dogs. In juvenile dogs, nerve effects were noted at lower daptomycin blood concentrations than in adult dogs following 28 days of dosing. In contrast to adult dogs, juvenile dogs also showed evidence of effects in nerves of the spinal cord as well as peripheral nerves after 28 days of dosing. No nerve effects were noted in juvenile dogs following 14 days of dosing at doses up to 75 mg/kg/day. Administration of daptomycin to 7-week-old juvenile dogs for 28 days at doses of 50 mg/kg/day produced minimal degenerative effects on the peripheral nerve and spinal cord in several animals, with no corresponding clinical signs. A dose of 150 mg/kg/day for 28 days produced minimal degeneration in the peripheral nerve and spinal cord as well as minimal to mild degeneration of the skeletal muscle in a majority of animals, accompanied by slight to severe muscle weakness evident in most dogs. Following a 28-day recovery phase, microscopic examination revealed recovery of the skeletal muscle and the ulnar nerve effects, but nerve degeneration in the sciatic nerve and spinal cord was still observed in all 150 mg/kg/day dogs. Following once-daily administration of daptomycin to juvenile dogs for 28 days, microscopic effects in nerve tissue were noted at a Cmax value of 417 mcg/mL, which is approximately 3-fold less than the Cmax value associated with nerve effects in adult dogs treated once daily with daptomycin for 28 days (1308 mcg/mL). Neonatal Animals Neonatal dogs (4 to 31 days old) were more sensitive to daptomycin-related adverse nervous system and/or muscular system effects than either juvenile or adult dogs. In neonatal dogs, adverse nervous system and/or muscular system effects were associated with a Cmax value approximately 3-fold less than the Cmax in juvenile dogs, and 9-fold less than the Cmax in adult dogs following 28 days of dosing. At a dose of 25 mg/kg/day with associated Cmax and AUCinf values of 147 mcg/mL and 717 mcg∙h/mL, respectively (1.6 and 1.0-fold the adult human Cmax and AUC, respectively, at the 6 mg/kg/day dose), mild clinical signs of twitching and one incidence of muscle rigidity were observed with no corresponding effect on body weight. These effects were found to be reversible within 28 days after treatment had stopped. At higher dose levels of 50 and 75 mg/kg/day with associated Cmax and AUCinf values of ≥321 mcg/mL and ≥1470 mcg∙h/mL, respectively, marked clinical signs of twitching, muscle rigidity in the limbs, and impaired use of limbs were observed. Resulting decreases in body weights and overall body condition at doses ≥50 Reference ID: 5483234 mg/kg/day necessitated early discontinuation by postnatal day (PND) 19. Histopathological assessment did not reveal any daptomycin-related changes in the peripheral and central nervous system tissue, as well as in the skeletal muscle or other tissues assessed, at any dose level. No adverse effects were observed in the dogs that received daptomycin at 10 mg/kg/day, the NOAEL, with associated Cmax and AUCinf values of 62 mcg/mL and 247 mcg∙h/mL, respectively (or 0.6 and 0.4-fold the adult human Cmax and AUC, respectively at the 6 mg/kg dose). 14 CLINICAL STUDIES 14.1 Complicated Skin and Skin Structure Infections Adults with cSSSI Adult patients with clinically documented complicated skin and skin structure infections (cSSSI) (Table 16) were enrolled in two randomized, multinational, multicenter, investigator-blinded trials comparing daptomycin for injection (4 mg/kg IV every 24h) with either vancomycin (1 g IV q12h) or an anti-staphylococcal semi- synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g IV per day). Patients could switch to oral therapy after a minimum of 4 days of IV treatment if clinical improvement was demonstrated. Patients known to have bacteremia at baseline were excluded. Patients with creatinine clearance (CLCR) between 30 and 70 mL/min were to receive a lower dose of daptomycin for injection as specified in the protocol; however, the majority of patients in this subpopulation did not have the dose of daptomycin for injection adjusted. Table 16: Investigator's Primary Diagnosis in the cSSSI Trials in Adult Patients (Population: ITT) Primary Diagnosis Adult Patients (Daptomycin for Injection / Comparator*) Study 9801 N=264 / N=266 Study 9901 N=270 / N=292 Pooled N=534 / N=558 Wound Infection 99 (38%) / 116 (44%) 102 (38%) / 108 (37%) 201 (38%) / 224 (40%) Major Abscess 55 (21%) / 43 (16%) 59 (22%) / 65 (22%) 114 (21%) / 108 (19%) Ulcer Infection 71 (27%) / 75 (28%) 53 (20%) / 68 (23%) 124 (23%) / 143 (26%) Other Infection† 39 (15%) / 32 (12%) 56 (21%) / 51 (18%) 95 (18%) / 83 (15%) * Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g/day IV in divided doses). † The majority of cases were subsequently categorized as complicated cellulitis, major abscesses, or traumatic wound infections. One trial was conducted primarily in the United States and South Africa (study 9801), and the second was conducted at non-US sites only (study 9901). The two trials were similar in design but differed in patient characteristics, including history of diabetes and peripheral vascular disease. There were a total of 534 adult patients treated with daptomycin and 558 treated with comparator in the two trials. The majority (89.7%) of patients received IV medication exclusively. The efficacy endpoints in both trials were the clinical success rates in the intent-to-treat (ITT) population and in the clinically evaluable (CE) population. In study 9801, clinical success rates in the ITT population were 62.5% (165/264) in patients treated with daptomycin for injection and 60.9% (162/266) in patients treated with comparator drugs. Clinical success rates in the CE population were 76.0% (158/208) in patients treated with daptomycin for injection and 76.7% (158/206) in patients treated with comparator drugs. In study 9901, clinical success rates in the ITT population were 80.4% (217/270) in patients treated with daptomycin and 80.5% (235/292) in patients treated with comparator drugs. Clinical success rates in the CE population were 89.9% (214/238) in patients treated with daptomycin for injection and 90.4% (226/250) in patients treated with comparator drugs. Reference ID: 5483234 The success rates by pathogen for microbiologically evaluable patients are presented in Table 17. Table 17: Clinical Success Rates by Infecting Pathogen in the cSSSI Trials in Adult Patients (Population: Microbiologically Evaluable) Pathogen Success Rate n/N (%) Daptomycin for Injection Comparator* Methicillin-susceptible Staphylococcus aureus (MSSA)† 170/198 (86%) 180/207 (87%) Methicillin-resistant Staphylococcus aureus (MRSA)† 21/28 (75%) 25/36 (69%) Streptococcus pyogenes 79/84 (94%) 80/88 (91%) Streptococcus agalactiae 23/27 (85%) 22/29 (76%) Streptococcus dysgalactiae subsp. equisimilis 8/8 (100%) 9/11 (82%) Enterococcus faecalis (vancomycin- susceptible only) 27/37 (73%) 40/53 (76%) * Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 4 to 12 g/day IV in divided doses). † As determined by the central laboratory. Pediatric Patients (1 to 17 Years of Age) with cSSSI The cSSSI pediatric trial was a single prospective multi-center, randomized, comparative trial. A total of 396 pediatric patients aged 1 to 17 years with cSSSI caused by Gram positive pathogens were enrolled into the study. Patients known to have bacteremia, osteomyelitis, endocarditis, and pneumonia at baseline were excluded. Patients were enrolled in a stepwise approach into four age groups and given age-dependent doses of daptomycin once daily for up to 14 days. The different age groups and doses evaluated were as follows: Adolescents (12 to 17 years) treated with 5 mg/kg of daptomycin (n=113), Children (7 to 11 years) treated with 7 mg/kg of daptomycin for injection (n=113), Children (2 to 6 years) treated with 9 mg/kg of daptomycin for injection (n=125) and Infants (1 to <2 years) treated with 10 mg/kg (n= 45). Patients were randomized 2:1 to receive daptomycin for injection or a standard of care (SOC) comparator, which included intravenous therapy with either vancomycin, clindamycin, or an anti-staphylococcal semi- synthetic penicillin (nafcillin, oxacillin, or cloxacillin). Patients could switch to oral therapy after clinical improvement was demonstrated (no minimum IV dosing was required). The primary objective of this study was to evaluate the safety of daptomycin for injection. The clinical outcome was determined by resolution or improvement of symptoms at the End-of-Treatment (EOT), 3 days after the last dose, and Test-of-Cure (TOC), 7 to14 days after the last dose. Investigator observed outcomes were verified in a blinded fashion. Of the 396 subjects randomized in the study, 389 subjects were treated with daptomycin for injection or comparator and included in the ITT population. Of these, 257 subjects were randomized to the daptomycin for injection group and 132 subjects were randomized to the comparator group. Approximately 95% of subjects switched to oral therapy. The mean day of switch was day 4, and ranged from day 1 to day 14. The clinical success rates determined at 7 to 14 days after last dose of therapy (IV and oral) (TOC visit) were 88% (227/257) for daptomycin for injection and 86% (114/132) for comparator. 14.2 S. aureus Bacteremia/Endocarditis Adults with S. aureus Bacteremia/Endocarditis The efficacy of daptomycin for injection in the treatment of adult patients with S. aureus bacteremia was demonstrated in a randomized, controlled, multinational, multicenter, open-label trial. In this trial, adult patients with at least one positive blood culture for S. aureus obtained within 2 calendar days prior to the first dose of study drug and irrespective of source were enrolled and randomized to either daptomycin injection (6 mg/kg IV every 24h) or standard of care [an anti-staphylococcal semi-synthetic penicillin 2 g IV q4h (nafcillin, oxacillin, Reference ID: 5483234 cloxacillin, or flucloxacillin) or vancomycin 1 g IV q12h, each with initial gentamicin 1 mg/kg IV every 8 hours for first 4 days]. Of the patients in the comparator group, 93% received initial gentamicin for a median of 4 days, compared with 1 patient (<1%) in the daptomycin for injection group. Patients with prosthetic heart valves, intravascular foreign material that was not planned for removal within 4 days after the first dose of study medication, severe neutropenia, known osteomyelitis, polymicrobial bloodstream infections, creatinine clearance <30 mL/min, and pneumonia were excluded. Upon entry, patients were classified for likelihood of endocarditis using the modified Duke criteria (Possible, Definite, or Not Endocarditis). Echocardiography, including a transesophageal echocardiogram (TEE), was performed within 5 days following study enrollment. The choice of comparator agent was based on the oxacillin susceptibility of the S. aureus isolate. The duration of study treatment was based on the investigator's clinical diagnosis. Final diagnoses and outcome assessments at Test of Cure (6 weeks after the last treatment dose) were made by a treatment-blinded Adjudication Committee, using protocol-specified clinical definitions and a composite primary efficacy endpoint (clinical and microbiological success) at the Test of Cure visit. A total of 246 patients ≥18 years of age (124 daptomycin for injection, 122 comparator) with S. aureus bacteremia were randomized from 48 centers in the US and Europe. In the ITT population, 120 patients received daptomycin for injection and 115 received comparator (62 received an anti-staphylococcal semi- synthetic penicillin and 53 received vancomycin). Thirty-five patients treated with an anti-staphylococcal semi- synthetic penicillin received vancomycin initially for 1 to 3 days, pending final susceptibility results for the S. aureus isolates. The median age among the 235 patients in the ITT population was 53 years (range: 21 to 91 years); 30/120 (25%) in the daptomycin for injection group and 37/115 (32%) in the comparator group were ≥65 years of age. Of the 235 ITT patients, there were 141 (60%) males and 156 (66%) Caucasians across the two treatment groups. In addition, 176 (75%) of the ITT population had systemic inflammatory response syndrome (SIRS) at baseline and 85 (36%) had surgical procedures within 30 days prior to onset of the S. aureus bacteremia. Eighty-nine patients (38%) had bacteremia caused by methicillin-resistant S. aureus (MRSA). Entry diagnosis was based on the modified Duke criteria and comprised 37 (16%) Definite, 144 (61%) Possible, and 54 (23%) Not Endocarditis. Of the 37 patients with an entry diagnosis of Definite Endocarditis, a l (100%) had a final diagnosis of infective endocarditis, and of the 144 patients with an entry diagnosis of Possible Endocarditis, 15 (10%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee. Of the 54 patients with an entry diagnosis of Not Endocarditis, 1 (2%) had a final diagnosis of infective endocarditis as assessed by the Adjudication Committee. In the ITT population, there were 182 patients with bacteremia and 53 patients with infective endocarditis as assessed by the Adjudication Committee, including 35 with right-sided endocarditis and 18 with left-sided endocarditis. The 182 patients with bacteremia comprised 121 with complicated S. aureus bacteremia and 61 with uncomplicated S. aureus bacteremia. Complicated bacteremia was defined as S. aureus isolated from blood cultures obtained on at least 2 different calendar days, and/or metastatic foci of infection (deep tissue involvement), and classification of the patient as not having endocarditis according to the modified Duke criteria. Uncomplicated bacteremia was defined as S. aureus isolated from blood culture(s) obtained on a single calendar day, no metastatic foci of infection, no infection of prosthetic material, and classification of the patient as not having endocarditis according to the modified Duke criteria. The definition of right-sided infective endocarditis (RIE) used in the clinical trial was Definite or Possible Endocarditis according to the modified Duke criteria and no echocardiographic evidence of predisposing pathology or active involvement of either the mitral or aortic valve. Complicated RIE comprised patients who were not intravenous drug users, had a positive blood culture for MRSA, serum creatinine ≥2.5 mg/dL, or evidence of extrapulmonary sites of infection. Patients who were intravenous drug users, had a positive blood culture for methicillin-susceptible S. aureus (MSSA), had serum creatinine <2.5 mg/dL, and were without evidence of extrapulmonary sites of infection were considered to have uncomplicated RIE. The coprimary efficacy endpoints in the trial were the Adjudication Committee success rates at the Test of Cure visit (6 weeks after the last treatment dose) in the ITT and Per Protocol (PP) populations. The overall Adjudication Committee success rates in the ITT population were 44.2% (53/120) in patients treated with daptomycin for injection and 41.7% (48/115) in patients treated with comparator (difference = 2.4% [95% CI Reference ID: 5483234 −10.2, 15.1]). The success rates in the PP population were 54.4% (43/79) in patients treated with daptomycin and 53.3% (32/60) in patients treated with comparator (difference = 1.1% [95% CI −15.6, 17.8]). Adjudication Committee success rates are shown in Table 18. Table 18: Adjudication Committee Success Rates at Test of Cure in the S. aureus Bacteremia/Endocarditis Trial in Adult Patients (Population: ITT) Population Success Rate n/N (%) Difference: Daptomycin for Injection−Comparator (Confidence Interval) Daptomycin for Injection 6 mg/kg Comparator* Overall 53/120 (44%) 48/115 (42%) 2.4% (−10.2, 15.1)† Baseline Pathogen Methicillin­ susceptible S. aureus 33/74 (45%) 34/70 (49%) −4.0% (−22.6, 14.6)‡ Methicillin-resistant S. aureus 20/45 (44%) 14/44 (32%) 12.6% (−10.2, 35.5)‡ Entry Diagnosis§ Definite or Possible Infective Endocarditis 41/90 (46%) 37/91 (41%) 4.9% (−11.6, 21.4)‡ Not Infective Endocarditis 12/30 (40%) 11/24 (46%) −5.8% (−36.2, 24.5)‡ Final Diagnosis Uncomplicated Bacteremia 18/32 (56%) 16/29 (55%) 1.1% (−31.7, 33.9)¶ Complicated Bacteremia 26/60 (43%) 23/61 (38%) 5.6% (−17.3, 28.6)¶ Right-Sided Infective Endocarditis 8/19 (42%) 7/16 (44%) −1.6% (−44.9, 41.6)¶ Uncomplicated Right-Sided Infective Endocarditis 3/6 (50%) 1/4 (25%) 25.0% (−51.6, 100.0)¶ Complicated Right- Sided Infective Endocarditis 5/13 (39%) 6/12 (50%) −11.5% (−62.4, 39.4)¶ Left-Sided Infective Endocarditis 1/9 (11%) 2/9 (22%) −11.1% (−55.9, 33.6)¶ * Comparator: vancomycin (1 g IV q12h) or an anti-staphylococcal semi-synthetic penicillin (i.e., nafcillin, oxacillin, cloxacillin, or flucloxacillin; 2 g IV q4h), each with initial low-dose gentamicin. † 95% Confidence Interval ‡ 97.5% Confidence Interval (adjusted for multiplicity) § According to the modified Duke criteria5 ¶ 99% Confidence Interval (adjusted for multiplicity) Reference ID: 5483234 Eighteen (18/120) patients in the daptomycin for injection arm and 19/116 patients in the comparator arm died during the trial. These comprise 3/28 daptomycin-treated patients and 8/26 comparator-treated patients with endocarditis, as well as 15/92 daptomycin-treated patients and 11/90 comparator-treated patients with bacteremia. Among patients with persisting or relapsing S. aureus infections, 8/19 daptomycin-treated patients and 7/11 comparator-treated patients died. Overall, there was no difference in time to clearance of S. aureus bacteremia between daptomycin and comparator. The median time to clearance in patients with MSSA was 4 days and in patients with MRSA was 8 days. Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (16%) daptomycin-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (10%) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with an anti- staphylococcal semi-synthetic penicillin). Among all failures, isolates from 6 daptomycin-treated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing during or following therapy. Most patients who failed due to persisting or relapsing S. aureus infection had deep-seated infection and did not receive necessary surgical intervention [see Warnings and Precautions (5.9)]. Pediatric Patients (1 to 17 Years of Age) with S. aureus Bacteremia The pediatric S. aureus bacteremia study was designed as a prospective multi-center, randomized, comparative trial to treat pediatric patients aged 1 to 17 years with bacteremia. Patients known to have endocarditis or pneumonia at baseline were excluded. Patients were enrolled in a stepwise approach into three age groups and given age-dependent doses of daptomycin once daily for up to 42 days. The different age groups and doses evaluated were as follows: Adolescents (12 to 17 years, n=14 patients) treated with daptomycin dosed at 7 mg/kg once daily, Children (7 to 11 years, n=19 patients) treated with daptomycin dosed at 9 mg/kg once daily and Children (2 to 6 years, n=22 patients) treated with daptomycin dosed at 12 mg/kg once daily. No patients 1 to <2 years of age were enrolled. Patients were randomized 2:1 to receive daptomycin or a standard of care comparator, which included intravenous therapy with vancomycin, semi-synthetic penicillin, first generation cephalosporin or clindamycin. Patients could switch to oral therapy after clinical improvement was demonstrated (no minimum IV dosing was required). The primary objective of this study was to assess the safety of daptomycin. The clinical outcome was determined by resolution or improvement of symptoms at test-of-cure (TOC) visit, 7 to 14 days after the last dose, which was assessed by the site level Blinded Evaluator. Of the 82 subjects randomized in the study, 81 subjects were treated with daptomycin for injection or comparator and included in the safety population, and 73 had a proven S. aureus bacteremia at Baseline. Of these, 51 subjects were randomized to the daptomycin for injection group and 22 subjects were randomized to the comparator group. The mean duration of IV therapy was 12 days, with a range of 1 to 44 days. Forty-eight subjects switched to oral therapy, and the mean duration of oral therapy was 21 days. The clinical success rates determined at 7 to 14 days after last dose of therapy (IV and oral) (TOC visit) were 88% (45/51) for daptomycin for injection and 77% (17/22) for comparator. 15 REFERENCES 1. Liu SL, Howard LC, Van Lier RBL, Markham JK: Teratology studies with daptomycin administered intravenously (iv) to rats and rabbits. Teratology 37(5):475, 1988. 2. Stroup JS, Wagner J, Badzinski T: Use of daptomycin in a pregnant patient with Staphylococcus aureus endocarditis. Ann Pharmacother 44(4):746-749, 2010. 3. Buitrago MI, Crompton JA, Bertolami S, North DS, Nathan RA. Extremely low excretion of daptomycin into breast milk of a nursing mother with methicillin-resistant Staphylococcus aureus pelvic inflammatory disease. Pharmacotherapy 2009;29(3):347–351. Reference ID: 5483234 4. Klibanov OM, Vickery S, Nortey C: Successful treatment of infective panniculitis with daptomycin in a pregnant, morbidly obese patient. Ann Pharmacother 48(5):652-655, 2014. 5. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T, Bashore T, Corey GR. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30:633–638. 16 HOW SUPPLIED/STORAGE AND HANDLING Daptomycin for Injection is supplied as a sterile pale yellow to light brown lyophilized powder in single- dose vials containing 350 mg or 500 mg of daptomycin: 350 mg/vial - Package of 1 vial (NDC 70511-181-10) 350 mg/vial - Package of 10 vials (NDC 70511-181-84) 500 mg/vial - Package of 1 vial (NDC 70511-182-15) 500 mg/vial - Package of 10 vials (NDC 70511-182-84) Store original packages at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Storage conditions for the reconstituted and diluted solutions are described in another section of the prescribing information [see Dosage and Administration (2.7)]. 17 PATIENT COUNSELING INFORMATION Allergic Reactions Advise patients that allergic reactions, including serious skin, kidney, lung, or other organ reactions, could occur and that these serious reactions require immediate treatment. Patients should report any previous allergic reactions to daptomycin [see Warnings and Precautions (5.1, 5.4, 5.5)]. Muscle Pain or Weakness (Myopathy and Rhabdomyolysis, Peripheral Neuropathy) Advise patients to report muscle pain or weakness, especially in the forearms and lower legs, as well as tingling or numbness [see Warnings and Precautions (5.2, 5.6)]. Cough, Breathlessness, or Fever (Eosinophilic Pneumonia) Advise patients to report any symptoms of cough, breathlessness, or fever [see Warnings and Precautions (5.3)]. C. difficile-Associated Diarrhea (CDAD) Advise patients that diarrhea is a common problem caused by antibacterials including Daptomycin for Injection, that usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, including Daptomycin for Injection, patients can develop watery and bloody stools (with or without stomach cramps and fever), even as late as 2 or more months after having received the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.8)]. Antibacterial Resistance Patients should be counseled that antibacterial drugs, including Daptomycin for Injection, should be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Daptomycin for Injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be administered exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Daptomycin for Injection or other antibacterial drugs in the future. Reference ID: 5483234 Manufactured for: MAIA Pharmaceuticals, Inc. 707 State Road, Suite 104 Princeton, NJ 08540 Manufactured in India Reference ID: 5483234
custom-source
2025-02-12T15:47:15.022360
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_______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ARTHROTEC safely and effectively. See full prescribing information for ARTHROTEC. ARTHROTEC (diclofenac sodium and misoprostol delayed-release tablets), for oral use Initial U.S. Approval:1997 WARNING: RISK OF UTERINE RUPTURE, ABORTION, PREMATURE BIRTH, BIRTH DEFECTS; SERIOUS CARDIOVASCULAR EVENTS; AND SERIOUS GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Administration of misoprostol, a component of ARTHROTEC, to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects. Uterine rupture has occurred when misoprostol was administered in pregnant women to induce labor or an abortion. (4, 5.1, 8.1) • ARTHROTEC is contraindicated in pregnancy and is not recommended in women of childbearing potential. Patients must be advised of the abortifacient property and warned not to give the drug to others. (5.1, 8.3) • Increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. (5.2) • ARTHROTEC is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.2) • Increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal and can occur at any time and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk. (5.3) RECENT MAJOR CHANGES Warnings and Precautions, Serious Skin Reactions (5.10) 11/2024 INDICATIONS AND USAGE ARTHROTEC is a combination of diclofenac sodium, a non-steroidal anti-inflammatory drug, and misoprostol, a prostaglandin-1 (PGE1) analog, indicated for the treatment of signs and symptoms of osteoarthritis or rheumatoid arthritis in adult patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications. (1) DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. (2.1) • Osteoarthritis: The recommended dosage for maximal GI protection is one tablet (containing 50 mg of diclofenac and 200 mcg of misoprostol) three times daily. A dosage of diclofenac higher than 150 mg/day is not recommended. (2.2) • Rheumatoid Arthritis: The recommended dosage for maximal GI protection is one tablet (containing 50 mg of diclofenac and 200 mcg of misoprostol) three or four times daily A dosage of diclofenac higher than 200 mg/day is not recommended. (2.3) • For dosage modifications due to intolerance, see the full Prescribing Information. (2.2, 2.3) DOSAGE FORMS AND STRENGTHS Delayed-release tablets: • 50 mg diclofenac sodium and 200 mcg misoprostol (3) • 75 mg diclofenac sodium and 200 mcg misoprostol (3) CONTRAINDICATIONS • Pregnancy (4) • In the setting of CABG surgery (4) • Active gastrointestinal bleeding (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs (4) • Known hypersensitivity to diclofenac sodium, misoprostol, or any components of the drug product (4) WARNINGS AND PRECAUTIONS • Embryo-Fetal Toxicity with NSAIDs: Use of NSAIDs, including diclofenac in women at about 20 weeks gestation and later in pregnancy may cause oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. (4, 5.1, 8.1) • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.4) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.5, 7) • Heart Failure and Edema: Avoid in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.6) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. (5.7) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.8) • Exacerbation of Asthma Related to Aspirin Sensitivity: Contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.9) • Serious Skin Reactions: Discontinue at first appearance of skin rash or other signs of hypersensitivity. (5.10) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically. (5.11) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. (5.12, 7) ADVERSE REACTIONS Most common adverse reactions (>2%) are: abdominal pain, diarrhea, dyspepsia, nausea, flatulence, gastritis, vomiting, constipation, headache, dizziness, alanine aminotransferase increased, hematocrit decreased (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc.at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS See full prescribing information for a list of clinically important drug interactions. (7) USE IN SPECIFIC POPULATIONS • Reversible Infertility: Consider withdrawal in women who have difficulties conceiving. (8.3) • Geriatric Patients: Avoid use in patients with cardiovascular and/or renal risk factors. (8.5) • Renal Impairment: Avoid use in patients with advanced renal disease. (8.6) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5482805 _______________________________________________________________________________________________________________________________________ FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF UTERINE RUPTURE, ABORTION, PREMATURE BIRTH, BIRTH DEFECTS; SERIOUS CARDIOVASCULAR EVENTS; AND SERIOUS GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage Information 2.2 Recommended Dosage in Patients with Osteoarthritis 2.3 Recommended Dosage in Patients with Rheumatoid Arthritis 2.4 Additional Dosage Recommendations 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Uterine Rupture, Abortion, Premature Birth, or Birth Defects with Misoprostol and Embryo-Fetal Toxicity with NSAIDs 5.2 Cardiovascular Thrombotic Events 5.3 Gastrointestinal Bleeding, Ulceration, and Perforation 5.4 Hepatotoxicity 5.5 Hypertension 5.6 Heart Failure and Edema 5.7 Renal Toxicity and Hyperkalemia 5.8 Anaphylactic Reactions 5.9 Exacerbation of Asthma Related to Aspirin Sensitivity 5.10 Serious Skin Reactions 5.11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482805 FULL PRESCRIBING INFORMATION WARNING: RISK OF UTERINE RUPTURE, ABORTION, PREMATURE BIRTH, BIRTH DEFECTS; SERIOUS CARDIOVASCULAR EVENTS; AND SERIOUS GASTROINTESTINAL EVENTS Uterine Rupture, Abortion, Premature Birth, and Birth Defects • Administration of misoprostol, a component of ARTHROTEC, to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects. Uterine rupture has occurred when misoprostol was administered in pregnant women to induce labor or an abortion [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • ARTHROTEC is contraindicated in pregnancy [see Contraindications (4)] and not recommended in women of childbearing potential. Patients must be advised of the abortifacient property and warned not to give the drug to others [see Warnings and Precautions (5.1)]. • If ARTHROTEC is prescribed, verify the pregnancy status of females of reproductive potential prior to initiation of treatment and advise them to use effective contraception during treatment [see Use in Specific Populations (8.3)]. Cardiovascular Thrombotic Events • NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.2)]. • ARTHROTEC is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.2)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE ARTHROTEC is indicated for treatment of the signs and symptoms of osteoarthritis or rheumatoid arthritis in adult patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications. For a list of factors that may increase the risk of NSAID-induced gastric and duodenal ulcers and their complications [see Warnings and Precautions (5.3)]. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage Information • Carefully consider the potential benefits and risks of ARTHROTEC and other treatment options before deciding to use ARTHROTEC. Use the lowest effective dosage for the Reference ID: 5482805 shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. • After observing the response to initial therapy with ARTHROTEC, the dose and frequency should be adjusted to suit an individual patient’s needs. • ARTHORTEC is not recommended for patients who would not receive the appropriate dosage of both active ingredients. • ARTHROTEC, a fixed combination product, is administered as ARTHROTEC 50 (50 mg diclofenac sodium and 200 mcg misoprostol) or ARTHROTEC 75 (75 mg diclofenac sodium and 200 mcg misoprostol). 2.2 Recommended Dosage in Patients with Osteoarthritis The recommended dosage for the treatment of osteoarthritis for maximal GI mucosal protection is ARTHROTEC 50 three times a day. For patients who experience intolerance, ARTHROTEC 75 two times a day or ARTHROTEC 50 two times a day can be used, but these dosages are less effective in preventing ulcers. A daily dosage of diclofenac sodium greater than 150 mg/day is not recommended. Daily doses of the components delivered with these regimens are as follows: Osteoarthritis Diclofenac sodium Misoprostol Regimen (mg/day) (mcg/day) ARTHROTEC 50 three times a day 150 600 two times a day* 100 400 ARTHROTEC 75 two times a day* 150 400 *For patients who experience intolerance; these dosages are less effective in preventing ulcers 2.3 Recommended Dosage in Patients with Rheumatoid Arthritis The recommended dosage for the treatment of rheumatoid arthritis is ARTHROTEC 50 three or four times a day. For patients who experience intolerance, ARTHROTEC 75 two times a day or ARTHROTEC 50 two times a day can be used, but are less effective in preventing ulcers. A daily dosage of diclofenac sodium greater than 200 mg/day is not recommended. Daily doses of the components delivered with these regimens are as follows: Rheumatoid Diclofenac sodium Misoprostol Arthritis (mg/day) (mcg/day) Regimen ARTHROTEC 50 four times a day 200 800 three times a day 150 600 two times a day* 100 400 ARTHROTEC 75 two times a day* 150 400 * For patients who experience intolerance; these dosages are less effective in preventing ulcers 2.4 Additional Dosage Recommendations ARTHROTEC contains misoprostol, which provides protection against gastric and duodenal ulcers [see Clinical Studies (14)]. For gastric ulcer prevention, the 200 mcg four and three times a day regimens are therapeutically equivalent, but more protective than the two times a day regimen. For duodenal ulcer prevention, the four times a day regimen Reference ID: 5482805 is more protective than the three or two times a day regimens. However, the four times a day regimen is less well tolerated than the three times a day regimen because of usually self-limited diarrhea related to the misoprostol dose [see Adverse Reactions (6.1)], and the two times a day regimen may be better tolerated than three times a day in some patients. Dosages may be individualized using the separate products (misoprostol and diclofenac sodium), after which the patient may be switched to the appropriate ARTHROTEC dosage. If clinically indicated, misoprostol co-therapy with ARTHROTEC to optimize the misoprostol dose and/or frequency of administration, may be appropriate. Do not exceed a total misoprostol dose of 800 mcg/day and do not administer more than 200 mcg of misoprostol at any one time. When concomitant use of CYP2C9 inhibitors is necessary, the maximum total daily dose of diclofenac is 100 mg per day. Do not exceed a dosage of ARTHOTEC 50 mg twice daily [see Drug Interactions (7)]. For additional information, refer to the Prescribing Information for the individual products of diclofenac sodium and misoprostol. 3 DOSAGE FORMS AND STRENGTHS Delayed-release tablets: • 50 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off-white tablets imprinted with four “A’s” encircling a “50” in the middle on one side and “SEARLE” and “1411” on the other. • 75 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off-white tablets imprinted with four “A’s” encircling a “75” in the middle on one side and “SEARLE” and “1421” on the other. 4 CONTRAINDICATIONS ARTHROTEC is contraindicated in the following patients: • Pregnancy. Use of misoprostol, a component of ARTHROTEC, during pregnancy can result in maternal and fetal harm, including uterine rupture, abortion, premature birth, or birth defects [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)] • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.2)] • Active gastrointestinal bleeding [see Warnings and Precautions (5.3)] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.8, 5.9)] • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac sodium and misoprostol, other prostaglandins, or any components of the drug product [see Warnings and Precautions (5.8, 5.10)] Reference ID: 5482805 5 WARNINGS AND PRECAUTIONS 5.1 Uterine Rupture, Abortion, Premature Birth, or Birth Defects with Misoprostol and Embryo-Fetal Toxicity with NSAIDs Misoprostol Administration of misoprostol, a component of ARTHROTEC, to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects. Uterine rupture has occurred when misoprostol was administered to pregnant women to induce labor or an abortion. ARTHROTEC is contraindicated in pregnant women. ARTHROTEC is not recommended in women of childbearing potential. Patients must be advised of the abortifacient property and warned not to give the drug to others [see Use in Specific Populations (8.1)]. If ARTHROTEC is prescribed, verify the pregnancy status of females of reproductive potential prior to initiation of treatment and advise the use effective contraception during treatment with ARTHROTEC [see Use in Specific Populations (8.3)]. Diclofenac Premature Closure of Fetal Ductus Arteriosus NSAIDs, including diclofenac, a component of ARTHROTEC, increase the risk of premature closure of the fetal ductus arteriosus at about 30 weeks of gestation and later. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including diclofenac, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required [see Use in Specific Populations (8.1)]. 5.2 Cardiovascular Thrombotic Events Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the Reference ID: 5482805 absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.3)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of ARTHROTEC in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ARTHROTEC is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.3 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Reference ID: 5482805 Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue ARTHROTEC until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.4 Hepatotoxicity In clinical trials with ARTHROTEC, meaningful elevation of alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT], more than 3 times the upper limit of the normal range [ULN]) occurred in 1.6% of 2,184 patients treated with ARTHROTEC and in 1.4% of 1,691 patients treated with diclofenac sodium. These increases were generally transient, and enzyme levels returned to within the normal range upon discontinuation of therapy with ARTHROTEC. The misoprostol component of ARTHROTEC does not appear to exacerbate the hepatic effects caused by the diclofenac sodium component. In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In Reference ID: 5482805 this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days. Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), ARTHROTEC should be discontinued immediately. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue ARTHROTEC immediately, and perform a clinical evaluation of the patient. To minimize the potential risk for an adverse liver related event in patients treated with ARTHROTEC, the lowest effective dose should be used for the shortest duration possible. Exercise caution when prescribing ARTHROTEC with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics). 5.5 Hypertension NSAIDs, including diclofenac, a component of ARTHROTEC, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.6 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to Reference ID: 5482805 treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of ARTHROTEC in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ARTHROTEC is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.7 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of ARTHROTEC in patients with advanced renal disease. The renal effects of ARTHROTEC may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating ARTHROTEC. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of ARTHROTEC [see Drug Interactions (7)]. Avoid the use of ARTHROTEC in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If ARTHROTEC is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.8 Anaphylactic Reactions ARTHROTEC has been associated with anaphylactic reactions in patients with and without known hypersensitivity to the individual components of diclofenac sodium and misoprostol and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.9)]. Seek emergency help if an anaphylactic reaction occurs. 5.9 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal Reference ID: 5482805 bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, ARTHROTEC is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When ARTHROTEC is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.10 Serious Skin Reactions NSAIDs, including diclofenac, a component of ARTHROTEC, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of ARTHROTEC at the first appearance of skin rash or any other sign of hypersensitivity. ARTHROTEC is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ARTHROTEC. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue ARTHROTEC and evaluate the patient immediately. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with ARTHROTEC has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including diclofenac a component ARTHROTEC, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet drugs (e.g., aspirin), and SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. Reference ID: 5482805 5.13 Masking of Inflammation and Fever The pharmacological activity of diclofenac, a component of ARTHROTEC, in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a complete blood count (CBC) and a chemistry profile periodically [see Warnings and Precautions (5.3, 5.7)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.2)] • GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.3)] • Hepatotoxicity [see Warnings and Precautions (5.4)] • Hypertension [see Warnings and Precautions (5.5)] • Heart Failure and Edema [see Warnings and Precautions (5.6)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.7)] • Anaphylactic Reactions [see Warnings and Precautions (5.8)] • Serious Skin Reactions [see Warnings and Precautions (5.10)] • Hematologic Toxicity [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reaction information for ARTHROTEC is derived from multinational controlled clinical trials in over 2,000 patients receiving ARTHROTEC 50 or ARTHROTEC 75, as well as from blinded, controlled trials of diclofenac sodium delayed-release tablets and misoprostol tablets. Gastrointestinal GI disorders had the highest reported incidence of adverse reactions for patients receiving ARTHROTEC. These events were generally minor, but led to discontinuation of therapy in 9% of patients on ARTHROTEC and 5% of patients on diclofenac sodium. For GI ulcer rates, [see Clinical Studies (14)]. Reference ID: 5482805 GI disorder ARTHROTEC Diclofenac Sodium Abdominal pain 21% 15% Diarrhea 19% 11% Dyspepsia 14% 11% Nausea 11% 6% Flatulence 9% 4% ARTHROTEC can cause more abdominal pain, diarrhea, and other GI symptoms than diclofenac alone. Diarrhea and abdominal pain developed early in the course of therapy, and were usually self-limited (resolved after 2 to 7 days). Rare instances of profound diarrhea leading to severe dehydration have been reported in patients receiving misoprostol. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if ARTHROTEC is prescribed. The incidence of diarrhea can be minimized by administering ARTHROTEC with food and by avoiding coadministration with magnesium-containing antacids. Gynecological Gynecological disorders previously reported with misoprostol use have also been reported for women receiving ARTHROTEC (see below). Postmenopausal vaginal bleeding may be related to administration of ARTHROTEC. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology [see Boxed Warnings, Contraindications (4) and Warnings and Precautions (5)]. Other adverse experiences reported occasionally with ARTHROTEC, diclofenac or other NSAIDs, or misoprostol are: Body as a whole: asthenia, fatigue, malaise. Central and peripheral nervous system: dizziness, drowsiness, headache, insomnia, paresthesia, vertigo. Digestive: anorexia, appetite changes, constipation, dry mouth, dysphagia, esophageal ulceration, esophagitis, eructation, gastritis, gastroesophageal reflux, GI neoplasm benign, peptic ulcer, tenesmus, vomiting. Female reproductive disorders: breast pain, dysmenorrhea, menstrual disorder, menorrhagia, vaginal hemorrhage. Hemic and lymphatic system: epistaxis, leukopenia, melena, purpura, decreased hematocrit. Metabolic and nutritional: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, dehydration, hyponatremia. Musculoskeletal system: arthralgia, myalgia. Psychiatric: anxiety, concentration impaired, depression, irritability. Reference ID: 5482805 Respiratory system: asthma, coughing, hyperventilation. Skin and appendages: alopecia, eczema, pemphigoid reaction, photosensitivity, sweating increased, pruritus. Special senses: taste perversion, tinnitus. Renal and urinary disorders: dysuria, nocturia, polyuria, proteinuria, urinary tract infection. Vision: diplopia. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval of ARTHROTEC, diclofenac or misoprostol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliable estimate their frequency or establish a causal relationship to drug exposure. Body as a whole: death, fever, infection, sepsis, chills, edema. Cardiovascular system: arrhythmia, atrial fibrillation, congestive heart failure, hypertension, hypotension, increased creatine phosphokinase (CPK), increased lactate dehydrogenase (LDH), myocardial infarction, palpitations, phlebitis, premature ventricular contractions, syncope, tachycardia, vasculitis. Central and peripheral nervous system: coma, convulsions, hyperesthesia, hypertonia, hypoesthesia, meningitis, migraine, neuralgia, somnolence, stroke, tremor. Congenital, familial and genetic disorders: birth defects. Digestive: enteritis, GI bleeding, glossitis, heartburn, hematemesis, hemorrhoids, intestinal perforation, stomatitis and ulcerative stomatitis. Female reproductive disorders: intermenstrual bleeding, leukorrhea, vaginitis, uterine cramping, uterine hemorrhage. Hemic and lymphatic system: agranulocytosis, anemia, aplastic anemia, coagulation time increased, ecchymosis, eosinophilia, hemolytic anemia, leukocytosis, lymphadenopathy, pancytopenia, pulmonary embolism, rectal bleeding, thrombocythemia, thrombocytopenia. Hypersensitivity: angioedema, laryngeal/pharyngeal edema, urticaria. Liver and biliary system: abnormal hepatic function, bilirubinemia, liver failure, pancreatitis, hepatitis, jaundice. Male reproductive disorders: impotence, perineal pain. Metabolic and nutritional: blood urea nitrogen (BUN) increased, glycosuria, gout, Reference ID: 5482805 hypercholesterolemia, hyperglycemia, hyperuricemia, hypoglycemia, periorbital edema, porphyria, weight changes, fluid retention. Pregnancy, puerperium and perinatal conditions: abnormal uterine contractions, uterine rupture/perforation, retained placenta, amniotic fluid embolism, incomplete abortion, premature birth, fetal death. Psychiatric: confusion, disorientation, dream abnormalities, hallucinations, nervousness, paranoia, psychotic reaction. Reproductive system and breast disorders: female fertility decreased. Respiratory system: dyspnea, pneumonia, respiratory depression. Skin and appendages: acne, bruising, erythema multiforme, exfoliative dermatitis, pruritus ani, rash, skin ulceration, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), fixed drug eruption (FDE), cutaneous reactions (bullous eruption). Special senses: hearing impairment, taste loss. Renal and urinary disorders: cystitis, hematuria, interstitial nephritis, micturition frequency, nephrotic syndrome, oliguria, papillary necrosis, renal failure, glomerulonephritis membranous, glomerulonephritis minimal lesion, glomerulonephritis. Vision: amblyopia, blurred vision, conjunctivitis, glaucoma, iritis, lacrimation abnormal, night blindness, vision abnormal. 7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with diclofenac and misoprostol. Table 1: Clinically Significant Drug Interactions with Diclofenac and Misoprostol Drugs That Interfere with Hemostasis Clinical Impact: • Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of ARTHROTEC with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding [see Warnings and Precautions (5.12)]. Reference ID: 5482805 Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.3)]. Intervention: Concomitant use of ARTHROTEC and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. ARTHROTEC is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • The concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter. • During concomitant use of ARTHROTEC and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of ARTHROTEC and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.7)]. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of ARTHROTEC with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.7)]. Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of ARTHROTEC and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of ARTHROTEC and lithium, monitor patients for Reference ID: 5482805 signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of ARTHROTEC and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of diclofenac and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of ARTHROTEC and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.3)]. Intervention: The concomitant use of ARTHROTEC with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of ARTHROTEC and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Avoid ARTHROTEC for a period of two days before, the day of, and two days following administration of pemetrexed. Antacids Clinical Impact: Antacids reduce the bioavailability of misoprostol acid. Antacids may also delay absorption of diclofenac. Magnesium-containing antacids exacerbate misoprostol-associated diarrhea. Intervention: Concomitant use of ARTHROTEC and magnesium-containing antacids is not recommended. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with diclofenac may increase the risk of GI ulceration or bleeding. Intervention Monitor patients with concomitant use of ARTHROTEC with corticosteroids for signs of bleeding [see Warnings and Precautions (5.3)]. CYP2C9 Inhibitors or Inducers Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g., voriconzaole) may enhance the exposure and toxicity of diclofenac [see Clinical Pharmacology (12.3)] whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of diclofenac. Intervention: CYP2C9 inhibitors: When concomitant use of CYP2C9 inhibitors is necessary, the total daily dose of diclofenac should not exceed the lowest recommended dose of ARTHROTEC 50 twice daily [see Dosage and Administration (2.4)]. CYP2C9 inducers: A dosage adjustment may be warranted when Reference ID: 5482805 ARTHROTEC is administered with CYP2C9 inducers. Administer the separate products of misoprostol and diclofenac if a higher dose of diclofenac is deemed necessary. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary ARTHROTEC is contraindicated in pregnant women [see Contraindications (4)]. If a woman becomes pregnant while taking ARTHROTEC, discontinue the drug and advise the woman of the potential risks to her and to a fetus. There are no adequate and well-controlled studies of ARTHROTEC in pregnant women; however, there is information available about the active drug components of ARTHROTEC, diclofenac sodium and misoprostol. Administration of misoprostol to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects [see Warnings and Precautions (5.1)]. Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug’s teratogenic mechanism has not been demonstrated. Use of NSAIDS, including diclofenac a component of ARTHROTEC, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment (see Data). There are clinical considerations when misoprostol and diclofenac are used in pregnant women (see Clinical Considerations). In reproduction studies with pregnant rabbits, there were no skeletal or visceral malformations when the combination of diclofenac sodium and misoprostol was administered during organogenesis at doses less than the maximum recommended human doses (MRHD); however, embryotoxicity was observed at this exposure (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Maternal Adverse Reactions Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Misoprostol has been used to ripen the cervix, to induce labor, and to treat postpartum hemorrhage, outside of its approved indication. A major adverse effect of these uses is hyperstimulation of the uterus. Uterine rupture, amniotic fluid embolism, severe bleeding, shock, and maternal death have been reported when misoprostol was administered to pregnant women to induce labor to induce abortion beyond the eighth week of pregnancy. Higher doses of misoprostol, including the 100 mcg tablet, may increase the risk of complications from uterine hyperstimulation. ARTHROTEC, which contains 200 mcg of misoprostol, is likely to have a greater risk of uterine hyperstimulation than the 100 mcg tablet of misoprostol. Abortions caused by misoprostol may be incomplete. Reference ID: 5482805 Cases of amniotic fluid embolism, which resulted in maternal and fetal death, have been reported with use of misoprostol during pregnancy. Severe vaginal bleeding, retained placenta, shock, and pelvic pain have also been reported. These women were administered misoprostol vaginally and/or orally over a range of doses. ARTHROTEC is contraindicated in pregnant women [see Contraindications (4)]. If a woman is or becomes pregnant while taking this drug, the drug should be discontinued and the patient apprised of the potential hazard to the fetus. Fetal/Neonatal Adverse Reactions Misoprostol Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Use of misoprostol for the induction of labor in the third trimester was associated with uterine hyperstimulation with resulting changes in the fetal heart rate (fetal bradycardia) and fetal death (misoprostol is not approved for this use). ARTHROTEC is contraindicated in pregnant women [see Contraindications (4)]. Diclofenac Premature Closure of Fetal Ductus Arteriosus: NSAIDs, including diclofenac, can cause premature closure of the fetal ductus arteriosus at about 30 weeks gestation and later in pregnancy (see Data). Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including diclofenac, at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment (see Data). Labor or Delivery There are no studies on the effects of ARTHROTEC or diclofenac during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. In humans, some case reports and studies have associated misoprostol with risk of stillbirth, uterine hyperstimulation, perineal tear, amniotic fluid embolism, severe bleeding, shock, uterine rupture and death. The risk of uterine rupture associated with misoprostol use in pregnancy may occur at any gestational age, and increases with advancing gestational age and with prior uterine surgery, including cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture. Data Human Data Misoprostol Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects. Diclofenac Data from observational studies regarding potential embryo-fetal risks of NSAID use (including diclofenac) in the first or second trimesters of pregnancy are inconclusive. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Reference ID: 5482805 Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data The reproductive and developmental effects of both the combination of diclofenac sodium and misoprostol and each component of ARTHROTEC alone have been studied in animals. In all studies there was no evidence of teratogenicity. In an oral teratology study in pregnant rabbits, ARTHROTEC was administered at dose combinations (diclofenac and misoprostol, 250:1 ratio) up to 10 mg/kg/day diclofenac sodium (120 mg/m2/day, 0.8 times the MRHD based on body surface area) and 0.04 mg/kg/day misoprostol (0.48 mg/m2/day, 0.8 times the MRHD based on body surface area) and there was no evidence of teratogenicity. At the high dose, there was evidence of embryotoxicity (resorption and decreased fetal body weight) and maternal toxicity (decreased food intake and weight gain). In oral teratology studies with misoprostol in pregnant rats at doses up to 1.6 mg/kg/day (9.6 mg/m2/day, 16 times the MRHD based on body surface area) and pregnant rabbits at doses up to 1.0 mg/kg/day (12 mg/m2/day, 20 times the MRHD based on body surface area), there was no evidence of teratogenicity. In oral teratology studies with diclofenac sodium in pregnant mice at doses up to 20 mg/kg/day (60 mg/m2/day, 0.4 times the MRHD based on body surface area), pregnant rats at doses up to 10 mg/kg/day (60 mg/m2/day, 0.4 times the MRHD based on body surface area) and pregnant rabbits at doses up to 10 mg/kg/day (120 mg/m2/day, 0.8 times the MRHD based on body surface area), there was no evidence of teratogenicity. 8.2 Lactation Risk Summary No lactation studies have been conducted with ARTHROTEC; however, limited published literature reports that diclofenac and the active metabolite of misoprostol are present in breast milk [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ARTHROTEC Reference ID: 5482805 and any potential adverse effects on the breastfed infant from the ARTHROTEC or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential ARTHROTEC is not recommended in women of childbearing potential [see Warnings and Precautions (5.1)]. If ARTHROTEC is prescribed, patients must be advised of the abortifacient property and warned not to give the drug to others. Pregnancy Testing Verify pregnancy status for females of reproductive potential within 2 weeks prior to initiating ARTHROTEC. Contraception Females ARTHROTEC can cause fetal harm when administered to a pregnant woman [see Contraindications (4) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ARTHROTEC. ARTHROTEC may be prescribed if the patient: • has had a negative serum pregnancy test within 2 weeks prior to beginning therapy. • is capable of complying with effective contraceptive measures. • has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake. • will begin ARTHROTEC only on the second or third day of the next normal menstrual period. Advise females to inform their healthcare provider of a known or suspected pregnancy. Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac, a component of ARTHROTEC, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology (12.1)]. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including ARTHROTEC, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness of ARTHROTEC in pediatric patients have not been established. Reference ID: 5482805 8.5 Geriatric Use Geriatric patients (those 65 years of age and older), compared to younger adult patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions [see Warnings and Precautions (5.2, 5.3, 5.7)]. In addition, the risk of diclofenac-associated adverse reactions may be greater in geriatric patients with renal impairment or those taking concomitant ACE inhibitors or ARBs [see Drug Interactions (7) and Use in Specific Populations (8.6)]. Avoid use of ARTHROTEC in geriatric patients with cardiovascular and/or renal risk factors. If use cannot be avoided, use the lowest recommended dosage for the shortest duration and monitor for cardiac and renal adverse reactions [see Dosage and Administration (2.1)]. Monitor renal function in geriatric patients during treatment with ARTHROTEC, especially in patients with concomitant use of ACE inhibitors or ARBs. Of the 2,184 patients in clinical studies with ARTHROTEC, 557 (25.5%) were 65 years of age and over. No overall differences in effectiveness were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in effectiveness between geriatric patients and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. No clinically meaningful differences in the pharmacokinetics of diclofenac and misoprostol were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment Diclofenac and misoprostol are primarily excreted by the kidney. Long-term administration of NSAIDs has resulted in renal toxicity. Correct volume status in dehydrated or hypovolemic patients prior to initiating ARTHROTEC. Monitor renal function, especially during concomitant use of ACE inhibitors or ARBs. Also, monitor renal function in patients with hepatic impairment. Avoid the use of ARTHROTEC in patients with advanced renal disease. If use cannot be avoided in patients with advanced renal disease, use the lowest dosage for the shortest duration, monitor the patient’s renal function and monitor for clinical signs of worsening renal function [see Warnings and Precautions (5.7), Drug Interactions (7) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Manage patients with symptomatic and supportive care following an acute NSAID overdosage. There are no specific antidotes. It is advisable to contact a poison control center (1-800-222-1222) to determine the latest recommendations because strategies for the management of overdose are continually evolving. The toxic dose of ARTHROTEC has not been determined. However, signs of overdosage from the components of the product have been described. Diclofenac Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with Reference ID: 5482805 supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.2, 5.3, 5.5, 5.7)]. Clinical signs that may suggest diclofenac sodium overdose include GI complaints, confusion, drowsiness, or general hypotonia. If gastric decontamination may be potentially beneficial to the patient, e.g., short time since ingestion or a large overdosage (5 to 10 times the recommended dosage), consider emesis and/or activated charcoal (60 grams to 100 grams in adults, 1 gram to 2 grams per kg of body weight in pediatric patients) and/or an osmotic cathartic in symptomatic patients. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. Misoprostol The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of GI discomfort being reported. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. ARTHROTEC Symptoms of acute overdosage with ARTHROTEC should be treated with supportive and symptomatic therapy. There are no specific antidotes. In case of acute overdosage, emesisis and/or gastric lavage may be considered dependent upon amount ingested and time since ingestion. The use of oral activated charcoal may help to reduce the absorption of diclofenac sodium and misoprostol. Induced diuresis may be beneficial because diclofenac sodium and misoprostol metabolites are excreted in the urine. The effect of dialysis or hemoperfusion on the elimination of diclofenac sodium (99% protein bound) and misoprostol acid remains unproven. 11 DESCRIPTION ARTHROTEC is a combination product containing diclofenac sodium, an NSAID with analgesic properties, and misoprostol, a gastrointestinal (GI) mucosal protective prostaglandin-1 (PGE1) analog. ARTHROTEC tablets are white to off-white, round, biconvex, and approximately 11 mm in diameter. Each tablet consists of an enteric-coated core containing 50 mg (ARTHROTEC 50) or 75 mg (ARTHROTEC 75) of diclofenac sodium (equivalent to 46.39 mg or 69.58 mg of diclofenac, respectively) surrounded by an outer mantle containing 200 mcg misoprostol. Diclofenac sodium is a phenylacetic acid derivative that is a white to off-white, virtually odorless, crystalline powder. Diclofenac sodium is freely soluble in methanol, soluble in ethanol, and practically insoluble in chloroform and in dilute acid. Diclofenac sodium is sparingly soluble in water. Its chemical formula and name are: C14H10Cl2NO2Na [M.W. = 318.14] 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. Reference ID: 5482805 Misoprostol is a water-soluble, viscous liquid that contains approximately equal amounts of two diastereomers. Its chemical formula and name are: C22H38O5 [M.W. = 382.54] (±) methyl 11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en­ 1-oate. Inactive ingredients in ARTHROTEC include: colloidal silicon dioxide; crospovidone; hydrogenated castor oil; hypromellose; lactose; magnesium stearate; methacrylic acid copolymer; microcrystalline cellulose; povidone (polyvidone) K-30; sodium hydroxide; starch (corn); talc; triethyl citrate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ARTHROTEC is a combination product containing diclofenac sodium, an NSAID with analgesic, anti-inflammatory and antipyretic properties, and misoprostol, a GI mucosal protective prostaglandin-1 (PGE1) analog. Diclofenac The mechanism of action of diclofenac, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Diclofenac is a potent inhibitor of prostaglandin (PG) synthesis in vitro. Diclofenac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Misoprostol Misoprostol is a synthetic PGE1 analog with gastric antisecretory and mucosal protective properties. NSAIDs inhibit prostaglandin synthesis. A deficiency of prostaglandins within the gastric and duodenal mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by NSAIDs. Misoprostol can increase bicarbonate and mucus production, but it has been shown at doses 200 mcg and above that are also antisecretory. It is therefore not possible to differentiate whether the ability of misoprostol to reduce the risk of gastric and duodenal ulcers is the result of its antisecretory effect, its mucosal protective effect, or both. In vitro studies on canine parietal cells using titrated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. Receptor binding is saturable, reversible, and stereo-specific. The sites have a high affinity for misoprostol, for its acid metabolite, and for other E type prostaglandins, but not for F or I prostaglandins and other unrelated compounds, such as histamine or cimetidine. Receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. It is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained. Reference ID: 5482805 ------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------- Misoprostol, over the range of 50 mcg to 200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter-lived, and only the 200 mcg dose had substantial effects on nocturnal secretion or on histamine- and meal-stimulated secretion. Misoprostol also produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. It has no significant effect on fasting or postprandial gastrin nor intrinsic factor output. 12.3 Pharmacokinetics General Pharmacokinetic Characteristics The pharmacokinetic profiles of diclofenac and misoprostol administered as the fixed combination (ARTHROTEC 50 or 75) are similar to the profiles when the two drugs are administered as separate tablets (see Table 2). No pharmacokinetic interaction between the two drugs has been observed following multiple dosing. The diclofenac total exposure [area under the curve (AUC)] is dose-proportional within the range of 25 mg to 150 mg. Approximately dose-proportional increase in misoprostol exposure was also observed within the range of 200 mcg to 400 mcg. Neither diclofenac nor misoprostol accumulated in plasma following repeated doses of ARTHROTEC given every 12 hours under fasted conditions. Table 2: Pharmacokinetic Parameters of Diclofenac and Misoprostol Acid Following Single Oral Doses of ARTHROTEC or Separate Products in Healthy Subjects MISOPROSTOL ACID Mean (SD) Treatment (n=36) Cmax (pg/mL) Tmax (hr) AUC(0–4h) (pg·hr/mL) ARTHROTEC 50 441 (137) 0.30 (0.13) 266 (95) Misoprostol 478 (201) 0.30 (0.10) 295 (143) ARTHROTEC 75 304 (110) 0.26 (0.09) 177 (49) Misoprostol 290 (130) 0.35 (0.12) 176 (58) DICLOFENAC Mean (SD) AUC(0–12h) Treatment (n=36) Cmax (ng/mL) Tmax (hr) (ng·hr/mL) ARTHROTEC 50 1207 (364) 2.4 (1.0) 1380 (272) Diclofenac Sodium 1298 (441) 2.4 (1.0) 1357 (290) ARTHROTEC 75 2025 (2005) 2.0 (1.4) 2773 (1347) Diclofenac Sodium 2367 (1318) 1.9 (0.7) 2609 (1185) SD: Standard deviation of the mean; AUC: Area under the curve; Cmax: Peak concentration; Tmax: Time to peak concentration Absorption Diclofenac: Diclofenac is completely absorbed from the GI tract after oral administration under fasted condition, and peak plasma levels are achieved in 2 hours (range 1–4 hours), and the area under the plasma concentration curve (AUC) is dose-proportional within the range of 25 mg to 150 mg. Peak plasma levels are less than dose-proportional and are approximately 1.5 and 2.0 mcg/mL for 50 mg and 75 mg doses, respectively. The diclofenac in ARTHROTEC is in a pharmaceutical formulation that resists dissolution in the low pH of gastric fluid but allows a rapid release of drug in the higher pH environment of the Reference ID: 5482805 duodenum. Only 50% of the absorbed dose is systemically available due to first pass metabolism (i.e., oral bioavailability is 50%). Misoprostol: Misoprostol is rapidly absorbed following oral administration of ARTHROTEC, and misoprostol acid (active metabolite) reaches a maximum plasma concentration in approximately 20 minutes. Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with food, and total availability of misoprostol acid is reduced by use of concomitant antacid. Clinical trials were conducted with concomitant antacid; this effect does not appear to be clinically important. Food decreases the multiple-dose bioavailability profile of ARTHROTEC 50 and ARTHROTEC 75. Distribution Diclofenac: The volume of distribution of diclofenac is approximately 0.55 L/kg. More than 99% of diclofenac is bound to plasma albumin. Misoprostol: The plasma protein binding of misoprostol acid is less than 90% and is concentration-independent in the therapeutic range. After a single oral dose of misoprostol to nursing mothers, misoprostol acid was excreted in breast milk. The maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/mL (CV 37%) and 20.9 pg/mL (CV 77%) after single 200 mcg and 600 mcg misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to <1 pg/mL at 5 hours post-dose. These data may not reflect drug level in mature milk and in a daily dosing regimen for osteoarthritis or rheumatoid arthritis. Elimination Metabolism Diclofenac: Metabolism is predominantly mediated via CYP2C9 in the liver. Five metabolites (4'hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac) have been identified. The major metabolite (4'-hydroxy-diclofenac) has very weak pharmacologic activity. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy-diclofenac. Misoprostol: Undergoes rapid and extensive metabolism to its biologically active metabolite, misoprostol acid. Excretion Diclofenac: Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Approximately 65% of the dose is excreted in the urine and 35% in the bile. The elimination half-life of diclofenac is approximately 2 hours. The clearance of diclofenac is approximately 350 mL/min (equivalent to 21 L/h). Reference ID: 5482805 Conjugates of unchanged diclofenac account for 5% to 10% of the dose excreted in the urine and for less than 5% excreted in the bile. Little or no unchanged unconjugated drug is excreted. Conjugates of the principal metabolite account for 20% to 30% of the dose excreted in the urine and for 10% to 20% of the dose excreted in the bile. Conjugates of three other metabolites together account for 10% to 20% of the dose excreted in the urine and for small amounts excreted in the bile. The elimination half-life values for these metabolites are shorter than those for the parent drug. Urinary excretion of an additional metabolite (half-life = 80 hours) accounts for only 1.4% of the oral dose. The degree of accumulation of diclofenac metabolites is unknown. Some of the metabolites may have activity. Misoprostol: After oral administration of radio-labeled misoprostol, approximately 70% of detected radioactivity appears in the urine. The elimination half-life is approximately 30 minutes. Specific Populations Geriatric Patients No differences in the pharmacokinetics of diclofenac were observed in geriatric subjects (66 to 81 years; N=10) compared to younger adult subjects (26 to 46 years; N=10) following administration of diclofenac 50 mg twice daily for 4 weeks. Though the mean AUC value of misoprostol acid for elderly subjects was 41% higher in geriatric healthy subjects (mean age, 69.5±4.6 years, N=24) compared to younger adult healthy subjects (mean age, 25.4±4.2 years, N=24) following single dose of misoprostol 400 µg, the increase in exposure is not clinically meaningful. In a multiple-dose crossover study of ARTHROTEC administered twice daily to 24 subjects aged 65 years of age and older, misoprostol did not affect the pharmacokinetics of diclofenac [see Use in Specific Populations (8.5)]. Racial or Ethnic Groups Pharmacokinetic differences due to race have not been identified. Patients with Renal Impairment In patients with renal impairment (N=5, creatinine clearance 3 to 42 mL/min) following intravenous administration of 50 mg diclofenac, AUC values and elimination rates were comparable to those in healthy subjects. Pharmacokinetic studies with misoprostol in patients with severe renal impairment requiring hemodialysis (n=8, mean creatinine clearance 6.2±3.3 mL/min/1.73m2) who received a single dose of 400 mcg misoprostol during a interdialytic period showed an approximate doubling of elimination half-life, Cmax, and AUC of misoprostol acid compared to healthy subjects [see Use in Specific Populations (8.6)]. Patients with Hepatic Impairment In patients with biopsy-confirmed cirrhosis or chronic active hepatitis (variably elevated transaminases and mildly elevated bilirubin, N=10), diclofenac concentrations and urinary elimination values following administration of 100 mg oral solution were comparable to those in healthy subjects. Reference ID: 5482805 In a study of subjects with mild to moderate hepatic impairment, mean misoprostol acid AUC and Cmax showed approximately twice high as the mean values obtained in healthy subjects. Three subjects who had the lowest antipyrine and lowest indocyanine green clearance values had the highest misoprostol acid AUC and Cmax values. Drug Interaction Studies Diclofenac Aspirin: When ARTHROTEC was administered with aspirin, the protein binding of diclofenac was reduced, although the clearance of the free diclofenac was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Voriconazole: When a single dose diclofenac (50 mg) was coadministered with the last dose of voriconazole (400 mg every 12 hours on Day 1, followed by 200 mg every 12 hours on Day 2), the mean Cmax and AUC of diclofenac were increased by 114% and 78%, respectively, when compared to diclofenac alone [see Drug Interactions (7)]. In vitro, diclofenac interferes minimally with the protein binding of prednisolone (10% decrease in binding). Benzylpenicillin, ampicillin, oxacillin, chlortetracycline, doxycycline, cephalothin, erythromycin, and sulfamethoxazole have no influence, in vitro, on the protein binding of diclofenac in human serum. Other drugs: In small groups of patients (7 to 10 patients/interaction study), the concomitant administration of azathioprine, gold, chloroquine, D-penicillamine, prednisolone, doxycycline or digitoxin did not significantly affect Cmax and AUC of diclofenac. Misoprostol Diazepam: Misoprostol given for 1 week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart. Other drugs: Pharmacokinetic studies also showed a lack of drug interaction with antipyrine or propranolol given with misoprostol. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term animal studies to evaluate the potential for carcinogenesis and animal studies to evaluate the effects on fertility have been performed with each component of ARTHROTEC given alone. In a 24 month rat carcinogenicity study, misoprostol administered orally at doses up to 2.4 mg/kg/day (14.4 mg/m2/day, 24 times the MRHD of 0.6 mg/m2/day) was not tumorigenic. In a 21-month mouse carcinogenicity study, misoprostol administered orally at doses up to 16 mg/kg/day (48 mg/m2/day), 80 times the MRHD based on body surface area, was not tumorigenic. Reference ID: 5482805 In a 24-month rat carcinogenicity study, diclofenac sodium administered orally at up to 2 mg/kg/day (12 mg/m2/day) was not tumorigenic. In a 24-month mouse carcinogenicity study, oral diclofenac sodium at doses up to 0.3 mg/kg/day (0.9 mg/m2/day, 0.006 times the MRHD based on body surface area) in males and 1 mg/kg/day (3 mg/m2/day, 0.02 times the MRHD based on body surface area) in females was not tumorigenic. Mutagenesis Diclofenac sodium and misoprostol combination in 250:1 ratio was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the rat lymphocyte chromosome aberration test, or the mouse bone marrow micronucleus test. Impairment of Fertility The effects of diclofenac sodium and misoprostol on male or female fertility have not been studied in animals; however, there are data with diclofenac sodium and misoprostol given alone. Misoprostol, when administered to male and female breeding rats in an oral dose range of 0.1 to 10 mg/kg/day (0.6 to 60 mg/m2/day, 1 to 100 times the MRHD based on body surface area) produced dose-related pre- and post-implantation losses and a significant decrease in the number of live pups born at the highest dose (60 mg/m2/day, 100 times the MRHD based on body surface area). Diclofenac sodium at oral doses up to 4 mg/kg/day (24 mg/m2/day, 0.16 times the MRHD based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats. 13.2 Animal Toxicology A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse during long-term toxicology studies with misoprostol. No such increase has been observed in humans administered misoprostol for up to 1 year. An apparent response of the female mouse to misoprostol in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with misoprostol. 14 CLINICAL STUDIES Osteoarthritis Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of osteoarthritis. Rheumatoid Arthritis Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of rheumatoid arthritis. Upper Gastrointestinal Safety Diclofenac, and other NSAIDs, have caused serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine. Misoprostol has been shown to reduce the incidence of endoscopically diagnosed NSAID-induced gastric and duodenal ulcers. In a 12-week, randomized, double-blind, dose-response study, misoprostol 200 mcg administered four, three or two times a day, was significantly more effective than placebo in reducing the incidence of gastric ulcer in Reference ID: 5482805 osteoarthritis and rheumatoid arthritis patients using a variety of NSAIDs. The three times a day regimen was therapeutically equivalent to misoprostol 200 mcg four times a day with respect to the prevention of gastric ulcers. Misoprostol 200 mcg given two times a day was less effective than 200 mcg given three or four times a day. The incidence of NSAID-induced duodenal ulcer was also significantly reduced with all three regimens of misoprostol compared to placebo (see Table 3). Table 3 Misoprostol 200 mcg Dosage Regimen Placebo two times a day three times a day four times a day Gastric ulcer 11% 6%* 3%* 3%* Duodenal ulcer 6% 2%* 3%* 1%* N=1623; 12 weeks *Misoprostol significantly different from placebo (p<0.05) Results of a study in 572 patients with osteoarthritis demonstrate that patients receiving ARTHROTEC have a lower incidence of endoscopically defined gastric ulcers compared to patients receiving diclofenac sodium (see Table 4). Table 4 Osteoarthritis patients with history of Incidence of ulcers ulcer or erosive disease (N=572), 6 weeks Gastric Duodenal ARTHROTEC 50 three times a day 3%* 6% ARTHROTEC 75 two times a day 4%* 3% Diclofenac sodium 75 mg two times a day 11% 7% Placebo 3% 1% *Statistically significantly different from diclofenac (p<0.05) 16 HOW SUPPLIED/STORAGE AND HANDLING ARTHROTEC (diclofenac sodium and misoprostol delayed-release tablets) are supplied as: • 50 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off- white tablets imprinted with four “A’s” encircling a “50” in the middle on one side and “SEARLE” and “1411” on the other. • 75 mg diclofenac sodium and 200 mcg misoprostol as round, biconvex, white to off- white tablets imprinted with four “A’s” encircling a “75” in the middle on one side and “SEARLE” and “1421” on the other. The dosage strengths are supplied in: Strength NDC Number Size 50 mg diclofenac sodium 0025-1411-60 bottle of 60 ARTHROTEC 50 and 200 mcg misoprostol 0025-1411-90 bottle of 90 ARTHROTEC 75 75 mg diclofenac sodium and 200 mcg misoprostol 0025-1421-60 bottle of 60 Reference ID: 5482805 Store at 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients, families, or their caregivers of the following information before initiating therapy with ARTHROTEC and periodically during the course of ongoing therapy. Uterine Rupture, Abortion, Premature Birth, or Birth Defects with Misoprostol and Embryo-Fetal Toxicity with NSAIDs • Advise females that ARTHROTEC is contraindicated in pregnant women. Use of misoprostol, a component of ARTHROTEC during pregnancy can result in maternal and fetal harm, including uterine rupture, abortion, premature birth, or birth defects. Use of diclofenac may cause oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. • Advise patients not to give ARTHROTEC to others. • Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with ARTHROTEC. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)]. Infertility Advise females of reproductive potential that ARTHROTEC may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Use in Specific Populations (8.3)]. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.2)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.3)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop ARTHROTEC and seek immediate medical therapy [see Warnings and Precautions (5.4)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.6)]. Reference ID: 5482805 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.8)]. Serious Skin Reactions, including DRESS Advise patients to stop taking ARTHROTEC immediately if they develop any type of rash or fever and contact their healthcare provider as soon as possible [see Warnings and Precautions (5.10, 5.11)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of ARTHROTEC with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.3) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with ARTHROTEC until they talk to their healthcare provider [see Drug Interactions (7)]. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. For medical information about Arthrotec, please visit www.pfizermedinfo.com or call 1-800-438-1985. LAB-0061-31.1 Reference ID: 5482805 MEDICATION GUIDE Medication Guide for ARTHROTEC (ARTH’ roe-tek) (diclofenac sodium and misoprostol delayed- release tablets) for oral use What is the most important information I should know about ARTHROTEC? ARTHROTEC contains diclofenac (a nonsteroidal anti-inflammatory drug (NSAID)) and misoprostol, and can cause uterus to tear (uterine rupture), abortion, premature birth, or birth defects. The risk of uterine rupture increases as your pregnancy advances, if you have given birth to 5 or more children, and if you have had surgery on the uterus, such as a cesarean delivery. Do not take ARTHROTEC if you are pregnant. • Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with ARTHROTEC. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with ARTHROTEC. Females who are able to become pregnant should use an effective form of birth control (contraception) during treatment with ARTHROTEC. What is the most important information I should know about medicines containing Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAID containing medicines right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAID containing medicines after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “antiplatelet drugs”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease Reference ID: 5482805 o drinking alcohol o bleeding problems NSAID containing medicines should only be used: o exactly as prescribed o at the lowest dose possible for your treatment o for the shortest time needed What is ARTHROTEC? ARTHROTEC contains 2 medicines: 1. Diclofenac is a non-steroidal anti-inflammatory drug (NSAID). See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? 2. Misoprostol is a medicine used to protect the lining of the esophagus, stomach and intestines while taking diclofenac. ARTHROTEC is a prescription medicine used to treat: • symptoms of osteoarthritis or rheumatoid arthritis in adults at high risk of developing stomach (gastric) and intestinal (duodenal) ulcers while taking NSAIDs. It is not known if ARTHROTEC is safe and effective for use in children. What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis. Who should not take ARTHROTEC? Do not take ARTHROTEC: • if you are pregnant. • right before or after heart bypass surgery. • if you currently have bleeding in your stomach (gastrointestinal bleeding). • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • if you are allergic to diclofenac sodium and misoprostol, other prostaglandins or any other ingredients in ARTHROTEC. See the end of this Medication Guide for a list of ingredients in ARTHROTEC. Before taking ARTHROTEC, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems. • have high blood pressure. • have heart problems, including a history of heart failure or heart attack. • have asthma. • are pregnant or plan to become pregnant. See “Who should not take ARTHROTEC?” • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. Reference ID: 5482805 What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • asthma attacks in people who have asthma • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel • diarrhea movement or it is black and sticky • itching like tar • your skin or eyes look yellow • unusual weight gain • indigestion or stomach pain • skin rash or blisters with fever • flu-like symptoms • swelling of the arms, legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. Reference ID: 5482805 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Active ingredients: diclofenac sodium, misoprostol. Inactive ingredients: colloidal silicon dioxide, crospovidone, hydrogenated castor oil, hypromellose, lactose, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, povidone (polyvidone) K-30, sodium hydroxide, starch (corn), talc, triethyl citrate. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. For more information, go to www.pfizer.com or call 1-800-438-1985. LAB: 0793-8.1 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5482805
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2025-02-12T15:47:15.742906
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VIMOVO safely and effectively. See full prescribing information for VIMOVO. VIMOVO (naproxen and esomeprazole magnesium) delayed-release tablets, for oral use Initial US Approval: 2010 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINALEVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.1) • VIMOVO is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) • NSAIDs, including naproxen, a component of VIMOVO, cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2) --------------------------RECENT MAJOR CHANGES--------------------------­ Warnings and Precautions, Serious or Severe Skin Reactions (5.9) 11/2024 ---------------------------INDICATIONSANDUSAGE--------------------------­ VIMOVO is a combination of naproxen, a non-steroidal anti-inflammatory drug (NSAID), and esomeprazole magnesium, a proton pump inhibitor (PPI) indicated in adult and adolescent patients 12 years of age and older weighing at least 38 kg, requiring naproxen for symptomatic relief of arthritis and esomeprazole magnesium to decrease the risk of developing naproxen­ associated gastric ulcers. The naproxen component of VIMOVO is indicated for relief of signs and symptoms of: • osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. • juvenile idiopathic arthritis (JIA) in adolescent patients. The esomeprazole magnesium component of VIMOVO is indicated to decrease the risk of developing naproxen-associated gastric ulcers. (1) Limitations of Use: • Do not substitute VIMOVO with the single-ingredient products of naproxen and esomeprazole magnesium. (1) • VIMOVO is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products. (1) • Controlled studies do not extend beyond 6 months. (1) -----------------------DOSAGEANDADMINISTRATION---------------------­ Administration • Use the lowest naproxen dose for the shortest duration consistent with individual patient treatment goals. (2.1, 5.1). • If a total daily dose of less than 40 mg esomeprazole is more appropriate, a different treatment should be considered. (2.1) • Swallow VIMOVO tablets whole with liquid at least 30 minutes before meals. (2.1) Recommended Dosage (2.2) Adolescents 12 years of age and older weighing 38 kg to less than 50 kg: One VIMOVO tablet twice daily of 375 mg naproxen/20 mg of esomeprazole Adults and adolescents 12 years of age and older greater than 50 kg: One VIMOVO tablet twice daily of either: • 375 mg naproxen/20 mg of esomeprazole; or • 500 mg of naproxen/20 mg of esomeprazole Renal or Hepatic Impairment (2.3) • Avoid in moderate/severe renal impairment or severe hepatic impairment. • Consider dose reduction in mild/moderate hepatic impairment. ---------------------DOSAGE FORMS AND STRENGTHS--------------------­ VIMOVO delayed-release tablets (3): • 375 mg enteric-coated naproxen /20 mg immediate-release esomeprazole • 500 mg enteric-coated naproxen /20 mg immediate-release esomeprazole -----------------------------CONTRAINDICATIONS-----------------------------­ • Known hypersensitivity to naproxen, esomeprazole magnesium, substituted benzimidazoles, or to any components of the drug product including omeprazole. (4) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. (4) • In the setting of coronary artery bypass graft (CABG) surgery. (4) • In patients receiving rilpivirine-containing products. (4, 7) -----------------------WARNINGSANDPRECAUTIONS----------------------­ • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.3) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.4, 7) • Heart Failure and Edema: Avoid use of VIMOVO in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.5) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of VIMOVO in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. (5.6) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.7) • Exacerbation of Asthma Related to Aspirin Sensitivity: VIMOVO is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.8) • Serious or Severe Skin Reactions: Discontinue VIMOVO at first appearance of skin rash or other signs of hypersensitivity and consider further evaluation. (5.9) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.10) • Fetal Toxicity: Limit use of NSAIDs, including VIMOVO, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs of symptoms of anemia. (5.12, 7) • Masking of Inflammation and Fever: Potential for diminished utility of diagnostic signs in detecting infections. (5.13) • Laboratory Monitoring: Obtain CBC and chemistry profile periodically during treatment. Monitor hemoglobin periodically in patients on long- term treatment who have an initial value of 10 g or less. (5.14) • Active Bleeding: Withdraw treatment in patients who experience active and clinically significant bleeding. (5.15) • Concomitant NSAID Use: Do not use VIMOVO with other naproxen­ containing products or other non-aspirin NSAIDs. (5.16) • Gastric Malignancy: In adults, symptomatic response to esomeprazole does not preclude the presence of gastric malignancy. Consider additional follow­ up and diagnostic testing. (5.17) • Acute Tubulointerstitial Nephritis: Discontinue treatment and evaluate patients. (5.18) • Clostridium difficile-Associated Diarrhea: PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. (5.19) • Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. (5.20) • Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous, new onset or exacerbation of existing disease; discontinue VIMOVO and refer to specialist for evaluation. (5.21) • Interaction with Clopidogrel: Avoid concomitant use. (5.22, 7) • Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. (5.23) • Hypomagnesemia and Mineral Metabolism: Reported rarely with prolonged treatment with PPIs. (5.24) • Interaction with St. John’s Wort or Rifampin: Avoid concomitant use. (5.25, 7) • Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Reference ID: 5482809 Increases in intragastric pH may result in hypergastrinemia, enterochromaffin-like cell hyperplasia, and increased Chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. (5.26) • Interaction with Methotrexate: Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. (5.27, 7) • Fundic Gland Polyps: Risk increases with long-term PPI use, especially beyond one year. Use the shortest duration of therapy. (5.28) -----------------------------ADVERSE REACTIONS------------------------------­ Most common adverse reactions in clinical trials (>5%) are gastritis and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Horizon at 1-866-479-6742 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------------DRUG INTERACTIONS-------------------------------­ See full prescribing information for a list of clinically important drug interactions. (7) -----------------------USE IN SPECIFIC POPULATIONS----------------------­ • Females and Males of Reproductive Potential: NSAIDs are associated with reversible infertility. Consider withdrawal of VIMOVO in women who have difficulties conceiving. (8.3) SEE 17 FOR PATIENT COUNSELING INFORMATION and FDA- Approved Medication Guide Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINALEVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions 2.2 Recommended Dosage 2.3 Use in Renal Impairment or Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Hepatotoxicity 5.4 Hypertension 5.5 Heart Failure and Edema 5.6 Renal Toxicity and Hyperkalemia 5.7 Anaphylactic Reactions 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 5.9 Serious or Severe Skin Reactions 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.11 Fetal Toxicity 5.12 Hematologic Toxicity 5.13 Masking of Inflammation and Fever 5.14 Laboratory Monitoring 5.15 Active Bleeding 5.16 Concomitant NSAID Use 5.17 Presence of Gastric Malignancy 5.18 Acute Tubulointerstitial Nephritis 5.19 Clostridium difficile-Associated Diarrhea 5.20 Bone Fracture 5.21 Cutaneous and Systemic Lupus Erythematosus 5.22 Interaction with Clopidogrel 5.23 Cyanocobalamin (Vitamin B-12) Deficiency 5.24 Hypomagnesemia and Mineral Metabolism 5.25 Concomitant Use of St. John's Wort or Rifampin with VIMOVO 5.26 Interactions with Diagnostic Investigations for Neuroendocrine Tumors 5.27 Concomitant Use of VIMOVO with Methotrexate 5.28 Fundic Gland Polyps 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482809 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Non-Steroidal Anti-inflammatory Drugs (NSAIDs), a component of VIMOVO, cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • VIMOVO is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4), and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs, a component of VIMOVO cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE VIMOVO, a combination of naproxen and esomeprazole magnesium, is indicated in adult and adolescent patients 12 years of age and older weighing at least 38 kg, requiring naproxen for symptomatic relief of arthritis and esomeprazole magnesium to decrease the risk for developing naproxen-associated gastric ulcers. The naproxen component of VIMOVO is indicated for relief of signs and symptoms of: • osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. • juvenile idiopathic arthritis (JIA) in adolescent patients. The esomeprazole magnesium component of VIMOVO is indicated to decrease the risk of developing naproxen-associated gastric ulcers. Limitations of Use: • Do not substitute VIMOVO with the single-ingredient products of naproxen and esomeprazole magnesium. • VIMOVO is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products. • Controlled studies do not extend beyond 6 months [see Use in Specific Populations (8.4), Clinical Studies (14)]. 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions • Use the lowest naproxen dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5.1)]. • Carefully consider the potential benefits and risks of VIMOVO and other treatment options before deciding to use VIMOVO. • VIMOVO does not allow for administration of a lower daily dose of esomeprazole magnesium. If a total daily dose of less than 40 mg esomeprazole is more appropriate, a different treatment should be considered. Reference ID: 5482809 • Swallow VIMOVO tablets whole with liquid. Do not split, chew, crush or dissolve the tablet. Take VIMOVO at least 30 minutes before meals. • Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose. • Antacids may be used while taking VIMOVO. 2.2 Recommended Dosage The recommended dosage of VIMOVO by indication is shown in the table: Indication Patient Population Recommended Dosage Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis Adults One VIMOVO tablet twice daily of either: 375 mg naproxen/20 mg of esomeprazole; or 500 mg naproxen/20 mg of esomeprazole Juvenile Idiopathic Arthritis in Adolescent Greater than 50 kg Patients 12 Years of Age and Older and Weighing at Least 38 kg 38 kg to less than 50 kg One VIMOVO tablet twice daily of: 375 mg naproxen/20 mg of esomeprazole 2.3 Use in Renal Impairment or Hepatic Impairment Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe or severe renal impairment (creatinine clearance less than 30 mL/min) [see Warnings and Precautions (5.6), Use in Specific Populations (8.7)]. Hepatic Impairment Monitor patients with mild to moderate hepatic impairment closely and consider a possible dose reduction based on the naproxen component of VIMOVO. VIMOVO should be avoided in patients with severe hepatic impairment [see Warnings and Precautions (5.3), Use in Specific Populations (8.6)]. 3 DOSAGE FORMS AND STRENGTHS VIMOVO is an oval, yellow, delayed-release tablets for oral administration containing either: • 375 mg enteric-coated naproxen and 20 mg immediate-release esomeprazole tablets printed with 375/20 in black, or • 500 mg enteric-coated naproxen and 20 mg immediate-release esomeprazole tablets printed with 500/20 in black. 4 CONTRAINDICATIONS VIMOVO is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen, esomeprazole magnesium, substituted benzimidazoles, or to any components of the drug product, including omeprazole. Hypersensitivity reactions to esomeprazole may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions (5.7, 5.8, 5.9, 5.18), Adverse Reactions (6.2)]. Reference ID: 5482809 • History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]. • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]. • Proton pump inhibitors (PPIs), including esomeprazole magnesium, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7)]. 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDS. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100-person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years after follow-up. Avoid the use of VIMOVO in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If VIMOVO is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including naproxen, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, Reference ID: 5482809 or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events are in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such as patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue VIMOVO until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of the normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, and sometimes fatal, cases of severe hepatic injury, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue VIMOVO immediately, and perform a clinical evaluation of the patient. VIMOVO should be avoided in patients with severe hepatic impairment [see Dosage and Administration (2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. 5.4 Hypertension NSAIDs, including VIMOVO, can lead to new onset of hypertension or worsening of pre­ existing hypertension, either of which may contribute to the increased incidence of CV events. Reference ID: 5482809 Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of VIMOVO in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If VIMOVO is used in patients with severe heart failure, monitor patients for signs and symptoms of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of VIMOVO in patients with advanced renal disease. The renal effects of VIMOVO may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating VIMOVO. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of VIMOVO [see Drug Interactions (7)]. Avoid the use of VIMOVO in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal failure. If VIMOVO is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. Reference ID: 5482809 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, VIMOVO is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When VIMOVO is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious or Severe Skin Reactions Naproxen NSAIDs, including naproxen, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Esomeprazole PPIs can cause severe cutaneous adverse reactions, including SJS, TEN, and acute generalized exanthematous pustulosis (AGEP) [see Adverse Reactions (6.2)]. VIMOVO Inform patients about the signs and symptoms of serious or severe skin reactions, and to discontinue the use of VIMOVO at the first appearance of skin rash or any other sign of hypersensitivity and consider further evaluation. VIMOVO is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs and PPIs such as those contained in VIMOVO. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue VIMOVO and evaluate the patient immediately [see also Warnings and Precautions (5.9)]. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including VIMOVO, in pregnant women at about 30 weeks gestation and later. NSAIDs, including VIMOVO, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including VIMOVO, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit VIMOVO use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of Reference ID: 5482809 amniotic fluid if VIMOVO treatment is needed in a pregnant woman. Discontinue VIMOVO if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with VIMOVO has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including VIMOVO, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase the risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of VIMOVO in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically. 5.15 Active Bleeding When active and clinically significant bleeding from any source occurs in patients receiving VIMOVO, the treatment should be withdrawn. 5.16 Concomitant NSAID Use VIMOVO contains naproxen as one of its active ingredients. It should not be used with other naproxen-containing products since they all circulate in the plasma as the naproxen anion. The concomitant use of VIMOVO with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions. 5.17 Presence of Gastric Malignancy In adults, response to gastric symptoms with VIMOVO does not preclude the presence of gastric malignancy. Consider additional gastrointestinal follow-up and diagnostic testing in adult patients who experience gastric symptoms during treatment with VIMOVO or have a symptomatic relapse after completing treatment. In older patients, also consider an endoscopy. 5.18 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue VIMOVO and evaluate patients with suspected acute TIN [see Contraindications (4)]. 5.19 Clostridium difficile-Associated Diarrhea Published observational studies suggest that proton pump inhibitor (PPI) therapy like VIMOVO may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in Reference ID: 5482809 hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2)]. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated [see Dosage and Administration (2)]. 5.20 Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines [see Dosage and Administration (2), Adverse Reactions (6.2)]. VIMOVO (a combination PPI/NSAID) is approved for use twice a day and does not allow for administration of a lower daily dose of the PPI [see Dosage and Administration (2)]. 5.21 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including esomeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI- induced lupus erythematous cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy inpatients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. SLE is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving VIMOVO, discontinue drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations. 5.22 Interaction with Clopidogrel Avoid concomitant use of esomeprazole with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 40 mg esomeprazole reduces the pharmacological activity of clopidogrel. When using esomeprazole, a component of VIMOVO, consider alternative anti-platelet therapy [see Drug Interactions (7), Clinical Pharmacology (12.3)]. 5.23 Cyanocobalamin(Vitamin B-12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo-or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid- suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed. 5.24 Hypomagnesemia and Mineral Metabolism Reference ID: 5482809 Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2)]. Consider monitoring magnesium and calcium levels prior to initiation of VIMOVO and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium, as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the VIMOVO. 5.25 Concomitant Use of St. John’s Wort or Rifampin with VIMOVO Drugs that induce CYP2C19 or CYP3A4 (such as St. John’s Wort or rifampin) can substantially decrease esomeprazole concentrations. Avoid concomitant use of VIMOVO with St. John’s Wort or rifampin [see Drug Interactions (7)]. 5.26 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop esomeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Drug Interactions (7), Clinical Pharmacology (12.2)]. 5.27 Concomitant Use of VIMOVO with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7)]. 5.28 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration and Perforations [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Heart Failure and Edema [see Warnings and Precautions (5.5)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] • Anaphylactic Reactions [see Warnings and Precautions (5.7)] • Serious or Severe Skin Reactions [see Warnings and Precautions (5.9)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.10)] • Fetal Toxicity [see Warnings and Precautions (5.11)] Reference ID: 5482809 • Hematologic Toxicity [see Warnings and Precautions (5.12)] • Active Bleeding [see Warnings and Precautions (5.15)] • Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.18)] • Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.19)] • Bone Fracture [see Warnings and Precautions (5.20)] • Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.21)] • Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.23)] • Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.24)] • Fundic Gland Polyps [see Warnings and Precautions (5.28)] 6.1 Clinical Trials Experience Clinical Trials Experience with VIMOVO Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reactions reported below are specific to the clinical trials with VIMOVO. The safety of VIMOVO was evaluated in clinical studies involving 2317 patients (aged 27 to 90 years) and ranging from 3 to 12 months. Patients received either 500 mg/20 mg of VIMOVO twice daily (n=1157), 500 mg of enteric-coated naproxen twice daily (n=426), or placebo (n=246). The average number of VIMOVO doses taken over 12 months was 696+44. The table below lists all adverse reactions, regardless of causality, occurring in >2% of patients receiving VIMOVO and higher in the VIMOVO group than control from two clinical studies (Study 1 and Study 2). Both of these studies were randomized, multi-center, double-blind, parallel studies. The majority of patients were female (67%), white (86%). The majority of patients were 50-69 years of age (83%). Approximately one quarter were on low-dose aspirin. Table 1: Adverse Reactions* in Study 1 and Study 2 (endoscopic studies) Preferred term VIMOVO 500 mg/20 mg twice daily (n=428) % EC-Naproxen 500 mg twice daily (n=426) % Gastritis 17 14 Diarrhea 6 5 Upper respiratory tract infection 5 4 Flatulence 4 3 Headache 3 1 Urinary tract infection 2 1 Dysgeusia 2 1 *reported in >2% of patients and higher in the VIMOVO group than control In Study 1 and Study 2, patients taking VIMOVO had fewer premature discontinuations due to adverse reactions compared to patients taking enteric-coated naproxen alone (7.9% vs. 12.5% respectively). The most common reasons for discontinuations due to adverse events in the VIMOVO treatment group were upper abdominal pain (1.2%, n=5), duodenal ulcer (0.7%, n=3) and erosive gastritis (0.7%, n=3). Among patients receiving enteric-coated naproxen, the most common reasons for discontinuations due to adverse events were duodenal ulcer 5.4% (n=23), dyspepsia 2.8% (n=12) and upper abdominal pain 1.2% (n=5). The proportion of patients discontinuing treatment due to any upper gastrointestinal adverse events (including duodenal ulcers) in patients treated with VIMOVO was 4% compared to 12% for patients taking enteric­ coated naproxen. Reference ID: 5482809 The table below lists all adverse reactions, regardless of causality, occurring in >2% of patients and higher in the VIMOVO group than placebo from 2 clinical studies conducted in patients with osteoarthritis of the knee (Study 3 and Study 4). Table 2: Adverse Reactions* in Study 3 and Study 4 Preferred term VIMOVO 500 mg/20 mg twice daily (n=490) % Placebo (n=246) % Diarrhea 6 4 Abdominal Pain Upper 4 3 Constipation 4 1 Dizziness 3 2 Peripheral edema 3 1 *reported in >2% of patients and higher in the VIMOVO group than placebo The percentage of subjects who withdrew from the VIMOVO treatment group in these studies due to treatment-emergent adverse events was 7%. There were no preferred terms in which more than 1% of subjects withdrew from any treatment group. The long-term safety of VIMOVO was evaluated in an open-label clinical trial of 239 patients, of which 135 patients received 500 mg/20 mg of VIMOVO for 12 months. There were no differences in frequency or types of adverse reactions seen in the long-term safety study compared to shorter-term treatment in the randomized controlled studies. Clinical Trials Experience with Naproxen and Other NSAIDs In patients taking naproxen in clinical trials, the most frequent reported adverse experiences in approximately 1% to 10% of patients are: Gastrointestinal: heartburn, nausea, dyspepsia, stomatitis Central Nervous System: drowsiness, lightheadedness, vertigo Dermatologic: pruritus, skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Cardiovascular: palpitations General: dyspnea, thirst In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal: gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials. Gastrointestinal: pancreatitis Reference ID: 5482809 Hepatobiliary: jaundice Hemic and Lymphatic: melena, thrombocytopenia, agranulocytosis Nervous System: inability to concentrate Dermatologic: skin rashes In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, glossitis, eructation Hepatobiliary: hepatitis, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremor, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria Clinical Trials Experience with Esomeprazole Magnesium Additional adverse reactions that were reported as possibly or probably related to esomeprazole magnesium with an incidence of <1% are listed below by body system: Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, malaise, pain, rigors Cardiovascular: flushing, hypertension, tachycardia Endocrine: goiter Gastrointestinal: dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting Hearing: earache, tinnitus Hematologic: anemia, anemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia Reference ID: 5482809 Hepatic: bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased Metabolic/Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect Reproductive: dysmenorrhea, menstrual disorder, vaginitis Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis Skin and Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria Special Senses: otitis media, parosmia, taste loss Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria Visual: conjunctivitis, vision abnormal The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to esomeprazole magnesium, were reported in ≤ 1% of patients: increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid stimulating hormone. Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine. Endoscopic findings that were reported as adverse reactions include: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, hernia, benign polyps or nodules, Barrett’s esophagus, and mucosal discoloration. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of VIMOVO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. VIMOVO Body as a Whole: gait disturbance Gastrointestinal: abdominal distension, abdominal pain, gastroesophageal reflux, hematochezia Injury, Poisoning and Procedural Complications: contusion, fall Musculoskeletal and Connective Tissue: joint swelling, muscle spasms Urogenital: renal tubular necrosis Naproxen Reference ID: 5482809 Body as a Whole: angioneurotic edema, menstrual disorders Cardiovascular: congestive heart failure, vasculitis, pulmonary edema Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, and obstruction of the upper or lower gastrointestinal tract, esophagitis, stomatitis, hematemesis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) Hepatobiliary: hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis Dermatologic: alopecia, urticaria, toxic epidermal necrolysis (TEN), erythema multiforme, erythema nodosum, fixed drug eruption (FDE), lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), fixed drug eruption (FDE), photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine Reproduction (female): infertility Esomeprazole Magnesium Blood and Lymphatic: agranulocytosis Eye: blurred vision Gastrointestinal: pancreatitis, microscopic colitis, fundic gland polyps Hepatobiliary: hepatic failure, hepatitis with or without jaundice Immune System: anaphylactic reaction/shock, systemic lupus erythematosus Infections and Infestations: GI candidiasis, Clostridium difficile associated diarrhea Metabolism and Nutritional Disorders: hypomagnesemia, hypocalcemia, hypokalemia [see Warnings and Precautions (5.24)], hyponatremia Musculoskeletal and Connective Tissue: muscular weakness, myalgia, bone fracture Nervous System: hepatic encephalopathy Reference ID: 5482809 Psychiatric: aggression, agitation, hallucination Renal and Urinary: interstitial nephritis Reproductive System and Breast: gynecomastia, erectile dysfunction Respiratory, Thoracic, and Mediastinal: bronchospasm Skin and Subcutaneous Tissue: alopecia, erythema multiforme, photosensitivity, SJS, TEN (some fatal), DRESS, AGEP, cutaneous lupus erythematosus 7 DRUG INTERACTIONS See Table 3 and Table 4 for clinically significant drug interactions and interactions with diagnostics with naproxen and esomeprazole magnesium. Table 3: Clinically Significant Drug Interactions with Naproxen and Esomeprazole Magnesium – Affecting Drugs Co-Administered with VIMOVO and Interactions with Diagnostics Clinical Impact: Naproxen • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have increased the risk of serious bleeding compared to the use of either drug alone • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Esomeprazole Magnesium • Increased INR and prothrombin time in patients treated with PPIs, including esomeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. • Concomitant use of esomeprazole 40 mg resulted in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. • There are no adequate combination studies of a lower dose of esomeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. Intervention: Monitor patients with concomitant use of VIMOVO with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.14)]. Clopidogrel: Avoid concomitant use of clopidogrel with VIMOVO. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.22)]. Aspirin Reference ID: 5482809 Clinical Impact: A pharmacodynamics (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen [see Clinical Pharmacology (12.2.)]. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics where appropriate. Concomitant use of VIMOVO and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. VIMOVO is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: • During concomitant use of VIMOVO and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VIMOVO and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of VIMOVO with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Antiretrovirals Reference ID: 5482809 Clinical Impact: The effect of esomeprazole magnesium on antiretroviral drugs is variable. The clinical importance and mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with esomeprazole magnesium may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole magnesium may increase toxicity [see Clinical Pharmacology (12.3)]. • There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole magnesium. Intervention: Rilpivirine-containing products: Concomitant use with VIMOVO is contraindicated [see Contraindications (4)]. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with VIMOVO. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information of specific drugs. Cilostazol Clinical Impact: Increased exposure of cilostazol and one of its active metabolites (3,4­ dihydro-cilostazol) when coadministered with omeprazole magnesium, the racemate of esomeprazole [see Clinical Pharmacology (12.3)]. Intervention: Consider reducing the dose of cilostazol to 50 mg twice daily. Digoxin Clinical Impact: Naproxen • The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Esomeprazole Magnesium • Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)]. Intervention: Monitor digoxin concentrations during concomitant use of VIMOVO. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. Lithium Clinical Impact: NSAIDs have produced elevations of plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of VIMOVO and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Naproxen • Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Esomeprazole Magnesium • Concomitant use of esomeprazole magnesium with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities [see Warnings and Precautions (5.27)]. Reference ID: 5482809 Intervention: During concomitant use of VIMOVO and methotrexate, monitor patients for methotrexate toxicity. A temporary withdrawal of VIMOVO may be considered in some patients receiving high-dose methotrexate. Cyclosporine Clinical Impact: Concomitant use of naproxen and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of VIMOVO and cyclosporine, monitor patients for signs of worsening renal function. Tacrolimus Clinical Impact: Concomitant use of esomeprazole magnesium and tacrolimus may increase exposure of tacrolimus Intervention: During concomitant use of VIMOVO and tacrolimus, monitor tacrolimus whole blood concentrations. NSAIDs and Salicylates Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of VIMOVO with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of VIMOVO and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of VIMOVO and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, mycophenoloate mofetil, ketoconazole) Clinical Impact: Esomeprazole magnesium can reduce the absorption of other drugs due to its effect on reducing intragastric acidity Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole magnesium is an enantiomer, in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving esomeprazole and MMF. Use VIMOVO with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.26), Clinical Pharmacology (12.2)]. Intervention: Temporarily stop VIMOVO treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. Diazepam Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology (12.3)]. Reference ID: 5482809 Intervention: Monitor patients for increased sedation and adjust the dose of diazepam as needed. Table 4: Clinically Significant Interactions with Esomeprazole Magnesium -- Affecting Co- Administered Drugs CYP2C19 or CYP3A4 Inducers Clinical Impact: Decreased exposure of esomeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)]. Intervention: St. John’s Wort, rifampin: Avoid concomitant use with VIMOVO [see Warnings and Precautions (5.25)]. CYP2C19 or CYP3A4 Inhibitors Clinical Impact: Increased exposure of esomeprazole [see Clinical Pharmacology (12.3)]. Intervention: Voriconazole: Avoid concomitant use with VIMOVO. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including VIMOVO, can cause premature closure of the fetal ductus arteriosus and fetal and renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of VIMOVO use between about 20 and 30 weeks of gestation and avoid VIMOVO use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of the Fetal Ductus Arteriosus Use of NSAIDs, including VIMOVO, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. VIMOVO contains naproxen and esomeprazole magnesium. Esomeprazole is the S- isomer of omeprazole. Naproxen Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, naproxen administered during organogenesis to rats and rabbits at doses less than the maximum recommended human daily dose of 1500 mg/day showed no evidence of harm to the fetus (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Esomeprazole There are no human data for esomeprazole. However, available epidemiologic data for omeprazole (esomeprazole is the S-isomer of omeprazole) fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use (see Data). In animal studies with administration of oral esomeprazole magnesium in rats, changes in bone morphology were observed in offspring of rats dosed Reference ID: 5482809 through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data]. The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including VIMOVO, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If VIMOVO treatment is needed in pregnant women, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue VIMOVO and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of VIMOVO during labor or delivery. In animal studies, NSAIDs, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Naproxen When used to delay preterm labor, inhibitors of prostaglandin synthesis, including NSAIDs such naproxen, may increase the risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable Reference ID: 5482809 estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Esomeprazole Esomeprazole is the S-isomer of omeprazole. Four epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls. A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995-99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 1996­ 2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data There are no reproduction studies in animals with VIMOVO, a combination of naproxen and esomeprazole. Naproxen Reproduction studies with naproxen administered during the period of organogenesis have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison) rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.56 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of harm to the fetus due to the drug. Esomeprazole No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral Reference ID: 5482809 human dose of 40 mg on a body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis) administered during organogenesis and have revealed no evidence of harm to the fetus due to esomeprazole magnesium. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development were performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times a daily human dose of 40 mg on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg /kg/day (about 17 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times a daily human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times the daily human dose of 40 mg on a body surface area basis). Effects on maternal bone were observed in pregnant and lactating rats in the pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg /kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age. 8.2 Lactation Risk Summary Limited data from published literature report that naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. Esomeprazole is the S-isomer of omeprazole and limited data from published literature suggest omeprazole may be present in human milk. There is no information on the effects of naproxen or omeprazole on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VIMOVO and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including VIMOVO, may delay or prevent rupture of ovarian follicles that may lead to reversible infertility in some women. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Published animal studies have shown that administration of prostaglandin synthesis inhibitors have the potential to disrupt prostaglandin-mediated follicular rupture required for Reference ID: 5482809 ovulation. Consider withdrawal of NSAIDs, including VIMOVO, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of VIMOVO have been established in adolescent patients 12 years of age and older weighing at least 38 kg for the symptomatic relief of JIA and to decrease the risk of developing naproxen-associated gastric ulcers. Use of VIMOVO in this age group is based on extrapolation of adequate and well-controlled studies in adults and supported by a 6 month safety study including pharmacokinetic assessment of naproxen and esomeprazole magnesium in 36 adolescent patients with JIA. Based on the limited data, the plasma naproxen and plasma esomeprazole concentrations were found to be within the range to that observed to those found in healthy adults. The safety profile of VIMOVO in adolescent patients with JIA was similar to adults with RA. The safety and effectiveness of VIMOVO in pediatric patients less than 12 years of age or less than 38 kg with JIA have not been established. Juvenile Animal Data In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 68 times a daily human dose of 40 mg based on body surface area. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology (13.2)]. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. Of the total number of patients who received VIMOVO (n=1157) in clinical trials, 387 were ≥65 years of age, of which 85 patients were 75 years and over. No meaningful differences in efficacy or safety were observed between these subjects and younger subjects [see Adverse Reactions (6)]. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose [see Dosage and Administration (2), Clinical Pharmacology (12.3)]. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of NSAIDs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population [see Warnings and Precautions (5.2)]. Naproxen and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of NSAIDs [see Warnings and Precautions (5.6)]. 8.6 Hepatic Impairment VIMOVO should be avoided in patients with severe hepatic impairment because naproxen may increase the risk of renal failure or bleeding and esomeprazole doses should not exceed 20 mg daily in these patients [see Dosage and Administration (2), Warnings and Precautions (5.3), Clinical Pharmacology (12.3)]. Reference ID: 5482809 8.7 Renal Impairment Naproxen-containing products, including VIMOVO, are not recommended for use in patients with advanced renal disease [see Dosage and Administration (2), Warnings and Precautions (5.6)]. 10 OVERDOSAGE There is no clinical data on overdosage with VIMOVO. Overdosage of naproxen: Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. A few patients have experienced seizures, but it is not clear whether or not these were drug- related. It is not known what dose of the drug would be life threatening. The oral LD50 of the drug is 500 mg/kg in rats, 1200 mg/kg in mice, 4000 mg/kg in hamsters and greater than 1000 mg/kg in dogs. In animals 0.5 g/kg of activated charcoal was effective in reducing plasma levels of naproxen. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. Overdosage of esomeprazole: A single oral dose of esomeprazole at 510 mg/kg (about 124 times the human dose on a body surface area basis) was lethal to rats. The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia, and intermittent clonic convulsions. The symptoms described in connection with deliberate esomeprazole overdose (limited experience of doses in excess of 240 mg/day) are transient. Single doses of 80 mg of esomeprazole were uneventful. Reports of overdosage with omeprazole in humans may also be relevant. Doses ranged up to 2,400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience (see omeprazole package insert - Adverse Reactions). No specific antidote for esomeprazole is known. Since esomeprazole is extensively protein bound, it is not expected to be removed by dialysis. In the event of overdosage, treatment should be symptomatic and supportive. If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage. 11 DESCRIPTION The active ingredients of VIMOVO are naproxen which is an NSAID and esomeprazole magnesium which is a Proton Pump Inhibitor (PPI). VIMOVO (naproxen and esomeprazole magnesium) is combination of a nonsteroidal anti- inflammatory drug and a PPI available as an oval, yellow, multi-layer, delayed-release tablet combining an enteric-coated naproxen core and an immediate-release esomeprazole magnesium layer surrounding the core. Reference ID: 5482809 Each strength contains either 375 mg of naproxen and 20 mg of esomeprazole (equivalent to 22.3 mg esomeprazole magnesium trihydrate) or 500 mg of naproxen and 20 mg of esomeprazole (equivalent to 22.3 mg esomeprazole magnesium trihydrate) for oral administration. The inactive ingredients are carnauba wax, colloidal silicon dioxide, croscarmellose sodium, iron oxide yellow, glyceryl monostearate, hypromellose, iron oxide black, magnesium stearate, methacrylic acid copolymer dispersion, methylparaben, polysorbate 80, polydextrose, polyethylene glycol, povidone, propylene glycol, propylparaben, titanium dioxide, and triethyl citrate. The chemical name for naproxen is (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid. Naproxen has the following structure: 3 H CH O OH O H3C Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. Naproxen is an odorless, white to off-white crystalline substance. It is lipid soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. The chemical name for esomeprazole is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2­ pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl) magnesium trihydrate. Esomeprazole is the S- isomer of omeprazole, which is a mixture of the S- and R- isomers. Its molecular formula is (C17H18N3O3S)2Mg x 3 H2O with molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis. The structural formula is: 3 H2O CH2 N OCH3 CH3 H3C O OCH3 S N N _ 2 . Mg2+ The magnesium salt is a white to slightly colored crystalline powder. It contains 3 moles of water of solvation and is slightly soluble in water. The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions. At pH 6.8 (buffer), the half-life of the magnesium salt is about 19 hours at 25°C and about 8 hours at 37°C. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action VIMOVO consists of an immediate-release esomeprazole magnesium layer and an enteric-coated naproxen core. As a result, esomeprazole is released first in the stomach, prior to the dissolution of naproxen in the small intestine. The enteric coating prevents naproxen release at pH levels below 5.5. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but inhibition of cyclooxygenase (COX-1 and COX-2). VIMOVO has analgesic, anti-inflammatory, and antipyretic properties contributed by the naproxen component. Naproxen is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal Reference ID: 5482809 models. Prostaglandins are mediators of inflammation. Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to an increase of prostaglandins in peripheral tissues. Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H+/K+-ATPase in the gastric parietal cell. Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion. 12.2 Pharmacodynamics Interaction with Aspirin In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once- daily with low-dose immediate-release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B2 inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%]. Following administration of naproxen 220 mg twice-daily with low-dose immediate-release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%] [see Drug Interactions (7)]. Antisecretory Activity The effect of VIMOVO on intragastric pH was determined in 25 healthy volunteers in one study. Three VIMOVO combinations (naproxen 500 mg combined with either esomeprazole 10, 20, or 30 mg) were administered twice daily over 9 days. The results are shown in the following table: Table 5: Effect on Intragastric pH on Day 9 (N=25) Naproxen 500 mg combined with esomeprazole 10 mg 20 mg 30 mg % Time Gastric 41.1 71.5 (3.0) 76.8 (3.0) pH >4† (3.0) Coefficient of 55% 18% 16% variation † Gastric pH was measured over a 24-hour period LS Mean (SE) Reference ID: 5482809 Serum Gastrin Effects The effect of esomeprazole on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 patients for up to 6-12 months. The mean fasting gastrin level increased in a dose-related manner. This increase reached a plateau within two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy. Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop esomeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. Enterochromaffin-like (ECL) Cell Effects In over 1,000 patients treated with esomeprazole (10, 20 or 40 mg/day) up to 6-12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa. Endocrine Effects Esomeprazole had no effect on thyroid function when given in oral doses of 20 or 40 mg for 4 weeks. Other effects of esomeprazole on the endocrine system were assessed using omeprazole studies. Omeprazole given in oral doses of 30 or 40 mg for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. Effects on Gastrointestinal Microbial Ecology Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalized patients, possibly also Clostridium difficile. 12.3 Pharmacokinetics Absorption Naproxen At steady state following administration of VIMOVO twice daily, peak plasma concentrations of naproxen are reached on average 3 hours following both the morning and the evening dose. Bioequivalence between VIMOVO and enteric-coated naproxen, based on both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of naproxen, has been demonstrated for both the 375 mg and 500 mg doses. Naproxen is absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. Steady-state levels of naproxen are reached in 4 to 5 days. Esomeprazole Following administration of VIMOVO twice daily, esomeprazole is rapidly absorbed with peak plasma concentration reached within on average, 0.43 to 1.2 hours, following the morning and evening dose on both the first day of administration and at steady state. The peak plasma concentrations of esomeprazole are higher at steady state compared to on first day of dosing of VIMOVO. Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of VIMOVO 500 mg/20 mg. Reference ID: 5482809 400 100 = 80 = 300 = .: ('d = i .: ('d .., 60 is = ~ ., - = .., ...:i .., t 200 el .§ ~ .., bJI = s 8 -=, '" ('d 40 ~ ... ~ = 15. = ('d = 100 z "' L,.J 20 0 0 0 4 8 12 16 20 24 Time (hours) ----0- Isornep razole ----- Naproxen Figure 1: Mean plasma concentrations of naproxen and esomeprazole following single dose administration of VIMOVO (500mg/20 mg) Food Effect Administration of VIMOVO together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs tmax by 10 hours and decreases peak plasma concentration (Cmax) by about 12%. Administration of VIMOVO together with high-fat food in healthy volunteers delays tmax of esomeprazole by 1 hour and significantly reduces the extent of absorption, resulting in 52% and 75% reductions of area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax), respectively. Administration of VIMOVO 30 minutes before high-fat food intake in healthy volunteers does not affect the extent of absorption of naproxen but delays the absorption by about 4 hours and decreases peak plasma concentration (Cmax) by about 17%, but has no significant effect on the rate or extent of esomeprazole absorption compared to administration under fasted conditions [see Dosage and Administration (2)]. Administration of VIMOVO 60 minutes before high-fat food intake in healthy volunteers has no effect on the rate and extent of naproxen absorption; however, increases the esomeprazole AUC by 25% and Cmax by 50% compared to administration under fasted conditions. This increase in esomeprazole Cmax does not raise a safety issue since the approved dosing regimen of esomeprazole at 40 mg QD would result in higher Cmax [see Dosage and Administration (2)]. Therefore, VIMOVO should be taken at least 30 minutes before the meal. Distribution Naproxen Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma [see Use in Specific Populations (8.2)]. Reference ID: 5482809 Esomeprazole The apparent volume of distribution at steady state in healthy subjects is approximately 16L. Esomeprazole is 97% plasma protein bound. Elimination Metabolism Naproxen Naproxen is extensively metabolized in the liver by the cytochrome P450 system (CYP), CYP2C9 and CYP1A2, to 6-0-desmethyl naproxen. Neither the parent drug nor the metabolites induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Consistent with the half- life of naproxen, the area under the plasma concentration time curve increases with repeated dosing of VIMOVO twice daily. Esomeprazole Esomeprazole is extensively metabolized in the liver by the CYP enzyme system. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxyl- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. The major metabolites of esomeprazole have no effect on gastric acid secretion. The area under the plasma esomeprazole concentration-time curve increases with repeated administration of VIMOVO. This increase is dose-dependent and results in a non-linear dose- AUC relationship after repeated administration. An increased absorption of esomeprazole with repeated administration of VIMOVO probably also contributes to the time-and dose-dependency. Excretion Naproxen Following administration of VIMOVO twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing. The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure, metabolites may accumulate [see Warnings and Precautions (5.6)]. Esomeprazole Following administration of VIMOVO twice daily, the mean elimination half-life of esomeprazole is approximately 1 hour following both the morning and evening dose on day 1, with a slightly longer elimination half-life at steady state (1.2-1.5 hours). Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine. Specific Populations Geriatric Patients There is no specific data on the pharmacokinetics of VIMOVO in patients over age 65. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an Reference ID: 5482809 increase in the rate of adverse events per a given dosage in some elderly patients [see Adverse Reactions (6) and Use in Specific Populations (8.5)]. The AUC and Cmax values of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment for the esomeprazole component based on age is not necessary. Male and Female Patients The AUC and Cmax values of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary. Racial or Ethnic Groups Pharmacokinetic differences due to race have not been studied for naproxen. Approximately 3% of Caucasians and 15 to 20% of Asians lack a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers). Patients with Renal Impairment The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with renal impairment. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal impairment. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen­ containing products, including VIMOVO, is not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min) [see Dosage and Administration (2), Warnings and Precautions (5.6), Use in Specific Populations (8.7)]. No studies have been performed with esomeprazole in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function. Patients with Hepatic Impairment The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with hepatic impairment. In patients with severe hepatic impairment, VIMOVO should be avoided due to increase of risk of NSAID associated bleeding and/or renal failure associated with naproxen. Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for the naproxen component of VIMOVO dosing is unknown but it is prudent to use the lowest effective dose. The AUCs of esomeprazole in patients with severe hepatic impairment (Child Pugh Class C) have been shown to be 2-3 times higher than in patients with normal liver function. For this reason, it has been recommended that esomeprazole doses not exceed 20 mg daily in patients with severe hepatic impairment. However, there is no dose adjustment necessary for patients with Child Pugh Class A and B for the esomeprazole component of VIMOVO. There is no VIMOVO dosage form that contains less than 20 mg esomeprazole for twice daily dosing [see Dosage and Administration (2), Warnings and Precautions (5.3)]. Reference ID: 5482809 Drug Interaction Studies Effect of Naproxen on Other Drugs Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Effect of Esomeprazole on Other Drugs Cytochrome P 450 Interactions Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin. Clopidogrel: Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. once daily) when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite [see Warnings and Precautions (5.22), Drug Interactions (7)]. Mycophenolate Mofetil: Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of MPA [see Drug Interactions (7)]. Cilostazol: Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. Cmax and AUC of one of its active metabolites, 3,4­ dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively [see Drug Interactions (7)]. Nelfinavir: Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg once a day), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and main oxidative metabolite, hydroxy-t-butylamide (M8) [see Drug Interactions (7)]. Atazanavir: Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95% [see Drug Interactions (7)]. Saquinavir: Elevated serum levels have been reported with an increase in AUC by 82% in Cmax by 75% and in Cmin by 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice a day for 15 days with omeprazole 40 mg once a day co-administered on days 11 to 15 [see Drug Interactions (7)]. Diazepam: Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam [see Drug Interactions (7)]. Digoxin: Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects) [see Drug Interactions (7)]. Effect of Other Drugs on Esomeprazole Reference ID: 5482809 Because esomeprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of esomeprazole. St. John’s Wort: In a cross-over study in 12 healthy male subjects, St. John’s Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (Cmax and AUC decreased by 49.6% and 43.9%, respectively) [see Warnings and Precautions (5.25), Drug Interactions (7)]. Voriconazole: Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state Cmax and AUC0-24 of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole [see Drug Interactions (7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Naproxen A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose of 1500 mg/day based on a body surface area comparison). The maximum dose used was 0.28 times the highest recommended human dose. No evidence of tumorigenicity was found. Esomeprazole The carcinogenic potential of esomeprazole was assessed using omeprazole studies, of which esomeprazole is an enantiomer. In two 24-month oral carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44 and 140.8 mg/kg/day (about 0.41 to 34.2 times the human dose of 40 mg/day expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 3.36 times the human dose of 40 mg/day on a body surface area basis) for 1 year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of 1 year (94% treated vs 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for 2 years. For this strain of rat, no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. Mutagenesis Esomeprazole was negative in the Ames mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. Esomeprazole, however, was positive in the in vitro human lymphocyte chromosome aberration test. Omeprazole was positive in the in vitro human lymphocyte chromosome aberration test, the in vivo mouse bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. Impairment of Fertility The potential effects of esomeprazole on fertility and reproductive performance were assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 33.6 times the human dose of 40 mg/day on a body surface area basis) was found to have no effect on reproductive performance of parental animals. Reference ID: 5482809 Studies to evaluate the impact of naproxen on male or female fertility have not been completed. 13.2 Animal Toxicology and/or Pharmacology Naproxen Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the maximum recommended human dose), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the maximum recommended human dose), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the maximum recommended human dose) with no evidence of impaired fertility or harm to the fetus due to the drug. However, animal reproduction studies are not always predictive of human response. Esomeprazole – Reproduction Studies Reproduction studies have been performed in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole [see Use in Specific Populations (8.1)]. Esomeprazole – Juvenile Animal Data A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg /kg/day (about 17 to 68 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the Reference ID: 5482809 high dose of 280 mg /kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole. 14 CLINICAL STUDIES Two randomized, multi-center, double-blind trials (Study 1 and Study 2) compared the incidence of gastric ulcer formation in 428 patients taking VIMOVO and 426 patients taking enteric-coated naproxen. Subjects were at least 18 years of age with a medical condition expected to require daily NSAID therapy for at least 6 months, and, if less than 50 years old, with a documented history of gastric or duodenal ulcer within the past 5 years. The majority of patients were female (67%), white (86%). The majority of patients were 50-69 years of age (83%). Approximately one quarter were on low-dose aspirin. Studies 1 and 2 showed that VIMOVO given as 500 mg/20 mg twice daily statistically significantly reduced the 6-month cumulative incidence of gastric ulcers compared to enteric­ coated naproxen 500 mg twice daily (see Table 6). Approximately a quarter of the patients in Studies 1 and 2 were taking concurrent low-dose aspirin (≤ 325 mg daily). The results for this subgroup analysis in patients who used aspirin were consistent with the overall findings of the study. The results at one month, three months, and six months are presented in Table 6. Table 6 – Cumulative Observed Incidence of Gastric Ulcers at 1, 3 and 6 Months Study 1 Study 2 VIMOVO N=218 number (%) EC­ naproxen N=216 number (%) VIMOVO N=210 number (%) EC­ naproxen N=210 number (%) 0-1 Month 0-3 Months 0-6 Months† 3 (1.4) 4 (1.8) 9 (4.1) 28 (13.0) 42 (19.4) 50 (23.1) 4 (1.9) 10 (4.8) 15 (7.1) 21 (10.0) 37 (17.6) 51 (24.3) † For both Studies, p < 0.001 for treatment comparisons of cumulative GU incidence at six months. In these trials, patients receiving VIMOVO had a mean duration of therapy of 152 days compared to 124 days in patients receiving enteric-coated naproxen alone. A higher proportion of patients taking EC-naproxen (12%) discontinued the study due to upper GI adverse events (including duodenal ulcers) compared to VIMOVO (4%) in both trials [see Adverse Reactions (6)]. The efficacy of VIMOVO in treating the signs and symptoms of osteoarthritis was established in two 12-week randomized, double-blind, placebo-controlled trials in patients with osteoarthritis (OA) of the knee. In these two trials, patients were allowed to remain on low-dose aspirin for cardioprophylaxis. VIMOVO was given as 500 mg/20 mg twice daily. In each trial, patients receiving VIMOVO had significantly better results compared to patients receiving placebo as measured by change from baseline of the WOMAC pain subscale and the WOMAC physical function subscale and a Patient Global Assessment Score. Reference ID: 5482809 Based on studies with enteric-coated naproxen, improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. 16 HOW SUPPLIED/STORAGE AND HANDLING VIMOVO (375 mg naproxen /20 mg esomeprazole magnesium) delayed-release tablets are oval, yellow film-coated tablets printed with 375/20 in black ink, supplied as: NDC 75987-031-04 Bottles of 60 tablets VIMOVO (500 mg naproxen /20 mg esomeprazole magnesium) delayed-release tablets are oval, yellow film-coated tablets printed with 500/20 in black ink, supplied as: NDC 75987-030-04 Bottles of 60 tablets Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Store in the original container and keep the bottle tightly closed to protect from moisture. Dispense in a tight container if package is subdivided. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients, families, or caregivers of the following before initiating therapy with VIMOVO and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop VIMOVO and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their health care provider if such symptoms occur [see Warnings and Precautions (5.5)]. Reference ID: 5482809 Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help [see Contraindications (4), Warnings and Precautions (5.7)]. Serious or Severe Skin Reactions, Including DRESS Advise patients to stop taking VIMOVO immediately if they develop any type of rash or fever and contact their health care provider as soon as possible [see Warnings and Precautions (5.9, 5.10)]. Fetal Toxicity Inform pregnant women to avoid use of VIMOVO and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closure of the fetal ductus arteriosus. If treatment with VIMOVO is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. Infertility Advise females of reproductive potential that NSAIDs, including VIMOVO, may be associated with reversible infertility [see Use in Specific Populations (8.3)]. Gastric Malignancy To return to their healthcare provider if they have gastric symptoms while taking VIMOVO or after completing treatment [see Warnings and Precautions (5.17)]. Acute Tubulointerstitial Nephritis Advise patients to report to their health care provider immediately if they experience a decrease in the amount they urinate or have blood in their urine [see Warnings and Precautions (5.18)]. Clostridium difficile-Associated Diarrhea Advise patients to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea [see Warnings and Precautions (5.19)]. Bone Fracture Advise patients to report any sign or symptom of osteoporosis (e.g., recent bone fracture, low bone density) to their health care provider [see Warnings and Precautions (5.20)]. Cutaneous and Systemic Lupus Erythematosus Advise patients to immediately call their healthcare provider any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus [see Warnings and Precautions (5.21)]. Cyanocobalamin (Vitamin B-12) Deficiency Advise patients taking VIMOVO for long periods of time, to report to their healthcare provider if they experience weakness, tiredness, or light-headedness or rapid heartbeat and breathing or pale skin [see Warnings and Precautions (5.23)]. Hypomagnesemia and Mineral Metabolism Advise patients to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, and/or hypokalemia to their healthcare provider, if they have been receiving VIMOVO for at least 3 months [see Warnings and Precautions (5.24)]. Drug Interactions • Inform patients that the concomitant use of VIMOVO with other NSAIDs or salicylates (e.g., diflunisal, salsalate) it is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.16), Drug Interactions (7)]. Alert patients that NSAIDs may be present in the “over the counter” medications for treatment of colds, fever or insomnia. • Advise patients to report to their healthcare provider if they start treatment with Reference ID: 5482809 clopidogrel, St. John’s Wort or rifampin; or, if they take high-dose methotrexate [see Warnings and Precautions (5.22, 5.25, 5.27)]. • Inform patients not to use low-dose aspirin concomitantly with VIMOVO until they talk to their health care provider [see Drug Interactions (7)]. Administration • Inform patients that VIMOVO tablets should be swallowed whole with liquid. Tablets should not be split, chewed, crushed or dissolved. VIMOVO tablets should be taken at least 30 minutes before meals [see Dosage and Administration (2)]. • Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose. • Inform patients that antacids may be used while taking VIMOVO. VIMOVO is a trademark of the AstraZeneca group of companies. The VIMOVO trademark has been licensed to Horizon for use in the US. Other trademarks are the property of AstraZeneca respective companies. Distributed by: Horizon Medicines, LLC. Deerfield, IL 60015 VIM-US-PI-005 Reference ID: 5482809 Medication Guide VIMOVO (vi-moh-voh) (naproxen and esomeprazole magnesium) delayed-release tablets What is the most important information I should know about VIMOVO? You should take VIMOVO exactly as prescribed, at the lowest dose possible and for the shortest time needed. VIMOVO may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your healthcare provider. VIMOVO contains naproxen, a nonsteroidal anti-inflammatory drug (NSAID) and esomeprazole magnesium, a proton pump inhibitor (PPI) medicine. VIMOVO can cause serious side effects including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take VIMOVO right before or after a heart surgery called a “coronary artery bypass graft (CABG).” Avoid taking VIMOVO after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” o increasing doses of NSAIDs o older age o longer use of NSAIDs o poor health o smoking o advanced liver disease o drinking alcohol o bleeding problems Talk to your healthcare provider or pharmacist before using other medicines that contain NSAIDs, including low-dose aspirin, during treatment with VIMOVO. Some NSAIDs are sold in lower doses without a prescription (over-the-counter). ● A type of kidney problem (acute tubulointerstitial nephritis). Some people who take proton pump inhibitor (PPI) medicines, including VIMOVO, may develop a kidney problem called acute tubulointerstitial nephritis that can happen at any time during treatment with VIMOVO. Call your healthcare provider right away if you have a decrease in the amount that you urinate or if you have blood in your urine. • Diarrhea caused by an infection (Clostridium difficile) in your intestines. Call your healthcare provider right away if you have watery stools or stomach pain that does not go away. You may or may not have a fever. • Bone fractures (hip, wrist, or spine). Bone fractures in the hip, wrist, or spine may happen in people who take multiple daily doses of PPI medicines and for a long period of time (a year or longer). Tell your healthcare provider if you have a bone fracture, especially in the hip, wrist, or spine. • Certain types of lupus erythematosus. Lupus erythematosus is an autoimmune disorder (the body’s immune cells attack other cells or organs in the body). Some people who take PPI medicines, including VIMOVO, may develop certain types of lupus erythematosus or have worsening of the lupus they already have. Call your healthcare provider right away if you have new or worsening joint pain or a rash on your cheeks or arms that gets worse in the sun. Talk to your healthcare provider about your risk of these serious side effects. VIMOVO can have other serious side effects. See “What are the possible side effects of VIMOVO?” What is VIMOVO? VIMOVO is a prescription medicine used in adults and adolescents, 12 years of age and older who weigh at least 84 pounds (38 kg), who need to take naproxen for relief of symptoms of arthritis and who also need to decrease the risk of developing stomach ulcers caused by naproxen. The naproxen in VIMOVO is used for the relief of signs and symptoms of: • osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis in adults • juvenile idiopathic arthritis (JIA) in adolescents The esomeprazole magnesium in VIMOVO is used to: • decrease the risk of developing stomach ulcers in people who are taking naproxen It is not known if VIMOVO is safe and effective in children less than 12 years of age or who weigh less than 84 pounds (38 kg). You should not take a naproxen tablet and an esomeprazole magnesium tablet together instead of taking VIMOVO, because they will not work the same way. Studies in people who take VIMOVO have not extended past 6 months. Do not take VIMOVO: • if you are allergic to naproxen, esomeprazole magnesium, omeprazole, any other PPI medicine, or any of the ingredients in VIMOVO. See the end of this Medication Guide for a complete list of ingredients in VIMOVO. Reference ID: 5482809 • if you have had an asthma attack, hives, or other allergic reaction after taking aspirin or any other NSAIDs. • right before or after heart bypass surgery. • if you are taking a medicine that contains rilpivirine (Edurant, Complera, Odefsey) used to treat HIV-1 (Human Immunodeficiency Virus). Before taking VIMOVO, tell your healthcare provider about all of your medical conditions, including if you: • have liver, kidney, or heart problems. • have high blood pressure. • have asthma. • have low magnesium levels, low calcium levels and low potassium levels in your blood. • have ulcerative colitis or Crohn’s disease (inflammatory bowel disease or IBD). • are pregnant or plan to become pregnant. Taking VIMOVO at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take VIMOVO for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take VIMOVO after about 30 weeks of pregnancy. • are breastfeeding or plan to breastfeed. The naproxen in VIMOVO can pass into your breast milk. It is not known if VIMOVO will harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take VIMOVO. • are a female who can become pregnant. VIMOVO may be related to infertility in some women that is reversible when treatment with VIMOVO is stopped. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VIMOVO and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. Especially tell your healthcare provider if you take: • steroid hormones (corticosteroids) • antidepressant medicine • St. John’s Wort • medicine used to reduce the risk of blood clots, such as • rifampin (Rifater, Rifamate, Rimactane, Rifadin) warfarin (Coumadin, Jantoven) • medicine for high blood pressure or heart problems • methotrexate (Otrexup, Rasuvo, Trexall, Xatmep) How should I take VIMOVO? • Take VIMOVO exactly as prescribed by your healthcare provider. • Take 1 VIMOVO tablet 2 times each day. • Take VIMOVO at least 30 minutes before a meal. • Swallow VIMOVO tablets whole with liquid. Do not split, chew, crush or dissolve VIMOVO. • You may use antacids while taking VIMOVO. • If you forget to take your dose of VIMOVO, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take the next dose on time. Do not take 2 doses at one time to make up for a missed dose. • If you take too much VIMOVO, call your healthcare provider or your poison control center at 1-800-222-1222 right away or go to the nearest emergency room. What are the possible side effects of VIMOVO? VIMOVO can cause serious side effects, including: See “What is the most important information I should know about VIMOVO?” ● liver problems, including liver failure. ● new or worsening high blood pressure. ● heart failure. ● kidney problems, including kidney failure. ● life-threatening allergic reactions. ● asthma attacks in people who have asthma. ● life-threatening skin reactions. ● low red blood cells (anemia). ● hiding (masking) symptoms of an infection, such as swelling and fever. ● Low vitamin B-12 levels in your body can happen in people who have taken VIMOVO for a long time (more than 3 years). Tell your healthcare provider if you have symptoms of low vitamin B-12 levels, including shortness of breath, lightheadedness, irregular heartbeat, muscle weakness, pale skin, feeling tired, mood changes, and tingling or numbness in the arms or legs. ● Low magnesium levels in your body can happen in people who have taken VIMOVO for at least 3 months. Tell your healthcare provider if you have symptoms of low magnesium levels, including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, and spasms of hands, feet or voice. ● Stomach growths (fundic gland polyps) People who take PPI medicines for a long time have an increased risk of developing a certain type of stomach growths called fundic gland polyps, especially after taking PPI medicines for more than 1 year. Reference ID: 5482809 • Serious or Severe skin reactions. VIMOVO can cause rare but severe skin reactions that may affect any part of your body. These serious skin reactions may need to be treated in a hospital and may be life threatening: • Skin rash which may have blistering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet). • You may also have fever, chills, body aches, shortness of breath, or enlarged lymph nodes. Stop taking VIMOVO and call your doctor right away. These symptoms may be the first sign of a severe skin reaction. The most common side effects of VIMOVO include: inflammation of the lining of the stomach and diarrhea Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking VIMOVO and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is black • diarrhea and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands, and feet • flu-like symptoms If you take too much VIMOVO, call your healthcare provider or get medical help right away. These are not all the possible side effects of VIMOVO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store VIMOVO? • Store VIMOVO at room temperature between 68ºF to 77ºF (20ºC to 25ºC). • Store VIMOVO in the original container. • Keep the bottle of VIMOVO tightly closed to protect from moisture. Keep VIMOVO and all medicines out of the reach of children. What are the ingredients in VIMOVO? Active ingredients: naproxen and esomeprazole magnesium Inactive ingredients: carnauba wax, colloidal silicon dioxide, croscarmellose sodium, iron oxide yellow, glyceryl monostearate, hypromellose, iron oxide black, magnesium stearate, methacrylic acid copolymer dispersion, methylparaben, polysorbate 80, polydextrose, polyethylene glycol, povidone, propylene glycol, propylparaben, titanium dioxide, and triethyl citrate General information about the safe and effective use of VIMOVO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VIMOVO for a condition for which it was not prescribed. Do not give VIMOVO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about VIMOVO that is written for health professionals. Distributed by: Horizon Medicines, LLC., Deerfield, IL 60015 For more information, go to www.VIMOVO.com or call 1-866-479-6742. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5482809
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2025-02-12T15:47:16.095619
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DUEXIS® safely and effectively. See full prescribing information for DUEXIS. DUEXIS (ibuprofen and famotidine) tablets, for oral use Initial U.S. Approval: 2011 WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1) • DUEXIS is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1) • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2) ---------------------------RECENT MAJOR CHANGES---------------------------­ Warnings and Precautions, Serious Skin Reactions (5.11) 11/2024 --------------------------- INDICATIONS AND USAGE---------------------------­ DUEXIS, a combination of a nonsteroidal anti-inflammatory drug (NSAID) ibuprofen and the histamine H2-receptor antagonist famotidine, is indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and to decrease the risk of developing upper gastrointestinal ulcers, which in the clinical trials was defined as a gastric and/or duodenal ulcer, in patients who are taking ibuprofen for those indications. The clinical trials primarily enrolled patients less than 65 years of age without a prior history of gastrointestinal ulcer. Controlled trials do not extend beyond 6 months. (1) -----------------------DOSAGE AND ADMINISTRATION----------------------­ • One DUEXIS tablet administered orally three times per day. (2) • Use ibuprofen at the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. (2) • Do not substitute DUEXIS with the single-ingredient products of ibuprofen and famotidine. (2) --------------------- DOSAGE FORMS AND STRENGTHS---------------------­ • DUEXIS (ibuprofen and famotidine) Tablets: 800 mg ibuprofen and 26.6 mg famotidine. (3) ------------------------------ CONTRAINDICATIONS -----------------------------­ • Known hypersensitivity to ibuprofen or famotidine or any components of the drug product. (4) • History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. (4) • In the setting of CABG surgery. (4) • Known hypersensitivity to other H2-receptor antagonists. (4) ---------------------------WARNINGS AND PRECAUTIONS--------------------­ • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (5.4) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.5, 7) • Heart Failure and Edema: Avoid use of DUEXIS in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.6) • Active Bleeding: Active and clinically significant bleeding from any source can occur; discontinue DUEXIS if active bleeding occurs. (5.3) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of DUEXIS in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. (5.7) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.8) • Exacerbation of Asthma Related to Aspirin Sensitivity: DUEXIS is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin-sensitivity). (5.10) • Serious Skin Reactions: Discontinue DUEXIS at first appearance of skin rash or other signs of hypersensitivity (5.11). • Drug Reaction with Eosinophilia and Systematic Symptoms (DRESS): Discontinue and evaluate clinically (5.12). • Fetal Toxicity: Limit use of NSAIDs, including DUEXIS, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.13, 8.1) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patient with any signs or symptoms of anemia. (5.14) ------------------------------ ADVERSE REACTIONS -----------------------------­ Most common adverse reactions (≥1% and greater than ibuprofen alone) are nausea, diarrhea, constipation, upper abdominal pain, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Horizon at (1-866-479-6742) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS------------------------------­ See full prescribing information for a list of clinically important drug interactions. (7) ----------------------- USE IN SPECIFIC POPULATIONS ----------------------­ • Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation. (5.13, 8.1) • Females and Males of Reproductive Potential: NSAIDs are associated with reversible infertility. Consider withdrawal of DUEXIS in women who have difficulties conceiving. (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation 5.3 Active Bleeding 5.4 Hepatotoxicity 5.5 Hypertension 5.6 Heart Failure and Edema 5.7 Renal Toxicity and Hyperkalemia 5.8 Anaphylactic Reactions 5.9 Seizures 5.10 Exacerbation of Asthma Related to Aspirin Sensitivity 5.11 Serious Skin Reactions 5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.13 Fetal Toxicity 5.14 Hematologic Toxicity 5.15 Masking of Inflammation and Fever 5.16 Laboratory Monitoring 5.17 Concomitant NSAID Use 5.18 Aseptic Meningitis 5.19 Ophthalmological Effects 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS Reference ID: 5482811 8.1 Pregnancy 12.2 Pharmacodynamics 8.2 Lactation 12.3 Pharmacokinetics 8.3 Females and Males of Reproductive Potential 13 NONCLINICAL TOXICOLOGY 8.4 Pediatric Use 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 8.5 Geriatric Use 14 CLINICAL STUDIES 8.6 Renal Insufficiency 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 10 OVERDOSAGE 11 DESCRIPTION *Sections or subsections omitted from the full prescribing information are not 12 CLINICAL PHARMACOLOGY listed. 12.1 Mechanism of Action Reference ID: 5482811 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. • DUEXIS is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE DUEXIS, a combination of the NSAID ibuprofen and the histamine H2-receptor antagonist famotidine, is indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and to decrease the risk of developing upper gastrointestinal ulcers, which in the clinical trials was defined as a gastric and/or duodenal ulcer, in patients who are taking ibuprofen for those indications. The clinical trials primarily enrolled patients less than 65 years of age without a prior history of gastrointestinal ulcer. Controlled trials do not extend beyond 6 months [see Clinical Studies (14), Use in Specific Populations (8.5)]. 2 DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of DUEXIS and other treatment options before deciding to use DUEXIS. Use ibuprofen at the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. The recommended daily dose of DUEXIS (ibuprofen and famotidine) 800 mg/26.6 mg is a single tablet administered orally three times per day. DUEXIS tablets should be swallowed whole, and should not be cut to supply a lower dose. Do not chew, divide, or crush tablets. Patients should be instructed that if a dose is missed, it should be taken as soon possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose. Do not substitute DUEXIS with the single-ingredient products of ibuprofen and famotidine. 3 DOSAGE FORMS AND STRENGTHS DUEXIS (ibuprofen and famotidine) tablets: 800 mg/26.6 mg, are light blue, oval, biconvex, film-coated tablets debossed with “HZT” on one side. 4 CONTRAINDICATIONS DUEXIS is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to ibuprofen or famotidine or any components of the drug product [see Warnings and Precautions (5.8, 5.11)]. Reference ID: 5482811 • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.8, 5.10)]. • In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]. • DUEXIS should not be administered to patients with a history of hypersensitivity to other H2-receptor antagonists. Cross sensitivity with other H2-receptor antagonists has been observed. 5 WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDS. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ibuprofen, increases the risk of serious gastrointestinal GI events [see Warnings and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of DUEXIS in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If DUEXIS is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including ibuprofen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDS. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Reference ID: 5482811 Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated. Strategies to Minimize the GI Risks in NSAID-treated patients: • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue DUEXIS until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)]. 5.3 Active Bleeding When active and clinically significant bleeding from any source occurs in patients receiving DUEXIS, the treatment should be withdrawn. Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically. 5.4 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including ibuprofen. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue DUEXIS immediately, and perform a clinical evaluation of the patient. 5.5 Hypertension NSAIDs, including DUEXIS, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.6 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective treated patients and nonselective Reference ID: 5482811 NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)]. Avoid the use of DUEXIS in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If DUEXIS is used in patients with severe heart failure, monitor patients for signs and symptoms of worsening heart failure. 5.7 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of DUEXIS in patients with advanced renal disease. The renal effects of DUEXIS may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating DUEXIS. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of DUEXIS [see Drug Interactions (7)]. Avoid the use of DUEXIS in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal failure. If DUEXIS is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.8 Anaphylactic Reactions Ibuprofen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to ibuprofen and in patients with aspirin-sensitive asthma [see Contraindications (4), Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.9 Seizures Central nervous system (CNS) adverse effects including seizures, delirium, and coma have been reported with famotidine in patients with moderate (creatinine clearance <50 mL/min) and severe renal insufficiency (creatinine clearance <10 mL/min), and the dosage of the famotidine component in DUEXIS is fixed. Therefore, DUEXIS is not recommended in patients with creatinine clearance < 50 mL/min. 5.10 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, DUEXIS is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When DUEXIS is used in Reference ID: 5482811 patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.11 Serious Skin Reactions NSAIDs, including ibuprofen, which is a component of DUEXIS tablets, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of DUEXIS at the first appearance of skin rash or any other sign of hypersensitivity. DUEXIS is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as DUEXIS. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue DUEXIS and evaluate the patient immediately. 5.13 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including DUEXIS, in pregnant women at about 30 weeks gestation and later. NSAIDs, including DUEXIS, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including DUEXIS, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit DUEXIS use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if DUEXIS treatment is needed for a pregnant woman. Discontinue DUEXIS if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.14 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with DUEXIS has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including DUEXIS, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, and other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase the risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.15 Masking of Inflammation and Fever The pharmacological activity of DUEXIS in reducing inflammation, and possibly fever, may diminish the utility of Reference ID: 5482811 diagnostic signs in detecting infections. 5.16 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and chemistry profile periodically [see Warnings and Precautions (5.2, 5.4, 5.7)]. 5.17 Concomitant NSAID Use DUEXIS contains ibuprofen as one of its active ingredients. It should not be used with other ibuprofen-containing products. The concomitant use of NSAIDs, including aspirin, with DUEXIS may increase the risk of adverse reactions [see Adverse Reactions (6), Drug Interactions (7), Clinical Studies (14)]. 5.18 Aseptic Meningitis Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen, which is a component of DUEXIS. Although it is probably more likely to occur in patients with systemic lupus erythematosus (SLE) and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on DUEXIS, the possibility of its being related to ibuprofen should be considered. 5.19 Ophthalmological Effects Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported. If a patient develops such complaints while receiving DUEXIS, the drug should be discontinued, and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] • GI Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.2)] • Hepatotoxicity [see Warnings and Precautions (5.4)] • Hypertension [see Warnings and Precautions (5.5)] • Heart Failure and Edema [see Warnings and Precautions (5.6)] • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.7)] • Anaphylactic Reactions [see Warnings and Precautions (5. 8)] • Seizures [see Warnings and Precautions (5.9)] • Serious Skin Reactions [see Warnings and Precautions (5.11)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.12)] • Fetal Toxicity [see Warnings and Precautions (5.13)] • Hematologic Toxicity [see Warnings and Precautions (5.14)] • Aseptic Meningitis [see Warnings and Precautions (5.18)] • Ophthalmological Effects [see Warnings and Precautions (5.19)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of DUEXIS was evaluated in 1022 patients in controlled clinical studies, including 508 patients treated for at least 6 months and 107 patients treated for approximately 1 year. Patients treated with DUEXIS ranged in age from 39 to 80 years (median age 55 years), with 67% female, 79% Caucasian, 18% African-American, and 3% other races. Two randomized, active-controlled clinical studies (Study 301 and Study 303) were conducted for the reduction of the risk of Reference ID: 5482811 development of ibuprofen-associated, upper gastrointestinal ulcers in patients who required use of ibuprofen, which included 1022 patients on DUEXIS and 511 patients on ibuprofen alone. Approximately 15% of patients were on low- dose aspirin. Patients were assigned randomly, in a 2:1 ratio, to treatment with either DUEXIS or ibuprofen 800 mg three times a day for 24 consecutive weeks. Three serious cases of acute renal failure were observed in patients treated with DUEXIS in the two controlled clinical trials. All three patients recovered to baseline levels after discontinuation of DUEXIS. Additionally, increases in serum creatinine were observed in both treatment arms in the two clinical studies. Many of these patients were taking concomitant diuretics and/or angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers. There were patients with a normal baseline serum creatinine level who developed abnormal values in the controlled trials as presented in Table 1. Table 1: Shift Table of Serum Creatinine, Normal** to Abnormal*** in Controlled Studies Study 301 Study 303 Baseline Post-Baseline* DUEXIS N=414 % (n) Ibuprofen N=207 % (n) DUEXIS N=598 % (n) Ibuprofen N=296 % (n) Normal** Abnormal*** 4% (17) 2% (4) 2%(15) 4% (12) * At any point after baseline level ** serum creatinine normal range is 0.5 – 1.4 mg/dL or 44-124 micromol/L *** serum creatinine >1.4 mg/dL Most Commonly Reported Adverse Reactions The most common adverse reactions (≥2%), from pooled data from the two controlled studies are presented in Table 2. Reference ID: 5482811 Table 2: Incidence of Adverse Reactions in Controlled Studies DUEXIS N=1022 Ibuprofen N=511 % % Blood and lymphatic system disorders Anemia 2 1 Gastrointestinal disorders Nausea 6 5 Dyspepsia 5 8 Diarrhea 5 4 Constipation 4 4 Abdominal pain upper 3 3 Gastroesophageal reflux disease 2 3 Vomiting 2 2 Stomach discomfort 2 2 Abdominal pain 2 2 General disorders and administration site conditions Edema peripheral 2 2 Infections and infestations Upper respiratory tract infection 4 4 Nasopharyngitis 2 3 Sinusitis 2 3 Bronchitis 2 1 Urinary tract infection 2 2 Influenza 2 2 Musculoskeletal and connective tissue disorders Arthralgia 1 2 Back pain 2 1 Nervous system disorders Headache 3 3 Respiratory, thoracic and mediastinal disorders Cough 2 2 Pharyngolaryngeal pain 2 1 Vascular disorders Hypertension 3 2 In controlled clinical studies, the discontinuation rate due to adverse events for patients receiving DUEXIS and ibuprofen alone were similar. The most common adverse reactions leading to discontinuation from DUEXIS therapy were nausea (0.9%) and upper abdominal pain (0.9%). There were no differences in types of related adverse reactions seen during maintenance treatment up to 12 months compared to short-term treatment. Reference ID: 5482811 6.2 Postmarketing Experience Ibuprofen The following adverse reactions have been identified during post-approval use of ibuprofen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system: Cardiac disorders: myocardial infarction Gastrointestinal disorders: nausea, vomiting, diarrhea, abdominal pain General disorders and administration site conditions: pyrexia, pain, fatigue, asthenia, chest pain, drug ineffective, edema peripheral Skin and Appendages: exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE) Musculoskeletal and connective tissue disorders: arthralgia Nervous system disorders: headache, dizziness Psychiatric disorders: depression, anxiety Renal and urinary disorders: renal failure acute Respiratory, thoracic, and mediastinal disorders: dyspnea Vascular disorders: hypertension Famotidine The following adverse reactions have been identified during post-approval use of famotidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system: Blood and lymphatic system disorders: anemia, thrombocytopenia Gastrointestinal disorders: nausea, diarrhea, vomiting, abdominal pain General disorders and administration site conditions: pyrexia, condition aggravated, asthenia, drug ineffective, chest pain, fatigue, pain, edema peripheral Hepatobiliary disorders: hepatic function abnormal Infections and infestations: pneumonia, sepsis Investigations: platelet count decreased, aspartate aminotransferase increased, alanine aminotransferase increased, hemoglobin decreased Metabolism and nutrition disorders: decreased appetite Nervous system disorders: dizziness, headache Respiratory, thoracic, and mediastinal disorders: dyspnea Vascular disorders: hypotension 7 DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with ibuprofen. Reference ID: 5482811 Table 3: Clinically Significant Drug Interactions with Ibuprofen and Famotidine Drugs That Interfere with Hemostasis Clinical Impact: • Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of DUEXIS with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.16)]. Aspirin Clinical Impact: Pharmacodynamic (PD) studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg, given three times daily, is administered with enteric-coated low-dose aspirin. The interaction exists even following a once-daily regimen of ibuprofen 400 mg, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once-daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin [see Clinical Pharmacology (12.2)]. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention: Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, where appropriate. Concomitant use of DUEXIS and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.3)]. DUEXIS is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers Clinical Impact: • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Reference ID: 5482811 Intervention: • During concomitant use of DUEXIS and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of DUEXIS and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.7)]. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of DUEXIS with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.7)]. Digoxin Clinical Impact: The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of DUEXIS and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations of plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of DUEXIS and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of DUEXIS and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of ibuprofen and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of DUEXIS and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of DUEXIS with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of ibuprofen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Reference ID: 5482811 Intervention: During concomitant use of DUEXIS and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between permetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Drugs Dependent on Gastric pH for Absorption Clinical Impact Because famotidine lowers intra-gastric acidity, this may result in reduced absorption and loss of efficacy of concomitant drugs. Intervention Concomitant administration of DUEXIS is not recommended with dasatinib, delavirdine mesylate, cefditoren, and fosamprenavir. For administration instructions of other drugs whose absorption is dependent on gastric pH, refer to their prescribing information (e.g., atazanavir, erlotinib, ketoconazole, itraconazole, nilotinib, ledipasvir/sofosbuvir, and rilpivirine). Tizanidine (CYP1A2 Substrate) Clinical Impact Famotidine is considered a weak CYP1A2 inhibitor and may lead to substantial increases in blood concentrations of tizanidine, a CYP1A2 substrate. Intervention Avoid concomitant use with DUEXIS. If concomitant use is necessary, monitor for hypotension, bradycardia or excessive drowsiness. Refer to the full prescribing information for tizanidine. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including DUEXIS, can cause premature closure of the the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of DUEXIS use between about 20 and 30 weeks of gestation and avoid DUEXIS use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including DUEXIS, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. There are no available data with DUEXIS use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage; however, there are published studies with each individual component of DUEXIS. Ibuprofen Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second Reference ID: 5482811 trimesters of pregnancy are inconclusive. In animal reproduction studies, there were no clear developmental effects at doses up to 0.4- times the maximum recommended human dose (MRHD) in the rabbit and 0.5-times in the MRHD rat when dosed throughout gestation. In contrast, an increase in membranous ventricular septal defects was reported in rats treated on Gestation Days 9 & 10 with 0.8-times the MRHD. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post- implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Famotidine Limited published data do not report an increased risk of congenital malformations or other adverse pregnancy effects with use of H2- receptor antagonists, including DUEXIS, during pregnancy; however, these data are insufficient to adequately determine a drug-associated risk. Reproductive studies with famotidine have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day (approximately 243 and 122 times the recommended human dose, respectively, based on body surface area) and in both species at intravenous (I.V.) doses of up to 200 mg/kg/day, and have revealed no significant evidence of impaired fertility or harm to the fetus due to famotidine. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15­ 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including DUEXIS, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If DUEXIS treatment is needed for a pregnant woman, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue DUEXIS and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of DUEXIS during labor or delivery. In animal studies, NSAIDs, including ibuprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data When used to delay preterm labor, inhibitors of prostaglandin synthesis, including NSAIDs such ibuprofen, may increase the risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Ibuprofen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Ibuprofen Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports Reference ID: 5482811 of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. When used to delay preterm labor, inhibitors of prostaglandin synthesis, including NSAIDs such as ibuprofen, may increase the risk of other neonatal complications such as necrotizing enterocolitis and intracranial hemorrhage. Ibuprofen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Animal Data Animal reproduction studies have not been conducted with DUEXIS. Ibuprofen In a published study, female rabbits given 7.5, 20, or 60 mg/kg ibuprofen (0.04, 0.12, or 0.36-times the maximum recommended human daily dose of 3200 mg of ibuprofen based on body surface area) from Gestation Days 1 to 29, no clear treatment-related adverse developmental effects were noted. Doses of 20 and 60 mg/kg were associated with significant maternal toxicity (stomach ulcers, gastric lesions). In the same publication, female rats were administered 7.5, 20, 60, 180 mg/kg ibuprofen (0.02, 0.06, 0.18, 0.54-times the maximum daily dose) did not result in clear adverse developmental effects. Maternal toxicity (gastrointestinal lesions) was noted at 20 mg/kg and above. In a published study, rats were orally dosed with 300 mg/kg ibuprofen (0.912-times the maximum human daily dose of 3200 mg based on body surface area) during Gestation Days 9 and 10 (critical time points for heart development in rats). Ibuprofen treatment resulted in an increase in the incidence of membranous ventricular septal defects. This dose was associated with significant maternal toxicity including gastrointestinal toxicity. One incidence each of a membranous ventricular septal defect and gastroschisis was noted in fetuses from rabbits treated with 500 mg/kg (3-times the maximum human daily dose) from Gestation Day 9-11. Famotidine Reproductive studies with famotidine have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day (approximately 243 and 122 times the recommended human dose of 80 mg per day, respectively, based on body surface area) and in both species at intravenous doses of up to 200 mg/kg/day (about 24 and 49 times the recommended human dose of 80 mg per day, respectively, based on body surface area), and have revealed no significant evidence of harm to the fetus due to famotidine. While no direct fetotoxic effects have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral doses of 200 mg/kg/day (approximately 49 times the recommended human dose of 80 mg per day, respectively, based on body surface area) or higher. Animal reproduction studies are not always predictive of human response. 8.2 Lactation Risk Summary No studies have been conducted with the use of DUEXIS in lactating women. Limited data from published literature report famotidine is present in human milk in low amounts. Published literature also reports the presence of ibuprofen in human milk in low amounts. No information is available on the effects of famotidine or ibuprofen on milk production or on a breastfed infant. Famotidine is present in the milk of lactating rats (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DUEXIS and any potential adverse effects on the breastfed infant from DUEXIS or from the underlying maternal condition. Data Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 300 times the usual human dose of famotidine. Reference ID: 5482811 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including DUEXIS, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin­ mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including DUEXIS, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness of DUEXIS in pediatric patients have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.4, 5.7, 5.16)]. The clinical trials primarily enrolled patients less than 65 years of age. Of the 1022 patients in clinical studies of DUEXIS, 18% (249 patients) were 65 years of age or older. Efficacy results in patients who are greater than or equal to 65 years of age are summarized in the CLINICAL STUDIES section [see Clinical Studies (14)]. Famotidine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and adjusting dose interval, and it may be useful to monitor renal function [see Warnings and Precautions (5.7)]. 8.6 Renal Insufficiency In adult patients with renal insufficiency (creatinine clearance < 50 mL/min), the elimination half-life of famotidine is increased. Since CNS adverse effects have been reported in patients with creatinine clearance < 50 mL/min and the dosage of the famotidine component in DUEXIS is fixed, DUEXIS is not recommended in these patients [see Warnings and Precautions (5.7)]. 10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.5, 5.7, 5.9)]. No data are available with regard to overdose of DUEXIS. Findings related to the individual active substances are listed below. Ibuprofen Approximately 1 1/2 hours after the reported ingestion of from 7 to 10 ibuprofen tablets (400 mg), a 19-month-old child weighing 12 kg was seen in the hospital emergency room, apneic and cyanotic, responding only to painful stimuli. This type of stimulus, however, was sufficient to induce respiration. Oxygen and parenteral fluids were given; a greenish- yellow fluid was aspirated from the stomach with no evidence to indicate the presence of ibuprofen. Two hours after ingestion the child's condition seemed stable; she still responded only to painful stimuli and continued to have periods of apnea lasting from 5 to 10 seconds. She was admitted to intensive care and sodium bicarbonate was administered as well as infusions of dextrose and normal saline. By 4 hours post-ingestion she could be aroused easily, sit by herself, and respond to spoken commands. Blood level of ibuprofen was 102.9 μg/mL approximately 8.5 hours after accidental ingestion. At 12 hours she appeared to be completely recovered. In two other reported cases where children (each weighing approximately 10 kg) accidentally, acutely ingested Reference ID: 5482811 approximately 120 mg/kg, there were no signs of acute intoxication or late sequelae. Blood level in one child 90 minutes after ingestion was 700 μg/mL — about 10 times the peak levels seen in absorption-excretion studies. A 19-year-old male who had taken 8,000 mg of ibuprofen over a period of a few hours complained of dizziness, and nystagmus was noted. After hospitalization, parenteral hydration and 3 days bed rest, he recovered with no reported sequelae. Famotidine The adverse reactions in overdose cases are similar to the adverse reactions encountered in normal clinical experience. Oral doses of up to 640 mg/day have been given to adult patients with pathological hypersecretory conditions with no serious adverse effects. Manage patients with symptomatic and supportive care following an NSAID overdosage, including DUEXIUS overdose. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. If over-exposure occurs, call your poison control center at 1-800-222-1222 for current information on the management of poisoning or over-exposure. 11 DESCRIPTION DUEXIS (ibuprofen and famotidine) is supplied as a tablet for oral administration which combines the nonsteroidal anti- inflammatory drug, ibuprofen, and the histamine H2-receptor antagonist, famotidine. Ibuprofen is (±)-2-(p-isobutylphenyl)propionic acid. Its chemical formula is C13H18O2 and molecular weight is 206.28. Ibuprofen is a white powder that is very slightly soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone. Its structural formula is: Famotidine is N'-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide. Its chemical formula is C8H15N7O2S3 and molecular weight is 337.45. Famotidine is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol. Its structural formula is: Each DUEXIS tablet contains ibuprofen, USP (800 mg) and famotidine, USP (26.6 mg). The inactive ingredients in DUEXIS include: microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, purified water, povidone, titanium dioxide, polyethylene glycol, polysorbate 80, polyvinyl alcohol, hypromellose, talc, FD&C Blue #2/Indigo Carmine Aluminum Lake, and FD&C Blue #1/Brilliant Blue FCF Aluminum Lake. Reference ID: 5482811 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action DUEXIS is a fixed-combination tablet of ibuprofen and famotidine. The ibuprofen component has analgesic, anti- inflammatory, and antipyretic properties. The mechanism of action of the ibuprofen component of DUEXIS, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Ibuprofen is a potent inhibitor of prostaglandin synthesis in vitro. Ibuprofen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because ibuprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to an increase of prostaglandins in peripheral tissues. Famotidine is a competitive inhibitor of histamine H2-receptors. The primary clinically important pharmacologic activity of famotidine is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion are suppressed by famotidine, while changes in pepsin secretion are proportional to volume output. Systemic effects of famotidine in the CNS, cardiovascular, respiratory, or endocrine systems were not noted in clinical pharmacology studies. Also, no antiandrogenic effects were noted. Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with famotidine. 12.2 Pharmacodynamics In a healthy volunteer study, ibuprofen 400 mg given once daily, administered 2 hours prior to immediate-release aspirin (81 mg) for 6 days, showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B2 (TxB2) inhibition at 24 hours following the day-6 aspirin dose [53%]. An interaction was still observed, but minimized, when ibuprofen 400 mg given once-daily was administered as early as 8 hours prior to the immediate-release aspirin dose [90.7%]. However, there was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg, given once daily, was administered 2 hours after (but not concomitantly, 15 min, or 30 min after) the immediate-release aspirin dose [99.2%]. In another study, where immediate-release aspirin 81 mg was administered once daily with ibuprofen 400 mg given three times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, the mean % serum thromboxane B2 (TxB2) inhibition suggested no interaction with the antiplatelet activity of aspirin [98.3%]. However, there were individual subjects with serum TxB2 inhibition below 95%, with the lowest being 90.2%. When a similarly designed study was conducted with enteric-coated aspirin, where healthy subjects were administered enteric-coated aspirin 81 mg once daily for 6 days and ibuprofen 400 mg three times daily (2, 7, and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours following the day-6 aspirin dose [67%] [see Drug Interactions (7)]. 12.3 Pharmacokinetics Absorption Ibuprofen and famotidine are rapidly absorbed after a single dose administration of DUEXIS. Mean Cmax values for ibuprofen are 45 µg/mL and are reached approximately 1.9 hours after oral administration of DUEXIS. The Cmax and AUC0-24hours values for the 800 mg of ibuprofen contained in a DUEXIS tablet are bioequivalent to the values for 800 mg of ibuprofen administered alone. Cmax values for famotidine were 61 ng/mL and are reached at approximately 2 hours after oral administration of DUEXIS. A high-fat meal reduced famotidine Cmax and AUC by approximately by 15% and 11%, respectively, and reduced ibuprofen AUC by approximately 14% but did not change Cmax. Food delayed famotidine Tmax and ibuprofen Tmax by approximately 1 hour and 0.2 hour, respectively. Distribution Ibuprofen is extensively bound to plasma proteins. Reference ID: 5482811 Fifteen to 20% of famotidine in plasma is protein bound. Elimination Metabolism The only metabolite of famotidine identified in man is the S-oxide. Excretion Ibuprofen is eliminated from the systemic circulation with a mean half-life (t1/2) value of 2 hours following administration of a single dose of DUEXIS. Ibuprofen is rapidly metabolized and eliminated in the urine. The excretion of ibuprofen is virtually complete 24 hours after the last dose. Studies have shown that following ingestion of the drug, 45% to 79% of the dose was recovered in the urine within 24 hours as metabolite A (25%), (+)-2-[p-(2-hydroxymethyl-propyl) phenyl] propionic acid and metabolite B (37%), (+)­ 2-[p-(2-carboxypropyl)phenyl] propionic acid; the percentages of free and conjugated ibuprofen were approximately 1% and 14%, respectively. Famotidine is eliminated from the systemic circulation with a mean t1/2 value of 4 hours following administration of a single dose of DUEXIS. Famotidine is eliminated by renal (65-70%) and metabolic (30-35%) routes. Renal clearance is 250-450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65-70% of an intravenous dose are recovered in the urine as unchanged compound. Specific Populations Pediatrics: The pharmacokinetics of ibuprofen or famotidine after administration of DUEXIS have not been evaluated in a pediatric population considering the doses of ibuprofen and famotidine in DUEXIS are targeted for use in an adult population. Hepatic impairment: The effects of hepatic impairment on the pharmacokinetics of ibuprofen or famotidine after administration of DUEXIS have not been evaluated [see Warnings and Precautions (5.4)]. Renal impairment: There is a close relationship between creatinine clearance values and the elimination t1/2 of famotidine, which is a component of DUEXIS tablets. In patients with creatinine clearance <50 mL/min, the elimination t1/2 of famotidine is increased and may exceed 20 hours. Therefore, DUEXIS is not recommended in patients with creatinine clearance < 50 mL/min [see Warnings and Precautions (5.7)]. Drug Interaction Studies Co-administration of ibuprofen (800 mg) and famotidine (40 mg) increased ibuprofen Cmax by 15.6% but did not affect its AUC, and increased famotidine AUC and Cmax by 16% and 22%, respectively. Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interaction (7)]. Probenecid, an inhibitor of Organic Aniton Transporter 1 (OAT1) and OAT3 In vitro studies indicate that famotidine is a substrate for OAT1 and OAT3. Following coadministration of probenecid (1500 mg) with a single oral 20 mg dose of famotidine in 8 healthy subjects, the serum AUC0-10h of famotidine increased from 424 to 768 ng×hr/mL and the maximum serum concentration (Cmax) increased from 73 to 113 ng/mL. Renal clearance, urinary excretion rate and amount of famotidine excreted unchanged in urine were decreased. The clinical relevance of this interaction is unknown. Metformin: Famotidine is a selective inhibitor of multidrug and toxin extrusion transporter 1 (MATE-1) but no clinical significant interaction with metformin, a substrate for MATE-1, was observed. Reference ID: 5482811 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Studies to evaluate the potential effects of DUEXIS on carcinogenicity, mutagenicity, or impairment of fertility have not been conducted. In a 106-week study in rats and a 92-week study in mice, famotidine was given at oral doses of up to 2000 mg/kg/day (approximately 122 and 243 times the recommended human dose, respectively, based on body surface area). There was no evidence of carcinogenic potential for famotidine. Mutagenesis Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 µg/plate. In in vivo mouse micronucleus test and a chromosomal aberration test with famotidine, no evidence of a mutagenic effect was observed. In published studies, ibuprofen was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Impairment of Fertility In studies of famotidine in rats at oral doses of up to 2000 mg/kg/day (approximately 243 times the recommended human dose, based on body surface area), fertility and reproductive performance were not affected. In a published study, dietary administration of ibuprofen to male and female rats 8-weeks prior to and during mating at dose levels of 20 mg/kg (0.06-times the MRHD based on body surface area comparison) did not impact male or female fertility or litter size. In other studies, adult mice were administered ibuprofen intraperitoneally at a dose of 5.6 mg/kg/day (0.0085-times the MRHD based on body surface area comparison) for 35 or 60 days in males and 35 days in females. There was no effect on sperm motility or viability in males but decreased ovulation was reported in females. 14 CLINICAL STUDIES Two multicenter, double-blind, active-controlled, randomized, 24-week studies of DUEXIS were conducted in patients who were expected to require daily administration of an NSAID for at least the coming 6 months for conditions such as the following: osteoarthritis, rheumatoid arthritis, chronic low back pain, chronic regional pain syndrome, and chronic soft tissue pain. Patients were assigned randomly, in approximately a 2:1 ratio, to treatment with either DUEXIS or ibuprofen (800 mg) three times a day for 24 consecutive weeks. A total of 1533 patients were enrolled and ranged in age from 39 to 80 years (median age 55 years) with 68% females. Race was distributed as follows: 79% Caucasian, 18% African-American, and 3% Other. Approximately 15% of the patients in Studies 301 and 303 were taking concurrent low-dose aspirin (less than or equal to 325 mg daily), 18% were 65 years of age or older, and 6% had a history of previous upper gastrointestinal ulcer. Although H. pylori status was negative at baseline, H. pylori status was not reassessed during the trials. Studies 301 and 303 compared the incidence of upper gastrointestinal (gastric and/or duodenal) ulcer formation in a total 930 patients taking DUEXIS (ibuprofen and famotidine) and 452 patients taking ibuprofen only, either as a primary or secondary endpoint. In both trials, DUEXIS was associated with a statistically significantly reduction in the risk of developing upper gastrointestinal ulcers compared to taking ibuprofen only during the 6 month study period. The data are presented below in Tables 4 and 5. Two analyses for each endpoint were conducted. In one analysis patients who terminated early, without an endoscopic evaluation within 14 days of their last dose of study drug, were classified as not having an ulcer. In the second analysis, those patients were classified as having an ulcer. Both analyses exclude patients who terminated study prior to the first scheduled endoscopy at 8 weeks. Reference ID: 5482811 Table 4: Overall Incidence Rates of Patients Who Developed at Least One Upper Gastrointestinal or Gastric Ulcer - Study 301 DUEXIS % (n/N) Ibuprofen % (n/N) P-valuea Primary endpoint Upper gastrointestinal ulcer* 10.5% (40/380) 20.0% (38/190) 0.002 Upper gastrointestinal ulcer** 22.9% (87/380) 32.1% (61/190) 0.020 Secondary endpoint Gastric ulcer* 9.7% (37/380) 17.9% (34/190) 0.005 Gastric ulcer** 22.4% (85/380) 30.0% (57/190) 0.052 a Cochran-Mantel-Haenszel test * Classifying early terminated patients as NOT having an ulcer ** Classifying patients who early terminated due to an adverse event, were lost to follow-up, discontinued due to the discretion of the sponsor or the investigator, or did not have an endoscopy performed within 14 days of their last dose of study drug, as having an ulcer Table 5: Overall Incidence Rate of Patients Who Developed at Least One Gastric or Upper Gastrointestinal Ulcer - Study 303 DUEXIS % (n/N) Ibuprofen % (n/N) P-valuea Primary endpoint Gastric ulcer* 8.7% (39/447) 17.6% (38/216) 0.0004 Gastric ulcer** 17.4% (78/447) 31.0% (67/216) <0.0001 Secondary endpoint Upper gastrointestinal ulcer* 10.1% (45/447) 21.3% (46/216) <0.0001 Upper gastrointestinal ulcer** 18.6% (83/447) 34.3% (74/216) <0.0001 a Cochran-Mantel-Haenszel test * Classifying early terminated patients as NOT having an ulcer ** Classifying patients who early terminated due to an adverse event, were lost to follow-up, discontinued due to the discretion of the sponsor or the investigator, or did not have an endoscopy performed within 14 days of their last dose of study drug, as having an ulcer Subgroup analyses of patients who used low-dose aspirin (less than or equal to 325 mg daily), were 65 years and older, or had a prior history of gastrointestinal ulcer are summarized as follows: Of the 1022 patients in clinical studies of DUEXIS, 15% (213 patients) used low-dose aspirin and the results were consistent with the overall findings of the study. In these clinical studies 16% of patients who used low-dose aspirin who were treated with DUEXIS developed an upper gastrointestinal ulcer compared to 35% of those patients who received only ibuprofen. The clinical trials primarily enrolled patients less than 65 years without a prior history of gastrointestinal ulcer. Of the 1022 patients in clinical studies of DUEXIS, 18% (249 patients) were 65 years of age or older. In these clinical studies, 23% of patients 65 years of age and older who were treated with DUEXIS developed an upper gastrointestinal ulcer compared to 27% of those patients who received only ibuprofen [see Use in Specific Populations (8.5)]. Of the 1022 patients in clinical studies of DUEXIS, 6% had a prior history of gastrointestinal ulcer. In these clinical studies, 25% of patients with a prior history of gastrointestinal ulcer who were treated with DUEXIS developed an upper gastrointestinal ulcer compared to 24% of those patients who received only ibuprofen. Reference ID: 5482811 16 HOW SUPPLIED/STORAGE AND HANDLING DUEXIS (ibuprofen and famotidine) tablets, 800 mg/26.6 mg, are light blue, oval, biconvex, film-coated tablets debossed with “HZT” on one side and supplied as: NDC Number Size 75987-010-03 Bottle of 90 tablets Storage Store at 25C (77F); excursions permitted to 15-30C (59-86F). [See USP Controlled Room Temperature] 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients, families, or caregivers of the following before initiating therapy with DUEXIS and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop DUEXIS and seek immediate medical therapy [see Warnings and Precautions (5.4)]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their health care provider if such symptoms occur [see Warnings and Precautions (5.6)]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4), Warnings and Precautions (5.8)]. Serious Skin Reactions, including DRESS Advise patients to stop taking DUEXIS immediately if they develop any type of rash or fever and contact their health care provider as soon as possible [see Warnings and Precautions (5.11, 5.12)]. Infertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including DUEXIS, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of DUEXIS and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closure of the fetal ductus arteriosus. If treatment with DUEXIS is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios [see Warnings and Precautions (5.13) and Use in Specific Populations (8.1)]. Reference ID: 5482811 Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of DUEXIS with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2, 5.17), Drug Interactions (7)]. Alert patients that NSAIDs may be present in the “over the counter” medications for treatment of colds, fever or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with DUEXIS until they talk to their health care provider [see Drug Interactions (7)]. Nephrotoxicity Patients should be monitored for development of nephrotoxicity (e.g., azotemia, hypertension, and /or proteinuria). If these patients should be instructed to stop therapy and seek immediate medical therapy. Creatinine Clearance DUEXIS is not recommended in patients with creatinine clearance <50 mL/min because of seizures, delirium, coma and other CNS effect. Taking DUEXIS Inform patients that DUEXIS tablets should be swallowed whole, and should not be cut to supply a lower dose. Advise patient not to chew, divide, or crush tablets [see Dosage and Administration (2)]. Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose. Distributed by: Horizon Medicines LLC Deerfield, IL 60015 DUE-US-PI-002 Reference ID: 5482811 Medication Guide DUEXIS (dew-EX-iss) (ibuprofen and famotidine) tablets, for oral use What is the most important information I should know about DUEXIS? DUEXIS can cause serious side effects including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: o with increasing doses of medicine containing NSAIDs o with longer use of medicine containing NSAIDs Do not take DUEXIS right before or after a heart surgery called a “coronary artery bypass graft (CABG).” Avoid taking DUEXIS after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take DUEXIS after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: o anytime during use o without warning symptoms o that may cause death The risk of getting an ulcer or bleeding increases with: o past history of stomach ulcers, or stomach or o smoking intestinal bleeding with the use of NSAIDs o drinking alcohol o taking medicines called “corticosteroids”, o older age “anticoagulants”, “SSRIs”, or “SNRIs” o poor health o increasing doses of NSAIDs o advanced liver disease o longer use of NSAIDs o bleeding problems You should take DUEXIS exactly as prescribed, at the lowest dose possible and for the shortest time needed. DUEXIS contains a non-steroidal anti-inflammatory drug NSAID (ibuprofen). Do not use DUEXIS with other medicines to lessen pain or fever or with other medicines for colds or sleeping problems without talking to your healthcare provider first, because they may contain an NSAID also. DUEXIS may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your healthcare provider. DUEXIS contains ibuprofen, an NSAID and famotidine, a histamine H2 -receptor blocker medicine. What is DUEXIS? DUEXIS is a prescription medicine used to: • relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis. • decrease the risk of developing ulcers of the stomach and upper intestines (upper gastrointestinal ulcers) in people taking ibuprofen for rheumatoid arthritis and osteoarthritis. It is not known if DUEXIS is safe and effective in children. Do not take DUEXIS: • if you are allergic to ibuprofen, famotidine, any other histamine H2 -receptor blocker, or any of the ingredients in DUEXIS. See the end of this Medication Guide for a complete list of ingredients. • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking DUEXIS, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems. • have high blood pressure. • have heart problems. • have asthma. • have bleeding problems. • are pregnant or plan to become pregnant. Taking DUEXIS at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take DUEXIS when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take DUEXIS after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Ibuprofen and famotidine can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take DUEXIS. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. DUEXIS and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. Reference ID: 5482811 How should I take DUEXIS? • Take DUEXIS exactly as your healthcare provider tells you to take it. • Your healthcare provider will tell you how many DUEXIS to take and when to take it. • Do not change your dose or stop DUEXIS without first talking to your healthcare provider. • Swallow DUEXIS tablets whole with liquid. Do not split, chew, crush or dissolve the DUEXIS tablet. Tell your healthcare provider if you cannot swallow the tablet whole. You may need a different medicine. • If you forget to take your dose of DUEXIS, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take the next dose on time. Do not take 2 doses at one time to make up for a missed dose. • You should not take an ibuprofen tablet and famotidine tablet together instead of taking DUEXIS, because they will not work in the same way. What are the possible side effects of DUEXIS? DUEXIS can cause serious side effects, including: See “What is the most important information I should know about DUEXIS? • heart attack • kidney problems including kidney failure • stroke • life-threatening allergic reactions • liver problems including liver failure • asthma attacks in people who have asthma • new or worse high blood pressure • life-threatening skin reactions • heart failure • low red blood cells (anemia) Other side effects of DUEXIS include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking DUEXIS and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is black • diarrhea and sticky like tar • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands, and feet • flu-like symptoms If you take too much DUEXIS, call your poison control center at 1-800-222-1222. These are not all the possible side effects of DUEXIS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of DUEXIS Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DUEXIS for a condition for which it was not prescribed. Do not give DUEXIS to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. What are the ingredients in DUEXIS? Active ingredients: ibuprofen and famotidine Inactive ingredients: microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, purified water, povidone, titanium dioxide, polyethylene glycol, polysorbate 80, polyvinyl alcohol, hypromellose, talc, FD&C Blue#2/Indigo Carmine Aluminum Lake, and FD&C Blue #1/Brilliant Blue FCF Aluminum Lake. Distributed by: Horizon Medicines LLC., Deerfield, IL 60015 For more information, go to www.DUEXIS.com or call 1-866-479-6742. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 DUE-US-MG-001 Reference ID: 5482811
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2025-02-12T15:47:16.645187
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use YOSPRALA® safely and effectively. See full prescribing information for YOSPRALA. YOSPRALA (aspirin and omeprazole) delayed-release tablets, for oral use Initial US Approval: 2016 ---------------------------RECENT MAJOR CHANGES---------------------------­ Warnings and Precautions, Serious or Severe Skin Reactions (5.11) 11/2024 -----------------------------INDICATIONS AND USAGE--------------------------­ YOSPRALA is a combination of aspirin, an anti-platelet agent, and omeprazole, a proton pump inhibitor (PPI), indicated for patients who require aspirin for secondary prevention of cardiovascular and cerebrovascular events and who are at risk of developing aspirin associated gastric ulcers. The aspirin component of YOSPRALA is indicated for: • reducing the combined risk of death and nonfatal stroke in patients who have had ischemic stroke or transient ischemia of the brain due to fibrin platelet emboli, • reducing the combined risk of death and nonfatal MI in patients with a previous MI or unstable angina pectoris, • reducing the combined risk of MI and sudden death in patients with chronic stable angina pectoris, • use in patients who have undergone revascularization procedures (Coronary Artery Bypass Graft [CABG] or Percutaneous Transluminal Coronary Angioplasty [PTCA]) when there is a pre-existing condition for which aspirin is already indicated. The omeprazole component of YOSPRALA is indicated for decreasing the risk of developing aspirin associated gastric ulcers in patients at risk for developing aspirin-associated gastric ulcers due to age (≥ 55) or documented history of gastric ulcers. (1) Limitations of Use: • Not for use as the initial dose of aspirin therapy during onset of acute coronary syndrome, acute myocardial infarction or before percutaneous coronary intervention. (1) • Has not been shown to reduce the risk of gastrointestinal bleeding due to aspirin. (1) • Do not substitute YOSPRALA with the single-ingredient products of aspirin and omeprazole. (1) -------------------------DOSAGE AND ADMINISTRATION--------------------­ • Recommended dosage: One tablet daily at least 60 minutes before a meal. (2.1, 2.2) • Do not split, chew, crush or dissolve the tablet. (2.2) ----------------------DOSAGE FORMS AND STRENGTHS-------------------­ Delayed-Release Tablets (3): • 81 mg delayed-release aspirin/40 mg immediate-releaseomeprazole • 325 mg delayed-release aspirin/40 mgimmediate-release omeprazole --------------------------------CONTRAINDICATIONS---------------------------­ • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. (4) • In pediatric patients with suspected viral infections, with or without fever, because of the risk of Reye's Syndrome. (4) • Known hypersensitivity to aspirin, omeprazole, substituted benzimidazoles or to any of the excipients of YOSPRALA. (4) • Patients receiving rilpivirine-containing products. (4,7) ------------------------WARNINGS AND PRECAUTIONS----------------------­ • Coagulation Abnormalities: Risk of increased bleeding time with aspirin, especially in patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders. Monitor patients for signs of increased bleeding. (5.1) • GI Adverse Reactions (including ulceration and bleeding): Monitor for signs and symptoms and discontinue treatment if bleeding occurs. (5.2) • Bleeding Risk with Use of Alcohol: Avoid heavy alcohol use (three or more drinks every day). (5.3) • Reduction in Antiplatelet Activity with Clopidogrel due to Interference with CYP2C19 Metabolism: Consider other antiplatelet therapy. (5.4,7) • Reduction in Efficacy of Ticagrelor: Avoid use with the 325/40 strength of YOSPRALA. (5.5, 7) • Renal Failure: Avoid YOSPRALA in patients with severe renal failure. (5.6, 8.6) • Gastric Malignancy: In adults, response to gastric symptoms does not preclude the presence of gastric malignancy; Consider additional follow­ up and diagnostic testing. (5.7) • Acute Tubulointerstitial Nephritis: Discontinue treatment and evaluate patients.(5.8) • Clostridium difficile-Associated Diarrhea: PPI therapy may be associated with increased risk; use lowest dose and shortest duration of treatment. (5.9) • Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine; use lowest dose and shortest duration of treatment. (5.10) • Serious or Severe Skin Reactions: Discontinue at the first appearance of skin rash or other signs of hypersensitivity and consider further evaluation. .(5.11) • Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue YOSPRALA and refer to specialist for evaluation. (5.12) • Hepatic Impairment: Avoid YOSPRALA in patients with all degrees of hepatic impairment. (5.13, 8.7) • Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) of PPI may lead to malabsorption or deficiency. (5.14) • Hypomagnesemia and Mineral Metabolism: Reported rarely with prolonged treatment with PPIs. (5.15) • Reduced Effect of Omeprazole with St. John’s Wort or Rifampin:Avoid concomitant use. (5.16, 7) • Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Increased Chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors; temporarily stop YOSPRALA at least 14 days before assessing CgA levels. (5.17, 7) • Bone Marrow Toxicity with Methotrexate, especially in the elderly or renally impaired: Use with PPIs may elevate and/or prolong serum levels of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate, consider a temporary withdrawal of YOSPRALA. (5.18, 7) • Fetal Toxicity: Limit use of NSAIDs, including YOSPRALA, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. (5.19, 8.1) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically. (5.20) • Abnormal Laboratory Tests: Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. (5.21) • Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. (5.22) --------------------------------ADVERSE REACTIONS---------------------------­ Most common adverse reactions in adults (≥ 2%) are: gastritis, nausea, diarrhea, gastric polyps, and non-cardiac chest pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Allucent at 1­ 866-511-6754 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ---------------------------------DRUG INTERACTIONS---------------------------­ See full prescribing information for a list of clinically important drug interactions. (7) ------------------------USE IN SPECIFIC POPULATIONS--------------------­ • Lactation: Breastfeeding not recommended. (8.2) • Females and Males of Reproductive Potential Infertility: NSAIDsare associated with reversible infertility. Consider withdrawal of YOSPRALA in women who have difficulties conceiving. (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Coagulation Abnormalities 5.2 GI Adverse Reactions 5.3 Bleeding Risk with Use of Alcohol 5.4 Interaction with Clopidogrel 5.5 Interaction with Ticagrelor 5.6 Renal Failure 5.7 Presence of Gastric Malignancy 5.8 Acute Tubulointerstitial Nephritis 5.9 Clostridium difficile-Associated Diarrhea 5.10 Bone Fracture 5.11 Serious or Severe Skin Reactions 5.12 Cutaneous and Systemic Lupus Erythematosus 5.13 Hepatic Impairment 5.14 Cyanocobalamin (Vitamin B-12) Deficiency 5.15 Hypomagnesemia and Mineral Metabolism 5.16 Reduced Effect of Omeprazole with St. John's Wort or Rifampin 5.17 Interactions with Diagnostic Investigations for Neuroendocrine Tumors 5.18 Interaction with Methotrexate 5.19 Fetal Toxicity Reference ID: 5482813 5.20 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 5.21 Abnormal Laboratory Tests 5.22 Fundic Gland Polyps 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Post-Marketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 8.8 Asian Population 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5482813 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE YOSPRALA, a combination of aspirin and omeprazole, is indicated for patients who require aspirin for secondary prevention of cardiovascular and cerebrovascular events and who are at risk of developing aspirin associated gastric ulcers. The aspirin component of YOSPRALA is indicated for: • reducing the combined risk of death and nonfatal stroke in patients who have had ischemic stroke or transient ischemia of the brain due to fibrin platelet emboli, • reducing the combined risk of death and nonfatal MI in patients with a previous MI or unstable angina pectoris, • reducing the combined risk of MI and sudden death in patients with chronic stable angina pectoris, • use in patients who have undergone revascularization procedures (Coronary Artery Bypass Graft [CABG] or Percutaneous Transluminal Coronary Angioplasty [PTCA]) when there is a pre-existing condition for which aspirin is already indicated. The omeprazole component of YOSPRALA is indicated for decreasing the risk of developing aspirin-associated gastric ulcers in patients at risk for developing aspirin-associated gastric ulcers due to age (≥ 55) or documented history of gastric ulcers. Limitations of Use: • YOSPRALA contains a delayed-release formulation of aspirin and it is not for use as the initial dose of aspirin therapy during onset of acute coronary syndrome, acute myocardial infarction or before percutaneous coronary intervention (PCI), for which immediate-release aspirin therapy is appropriate. • YOSPRALA has not been shown to reduce the risk of gastrointestinal bleeding due to aspirin. • Do not substitute YOSPRALA with the single-ingredient products of aspirin and omeprazole. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage • Take one tablet daily. • YOSPRALA is available in combinations that contain 81 mg or 325 mg of aspirin. Generally 81 mg of aspirin has been accepted as an effective dose for secondary cardiovascular prevention. Providers should consider the need for 325 mg and refer to current clinical practice guidelines. 2.2 Administration Instructions • Take YOSPRALA once daily at least 60 minutes before a meal. • The tablets are to be swallowed whole with liquid. Do not split, chew, crush or dissolve the tablet. • Use the lowest effective dose of YOSPRALA based on the individual patient’s treatment goals and to avoid potential dose dependent adverse reactions including bleeding. • If a dose of YOSPRALA is missed, advise patients to take it as soon as it is remembered. If it is almost time for the next dose, skip the missed dose. Take the next dose at the regular time. Patients should not take 2 doses at the same time unless advised by their doctor. • Do not stop taking YOSPRALA suddenly as this could increase the risk of heart attack or stroke. 3 DOSAGE FORMS AND STRENGTHS Oval, blue-green, film-coated, delayed-release tablets for oral administration containing either: • 81 mg delayed-release aspirin and 40 mg immediate-release omeprazole, printed with 81/40, or • 325 mg delayed-release aspirin and 40 mg immediate-release omeprazole, printed with 325/40. 4 CONTRAINDICATIONS YOSPRALA is contraindicated in: 3 Reference ID: 5482813 5 5.1 5.2 5.3 5.4 5.5 5.6 5.7 • Patients with known allergy to aspirin and other nonsteroidal anti-inflammatory drug products (NSAIDs) and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma). • Pediatric patients with suspected viral infections, with or without fever, because of the risk of Reye's syndrome with concomitant use of aspirin in certain viral illnesses. • YOSPRALA is contraindicated in patients with known hypersensitivity to aspirin, omeprazole, substituted benzimidazoles, or to any of the excipients in the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions (5.8), Adverse Reactions (6.2)]. • Proton pump inhibitor (PPI)–containing products, including YOSPRALA, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7)]. WARNINGS AND PRECAUTIONS Coagulation Abnormalities Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders. Monitor patients for signs of increased bleeding. Gastrointestinal Adverse Reactions Aspirin is associated with serious gastrointestinal (GI) adverse reactions, including inflammation, bleeding ulceration and perforation of the upper and lower GI tract. Other adverse reactions with aspirin include stomach pain, heartburn, nausea, and vomiting. Serious GI adverse reactions reported in the clinical trials of YOSPRALA were: gastric ulcer hemorrhage in one of the 521 patients treated with YOSPRALA and duodenal ulcer hemorrhage in one of the 524 patients treated with enteric-coated aspirin. In addition, there were two cases of intestinal hemorrhage, one in each treatment group, and one patient treated with YOSPRALA experienced obstruction of the small bowel. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, monitor patients for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Inform patients about the signs and symptoms of GI adverse reactions. If active and clinically significant bleeding from any source occurs in patients receiving YOSPRALA, discontinue treatment. Bleeding Risk with Use of Alcohol Counsel patients who consume three or more alcoholic drinks every day about the bleeding risks involved with chronic, heavy alcohol use while taking YOSPRALA. Interaction with Clopidogrel Avoid concomitant use of YOSPRALA with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that interfere with CYP2C19 activity. Co-administration of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using YOSPRALA, consider alternative anti-platelet therapy [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Interaction with Ticagrelor Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor in preventing thrombotic cardiovascular events. Avoid concomitant use of ticagrelor with the 325 mg/40 mg tablet strength of YOSPRALA [see Drug Interactions (7)]. Renal Failure Avoid YOSPRALA in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute). Regular use of aspirin is associated in a dose-dependent manner with an increased risk of chronic renal failure. Aspirin use decreases glomerular filtration rate and renal blood flow especially with patients with pre-existing renal disease. [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Presence of Gastric Malignancy In adults, response to gastric symptoms with YOSPRALA does not preclude the presence of gastric malignancy. Consider additional gastrointestinal follow-up and diagnostic testing in 4 Reference ID: 5482813 adult patients who experience gastric symptoms during treatment with YOSPRALA or have a symptomatic relapse after completing treatment. In older patients, also consider an endoscopy. 5.8 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue YOSPRALA and evaluate patients with suspected acute TIN [see Contraindications (4)]. 5.9 Clostridium difficile-Associated Diarrhea Published observational studies suggest that PPI-containing therapy like YOSPRALA may be associated with an increased risk of Clostridium difficile-associated diarrhea (CDAD), especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2)]. Use the lowest dose and shortest duration of YOSPRALA appropriate to the condition being treated. 5.10 Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long­ term PPI therapy (a year or longer). Use the lowest dose and shortest duration of YOSPRALA therapy appropriate to the condition being treated. Manage patients at risk for osteoporosis- related fractures according to established treatment guidelines [see Adverse Reactions (6.2)]. 5.11 Serious or Severe Skin Reactions Aspirin NSAIDs, including aspirin, a component of YOSPRALA, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Omeprazole PPIs can cause severe cutaneous adverse reactions, including SJS, TEN, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) [see Adverse Reactions (6.2)]. YOSPRALA Inform patients about the signs and symptoms of serious or severe skin reactions, and to discontinue the use of YOSPRALA at the first appearance of skin rash or any other sign of hypersensitivity and consider further evaluation. YOSPRALA is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.12 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematous cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE), and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment, but some cases occurred days or years after initiating treatment. SLE occurred primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. 5 Reference ID: 5482813 Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving YOSPRALA, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serologicial testing (e.g., ANA) may be positive and elevated serologicial test results may take longer to resolve than clinical manifestations. 5.13 Hepatic Impairment Long-term moderate to high doses of aspirin may result in elevations in serum ALT levels. These abnormalities resolve rapidly with discontinuation of aspirin. The hepatotoxicity of aspirin is usually mild and asymptomatic. Bilirubin elevations are usually mild or absent. Systemic exposure to omeprazole is increased in patients with hepatic impairment [see ClinicalPharmacology (12.3)]. Avoid YOSPRALA in patients with any degree of hepatic impairment [see Use in Specific Populations (8.7)]. 5.14 Cyanocobalamin (Vitamin B-12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with YOSPRALA. 5.15 Hypomagnesemia and Mineral Metabolism Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse reactions include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2)]. Consider monitoring magnesium and calcium levels prior to initiation of YOSPRALA and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g. hypoparathyroidism). Supplement with magnesium and/or calcium, as necessary. If hypocalcemia is refractory to treatment, consider discontinuing YOSPRALA. 5.16 Reduced Effect of Omeprazole with St. John’s Wort or Rifampin Drugs which induce the CYP2C19 or CYP3A4 (such as St. John’s Wort or rifampin) can substantially decrease concentrations of omeprazole. Avoid concomitant use of YOSPRALA with St. John’s Wort or rifampin [see Drug Interactions (7)]. 5.17 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to omeprazole-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic interventions for neuroendocrine tumors. Temporarily discontinue treatment with YOSPRALA at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Drug Interactions (7) and Clinical Pharmacology (12.2)]. 5.18 Interaction with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of YOSPRALA may be considered in some patients [see Drug Interactions (7)]. 5.19 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including YOSPRALA, in pregnant women starting at about 30 weeks of gestation and later. NSAIDs, including YOSPRALA, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. 6 Reference ID: 5482813 Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including YOSPRALA, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit YOSPRALA use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if YOSPRALA treatment is needed for a pregnant woman. Discontinue YOSPRALA if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)]. 5.20 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as YOSPRALA. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue YOSPRALA and evaluate the patient immediately. 5.21 Abnormal Laboratory Tests Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. 5.22 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long­ term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Coagulation Abnormalities [see Warnings and Precautions (5.1)] • Gastrointestinal Adverse Reactions [see Warnings and Precautions(5.2)] • Bleeding Risk with Use of Alcohol [see Warnings and Precautions(5.3)] • Interaction with Clopidogrel [see Warnings and Precautions(5.4)] • Interaction with Ticagrelor [see Warnings and Precautions(5.5)] • Renal Failure [see Warnings and Precautions (5.6)] • Presence of Gastric Malignancy [see Warnings and Precautions(5.7)] • Acute Tubulointerstitial Nephritis [see Warnings and Precautions(5.8)] • Clostridium difficile-Associated Diarrhea [see Warnings and Precautions(5.9)] • Bone Fracture [see Warnings and Precautions(5.10)] • Serious or Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.11)] • Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions(5.12)] • Hepatic Impairment [see Warnings and Precautions (5.13)] • Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.14)] • Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.15)] • Reduced Effect of Omeprazole with St. John’s Wort or Rifampin [see Warnings and Precautions (5.16)] • Interactions with Diagnostic Investigations for Neuroendocrine Tumors [see Warnings and Precautions (5.17)] • Interaction with Methotrexate [see Warnings and Precautions (5.18)] • Fetal Toxicity [see Warnings and Precautions (5.19)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.20)] • Abnormal Laboratory Tests [see Warnings and Precautions (5.21)] 7 Reference ID: 5482813 • Fundic Gland Polyps [see Warning and Precautions (5.22)] 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. YOSPRALA 325 mg/40 mg was studied primarily in two randomized, double-blind controlled clinical trials (n=524) of 6 months duration. Table 1 lists adverse reactions that occurred in>2% of patients in the YOSPRALA arm and were more common than in the control arm, consisting of 325 mg of enteric coated (EC)-aspirin. Table 1: Most Common Adverse Reactions in Study 1 and Study 2* Preferred Term YOSPRALA 325 mg/40 mg once daily (n=521) % EC-Aspirin 325 mg once daily (n=524) % Gastritis 18 16 Nausea 3 2 Diarrhea 3 2 Gastric polyps 2 1 Non-cardiac chest pain 2 1 *Adverse reactions occurring in ≥2% of YOSPRALA-treated patients and more common than in the control arm In Study 1 and Study 2 combined, 7% of patients taking YOSPRALA discontinued due to adverse reactions compared to 11% of patients taking EC-aspirin alone. The most common reasons for discontinuations due to adverse reactions in the YOSPRALA treatment group were upper abdominal pain (<1%, n=2), diarrhea (<1%, n=2) and dyspepsia (<1%, n=2). Less Common Adverse Reactions In YOSPRALA-treated patients in the clinical trials there were 2 patients with upper GI bleeding (gastric or duodenal) and 2 patients with lower GI bleeding (hematochezia and large intestinal hemorrhage) and one additional patient experienced obstruction in the small bowel. See also the full prescribing information of aspirin and omeprazole products for additional adverse reactions. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of aspirin and omeprazole separately. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Aspirin Body as a Whole: Fever, hypothermia, thirst Cardiovascular: Dysrhythmias, hypotension, tachycardia Central Nervous System: Agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures Fluid and Electrolyte: Dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis Gastrointestinal: Dyspepsia, GI bleeding, ulceration and perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye's Syndrome [see Contraindications (4)], pancreatitis Hematologic: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia Hypersensitivity: Acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria Musculoskeletal: Rhabdomyolysis Metabolism: Hypoglycemia (in pediatrics), hyperglycemia Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding Respiratory: Hyperpnea, pulmonary edema, tachypnea Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). Special Senses: Hearing loss, tinnitus. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of 8 Reference ID: 5482813 salicylism. Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, renal impairment and failure Omeprazole Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm [see Contraindications (4)], interstitial nephritis, urticaria (see also Skin below), systemic lupus erythematosus, fever, pain, fatigue, malaise Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema Endocrine: Gynecomastia Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis, fundic gland polyps. Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors. Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leukocytosis Hepatic: Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin] Infections and Infestations: Clostridium difficile-associated diarrhea [see Warnings and Precautions (5.9)] Metabolism and Nutritional disorders: Hypoglycemia, hypomagnesemia, hypocalcemia, hypokalemia [Warnings and Precautions 5.15], hyponatremia, weight gain Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture Nervous System/Psychiatric: Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo Respiratory: Epistaxis, pharyngeal pain Skin: Severe generalized skin reactions including SJS/TEN, DRESS and AGEP [see Warnings and Precautions (5.11)], cutaneous lupus erythematosus and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis Special Senses: Tinnitus, taste perversion Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain, erectile dysfunction 7 DRUG INTERACTIONS Tables 2 and 3 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with YOSPRALA and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with omeprazole or aspirin. Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with YOSPRALA and Interaction with Diagnostics 9 Reference ID: 5482813 Antiretrovirals Clinical Impact: The effect of PPIs, such as omeprazole, on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. • There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. Intervention: Rilpivirine-containing products: Concomitant use with YOSPRALA is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with YOSPRALA. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with YOSPRALA. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs. Heparin and Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Aspirin can increase the anticoagulant activity of heparin and warfarin, increasing bleeding risk. Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. Monitor and adjust the dose of heparin and warfarin as needed. Methotrexate Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs, such as omeprazole, have been conducted [see Warnings and Precautions(5.17)]. Intervention: A temporary withdrawal of YOSPRALA may be considered in some patients receiving high-dose methotrexate. CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam) Clopidogrel Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. Intervention: Avoid concomitant use with YOSPRALA. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.4)]. Citalopram Clinical Impact: Concomitant use of omeprazole results in increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)]. Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. Cilostazol Clinical Impact: Concomitant use of omeprazole results in increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol). Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. Phenytoin 10 Reference ID: 5482813 Clinical Impact: Potential for increased exposure of phenytoin with concomitant omeprazole. Aspirin can displace protein-bound phenytoin leading to a decrease in the total concentration of phenytoin. Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. Diazepam Clinical Impact: Increased exposure of diazepam with concomitant omeprazole [see Clinical Pharmacology (12.3)]. Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed. Ticagrelor Clinical Impact: Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor. Intervention: Avoid concomitant use of ticagrelor with the 325 mg/40 mg tablet strength of YOSPRALA [see Warnings and Precautions (5.5)]. Digoxin Clinical Impact: Potential for increased exposure of digoxin with concomitant omeprazole [see Clinical Pharmacology (12.3)]. Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use Yosprala with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption. Tacrolimus Clinical Impact: Potential for increased exposure of tacrolimus with concomitant omeprazole, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. ACE-Inhibitors Clinical Impact: Aspirin may diminish the antihypertensive effect of ACE-inhibitors. Intervention: Monitor blood pressure as needed. Beta Blockers Clinical Impact: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin. Intervention: Monitor blood pressure as needed in patients taking YOSPRALA concomitantly with beta blockers for hypertension. Diuretics Clinical Impact: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin. Intervention: Monitor blood pressure as needed. NSAIDs Clinical Impact: The concurrent use of NSAIDs and aspirin may increase the risk of serious adverse events, including increased bleeding or decreased renal function. Intervention: Monitor for signs and symptoms of bleeding or decreased renal function. Oral Hypoglycemics Clinical Impact: Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia. Intervention: Monitor blood sugar as needed. Acetazolamide 11 Reference ID: 5482813 Clinical Impact: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity). Intervention: Adjust the dose of acetazolamide if signs of toxicity occur. Uricosuric Agents (Probenecid) Clinical Impact: Aspirin antagonizes the uricosuric action of uricosuric agents. Intervention: Monitor serum uric acid levels as needed. Valproic Acid Clinical Impact: Concomitant use of aspirin can displace protein-bound valproic acid, leading to an increase in serum concentrations of valproic acid. Intervention: Monitor valproic acid serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for valproic acid. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to omeprazole-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.16), Clinical Pharmacology (12.2)]. Intervention: Temporarily stop YOSPRALA treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. Interaction with Secretin Stimulation Test Clinical Impact: Omeprazole can cause a hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. Intervention: Temporarily stop YOSPRALA treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)]. False Positive Urine Tests for THC Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs such as omeprazole. Intervention: An alternative confirmatory method should be considered to verify positive results. Other Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram) with Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with YOSPRALA. Table 3: Clinically Relevant Interactions Affecting YOSPRALA When Co- Administered with Other Drugs CYP2C19 or CYP3A4 Inducers Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)]. Intervention: St. John’s Wort, rifampin: Avoid concomitant use with YOSPRALA [see Warnings and Precautions (5.15)]. Ritonavir-containing products: See prescribing information for specific drugs. CYP2C19 or CYP3A4 Inhibitors Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)]. Intervention: Voriconazole: Avoid concomitant use with YOSPRALA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Use of NSAIDs, including aspirin, a component of YOSPRALA, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of YOSPRALA use between about 20 and 30 weeks of gestation,and avoid YOSPRALA use at about 30 weeks gestation and later in pregnancy (see Clinical Considerations, Data). 12 Reference ID: 5482813 Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including aspirin, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. There are no available data with YOSPRALA use in pregnant women to inform a drug- associate risk for major birth defects and miscarriage; however, there are published studies with each individual component of YOSPRALA. Aspirin Data from observational studies regarding other potential embyofetal risks of aspirin use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, there were adverse developmental effects with oral administration of aspirin to pregnant rats at doses 15 to 19 times the maximum recommended human dose (MRHD) of 325 mg/day. Aspirin did not produce adverse developmental effects in rabbits [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin sythensis inhibitors such as aspirin resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Omeprazole Data from epidemiological and observational studies with omeprazole have not reported a clear association with major birth defects or miscarriage risk. Animal reproduction studies in pregnant rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 3.4 to 34 times an oral human dose of 40 mg. Changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data]. The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Maternal aspirin use during the third trimester of pregnancy may increase the risk of neonatal complications, including necrotizing enterocolitis, patent ductus arteriosus, intracranial hemorrhage in premature infants, low birth weight, stillbirth and neonatal death. Maternal Adverse Reactions An increased incidence of post-term pregnancy and longer duration of pregnancy in women taking aspirin has been reported. Avoid maternal use of aspirin, including Yosprala, in pregnant women during the third trimester. Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus Avoid use of aspirin in women at about 30 weeks gestation and later in pregnancy, because aspirin, including YOSPRALA, can cause premature closure of the fetal ductus arteriosus (see Data). Oligohydramnios/Neonatal Renal Impairment If an aspirin is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If YOSPRALA treatment is needed for a 13 Reference ID: 5482813 pregnant woman, considering monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue YOSPRALA and follow up according to clinical practice (see Data). Maternal Adverse Reactions An increased incidence of post-term pregnancy and longer duration of pregnancy in women taking aspirin has been reported. Labor or Delivery Aspirin, a component of YOSPRALA, should be avoided 1 week prior to and during labor and delivery because it can result in excessive blood loss at delivery. In animal studies, NSAIDS, including aspirin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Aspirin Data from several controlled and observational studies with aspirin use in the first or second trimesters of pregnancy have not reported a clear association with major birth defects or miscarriage risk. Published data on aspirin use during pregnancy has been mostly reported with low dose aspirin (60 to 100 mg). There are limited data regarding aspirin 325 mg or higher doses used during pregnancy. A prospective, cohort study of 50,282 mother-child pairs (the Collaborative Perinatal Project) assessing adverse outcomes by level of aspirin exposure did not report aspirin-induced teratogenicity, altered neonatal birth weight, or perinatal deaths at any exposure level. In a controlled, randomized trial, maternal risks during pregnancy were reported as low or absent, with no demonstrated increased risk of maternal bleeding or placental abruptio. A multinational study involving more than 9,000 women, CLASP (Collaborative Low-dose Aspirin Study in Pregnancy)], found that low-dose aspirin reduced fetal morbidity in a select population of women with early-onset preeclampsia, but did not identify adverse effects in the pregnant woman, fetus, or newborn (followed to 12 and 18 months of age) in association with the use of low-dose aspirin during pregnancy. In contrast, some case-control studies reported associations between human congenital malformations and aspirin use early in gestation, but these studies did not report a consistent outcome attributable to drug use. A report from EAGeR trial (Effects of Aspirin in Gestation and Reproduction trial), which evaluated 1078 women who were attempting to become pregnant and had prior miscarriages, reported use of low-dose aspirin without adverse maternal or fetal effects except for vaginal bleeding. Another trial of 3294 pregnant women of 14 to 20 weeks of gestation treated with aspirin showed no effect in the mothers' incidence of pre-eclampsia, hypertension, HELLP syndrome or placental abruptio, or in the incidence of perinatal deaths or low birth weight below the 10th percentile. The incidence of maternal side effects was higher in the aspirin group, principally because of a significantly higher rate of hemorrhage. Use of high-dose aspirin for long periods in pregnancy may increase the risk of bleeding in the brain of premature infants. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of aspirin at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal aspirin use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after aspirin initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal aspirin use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. 14 Reference ID: 5482813 Omeprazole Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls. A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995 to 1999, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 1996 to 2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837,317 live births whose mothers did not use any PPI. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% with first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease- paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data Aspirin Aspirin produced a spectrum of developmental anomalies when administered to Wistar rats as single, large doses (500 to 625 mg/kg) on gestational day (GD) 9, 10, or 11. These doses (500 to 625 mg/kg) in rats are about 15 to 19 times the maximum recommended human dose of aspirin (325 mg/day) based on body surface area. Many of the anomalies were related to closure defects and included craniorachischisis, gastroschisis and umbilical hernia, and cleft lip, in addition to diaphragmatic hernia, heart malrotation, and supernumerary ribs and kidneys. In contrast to the rat, aspirin was not developmentally toxic in rabbits. Omeprazole Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) during organogenesis did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138 mg/kg/day (about 3.4 to 34 times an oral human doses of 40 mg on a body surface area basis), administered prior to mating through the lactation period. Esomeprazole The data described below was generated from studies using esomeprazole, an enantiomer of omeprazole. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole. No effects on embryo-fetal development were observed in reproduction studies with esomeprazole 15 Reference ID: 5482813 magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis) administered during organogenesis. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about 17 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Effects on maternal bone were observed in pregnant and lactating rats in the pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age. 8.2 Lactation Risk Summary There is no information about the presence of YOSPRALA in human milk; however, the individual components of YOSPRALA, aspirin and omeprazole, are present in human milk. Limited data from clinical lactation studies in published literature describe the presence of aspirin in human milk at relative infant doses of 2.5% to 10.8% of the maternal weight-adjusted dosage. Case reports of breastfeeding infants whose mothers were exposed to aspirin during lactation describe adverse reactions, including metabolic acidosis, thrombocytopenia, and hemolysis. There is no information on the effects of aspirin on milk production. Limited data from a case report in published literature describes the presence of omeprazole in human milk at a relative infant dose of 0.9% of the maternal weight-adjusted dosage. There are no reports of adverse effects of omeprazole on the breastfed infant, and no information on the effects of omeprazole on milk production. Because of the potential for serious adverse reactions, including the potential for aspirin to cause metabolic acidosis, thrombocytopenia, hemolysis or 16 Reference ID: 5482813 Reye’s syndrome, advise patients that breastfeeding is not recommended during treatment with YOSPRALA. Clinical Considerations It is not known if maternal exposure to aspirin during lactation increases the risk of Reye’s syndrome in breastfed infants. The direct use of aspirin in infants and children is associated with Reye’s syndrome, even at low plasma levels. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including YOSPRALA, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also demonstrated a reversible delay in ovulation. Consider withdrawal of NSAIDs, including YOSPRALA, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and efficacy of YOSPRALA has not been established in pediatric patients. YOSPRALA is contraindicated in pediatric patients with suspected viral infections, with or without fever, because of the risk of Reye's syndrome with concomitant use of aspirin in certain viral illnesses [see Contraindications (4)]. Juvenile Animal Data In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 17 to 67 times a daily human dose of 40 mg based on body surface area. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology (13.2)]. 8.5 Geriatric Use Of the total number of patients who received YOSPRALA (n=900) in clinical trials, 62% were ≥65 years of age and 15% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience with aspirin and omeprazole has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment No dose reduction of YOSPRALA is necessary in patients with mild to moderate renal impairment. Avoid YOSPRALA in patients with severe renal impairment (glomerular filtration rate less than 10 mL/minute) due to the aspirin component [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Long-term moderate to high doses of aspirin may result in elevations in serum ALT levels [see Warnings and Precautions (5.12)]. Systemic exposure to omeprazole is increased in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. Avoid YOSPRALA in patients with any degree of hepatic impairment. 8.8 Asian Population In studies of healthy subjects, Asians had approximately a four-fold higher exposure to omeprazole than Caucasians. CYP2C19, a polymorphic enzyme, is involved in the metabolism of omeprazole. Approximately 15% to 20% of Asians are CYP2C19 poor metabolizers. Tests are available to identify a patient’s CYP2C19 genotype. Avoid use in Asian patients with unknown CYP2C19 genotype or those who are known to be poor metabolizers [see Clinical Pharmacology (12.5)]. 10 OVERDOSAGE There is no clinical data on overdosage with YOSPRALA. Aspirin 17 Reference ID: 5482813 Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. The early signs of salicylic overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approaching 200 mg/mL. Plasma concentrations of aspirin above 300 mg/mL are clearly toxic. Severe toxic effects are associated with levels above 400 mg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g. Signs and Symptoms: In acute overdose, severe acid-base and electrolyte disturbances may occur and are complicated by hyperthermia and dehydration. Respiratory alkalosis occurs early while hyperventilation is present, but is quickly followed by metabolic acidosis. Treatment: Treatment consists primarily of supporting vital functions, increasing salicylate elimination, and correcting the acid-base disturbance. Gastric emptying and/or lavage is recommended as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal, as a slurry, is beneficial, if less than 3 hours have passed since ingestion. Charcoal adsorption should not be employed prior to emesis and lavage. Severity of aspirin intoxication is determined by measuring the blood salicylate level. Serial salicylate levels should be obtained every 1 to 2 hours until concentrations have peaked and are declining. Acid-base status should be closely followed with serial blood gas and serum pH measurements. Fluid and electrolyte balance should also be maintained. In severe cases, hyperthermia and hypovolemia are the major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylate if renal function is normal. Infusion of glucose may be required to control hypoglycemia. Hemodialysis and peritoneal dialysis can be performed to reduce the body drug content. In patients with renal impairment or in cases of life-threatening intoxication, dialysis is usually required. Exchange transfusion may be indicated in infants and young children. Omeprazole Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg. Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen with recommended doses of omeprazole [see Adverse Reactions (6)]. Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was taken alone. No specific antidote for omeprazole overdosage is known. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive. If overexposure to YOSPRALA occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage. 11 DESCRIPTION The active ingredients of YOSPRALA are aspirin which is an antiplatelet agent and omeprazole which is a PPI. YOSPRALA (aspirin and omeprazole) is an oval, blue-green, multi-layer film-coated, delayed- release tablet consists of an enteric coated delayed-release aspirin core surrounded by an immediate-release omeprazole layer for oral administration. Each delayed-release tablet contains either 81 mg aspirin and 40 mg omeprazole printed with 81/40, or 325 mg aspirin and 40 mg omeprazole printed with 325/40. The excipients used in the formulation of YOSPRALA are all inactive and United States Pharmacopeia/National Formulary (USP/NF) defined. The inactive ingredients in YOSPRALA include: carnauba wax, colloidal silicon dioxide, corn starch, FD&C Blue #2, glyceryl monostearate, hydroxypropyl methycellulose, methacrylic acid copolymer dispersion, microcrystalline cellulose, polydextrose, polyethylene glycol, polysorbate 80, povidone, pre­ gelatinized starch, sodium phosphate dibasic anhydrous, stearic acid, talc, titanium dioxide, triacetin, triethyl citrate, yellow iron oxide. Aspirin is acetylsalicylic acid and is chemically known as benzoic acid, 2-(acetyloxy). Aspirin is an odorless white needle-like crystalline or powdery substance. When exposed to moisture, 18 Reference ID: 5482813 OH aspirin hydrolyzes into salicylic and acetic acids and gives off a vinegary odor. It is highly lipid soluble and slightly soluble in water. Aspirin irreversibly inhibits platelet COX-1. Omeprazole is a white to off-white crystalline powder which melts with decomposition at about 155°C. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of omeprazole is a function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions. Omeprazole is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2­ pyridinyl) methyl] sulfinyl]-1H- benzimidazole, a compound that inhibits gastric acid secretion. Structural Formula Aspirin Omeprazole Molecular Formula The empirical formula of aspirin is C9H8O4. The empirical formula of omeprazole is C17H19N3O3S. Molecular Weight The molecular weight of aspirin is 180.16. The molecular weight of omeprazole is 345.4. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Aspirin (acetylsalicylic acid) is an inhibitor of both prostaglandin synthesis and platelet aggregation. The differences in activity between aspirin and salicylic acid are thought to be due to the acetyl group on the aspirin molecule. This acetyl group is responsible for the inactivation of cyclo-oxygenase via acetylation. Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the [H+/K+]-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose- related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. 12.2 Pharmacodynamics Anti-platelet Activity Aspirin affects platelet aggregation by irreversibly inhibiting prostaglandin cyclo-oxygenase. This effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor thromboxane A2. Nonacetylated salicylates do not inhibit this enzyme and have no effect on platelet aggregation. At higher doses, aspirin reversibly inhibits the formation of prostaglandin I2 (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation. Antisecretory Activity 19 Reference ID: 5482813 The effect of YOSPRALA 325 mg/40 mg tablets on intragastric pH was determined in a study of 26 healthy subjects dosed for 7 days. The mean percent time intragastric pH >4.0 was 51%. Serum Gastrin Effects In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with histamine H2-receptor antagonists, the median increases produced by 20 mg doses of omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy. Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.16), Drug Interactions (7)]. Enterochromaffin-like (ECL) Cell Effects Human gastric biopsy specimens have been obtained from more than 3000 patients treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients. However, these studies are of insufficient duration and size to rule out the possible influence of long-term administration of omeprazole on the development of any premalignant or malignant conditions. Endocrine Effects Omeprazole given in oral doses of 30 or 40 mg for 2 to 4 weeks had no effect on thyroid function, carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. Effects on Gastrointestinal Microbial Ecology As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment. Other Effects Systemic effects of omeprazole in the CNS, cardiovascular and respiratory systems have not been found to date. No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of omeprazole 90 mg. In healthy subjects, a single intravenous dose of omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans. However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased. 12.3 Pharmacokinetics Absorption Aspirin: Following absorption, aspirin (acetylsalicylic acid) is hydrolyzed to salicylic acid. The rate of absorption from the GI tract is dependent upon the presence or absence of food, gastric pH (the presence or absence of GI antacids or buffering agents), and other physiologic factors. Enteric coated aspirin products are erratically absorbed from the GI tract. Following single dose administration of YOSPRALA, peak concentrations of acetylsalicylic acid were reached at 2.5 hours for YOSPRALA 81 mg/40 mg tablets and at 4 to 4.5 hours for YOSPRALA 325 mg/40 mg tablets. The Cmax and AUC of acetylsalicylic acid were 2.6 mcg/mL and 3 mcg.hr/mL following single dose administration of YOSPRALA 81 mg/40 mg tablets and were 2.5 mcg/mL and 2.9 mcg.hr/mL following single dose administration of YOSPRALA 325 mg/40 mg tablets. There is no significant accumulation of salicylic acid and acetylsalicylic acid following 7 days dosing of YOSPRALA 325 mg/40 mg tablets compared to the first day of dosing. The inter-subject variability (CV%) of acetylsalicylic acid pharmacokinetic parameters ranged from 17% to 96%. Omeprazole: Following administration of YOSPRALA, the peak plasma concentration of omeprazole is reached at 0.5 hours on both the first day of administration and at steady state. 20 Reference ID: 5482813 The Cmax and AUC of omeprazole ranged from 617 to 856 ng/mL and 880-1384 ng.hr/mL following single dose administration of YOSPRALA 325 mg/40 mg tablets. Dosing YOSPRALA 325 mg/40 mg for 7 days results in approximately 2.3-fold higher AUC and 2­ fold higher Cmax of omeprazole at steady state compared to the first day of dosing. The inter-subject variability of omeprazole pharmacokinetic parameters were high with % CVs ranging from 33% to 136%. Food Effect: Aspirin: Administration of YOSPRALA with high-fat (approximately 50%) and high-calorie (800-1000 calorie) meal in healthy subjects does not affect the extent of absorption of aspirin as measured by salicylic acid AUC and Cmax but significantly prolongs salicylic acid tmax by about 10 hours. Administration of YOSPRALA 60 minutes before a high-fat, high- calorie meal has essentially no effect on salicylic acid AUCs, Cmax and tmax. Omeprazole: Administration of YOSPRALA with high-fat (approximately 50%) and high- calorie (800-1000 calories) meal in healthy subjects significantly reduces the extent of absorption of omeprazole resulting in 67% and 84% reductions of AUCs and Cmax respectively relative to fasting conditions. Administration of YOSPRALA 60 minutes before high-fat, high- calorie meal reduced both the omeprazole AUC and Cmax by approximately 15% relative to fasting conditions [see Dosage and Administration (2.2)]. Distribution Aspirin: Salicylic acid is widely distributed to all tissues and fluids in the body including the central nervous system (CNS), breast milk, and fetal tissues. The highest concentrations are found in the plasma, liver, renal cortex, heart, and lungs. The protein binding of salicylate is concentration-dependent, i.e., nonlinear. At low concentrations (less than 100 mcg/mL), approximately 90% of plasma salicylate is bound to albumin while at higher concentrations (greater than 400 mcg/mL), only about 75% is bound. Omeprazole: Protein binding is approximately 95%. Elimination Metabolism Aspirin: Aspirin (acetylsalicylic acid) is rapidly hydrolyzed in the plasma to salicylic acid such that plasma levels of aspirin are essentially undetectable 1 to 2 hours after dosing with half-life of 0.35 hrs. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Omeprazole: Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system. The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. Excretion Aspirin: The elimination of salicylic acid follows zero order pharmacokinetics; (i.e., the rate of drug elimination is constant in relation to plasma concentration). Renal excretion of unchanged drug depends upon urine pH. As urinary pH rises above 6.5, the renal clearance of free salicylate increases from 5% to greater than 80%. Following therapeutic doses, approximately 10% is excreted in the urine as salicylic acid, 75% as salicyluric acid, and 10% phenolic and 5% acyl glucuronides of salicylic acid. Half-life of salicylic acid following YOSPRALA 325 mg/40 mg tablets is 2.4 hours. Omeprazole: Following single dose oral administration of a buffered solution of omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma — the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity. The half- life of the omeprazole component is 1 hour. Specific Populations Age: Geriatric Population There is no specific data on the pharmacokinetics of YOSPRALA in patients over age 65. 21 Reference ID: 5482813 Omeprazole: The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered solution) was administered to healthy elderly subjects, versus 58% in young subjects given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole and no unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min (about half that of young subjects) and its plasma half-life averaged one hour, about twice that of young healthy subjects. Race Pharmacokinetic differences of YOSPRALA due to race have not been studied. Renal Impairment The pharmacokinetics of YOSPRALA has not been determined in subjects with renal impairment. Omeprazole: In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73 m2, the disposition of omeprazole was very similar to that in healthy subjects, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. Hepatic Impairment The pharmacokinetics of YOSPRALA has not been determined in subjects with hepatic impairment. Omeprazole: In patients with chronic hepatic disease, classified as Child-Pugh Class A (n=3), B (n=4) and C (n=1), the bioavailability of omeprazole increased by approximately 100% compared to healthy subjects, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared with the half-life in healthy subjects of 0.5 to 1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500 to 600 mL/min in healthy subjects [see Use in Specific Populations (8.7)]. Drug Interaction Studies Effect of YOSPRALA on Other Drugs Omeprazole is a time-dependent inhibitor of CYP2C19 and can increase the systemic exposure of co-administered drugs that are CYP2C19 substrates. In addition, administration of omeprazole increases intragastric pH and can alter the systemic exposure of certain drugs that exhibit pH-dependent solubility. Antiretrovirals: For some antiretroviral drugs, such as rilpivirine, atazanavir and nelfinavir, decreased serum concentrations have been reported when given together with omeprazole [see Drug Interactions (7)]. Rilpivirine: Following multiple doses of rilpivirine (150 mg, daily) and omeprazole (20 mg, daily), AUC was decreased by 40%, Cmax by 40%, and Cmin by 33% for rilpivirine. Nelfinavir: Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Atazanavir: Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Saquinavir: Following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. AUC was increased by 82%, Cmax by 75%, and Cmin by 106%. The mechanism behind this interaction is not fully elucidated. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with omeprazole. Clopidogrel: In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and 22 Reference ID: 5482813 omeprazole 80 mg daily when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period. In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction [see Warnings and Precautions (5.4), Drug Interactions (7)]. Mycophenolate Mofetil: Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of MPA [see Drug Interactions (7)]. Cilostazol: Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. The Cmax and AUC of one of the active metabolites, 3,4-dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69%, respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and the above mentioned active metabolite [see Drug Interactions (7)]. Diazepam: Concomitant administration of omeprazole 20 mg once daily and diazepam 0.1 mg/kg given intravenously resulted in 27% decrease in clearance and 36% increase in diazepam half-life [see Drug Interactions (7)]. Digoxin: Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects) [see Drug Interactions (7)]. Effect of Other Drugs on Yosprala Voriconazole: Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state Cmax and AUC0-24 of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole [see Drug Interactions (7)]. 12.5 Pharmacogenomics CYP2C19, a polymorphic enzyme, is involved in the metabolism of omeprazole. The CYP2C19*1 allele is fully functional while the CYP2C19*2 and *3 alleles are nonfunctional. There are other alleles associated with no or reduced enzymatic function. Patients carrying two fully functional alleles are extensive metabolizers and those carrying two loss-of-function alleles are poor metabolizers. In extensive metabolizers, omeprazole is primarily metabolized by CYP2C19. The systemic exposure to omeprazole varies with a patient’s metabolism status: poor metabolizers > intermediate metabolizers > extensive metabolizers. Approximately 3% of Caucasians and 15 to 20% of Asians are CYP2C19 poor metabolizers. In a pharmacokinetic study of single 20 mg omeprazole dose, the AUC of omeprazole in Asian subjects was approximately four-fold of that in Caucasians [see Use in Specific Populations (8.8)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies to evaluate the potential effects of YOSPRALA on carcinogenicity, mutagenicity, or impairment of fertility have not been conducted. Aspirin Administration of aspirin for 68 weeks at 0.5% in the feed of rats was not carcinogenic. In the Ames Salmonella assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations in cultured human fibroblasts. Aspirin inhibits ovulation in rats. 23 Reference ID: 5482813 Omeprazole In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.35 to 34 times the human dose of 40 mg per day, based on body surface area) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 3.4 times the human dose of 40 mg per day, based on body surface area) for one year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.1 to 3.2 times the human dose of 40 mg/day, based on body surface area). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males and females at the high dose of 140.8 mg/kg/day (about 34 times the human dose of 40 mg per day, based on body surface area). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26­ week p53 (+/-) transgenic mouse carcinogenicity study was not positive. Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames Salmonella typhimurium assay, an in vitro mouse lymphoma cell forward mutation assay and an in vivo rat liver DNA damage assay. Omeprazole at oral doses up to 138 mg/kg/day (about 34 times the human dose of 40 mg per day, based on body surface area) was found to have no effect on fertility and reproductive performance. In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists. 13.2 Animal Toxicology and/or Pharmacology Aspirin The acute oral 50% lethal dose in rats is about 1.5 g/kg and in mice 1.1 g/kg. Renal papillary necrosis and decreased urinary concentrating ability occur in rodents chronically administered high doses. Dose-dependent gastric mucosal injury occurs in rats and humans. Mammals may develop aspirin toxicosis associated with GI symptoms, circulatory effects, and central nervous system depression [see Overdosage (10)]. Omeprazole Reproductive Toxicology Studies Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times the human dose on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 34 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times the human dose on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 3.4 to 34 times the human doses on a body surface area basis). Juvenile Animal Study A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at oral doses of 70 to 280 mg/kg/day (about 17 to 67 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses 24 Reference ID: 5482813 equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole. 14 CLINICAL STUDIES Aspirin Trials Ischemic Stroke and Transient Ischemic Attack (TIA) In clinical trials of subjects with TIA due to fibrin platelet emboli or ischemic stroke, aspirin has been shown to significantly reduce the risk of the combined endpoint of stroke or death and the combined endpoint of TIA, stroke, or death by about 13 to18%. Prevention of Recurrent MI and Unstable Angina Pectoris These indications are supported by the results of six large, randomized, multi-center, placebo- controlled trials of predominantly male post-MI subjects and one randomized placebo- controlled study of men with unstable angina pectoris. Aspirin therapy in MI subjects was associated with a significant reduction (about 20%) in the risk of the combined endpoint of subsequent death and/or nonfatal reinfarction in these patients. In aspirin-treated unstable angina patients the event rate was reduced to 5% from the 10% rate in the placebo group. Chronic Stable Angina Pectoris In a randomized, multi-center, double-blind trial designed to assess the role of aspirin for prevention of MI in patients with chronic stable angina pectoris, aspirin significantly reduced the primary combined endpoint of nonfatal MI, fatal MI, and sudden death by 34%. The secondary endpoint for vascular events (first occurrence of MI, stroke, or vascular death) was also significantly reduced (32%). Revascularization Procedures Most patients who undergo coronary artery revascularization procedures have already had symptomatic coronary artery disease for which aspirin is indicated. Similarly, patients with lesions of the carotid bifurcation sufficient to require carotid endarterectomy are likely to have had a precedent event. Aspirin is recommended for patients who undergo revascularization procedures if there is a preexisting condition for which aspirin is already indicated. YOSPRALA trials Two randomized, multi-center, double-blind trials (Study 1 and Study 2) evaluated the omeprazole component by comparing the incidence of gastric ulcer formation in 524 patients randomized to YOSPRALA 325 mg/40 mg tablets and 525 patients randomized to EC-aspirin 325 mg. Patients were included with a cerebro- or cardiovascular diagnosis if they had been taking daily aspirin 325 mg for at least 3 months, were expected to require daily aspirin 325 mg therapy for at least 6 months and were over 55 years old. Subjects between 18 and 55 years old were also required to have a documented history of gastric or duodenal ulcer within the past 5 years. The majority of patients were male (71%) and white (90%). The majority (57%) of patients were ≥65 years of age. Approximately 11% were also on chronic NSAID therapy. Studies 1 and 2 showed that YOSPRALA given as 325 mg/40 mg tablets once daily statistically significantly reduced the 6-month cumulative incidence of gastric ulcers compared to EC-aspirin 325 mg once daily. The results at one month, three months, and six months treatment are presented in Table 4. 25 Reference ID: 5482813 Table 4: Cumulative Incidence of Gastric Ulcers at 1, 3, and 6 Months Study 1 Study 2 YOSPRALA N=265 Number (%) EC- Aspirin N=265 Numbe r (%) YOSPRALA N=259 Number (%) EC- Aspirin N=260 Number (%) 0-1 Month 3 (1.1) 10 (3.8) 1 (0.4) 8 (3.1) 0-3 Months 8 (3.0) 18 (6.8) 1 (0.4) 17 (6.5) 0-6 † Months 10 (3.8) 23 (8.7) 7 (2.7) 22 (8.5) †Study 1: p=0.020 and Study 2: p=0.005 for treatment comparisons of cumulative GU incidence at 6 months. In both trials, patients receiving YOSPRALA 325 mg/40 mg tablets had a statistically significantly lower 6-month cumulative incidence of gastric and/or duodenal ulcers compared to EC-aspirin 325 mg (3% vs. 12%). Upper GI bleeding was reported as a serious adverse reaction in each treatment arm; 1 gastric ulcer hemorrhage in a subject receiving YOSPRALA and 1 duodenal ulcer hemorrhage in a subject receiving EC-aspirin alone. 16 HOW SUPPLIED/STORAGE AND HANDLING YOSPRALA (aspirin 81 mg/omeprazole 40 mg) and (aspirin 325 mg/omeprazole 40 mg) delayed-release tablets are oval, blue-green, film-coated tablets printed with 81/40 and 325/40 respectively in black ink. YOSPRALA tablets are packaged in high density polyethylene (HDPE) bottles with desiccants and are supplied as: NDC 64950-424-30 Bottles of 30 tablets YOSPRALA 81/40 NDC 64950-424-90 Bottles of 90 tablets YOSPRALA 81/40 NDC 64950-425-30 Bottles of 30 tablets YOSPRALA 325/40 NDC 64950-425-90 Bottles of 90 tablets YOSPRALA 325/40 Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59 to 86°F) [see USP Controlled Room Temperature]. Store in the original container with desiccant and keep the bottle tightly closed to protect from moisture. Dispense in a tight container if package is subdivided. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients, families, or caregivers of the following before initiating therapy with YOSPRALA and periodically during the course of ongoing therapy. Coagulation Abnormalities Advise patients to inform their health care provider if they experience any unanticipated, prolonged or excessive bleeding or bleeding time (e.g. bruising, nose bleed) [see Warnings and Precautions (5.1)]. GI Adverse Reactions Advise patients to stop taking YOSPRALA and call their health care provider right away if they have any of the following signs or symptoms: 1) black, bloody, or tarry stools; 2) coughing up blood or vomit that looks like coffee grounds; 3) severe nausea, vomiting, or stomach pain [see Warnings and Precautions (5.2)]. Bleeding Risk with Use of Alcohol Advise patients to avoid heavy alcohol use (three or more drinks every day) during treatment with YOSPRALA during treatment with YOSPRALA [see Warnings and Precautions (5.3)]. Drug Interactions Advise patients to report to their healthcare provider before starting treatment with any of the following: 26 Reference ID: 5482813 • Rilpivirine-containing products [see Contraindications (4)]. • Clopidogrel, ticagrelor, St. John’s Wort or rifampin; or, if they take high-dose methotrexate [see Warnings and Precautions (5.4, 5.5, 5.15, 5.17)]. Renal Failure Advise patients to report to their health care provider if they develop kidney problems (e.g. changes in urination, swelling, skin rash/itching, ammonia breath) [see Warnings and Precautions (5.6)]. Gastric Malignancy Advise patients to return to their healthcare provider if they have gastric symptoms while taking YOSPRALA or after completing treatment [see Warnings and Precautions (5.7)]. Acute Tubulointerstitial Nephritis Advise patients to call their healthcare provider immediately if they experience signs and/or symptoms associated with acute tubulointerstitial nephritis [see Warnings and Precautions (5.8)]. Clostridium difficile-Associated Diarrhea Advise patients to call their health care provider immediately if they experience diarrhea that does not improve [see Warnings and Precautions (5.9)]. Bone Fracture Advise patients to report any fractures, especially of the hip, wrist or spine, to their health care provider [see Warnings and Precautions (5.10)]. Serious or Severe Skin Reactions Advise patients to stop taking YOSPRALA and immediately call their health care provider at the first appearance of a skin rash or other sign of hypersensitivity [see Warnings and Precautions (5.11)]. Cutaneous and Systemic Lupus Erythematosus Advise patients to immediately call their health care provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus [see Warnings and Precautions (5.12)]. Hepatic Impairment Advise patients to report to their health care provider if they develop liver problems (e.g. skin and eyes that appear yellowish, abdominal pain and swelling, itchy skin, dark urine color) [see Warnings and Precautions (5.13)]. Cyanocobalamin (Vitamin B-12) Deficiency Advise patients to report any clinical symptoms that may be associated with cyanocobalamin deficiency to their health care provider if they have been receiving YOSPRALA for longer than 3 years [see Warnings and Precautions (5.14)]. Hypomagnesemia and Mineral Metabolism Advise patients to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, and/or hypokalemia to their health care provider, if they have been receiving YOSPRALA for at least 3 months [see Warnings and Precautions (5.15)]. Fetal Toxicity Inform pregnant women to avoid use of YOSPRALA and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closure of the fetal ductus arteriosus. If treatment with YOSPRALA is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios [see Warnings and Precautions (5.19) and Use in Specific Populations (8.1)]. Lactation Advise women that breastfeeding is not recommended during treatment with YOSPRALA [see Use in Specific Populations (8.2)]. Infertility Advise females of reproductive potential that NSAIDs, including YOSPRALA, may be associated with reversible infertility [see Use in Specific Populations (8.3)]. Administration [see Dosage and Administration (2.2)] Advise patients: • To take YOSPRALA once daily at least 60 minutes before a meal. 27 Reference ID: 5482813 • The tablets are to be swallowed whole with liquid. Do not split, chew, crush or dissolve the tablet. • If a dose is missed, administer as soon as possible. However, if the next scheduled dose is due, do not take the missed dose, and take the next dose on time. Do not take two doses at one time to make up for a missed dose, unless advised by their health care provider. • Not to stop taking YOSPRALA suddenly as this could increase the risk of heart attack or stroke. Manufactured for: Genus Lifesciences Inc. Allentown, PA 18102 28 Reference ID: 5482813 MEDICATION GUIDE YOSPRALA® (yo SPRA lah) (aspirin and omeprazole) delayed-release tablets What is the most important information I should know about YOSPRALA? You should take YOSPRALA exactly as prescribed, at the lowest dose possible and for the shortest time needed. YOSPRALA may help reduce the risk of stomach ulcers from aspirin use, but you could still have bleeding and stomach or intestine ulcers, or other serious stomach or intestine problems. Talk with your doctor. Tell your doctor if you have unexpected bleeding, if you bleed more than usual, or if your bleeding lasts longer than is normal for you, such as increased bruising or more frequent nose bleeds. YOSPRALA contains aspirin, a nonsteroidal anti-inflammatory drug (NSAID) and omeprazole, a proton pump inhibitor (PPI) medicine. Before taking YOSPRALA, tell your doctor if you take: • aspirin, or anyprescription or over-the-counter medicines containing aspirin or other NSAIDs. ® • clopidogrel bisulphate (PLAVIX ). You should not take clopidogrel bisulphate (PLAVIX®) if you take YOSPRALA. ® • ticagrelor (BRILINTA ). Do not stop taking YOSPRALA without talking with your doctor. Stopping YOSPRALA suddenly could increase your risk of having a heart attack or stroke. YOSPRALA can cause serious side effects, including: • A type of kidney problem (acute tubulointerstitial nephritis). Some people who take proton pump inhibitor (PPI) medicines, including YOSPRALA, may develop a kidney problem called acute tubulointerstitial nephritis that can happen at any time during treatment with YOSPRALA. Call your doctor right away if you have a decrease in the amount that you urinate or if you have blood in yoururine. • Diarrhea caused by an infection (Clostridium difficile) in your intestines. Call your doctor right away if you have watery stools or stomach pain that does not go away. You may or may not have a fever. • Bone fractures (hip, wrist, or spine). Bone fractures in the hip, wrist, or spine may happen in people who take multiple daily doses of PPI medicines and for a long period of time (a year or longer). Tell your doctor if you have a bone fracture, especially in the hip, wrist, orspine. • Certain types of lupus erythematosus. Lupus erythematosus is an autoimmune disorder (the body’s immune cells attack other cells or organs in the body). Some people who take PPI medicines, including YOSPRALA, may develop certain types of lupus erythematosus or have worsening of the lupus they already have. Call your doctor right away if you have new or worsening joint pain or a rash on your cheeks or arms that gets worse in the sun. Talk to your doctor about your risk of these serious side effects. YOSPRALA can have other serious side effects. See “What are the possible side effects of YOSPRALA?” What is YOSPRALA? YOSPRALA is a prescription medicine used: ● in people who have had heart problems or strokes caused by blood clots, to help reduce their risk of further heart problems or strokes, and ● who are at risk of developing stomach ulcers with aspirin. The aspirin in YOSPRALA is used: • to help reduce the risk of strokes and death in people who have previously had certain types of “mini strokes” (transient ischemic attacks or TIAs) or strokes. • to help reduce the risk of heart attack and death in people who have previously had a heart attack or a type of chest pain called unstable angina pectoris. • to help reduce the risk of heart attack and sudden death in people with a type of ongoing chest pain called chronic stable angina pectoris. • in people who have had surgery or a procedure to improve blood flow to their heart, such as coronary artery bypass grafting (CABG), or percutaneous transluminal coronary angioplasty (PTCA), and who already have another condition that is being treated withaspirin. The omeprazole in YOSPRALA is used: • to help decrease the risk of developing stomach ulcers due to aspirin in people who are 55 years of age or older, or who have a history of stomach ulcers. YOSPRALA should not be used to treat sudden signs and symptoms of a heart attack or stroke. YOSPRALA should only be used as directed by your doctor to help reduce the risk of further heart problems or strokes. It is not known if YOSPRALA is safe and effective in children. YOSPRALA has not been shown to reduce the risk of bleeding in the stomach or intestines that is caused by aspirin. You should not take an aspirin tablet and an omeprazole tablet together instead of taking YOSPRALA, because they will not work the same way. Do not take YOSPRALA if you: ● are allergic to aspirin, omeprazole, any other PPI medicine, or any of the ingredients in YOSPRALA. See the end of this Medication Guide for a complete list of ingredients in YOSPRALA. ● are allergic to any nonsteroidal anti-inflammatory drug (NSAID). ● have a medical condition with severe shortness of breath, chest tightness or pain, coughing or wheezing (asthma), sneezing, runny nose or itchy nose (rhinitis), and growths inside of your nose or sinuses (nasal polyps). • are taking a medicine that contains rilpivirine (EDURANT, COMPLERA, ODEFSEY) used to treat HIV-1 (Human Immunodeficiency Virus). Do not give YOSPRALA to a child who has a suspected viral infection, even if they do not have a fever. There is a risk of Reye’s syndrome with YOSPRALA because it contains aspirin. Before taking YOSPRALA, tell your doctor about all of your medical conditions, including if you: See “What is the most important information I should know about YOSPRALA?” • have any bleeding problems. • drink 3 or more drinks that contain alcohol everyday. • have kidney or liver problems. • have been told that you have low magnesium levels in yourblood. • are of Asian descent and have been told that your body’s ability to break down (metabolize) omeprazole is poor or if your genotype called CYP2C19 is not known. • are pregnant or plan to become pregnant. Taking NSAID-containing products like YOSPRALA at about 20weeks of 29 Reference ID: 5482813 pregnancy or later may harm your unborn baby. If you need to take YOSPRALA when you are between 20 and 30 weeks of pregnancy, your doctor may need to monitor the amount of fluid in your womb around your baby. You should not take YOSPRALA after about 30 weeks of pregnancy. • are breastfeeding or plan to breastfeed. The aspirin and omeprazole in YOSPRALA can pass into your breast milk and may harm your baby. Breastfeeding is not recommended during treatment with YOSPRALA. Talk to your doctor about the best way to feed your baby if you take YOSPRALA. • are a female who can become pregnant. YOSPRALA may be related to infertility in some women that is reversible when treatment with YOSPRALA isstopped. Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. YOSPRALA and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your doctor first. Especially tell your doctor if you take: ® • clopidogrel bisulphate (PLAVIX ) ® • ticagrelor (BRILINTA ) • St. John’s Wort (Hypericum perforatum) ® ® ® • rifampin (Rimactane, RIFATER , RIFAMATE RIFADIN ) • methotrexate (Otrexup, Rasuvo, Trexall, XATMEP) • digoxin (LANOXIN) • a water pill (diuretic) How should I take YOSPRALA? • Take YOSPRALA exactly as prescribed by yourdoctor. • Take 1 YOSPRALA tablet 1 time each day. • Take YOSPRALA at least 1 hour before ameal. • Swallow YOSPRALA tablets whole with liquid. Do not split, chew, crush, or dissolveYOSPRALA. • If you miss a dose of YOSPRALA, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take the next dose at your regular time. Do not take 2 doses at the same time unless your doctor tells you to. • If you take too much YOSPRALA, call your doctor or your poison control center at 1-800-222-1222 right away or go to the nearest emergency room. What should I avoid while taking YOSPRALA? Avoid heavy alcohol use during treatment with YOSPRALA. People who drink three or more drinks that contain alcohol every day have a higher risk of bleeding during treatment with YOSPRALA because it contains aspirin. What are the possible side effects of YOSPRALA? YOSPRALA can cause serious side effects, including: See “What is the most important information I should know about YOSPRALA?” • Stomach and intestine problems. Stop taking YOSPRALA and call your doctor right away if you have symptoms of stomach and intestine problems, including black, bloody, or tarry stools, coughing up blood or vomit that looks like coffee grounds, or severe nausea, vomiting, or stomachpain. • Kidney failure. Long-lasting (chronic) kidney failure can happen with regular use of aspirin, a medicine in YOSPRALA. This is more likely to happen in people who already have kidney problems before treatment with YOSPRALA. Tell your doctor if you have symptoms of kidney failure, including changes in urination, swelling of the hands, ankles or feet, skin rash or itching, or your breath smells likeammonia. • Liver problems. Long-term use of YOSPRALA at certain doses may cause liver problems. Tell your doctor if you have symptoms of liver problems, including yellowing of your skin or your eyes, stomach-area (abdominal) pain and swelling, itchy skin, and dark (tea-colored)urine. • Low vitamin B-12 levels. Low vitamin B-12 levels in your body can happen in people who have taken YOSPRALA for a long time (more than 3 years). Tell your doctor if you have symptoms of low vitamin B-12 levels, including shortness of breath, lightheadedness, irregular heartbeat, muscle weakness, pale skin, feeling tired, mood changes, and tingling or numbness in the arms or legs. • Low magnesium levels. Low magnesium levels in your body can happen in people who have taken YOSPRALA for at least 3 months. Tell your doctor if you have symptoms of low magnesium levels, including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, and spasms of hands, feet or voice. • Stomach growths (fundic gland polyps). People who take PPI medicines for a long time have an increased risk of developing a certain type of stomach growths called fundic gland polyps, especially after taking PPI medicines for more than 1 year. • Serious or Severe skin reactions. YOSPRALA can cause rare but serious or severe skin reactions that may affect any part of your body. These serious skin reactions may need to be treated in a hospital and may be life threatening: • Skin rash which may have blistering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet). • You may also have fever, chills, body aches, shortness of breath, or enlarged lymph nodes. Stop taking YOSPRALA and call your doctor right away. These symptoms may be the first sign of a severe skin reaction. The most common side effects of YOSPRALA include: indigestion or heartburn and stomach-area pain, nausea, diarrhea, and chest pain behind the breastbone, for example, with eating. These are not all the possible side effects of YOSPRALA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store YOSPRALA? • Store YOSPRALA at room temperature between 68°F to 77°F (20°C to 25°C). • Store YOSPRALA in the originalcontainer. • Keep the container of YOSPRALA tightly closed to protect frommoisture. • The YOSPRALA container may contain a desiccant packet to help keep your medicine dry (protect it from moisture). Keep the desiccant packet in the container. Do not throw away the desiccantpacket. Keep YOSPRALA and all medicines out of the reach of children. 30 Reference ID: 5482813 General information about the safe and effective use of YOSPRALA Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use YOSPRALA for a condition for which it was not prescribed. Do not give YOSPRALA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about YOSPRALA that is written for health professionals. What are the ingredients in YOSPRALA? Active ingredients: aspirin and omeprazole Inactive ingredients: carnauba wax, colloidal silicon dioxide, corn starch, FD&C Blue #2, glyceryl monostearate, hydroxypropyl methycellulose, methacrylic acid copolymer dispersion, microcrystalline cellulose, polydextrose, polyethylene glycol, polysorbate 80, povidone, pre-gelatinized starch, sodium phosphate dibasic anhydrous, stearic acid, talc, titanium dioxide, triacetin, triethyl citrate, yellow iron oxide. Manufactured for: Genus Lifesciences Inc, 514 North 12th Street, Allentown, PA 18102 YOSPRALA® is a trademark of Genus Lifesciences Inc. For more information, go to www.genuslifesciences.com or call 1-866-511-6754 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 31 Reference ID: 5482813
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2025-02-12T15:47:16.798537
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ACETADOTE safely and effectively. See full prescribing information for ACETADOTE. ACETADOTE (acetylcysteine) injection, for intravenous use Initial U.S. Approval: 2004 ------------------------ RECENT MAJOR CHANGES---------------------------­ Dosage and Administration (2.1, 2.2, 2.3, 2.4, 2.5) 11/2024 --------------------- INDICATIONS AND USAGE--------------­ ACETADOTE is an antidote for acetaminophen overdose indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in adults and pediatric patients who weigh 5 kg or greater with acute ingestion or from repeated supratherapeutic ingestion (RSI) (1). ----------------------DOSAGE AND ADMINISTRATION ---------------------­ Pre-Treatment Assessment Following Acute Ingestion (2.1): Prior to initiating treatment with ACETADOTE, decide whether the three-bag or two-bag regimen will be used. Obtain a plasma or serum sample to assay for acetaminophen concentration at least 4 hours after ingestion. • If the time of acetaminophen ingestion is unknown: o Administer a loading dose of ACETADOTE immediately. o Obtain an acetaminophen concentration to determine need for continued treatment. • If the acetaminophen concentration cannot be obtained (or is unavailable or uninterpretable) within the 8-hour time interval after acetaminophen ingestion or there is clinical evidence of acetaminophen toxicity: o Administer a loading dose of ACETADOTE immediately and continue treatment for a total of two doses over 20 hours or three doses over 21 hours (2.5). • If the patient presents more than 8 hours after ingestion and the time of acute acetaminophen ingestion is known: o Administer a loading dose of ACETADOTE immediately o Obtain acetaminophen concentration to determine need for continued treatment • If the patient presents less than 8 hours after ingestion and the time of acute acetaminophen ingestion is known and the acetaminophen concentration is known: o Use the revised Rumack-Matthew nomogram (Figure 1) to determine whether or not to initiate treatment with ACETADOTE (2.2) Nomogram for Estimating Potential for Hepatotoxicity from Acute Acetaminophen Ingestion (2.2): See Full Prescribing Information for instructions on how to use the nomogram to determine the need for dosing. Preparation and Storage of Diluted Solution Prior to Administration (2.3): • Calculate the dose (mg) based on the patient’s weight in kg; multiple vials of ACETADOTE may be required. o ACETADOTE is hyperosmolar (2,600 mOsmol/L), therefore ACETADOTE must be diluted in the recommended volume of sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water injection prior to intravenous administration. In general, 0.45% normal saline is the preferred diluent because it provides a more consistent osmolarity profile, reduces the amount of free water delivered to the patient, and better approximates physiologic fluids. See Full Prescribing Information for examples of osmolarity depending on the type of solution and ACETADOTE concentration. General Considerations for Selecting the Three-Bag or Two-Bag Regimen (2.4): • It is not known whether the two-bag regimen is comparable to the three- bag regimen in preventing hepatotoxicity. • Patients 40 kg or less should receive the three-bag regimen. • For patients weighing 41 kg or greater, the three-bag regimen may be preferred for those with early signs of severe liver injury or a large acetaminophen ingestion. Recommended Dosage for Acute Acetaminophen Ingestion (2.5): • ACETADOTE is for intravenous administration only • Total dosage of ACETADOTE is 300 mg/kg given intravenously as either: o 3 separate doses infused over a total of 21 hours OR o 2 separate doses infused over a total of 20 hours. • See Full Prescribing Information for weight-based dosage and weight- based dilution (2.5) See Full Prescribing Information for recommendations for continuing ACETADOTE treatment after 21 hours (2.2). Repeated Supratherapeutic Acetaminophen Ingestion (2.6): • Obtain acetaminophen concentration and other laboratory tests to guide treatment; revised Rumack-Matthew nomogram does not apply. -------------------DOSAGE FORMS AND STRENGTHS-----------------­ Injection: 6000 mg/30 mL (200 mg/mL) in a single-dose vial (3) ---------------------------CONTRAINDICATIONS---------------------------­ Patients with a previous hypersensitivity reaction to acetylcysteine (4) --------------------WARNINGS AND PRECAUTIONS---------------------­ • Hypersensitivity Reactions: Fatal or life-threatening anaphylaxis, rash, hypotension, wheezing, shortness of breath, and/or bronchospasm have been observed. Observe patients during and after the infusion; immediately discontinue infusion if a serious reaction occurs and initiate appropriate treatment. ACETADOTE infusion may be carefully restarted after treatment of hypersensitivity has been initiated and acute symptoms have resolved (5.1). • Fluid Overload: Total volume administered should be reduced for patients weighing less than 40 kg and for those requiring fluid restriction (5.2). ----------------------------ADVERSE REACTIONS----------------------------­ Most common adverse reactions (> 2%) are rash, urticaria/facial flushing and pruritus (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Cumberland Pharmaceuticals Inc. at 1-877-484-2700 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION Revised: 11/2024 Page 1 Reference ID: 5486282 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Pre-Treatment Assessment and Testing Following Acute Acetaminophen Ingestion 2.2 Nomogram for Estimating Potential for Hepatotoxicity from Acute Acetaminophen Ingestion and Need for ACETADOTE Treatment 2.3 Preparation and Storage of ACETADOTE Diluted Solution Prior to Administration 2.4 General Considerations for Selecting the Three-Bag or Two-Bag Regimen 2.5 Recommended Dosage for Acute Acetaminophen Ingestion 2.6 Recommendations for Repeated Supratherapeutic Acetaminophen Ingestion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Fluid Overload 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the Full Prescribing Information are not listed. Page 2 Reference ID: 5486282 I FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE ACETADOTE is indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in adults and pediatric patients who weigh 5 kg or greater with acute ingestion or from repeated supratherapeutic ingestion (RSI). 2 DOSAGE AND ADMINISTRATION 2.1 Pre-Treatment Assessment and Testing Following Acute Acetaminophen Ingestion Prior to initiating treatment with ACETADOTE, decide whether the three-bag or two-bag regimen will be used [see Dosage and Administration (2.4)]. The following recommendations are related to acute acetaminophen ingestion. For recommendations related to repeated supratherapeutic exposure [see Dosage and Administration (2.6)]. 1. Assess the history and timing of acetaminophen ingestion as an overdose. • The reported history of the quantity of acetaminophen ingested as an overdose is often inaccurate and is not a reliable guide to therapy. 2. Obtain the following laboratory tests to monitor hepatic and renal function and electrolyte and fluid balance: aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, international normalized ratio (INR), creatinine, blood urea nitrogen (BUN), blood glucose, and electrolytes. 3. Obtain a plasma or serum sample to assay for acetaminophen concentration at least 4 hours after ingestion. Acetaminophen concentrations obtained earlier than 4 hours post-ingestion may be misleading as they may not represent maximum acetaminophen concentrations. 4. If the time of acute acetaminophen ingestion is unknown: • Administer a loading dose of ACETADOTE immediately [see Dosage and Administration (2.5)]. • Obtain an acetaminophen concentration to determine need for continued treatment [see Dosage and Administration (2.2)]. 5. If the acetaminophen concentration cannot be obtained (or is unavailable or uninterpretable) within the 8­ hour time interval after acetaminophen ingestion or there is clinical evidence of acetaminophen toxicity: • Administer a loading dose of ACETADOTE immediately and continue treatment for a total of two doses over 20 hours or three doses over 21 hours [see Dosage and Administration (2.5)]. 6. If the patient presents more than 8 hours after ingestion and the time of acute acetaminophen ingestion is known: • Administer a loading dose of ACETADOTE immediately [see Dosage and Administration (2.5)] • Obtain an acetaminophen concentration to determine need for continued treatment [see Dosage and Administration (2.2)]. 7. If the patient presents less than 8 hours after ingestion and the time of acute acetaminophen ingestion is known and the acetaminophen concentration is known: • Use the revised Rumack-Matthew nomogram (Figure 1) to determine whether or not to initiate treatment with ACETADOTE [see Dosage and Administration (2.2)]. Page 3 Reference ID: 5486282 2.2 Nomogram for Estimating Potential for Hepatoxicity from Acute Acetaminophen Ingestion and Need for ACETADOTE Treatment ACETADOTE is an antidote for acetaminophen overdose. The critical ingestion-treatment interval for maximal protection against severe hepatic injury is between 0 and 8 hours. Efficacy diminishes progressively after 8 hours and treatment initiation between 15 and 24 hours post-ingestion of acetaminophen yields limited efficacy. However, it does not appear to worsen the condition of patients and it should not be withheld, since the reported time of ingestion may not be correct. If the timing of the acute acetaminophen ingestion is known and the results of the acetaminophen assay are available within 8 hours: • Refer to the revised Rumack-Matthew nomogram (see Figure 1) to determine whether or not to initiate treatment with ACETADOTE. • Initiation of ACETADOTE depends on the plasma or serum acetaminophen concentration and also the clinical presentation of the patient. The nomogram may underestimate the hepatotoxicity risk in patients with chronic alcoholism, malnutrition, or CYP2E1 enzyme inducing drugs (e.g., isoniazid), and consideration should be given to treating these patients even if the acetaminophen concentrations are in the nontoxic range. Loading dose For patients whose acetaminophen concentrations are at or above the “possible” treatment line (dotted line in nomogram): • Administer a loading dose of ACETADOTE [see Dosage and Administration (2.5)]. For patients with an acute overdose from an extended-release acetaminophen, if the acetaminophen concentration at 4 hours post ingestion is below the possible treatment line then obtain a second sample for acetaminophen concentration 8 to 10 hours after the acute ingestion. If the second value is at or above the “possible” treatment line (dotted line in nomogram): • Administer a loading dose of ACETADOTE [see Dosage and Administration (2.5)]. For patients whose values are below the “possible” treatment line, but time of ingestion was unknown or sample was obtained less than 4 hours after ingestion: ● Administer a loading dose of ACETADOTE [see Dosage and Administration (2.5)]. For patients whose values are below the “possible” treatment line and time of ingestion is known and the sample was obtained more than 4 hours after ingestion, do not administer ACETADOTE because there is minimal risk of hepatotoxicity. Page 4 Reference ID: 5486282 500 - 300 --»ltOlt-1.rill I lOO ISO ICQ ~ BO ·~ :il'. Iii) " I 40 ! 'E" IO I 1 .J lQ f ·~ lf 'lo II .. .. 0 Q , .. Figure 1. Revised Rumack-Matthew Nomogram for Estimating Potential for Hepatoxicity for Acetaminophen Poisioning – Plasma or Serum Acetaminophen Concentration versus Time (hours) Post- acetaminophen Ingestion (Dart et al., JAMA Network Open 2023; 6(89): e2337926) Maintenance Dose Determine the need for continued treatment with ACETADOTE after the loading dose. Choose ONE of the following based on the acetaminophen concentration: The acetaminophen concentration is above the possible treatment line according to the nomogram (see Figure 1): • Continue ACETADOTE treatment with the maintenance dose for a total of either two or three separate doses over an infusion time of 20 or 21 hours, respectively [see Dosage and Administration (2.5)]. • Monitor hepatic and renal function and electrolytes throughout treatment. The acetaminophen concentration could not be obtained: • Continue ACETADOTE treatment with the maintenance dose for a total of either two or three separate doses over an infusion time of 20 or 21 hours, respectively [see Dosage and Administration (2.5)]. • Monitor hepatic and renal function and electrolytes throughout treatment. For patients whose acetaminophen concentration is below the “possible” treatment line (see Figure 1) and time of ingestion is known and the sample was obtained more than 4 hours after ingestion: • Discontinue ACETADOTE. The acetaminophen concentration was in the non-toxic range, but time of ingestion was unknown or less than 4 hours: • Obtain a second sample for acetaminophen concentration and consider the patient’s clinical status to decide whether or not to continue ACETADOTE treatment. Page 5 Reference ID: 5486282 • If there is any uncertainty as to patient’s risk of developing hepatotoxicity, it is recommended to administer a complete treatment course. Continued Therapy After Completion of Loading and Maintenance Doses In cases of suspected massive overdose, or with concomitant ingestion of other substances, or in patients with preexisting liver disease; the absorption and/or the half-life of acetaminophen may be prolonged. In such cases, consideration should be given to the need for continued treatment with ACETADOTE beyond the total 300 mg/kg dose. Acetaminophen levels and ALT/AST and INR should be checked after the last maintenance dose. If acetaminophen levels are still detectable, or if the ALT/AST are still increasing or the INR remains elevated; dosing should be continued and the treating physician should contact a US regional poison center at 1-800-222-1222, alternatively, a “special health professional assistance line for acetaminophen overdose” at 1-800-525-6115 for assistance with dosing recommendations, or 1-877-484-2700 for additional information. 2.3 Preparation and Storage of ACETADOTE Diluted Solution Prior to Administration Refer to Table 2 and Table 3 to calculate the dose (mg) based on the patient’s weight in kg; multiple vials of ACETADOTE may be required [see Dosage and Administration (2.5)]. Discard any unused portion left in the vial. Because ACETADOTE is hyperosmolar (2,600 mOsmol/L), ACETADOTE must be diluted in the recommended volume of sterile water for injection, 0.45% sodium chloride injection (1/2 normal saline), or 5% dextrose in water prior to intravenous administration. The total injection volume will vary based on the patient’s weight and chosen dosage regimen (i.e., three-bag or two-bag) [see Dosage and Administration (2.5), Warnings and Precautions (5.2)]. The choice of diluent should be based on the individual patient’s clinical status, concurrent medical conditions, and institutional protocols. The treating clinician should assess each case individually and consult with their pharmacy if there are any concerns about the appropriate diluent choice. In general, 0.45% normal saline is the preferred diluent because it provides a more consistent osmolarity profile, reduces the amount of free water delivered to the patient, and better approximates physiologic fluids than 5% dextrose in water or sterile water for injection. However, consider 5% dextrose in water or sterile water for injection if sodium load is a concern for the patient. Dilution of ACETADOTE in each of these three solutions results in different osmolarity of the acetylcysteine solution for intravenous administration (see Table 1 for examples of different osmolarity of the solution depending on the type of solution and the ACETADOTE concentration). Table 1. Examples of Acetylcysteine Concentration and Osmolarity in Three Solutions Acetylcysteine Concentration Osmolarity Sterile Water for Injection 0.45% Sodium Chloride Injection 5% Dextrose in Water (D5W) 4 mg/mL (lowest concentration 3-bag protocol) 52 mOsmol/L* 194 mOsmol/L 311 mOsmol/L 54.5 mg/mL (highest concentration 3-bag protocol) 744 mOsmol/L 855 mOsmol/L 957 mOsmol/L 7.9 mg/mL (lowest concentration 2-bag protocol) 105 mOsmol/L 241 mOsmol/L 360 mOsmol/L 18.2 mg/mL (highest concentration 2-bag protocol) 239 mOsmol/L 368 mOsmol/L 487 mOsmol/L * Adjust osmolarity to a physiologically safe level (generally not less than 150 mOsmol/L in pediatric patients). The choice of diluent should be based on the individual patient’s clinical status, concurrent medical conditions, and institutional protocols. The treating clinician should assess each case individually and consult with their pharmacy if Page 6 Reference ID: 5486282 there are any concerns about the appropriate diluent choice. In general, 0.45% normal saline is the preferred diluent, as it provides a more consistent osmolarity profile, reduces the amount of free water delivered to the patient, and better approximates physiologic fluids than 5% dextrose in water or sterile water for injection. Visually inspect for particular matter and discoloration prior to administration. The color of the diluted solution ranges from colorless to a slight pink or purple once the stopper is punctured (the color change does not affect the quality of the product). The diluted solution can be stored for 24 hours at room temperature. Discard the unused portion. If a vial was previously opened, do not use for intravenous administration. 2.4 General Considerations for Selecting the Three-Bag or Two-Bag Regimen The total recommended dosage of ACETADOTE is 300 mg/kg given intravenously as either a three-bag regimen or a two-bag regimen [see Dosage and Administration (2.5)]. It is not known whether the two-bag regimen is comparable to the three-bag regimen for efficacy in preventing hepatotoxicity. There are insufficient data to recommend use of the two-bag regimen in patients 40 kg or less; these patients should receive the three-bag regimen. For patients weighing 41 kg or greater, the clinician should consider the following factors when deciding whether to select the three-bag or two-bag regimen: • The three-bag regimen administers more ACETADOTE in the first three hours and may be preferred for patients with early signs of severe liver injury or history of a large acetaminophen ingestion; however, there is the potential for a higher incidence of hypersensitivity reactions. • The two-bag regimen delivers a lower amount of ACETADOTE over the first three hours and may be associated with fewer hypersensitivity reactions than the three-bag regimen [see Adverse Reactions (6.2), Clinical Studies (14)]. 2.5 Recommended Dosage for Acute Acetaminophen Ingestion ACETADOTE is for intravenous administration only. The total recommended dosage of ACETADOTE is 300 mg/kg given intravenously as either a three-bag regimen administered as a loading, second, and third dose infused over a total of 21 hours or a two-bag regimen administered as a loading and second dose infused over a total of 20 hours. For the recommended weight-based dosage and weight-based dilution in patients see Table 2 for the three-bag regimen (for patients 5 kg or greater) or Table 3 for the two-bag regimen (for patients 41 kg or greater). Page 7 Reference ID: 5486282 Three-Bag Regimen Table 2. Three-Bag Recommended ACETADOTE Dosage and Dilution for Patients 5 kg or greater Body Weight Bag 1 (Loading Dose) Bag 2 (Second Dose) Bag 3 (Third Dose) Loading Dose Diluent Volume* Infusion time Second Dose Diluent Volume* Infusion time Third Dose Diluent Volume* Infusion time 5 kg** to 20 kg 150 mg/kg 3 mL/kg 50 mg/kg 7 mL/kg 100 mg/kg 14 mL/kg Infused over 16 hours 21 kg to 40 kg 150 mg/kg 100 mL Infused 50 mg/kg 250 mL Infused 100 mg/kg 500 mL 41 kg to 99 kg 150 mg/kg 200 mL over 1 hour 50 mg/kg 500 mL over 4 hours 100 mg/kg 1,000 mL 100 kg or greater*** 15,000 mg 200 mL 5,000 mg 500 mL 10,000 mg 1,000 mL * Dilute ACETADOTE in one of the following three solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water. **Recommended dosing for those less than 5 kg has not been studied. ***No specific studies have been conducted to evaluate the necessity of dose adjustments in patients weighing over 100 kg. Limited information is available regarding the dosing requirements of patients that weigh more than 100 kg. Two-Bag Regimen Table 3. Alternative Regimen for Patients 41 kg or Greater: Two-Bag Recommended ACETADOTE Dosage and Dilution Body Weight Bag 1 (Loading Dose) Bag 2 (Second Dose) Loading Dose Diluent Volume* Infusion time Second Dose Diluent Volume* Infusion time 41 kg to 99 kg 200 mg/kg 1,000 mL Infused over 4 100 mg/kg 500 mL Infused over 16 hours 100 kg or greater** 20,000 mg 1,000 mL hours 10,000 mg 500 mL *Dilute ACETADOTE in one of the following three solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water. **No specific studies have been conducted to evaluate the necessity of dose adjustments in patients weighing over 100 kg. Limited information is available regarding the dosing requirements of patients that weigh more than 100 kg. 2.6 Recommendations for Repeated Supratherapeutic Acetaminophen Ingestion Repeated supratherapeutic acetaminophen ingestion (RSI) is an ingestion of acetaminophen at dosages higher than those recommended for extended periods of time. The risk of hepatotoxicity and the recommendations for treatment of acute acetaminophen ingestion (i.e., the revised Rumack-Matthew nomogram) do not apply to patients with RSI. Therefore, obtain the following information to guide ACETADOTE treatment for RSI: Repeated supratherapeutic acetaminophen ingestion (RSI) is an ingestion of acetaminophen at dosages higher than those recommended for extended periods of time. The risk of hepatotoxicity and the recommendations for treatment of acute acetaminophen ingestion (i.e., the revised Rumack-Matthew nomogram) do not apply to patients with RSI. Therefore, obtain the following information to guide ACETADOTE treatment for RSI: • Acetaminophen serum or plasma concentrations. A reported history of the quantity of acetaminophen ingested is often inaccurate and is not a reliable guide to therapy. • Laboratory tests to monitor hepatic and renal function and electrolyte and fluid balance: AST, ALT, bilirubin, INR, creatinine, BUN, blood glucose, and electrolytes. Page 8 Reference ID: 5486282 For specific ACETADOTE dosage and administration information in patients with RSI, consider contacting your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115. 3 DOSAGE FORMS AND STRENGTHS Injection: 6000 mg/30 mL (200 mg/mL) of acetylcysteine in a single-dose vial. 4 CONTRAINDICATIONS ACETADOTE is contraindicated in patients with a previous hypersensitivity reaction to acetylcysteine [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious acute hypersensitivity reactions; including fatal or life-threatening anaphylaxis, rash, hypotension, wheezing, and/or shortness of breath; have been observed in patients receiving intravenous acetylcysteine for acetaminophen overdose and occurred soon after initiation of the infusion [see Adverse Reactions (6)]. If a severe hypersensitivity reaction occurs, immediately stop the infusion of ACETADOTE and initiate appropriate treatment. Patients with asthma should be closely monitored during initiation of ACETADOTE therapy and throughout ACETADOTE therapy. Acute flushing and erythema of the skin may occur in patients receiving acetylcysteine intravenously. These reactions usually occur 30 to 60 minutes after initiating the infusion and often resolve spontaneously despite continued infusion of acetylcysteine. If a reaction to acetylcysteine involves more than simply flushing and erythema of the skin, it should be treated as a hypersensitivity reaction. Management of less severe hypersensitivity reactions should be based upon the severity of the reaction and include temporary interruption of the infusion and/or administration of antihistaminic drugs. The ACETADOTE infusion may be carefully restarted after treatment of the hypersensitivity symptoms has been initiated and acute symptoms have resolved; however, if the hypersensitivity reaction returns upon re-initiation of treatment or increases in severity, ACETADOTE should be discontinued and alternative patient management should be considered. 5.2 Fluid Overload The total volume of ACETADOTE administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction. To avoid fluid overload, the volume of diluent should be reduced as needed [see Dosage and Administration (2)]. If volume is not adjusted fluid overload can occur, potentially resulting in hyponatremia, seizure and death. Intravenous administration of ACETADOTE can cause fluid overload, potentially resulting in hyponatremia, seizure and death. To avoid fluid overload, use the recommended dilutions [see Dosage and Administration (2.5)]. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience The following clinically significant adverse reactions are described elsewhere in labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.1)] • Fluid Overload [see Warnings and Precautions (5.2)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Page 9 Reference ID: 5486282 In the literature, the most frequently reported adverse reactions attributed to intravenous acetylcysteine administration were rash, urticaria and pruritus. The frequency of adverse reactions has been reported to be between 0.2% and 21%, and they most commonly occur during the initial loading dose of acetylcysteine. Loading Dose/Infusion Rate Study In a randomized, open-label, multi-center clinical study conducted in Australia in patients with acetaminophen poisoning, the rates of hypersensitivity reactions between a 15-minute and 60-minute intravenous infusion for the 150 mg/kg loading dose of acetylcysteine were compared. The incidence of drug-related adverse reactions occurring within the first 2 hours following acetylcysteine administration is presented in Table 4. Overall, 17% of patients developed an acute hypersensitivity reaction (18% in the 15-minute infusion group; 14% in the 60-minute infusion group) [see Warnings and Precautions (5.1), Clinical Studies (14)]. Table 4. Incidence of Drug-Related Adverse Reactions Occurring Within the First 2 Hours Following Study Drug Administration by Preferred Term: Loading Dose/Infusion Rate Study Treatment Group 15-minutes 60-minutes Number of Patients n=109 n=71 Cardiac disorders 5 (5%) 2 (3%) Severity: Tachycardia NOS Unkn Mild Moderate Severe Unkn Mild Moderate Severe 4 (4%) 1 (1%) 2 (3%) Gastrointestinal disorders 16 (15%) 7 (10%) Severity: Nausea Vomiting NOS Unkn Mild Moderate Severe Unkn Mild Moderate Severe 1 (1%) 6 (6%) 1 (1%) 1 (1%) 2 (2%) 11 (10%) 2 (3%) 4 (6%) Immune System Disorders 20 (18%) 10 (14%) Severity: Hypersensitivity reaction Unkn Mild Moderate Severe Unkn Mild Moderate Severe 2 (2%) 6 (6%) 11 (10%) 1 (1%) 4 (6%) 5 (7%) 1 (1%) Respiratory, thoracic and mediastinal disorders 2 (2%) 2 (3%) Severity: Pharyngitis Rhinorrhea Rhonchi Throat tightness Unkn Mild Moderate Severe Unkn Mild Moderate Severe 1 (1%) 1 (1%) 1 (1%) 1 (1%) Skin & subcutaneous tissue disorders 6 (6%) 5 (7%) Severity: Pruritus Rash NOS Unkn Mild Moderate Severe Unkn Mild Moderate Severe 1 (1%) 2 (3%) 3 (3%) 2 (2%) 3 (4%) Vascular disorders 2 (2%) 3 (4%) Severity: Flushing Unkn Mild Moderate Severe Unkn Mild Moderate Severe 1 (1%) 1 (1%) 2 (3%) 1 (1%) Unkn= Unknown; NOS= not otherwise specified Page 10 Reference ID: 5486282 Safety Study A large multi-center study was performed in Canada where data were collected from patients who were treated with intravenous acetylcysteine for acetaminophen overdose between 1980 and 2005. This study evaluated 4709 adult cases and 1905 pediatric cases. The incidence of hypersensitivity reactions in adult (overall incidence 8%) and pediatric (overall incidence 10%) patients is presented in Table 5 and Table 6. Table 5. Distribution of reported hypersensitivity reactions in adult patients receiving intravenous acetylcysteine Reaction Incidence (%) n=4709 Urticaria/Facial Flushing 6.1% Pruritus 4.3% Respiratory Symptoms* 1.9% Edema 1.6% Hypotension 0.1% Anaphylaxis 0.1% *Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm. Table 6. Distribution of reported hypersensitivity reactions in pediatric patients receiving intravenous acetylcysteine Reaction Incidence (%) n=1905 Urticaria/Facial Flushing 7.6% Pruritus 4.1% Respiratory Symptoms* 2.2% Edema 1.2% Anaphylaxis 0.2% Hypotension 0.1% *Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm. 6.2 Postmarketing Experience Adverse Reactions from Observational Studies Observational studies from published literature have described rates of hypersensitivity reactions identified by retrospective chart review in subjects receiving the two-bag regimen after adoption of this regimen as institutional policy in three non-US settings and one US setting compared to a historical control group that received the three-bag regimen. Table 7 displays the incidence of hypersensitivity reactions in patients who received two-bag or three-bag regimens of intravenous acetylcysteine admitted between 2009 to 2020. Table 7. Incidence of Hypersensitivity Reactions in Patients who Received Two-bag or Three-bag Regimens of Intravenous Acetylcysteine in Published Literature Study Hypersensitivity Reactions in Patients Receiving Two-Bag Regimen Hypersensitivity Reactions in Patients Receiving Three-Bag Regimen Study 1 (Three Danish hospitals) 4% (19/507) 16% (47/292) Study 2 (Four Australian hospitals) 5% (8/163) 14% (45/313) Study 3 (Nine Australian hospitals) 1% (17/1300) 7% (65/911) Study 4 (One US hospital) 19% (18/93) 23% (34/150) Page 11 Reference ID: 5486282 8 Adverse Reactions from Postmarketing Spontaneous Reports The following adverse reactions have been identified during post-approval use of ACETADOTE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: fatal anaphylaxis USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published case reports and case series of pregnant women exposed to acetylcysteine during various trimesters are not sufficient to inform any drug associated risk. Delaying treatment of acetaminophen overdose may increase the risk of maternal or fetal morbidity and mortality [see Clinical Considerations]. Reproduction studies in rats and rabbits following oral administration of acetylcysteine during the period of organogenesis at doses similar to the total intravenous dose (based on the body surface area) did not cause any adverse effects to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Acetaminophen and acetylcysteine cross the placenta. Delaying treatment in pregnant women with acetaminophen overdose and potentially toxic acetaminophen plasma levels may increase the risk of maternal and fetal morbidity and mortality. Data Animal Data Reproduction studies have been performed following administration of acetylcysteine during the period of organogenesis in rats at oral doses up to 2000 mg/kg/day (1.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface area comparison) and in rabbits at oral doses up to 1000 mg/kg/day (1.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface area comparison). No adverse developmental outcomes due to acetylcysteine were observed. 8.2 Lactation Risk Summary There are no data on the presence of acetylcysteine in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ACETADOTE and any potential adverse effects on the breastfed child from ACETADOTE or from the underlying maternal condition. Clinical Considerations Based on the pharmacokinetic data, acetylcysteine should be nearly completely cleared 30 hours after administration. Breastfeeding women may consider pumping and discarding their milk for 30 hours after administration. 8.4 Pediatric Use Safety and effectiveness of ACETADOTE in pediatric patients have not been established by adequate and well- controlled studies. Use of ACETADOTE in pediatric patients 5 kg and greater is based on clinical practice [see Dosage and Administration (2.5)]. Page 12 Reference ID: 5486282 10 OVERDOSAGE Fatal and life-threatening adverse events have been reported following acetylcysteine overdosage, including anaphylaxis, cerebral edema, and hemolytic-uremic syndrome (HUS). Stop acetylcysteine administration in the setting of suspected acetylcysteine overdosage and manage as clinically indicated. Anaphylaxis, including cases with a fatal outcome, has been reported following acetylcysteine overdosage. Patients who experienced anaphylaxis following acetylcysteine overdosage often became symptomatic during the loading dose and experienced hypotension, rash, angioedema, bronchospasm, or respiratory distress. Cases of anaphylaxis with acetylcysteine overdosage also described coagulopathy, renal failure, or respiratory failure. Cerebral edema, including cases with a fatal outcome, has been reported following acetylcysteine overdosage. Patients who experienced cerebral edema following acetylcysteine overdose presented with altered mental status, abnormal pupillary responses, seizures. Some cases of cerebral edema with acetylcysteine overdosage described brain herniation. HUS has been reported following acetylcysteine overdosage. Patients who experienced HUS presented with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Removal of acetylcysteine via hemodialysis has been reported in the literature outside of the context of acetylcysteine overdosage. Studies of hemodialysis in acetaminophen overdose report significant extracorporeal removal of acetylcysteine during hemodialysis. Contact the Poison Center (1-800-222-1222) for overdosage management recommendations for ACETADOTE including considerations for hemodialysis. 11 DESCRIPTION Acetylcysteine injection is an intravenous antidote for the treatment of acetaminophen overdose. Acetylcysteine is the nonproprietary name for the N-acetyl derivative of the naturally occurring amino acid, L-cysteine (N-acetyl-L­ cysteine,). The compound is a white crystalline powder, which melts in the range of 104° to 110°C and has a very slight odor. The molecular formula of the compound is C5H9NO3S, and its molecular weight is 163.2. Acetylcysteine has the following structural formula: H CH3 N SH I YI O COOH ACETADOTE is supplied as a sterile solution in vials containing 20% w/v (200 mg/mL) acetylcysteine. The pH of the solution ranges from 6.0 to 7.5. ACETADOTE contains the following inactive ingredients: sodium hydroxide (used for pH adjustment), and Water for Injection, USP. The amount of sodium in ACETADOTE is approximately 30 mg/mL. Because ACETADOTE is administered based on a patient’s weight, the amount of sodium administered in a course of treatment will vary from approximately 225 mg to 4500 mg. The use of ½ normal saline will contribute approximately an additional 1770 mg of sodium per liter of diluent. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Acetylcysteine has been shown to reduce the extent of liver injury following acetaminophen overdose. Acetaminophen doses of 150 mg/kg or greater have been associated with hepatotoxicity. Acetylcysteine probably protects the liver by Page 13 Reference ID: 5486282 12 maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite of acetaminophen. 12.3 Pharmacokinetics After a single intravenous dose of acetylcysteine, the plasma concentration of total acetylcysteine declined in a poly­ exponential decay manner with a mean terminal half-life (T1/2) of 5.6 hours. The mean clearance (CL) for acetylcysteine was 0.11 liter/hr/kg and renal CL constituted about 30% of the total CL. Distribution: The steady-state volume of distribution (Vdss) following administration of an intravenous dose of acetylcysteine was 0.47 liter/kg. The protein binding of acetylcysteine ranges from 66 to 87%. Elimination: Metabolism: Acetylcysteine (i.e., N-acetylcysteine) is postulated to form cysteine and disulfides (N,N-diacetylcysteine and N­ acetylcysteine). Cysteine is further metabolized to form glutathione and other metabolites. Excretion: After a single oral dose of [35S]-acetylcysteine 100 mg, between 13 to 38% of the total radioactivity administered was recovered in urine within 24 hours. In a separate study, renal clearance was estimated to be approximately 30% of total body clearance. Specific Populations: Hepatic Impairment: Following a 600 mg intravenous dose of acetylcysteine to subjects with mild (Child Pugh Class A, n=1), moderate (Child-Pugh Class B, n=4) or severe (Child-Pugh Class C; n=4) hepatic impairment and 6 healthy matched controls, mean T1/2 increased by 80%. Also, the mean CL decreased by 30% and the systemic acetylcysteine exposure (mean AUC) increased 1.6-fold in subjects with hepatic impairment compared to subjects with normal hepatic function. These changes are not considered to be clinically meaningful. Renal Impairment: Hemodialysis may remove some of total acetylcysteine. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of acetylcysteine. Mutagenesis Acetylcysteine was not genotoxic in the Ames test or the in vivo mouse micronucleus test. It was, however, positive in the in vitro mouse lymphoma cell (L5178Y/TK+/-) forward mutation test. Impairment of Fertility In a fertility study of acetylcysteine in rats, intravenous administration of 1,000 mg/kg/day (0.5 times the recommended human dose of 300 mg/kg based on body surface area) caused a profound reduction of fertility in females, which was correlated with morphological changes in oocytes and severe impairment of implantation (18 of 20 mated females had no implantations). The reversibility of this effect was not evaluated. No effects on fertility Page 14 Reference ID: 5486282 14 were observed in female rats at intravenous doses up to 300 mg/kg/day (0.2 times the recommended human dose based on body surface area), or in male rats at intravenous doses up to 1,000 mg/kg/day. Mating was unaffected in this study. In a reproduction study of acetylcysteine, male rats were treated orally for 15 weeks prior to mating and during the mating period. A slight non-dose related reduction in fertility was observed at oral doses of 500 and 1,000 mg/kg/day (0.3 and 0.5 times the recommended human intravenous dose, respectively, based on body surface area). Treatment of male rats with acetylcysteine at an oral dose of 250 mg/kg/day for 15 weeks (0.1 times the recommended human intravenous dose based on body surface comparison) did not affect fertility or general reproductive performance. CLINICAL STUDIES Loading Dose/Infusion Rate Study A randomized, open-label, multi-center clinical study was conducted in Australia in patients with acetaminophen poisoning to compare the rates of hypersensitivity reactions between two rates of infusion for the intravenous acetylcysteine loading dose. One hundred nine subjects were randomized to a 15-minute infusion rate and seventy-one subjects were randomized to a 60 minute infusion rate. The loading dose was 150 mg/kg followed by a maintenance dose of 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours. Of the 180 patients, 27% were male and 73% were female. Ages ranged from 15 to 83 years, with the mean age being 30 years (+13.0). A subgroup of 58 subjects (33 in the 15-minute infusion group; 25 in the 60-minute infusion group) was treated within 8 hours of acetaminophen ingestion. No hepatotoxicity occurred within this subgroup; however, with 95% confidence, the true hepatotoxicity rates could range from 0% to 9% for the 15-minute infusion group and from 0% to 12% for the 60-minute infusion group. Observational Study An open-label, observational database contained information on 1749 patients who sought treatment for acetaminophen overdose over a 16-year period. Of the 1749 patients, 65% were female, 34% were male and less than 1% was transgender. Ages ranged from 2 months to 96 years, with 72% of the patients falling in the 16- to 40-year-old age bracket. A total of 399 patients received acetylcysteine treatment. A post-hoc analysis identified 56 patients who (1) were at high or probable risk for hepatotoxicity (APAP greater than 150 mg/L at the four hours line according to the Australian nomogram) and (2) had a liver function test. Of the 53 patients who were treated with intravenous acetylcysteine (300 mg/kg intravenous acetylcysteine administered over 20-21 hours) within 8 hours, two (4%) developed hepatotoxicity (AST or ALT greater than 1000 U/L). Twenty-one of 48 (44%) patients treated with acetylcysteine after 15 hours developed hepatotoxicity. The actual number of hepatotoxicity outcomes may be higher than what is reported here. For patients with multiple admissions for acetaminophen overdose, only the first overdose treated with intravenous acetylcysteine was examined. Hepatotoxicity may have occurred in subsequent admissions. Evaluable data were available from a total of 148 pediatric patients (less than 16 years of age) who were admitted for poisoning following ingestion of acetaminophen, of whom 23 were treated with intravenous acetylcysteine. There were no deaths of pediatric patients. None of the pediatric patients receiving intravenous acetylcysteine developed hepatotoxicity while two patients not receiving intravenous acetylcysteine developed hepatotoxicity. The number of pediatric patients is too small to provide a statistically significant finding of efficacy; however the results appear to be consistent to those observed for adults. Three-Bag vs. Two-Bag Regimen Observational Study A multi-center, observational, retrospective cohort study investigated rates of hypersensitivity reactions in 493 patients treated with a two-bag intravenous acetylcysteine regimen compared to 274 patients treated with a three-bag regimen Page 15 Reference ID: 5486282 in Denmark between January 2012 and December 2014. The two-bag regimen consisted of a 4 hour loading dose at 200 mg/kg followed by a 16 hour infusion at 100 mg/kg. The three-bag regimen used a 150 mg/kg loading dose administered over 15 minutes, followed by a second dose of 50 mg/kg over 4 hours and a final dose of 100 mg/kg for 16 hours. Patients in this study were treated with acetylcysteine regardless of plasma acetaminophen concentration. The median (range) serum acetaminophen concentration at presentation was <1 mcg/mL (0-353 mcg/mL) in the total study population, and only 12/767 patients (1.6%) had a serum acetaminophen level that would have warranted acetylcysteine treatment based on the revised Rumack-Mathew nomogram. Hepatotoxicity was defined as peak ALT >1,000 U/L at any point during hospitalization. In this population that was low-risk for hepatotoxicity based on median acetaminophen level at presentation, no differences were observed in unadjusted hepatotoxicity rates between patients who received the two-bag regimen (4%, 20/493) compared to patients who received the three-bag regimen (4%, 11/274). However, this study has significant limitations and was not designed to establish non-inferiority. 16 HOW SUPPLIED/STORAGE AND HANDLING ACETADOTE (acetylcysteine) injection is available as a 20% solution (200 mg/mL) in 30 mL single-dose glass vials. Each single dose vial contains 6 g/30 mL (200 mg/mL) of ACETADOTE injection. ACETADOTE is sterile and can be used for intravenous administration. It is available as follows: • 30 mL vials, carton of 4 (NDC 66220-207-30) Do not use previously opened vials for intravenous administration. Note: The color of ACETADOTE may turn from essentially colorless to a slight pink or purple once the stopper is punctured. The color change does not affect the quality of the product. The stopper in the ACETADOTE vial is formulated with a synthetic base-polymer and does not contain natural rubber latex, dry natural rubber, or blends of natural rubber. Store unopened vials at controlled room temperature, 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] 17 PATIENT COUNSELING INFORMATION Hypersensitivity Reactions Advise patients and caregivers that hypersensitivity reactions related to administration and infusion may occur during and after ACETADOTE treatment, including hypotension, wheezing, shortness of breath and bronchospasm [see Warnings and Precautions (5.1)]. For specific treatment information regarding the clinical management of acetaminophen overdose, please contact your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115. Manufactured for: Cumberland Pharmaceuticals Inc. Nashville, TN 37203 U.S. Patent Nos. 8,148,356, 8,399,445, 8,653,061 8,722,738 and 9,327,028 Page 16 Reference ID: 5486282
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SUNLENCA safely and effectively. See full prescribing information for SUNLENCA. SUNLENCA® (lenacapavir) tablets, for oral use SUNLENCA® (lenacapavir) injection, for subcutaneous use Initial U.S. Approval: 2022 ----------------------------RECENT MAJOR CHANGES-------------------------­ Dosage and Administration (2.1, 2.3, 2.4) 11/2024 Warnings and Precautions (5.3) 11/2024 ----------------------------INDICATIONS AND USAGE---------------------------­ SUNLENCA, a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor, in combination with other antiretroviral(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 whose current antiretroviral regimen is failing due to resistance, intolerance, or safety considerations. (1) ------------------------DOSAGE AND ADMINISTRATION----------------------­ • Recommended dosage – Initiation with one of two options followed by once every 6 months maintenance injection dosing. Tablets may be taken without regard to food. (2.2) Initiation Option 1 Day 1 927 mg by subcutaneous injection (2 x 1.5 mL injections) 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Initiation Option 2 Day 1 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Day 8 300 mg orally (1 x 300 mg tablet) Day 15 927 mg by subcutaneous injection (2 x 1.5 mL injections) Maintenance 927 mg by subcutaneous injection (2 x 1.5 mL injections) every 6 months (26 weeks) from the date of the last injection +/-2 weeks. • Planned missed injections: If scheduled injection is to be missed by more than 2 weeks, SUNLENCA tablets may be used for oral bridging for up to 6 months until injections resume. Recommended dosage is 300 mg orally once every 7 days. (2.3) • Unplanned missed injections: If more than 28 weeks since last injection and tablets have not been taken for oral bridging, restart initiation from Day 1 (using Option 1 or Option 2) if clinically appropriate. (2.3) • SUNLENCA injection is for subcutaneous administration only. Two 1.5 mL injections are required for complete dose. (2.4) ----------------------DOSAGE FORMS AND STRENGTHS--------------------­ Tablets: 300 mg Injection: 463.5 mg/1.5 mL (309 mg/mL) in single-dose vials. (3) -------------------------------CONTRAINDICATIONS------------------------------­ Concomitant administration of SUNLENCA is contraindicated with strong CYP3A inducers. (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ • Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.1) • Residual concentrations of lenacapavir may remain in systemic circulation for up to 12 months or longer. Counsel patients regarding the dosing schedule; non-adherence could lead to loss of virologic response and development of resistance. (5.2) • May increase exposure and risk of adverse reactions to drugs primarily metabolized by CYP3A initiated within 9 months after the last subcutaneous dose of SUNLENCA. (5.2) • If discontinued, initiate an alternative, fully suppressive antiretroviral regimen where possible no later than 28 weeks after the final injection of SUNLENCA. If virologic failure occurs, switch to an alternative regimen if possible. (5.2) • Injection site reactions may occur, and nodules and indurations may be persistent. Improper administration (intradermal injection) has been associated with serious injection site reactions. (5.3) -------------------------------ADVERSE REACTIONS-----------------------------­ Most common adverse reactions (incidence greater than or equal to 3%, all grades) are nausea and injection site reactions. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------­ • Consult the Full Prescribing Information prior to and during treatment for important drug interactions. (4, 7, 12.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Adherence to Treatment Regimen 2.2 Recommended Dosage 2.3 Recommended Dosing Schedule for Missed Dose 2.4 Preparation and Administration of Subcutaneous Injection 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Immune Reconstitution Syndrome 5.2 Long-Acting Properties and Potential Associated Risks with SUNLENCA 5.3 Injection Site Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on SUNLENCA 7.2 Effect of SUNLENCA on Other Drugs 7.3 Established and Other Potentially Significant Drug Interactions 7.4 Drugs without Clinically Significant Interactions with SUNLENCA 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 5485227 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE SUNLENCA, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 whose current antiretroviral regimen is failing due to resistance, intolerance, or safety considerations. 2 DOSAGE AND ADMINISTRATION 2.1 Adherence to Treatment Regimen Prior to starting SUNLECA, healthcare providers should carefully select patients who agree to the required every 6 month injection dosing schedule and counsel patients about the importance of adherence to scheduled SUNLENCA dosing visits and concomitant oral antiretroviral therapy to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance with missed doses [see Warnings and Precautions (5.2), Microbiology (12.4)]. 2.2 Recommended Dosage SUNLENCA can be initiated using one of the two recommended dosage regimens in Table 1 and Table 2 below. Maintenance dosing is administered by subcutaneous injection every 6 months regardless of the initiation regimen. Healthcare providers should determine the appropriate initiation regimen for the patient. SUNLENCA oral tablets may be taken with or without food [see Clinical Pharmacology (12.3)]. Table 1 Recommended Treatment Regimen for SUNLENCA Initiation and Maintenance, Option 1 Treatment Time Dosage of SUNLENCA: Initiation Day 1 927 mg by subcutaneous injection (2 x 1.5 mL injections) 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Dosage of SUNLENCA: Maintenance Every 6 months (26 weeks) a +/-2 weeks 927 mg by subcutaneous injection (2 x 1.5 mL injections) a. From the date of the last injection. Reference ID: 5485227 2 Table 2 Recommended Treatment Regimen for SUNLENCA Initiation and Maintenance, Option 2 Treatment Time Dosage of SUNLENCA: Initiation Day 1 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Day 8 300 mg orally (1 x 300 mg tablet) Day 15 927 mg by subcutaneous injection (2 x 1.5 mL injections) Dosage of SUNLENCA: Maintenance Every 6 months (26 weeks) a +/-2 weeks 927 mg by subcutaneous injection (2 x 1.5 mL injections) a. From the date of the last injection. 2.3 Recommended Dosing Schedule for Missed Dose Planned Missed Injections During the maintenance period, if a patient plans to miss a scheduled 6-month injection visit by more than 2 weeks, SUNLENCA tablets may be taken for up to 6 months until injections resume. Refer to Table 3 below for the recommended dosage after planned missed injections. Table 3 Recommended Dosage after Planned Missed Injections: Weekly Oral Maintenance Time since Last Injection Recommendation 26 to 28 weeks Maintenance oral dosage of 300 mg taken once every 7 days for up to 6 months. Resume the maintenance injection dosage within 7 days after the last oral dose. Unplanned Missed Injections Patients who miss a scheduled injection visit should be clinically reassessed, including consideration of lenacapavir resistance testing, to ensure resumption of therapy remains appropriate. During the maintenance period, if more than 28 weeks have elapsed since the last injection and SUNLENCA tablets have not been taken, see Table 4 below for the recommended dosage after unplanned missed injections. Adherence to the injection dosing schedule is strongly recommended [see Dosage and Administration (2.1) and Microbiology (12.4)]. Reference ID: 5485227 3 Table 4 Recommended Dosage after Unplanned Missed Injections Time since Last Injection Recommendation More than 28 weeks Reinitiate with Option 1 (Table 1) or Option 2 (Table 2) and then continue with maintenance injection dosing. 2.4 Preparation and Administration of Subcutaneous Injection SUNLENCA injection is only for subcutaneous administration into the abdomen by a healthcare provider. Do NOT administer intradermally due to risk of serious injection site reactions [see Warnings and Precautions (5.3)]. Use aseptic technique. Visually inspect the solution in the vials and prepared syringe for particulate matter and discoloration prior to administration. SUNLENCA injection is a yellow solution. Do not use SUNLENCA injection if the solution is discolored or if it contains particulate matter. Once the solution is withdrawn from the vials, the subcutaneous injections should be administered as soon as possible [see How Supplied/Storage and Handling (16)]. There are two available injection kits, which differ only in how SUNLENCA injection is prepared (the components and associated method for withdrawal of the solution from the vials) [see How Supplied/Storage and Handling (16)]. Refer to the figures below for the relevant injection kit. The injection kit components are for single use only. Two 1.5 mL injections are required for a complete dose. Reference ID: 5485227 4 VIAL x2 VIAL ACCESS DEVICE x2 SYRINGE x2 NOTE: all components are for single use Prepare Vial Prepare Vial Access Device Make sure that: • Vial and prepared syringe contain a yellow solution with no particles • Contents are not damaged • Product is not expired Attach 22G Injection Needle to Syringe, Expel Air Bubbles, and Prime to 1.5 ml Clean an Injection Site on Patient's Abdomen e = Injection site options (at least 2 inches from navel) Push down Inject 1.5 ml ofSunlenca Subcutaneously Insert fully 22G, ½inch INJECTION NEEDLE x2 Attach and Fill Syringe Flip upside down and withdraw all contents Administer 2nd Injection Vial access device injection kit Figure 1 identifies the components for use in the administration steps for the vial access device injection kit, and the administration steps are provided in Figure 2. Use of a vial access device is required in this kit. Figure 1 SUNLENCA Vial Access Device Injection Kit Components Figure 2 SUNLENCA Injection Steps for Vial Access Device Injection Kit Reference ID: 5485227 5 VIAL x2 El SYRINGE ; 18G, 1½inch , llllJli x 2 WITHDRAWAL NEEDLE x2 NOTE: all components are for single use. 22G, ½ inch INJECTION NEEDLE x2 Prepare Vial Make sure that: Attach 18G Withdrawal Needle to Syringe Fill Syringe ~ ,-,----,----._ ----- Remove18G Withdrawal Needle from Syringe • Vial and prepared syringe contain a yellow solution with no particles • Contents are not damaged • Product is not expired Attach 22G Injection Needle to Syringe, Expel Air Bubbles, and Prime to 1.5 ml • Clean an Injection Site on Patient's Abdomen e = Injection site options (at least 2 inches from navel) Inject 1.5 ml of air into vial Inject 1.5 ml ofSunlenca Subcutaneously Administer 2nd Injection Withdrawal needle injection kit Figure 3 identifies the components for use in the administration steps for the withdrawal needle injection kit, and the administration steps are provided in Figure 4. The 18-gauge needle is for withdrawal only in this kit. Figure 3 SUNLENCA Withdrawal Needle Injection Kit Components Figure 4 SUNLENCA Injection Steps for Withdrawal Needle Injection Kit 3 DOSAGE FORMS AND STRENGTHS SUNLENCA tablets: Each tablet contains 300 mg of lenacapavir (present as 306.8 mg of lenacapavir sodium). The tablets are beige, capsule-shaped, film-coated, and debossed with ‘GSI’ on one side of the tablet and ‘62L’ on the other side of the tablet. Reference ID: 5485227 6 SUNLENCA injection: Each single-dose vial contains 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir (present as 473.1 mg/1.5 mL of lenacapavir sodium). The lenacapavir injectable solution is sterile, preservative-free, clear, and yellow with no visible particles. 4 CONTRAINDICATIONS Concomitant administration of SUNLENCA with strong CYP3A inducers is contraindicated due to decreased lenacapavir plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to SUNLENCA [see Drug Interactions (7.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.2 Long-Acting Properties and Potential Associated Risks with SUNLENCA Residual concentrations of lenacapavir may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer after the last subcutaneous dose). It is important to counsel patients that maintenance dosing by injection is required every 6 months, because missed doses or non-adherence to injections could lead to loss of virologic response and development of resistance [see Dosage and Administration (2.1)]. Lenacapavir, a moderate CYP3A inhibitor, may increase the exposure to, and therefore potential risk of adverse reactions from, drugs primarily metabolized by CYP3A initiated within 9 months after the last subcutaneous dose of SUNLENCA [see Drug Interactions and Clinical Pharmacology (7.2, 12.3)]. If SUNLENCA is discontinued, to minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen where possible no later than 28 weeks after the final injection of SUNLENCA. If virologic failure occurs during treatment, switch the patient to an alternative regimen if possible [see Dosage and Administration (2.1)]. Reference ID: 5485227 7 5.3 Injection Site Reactions Administration of SUNLENCA may result in local injection site reactions (ISRs). If clinically significant ISRs occur, evaluate and institute appropriate therapy and follow­ up. Manifestations of ISRs may include swelling, pain, erythema, nodule, induration, pruritus, extravasation or mass. Nodules and indurations at the injection site may take longer to resolve than other ISRs. In clinical studies, after a median follow-up of 553 days, 30% of nodules and 13% of indurations (in 10% and 1% of participants, respectively) associated with the first injections of SUNLENCA had not fully resolved. Measurements and qualitative assessments of ISRs were not routinely reported. Where described, the majority of the injection site nodules and indurations were palpable but not visible, and had a maximum size of approximately 1 to 4 cm [see Adverse Reactions (6.1)]. The mechanism driving the persistence of injection site nodules and indurations in some patients is not fully understood, but based on available data, they may be related to the presence of the subcutaneous drug depot. In some patients who had a skin biopsy performed of an injection site nodule or induration, dermatopathology revealed foreign body inflammation or granulomatous response. Improper administration (intradermal injection) has been associated with serious injection site reactions, including necrosis and ulcer [see Adverse Reactions (6)]. Ensure SUNLENCA is only administered subcutaneously in the abdomen [see Dosage and Administration (2.4)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Immune Reconstitution Syndrome [see Warnings and Precautions (5.1)] • Injection Site Reactions [see Warnings and Precautions (5.3)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The primary safety assessment of SUNLENCA was based on data from heavily treatment-experienced adult participants with HIV who received SUNLENCA in a Phase 2/3 trial (CAPELLA; N=72) through Week 52 (median duration on study of 71 weeks) [see Clinical Studies (14)], as well as supportive data in treatment-naïve adult participants with HIV who received SUNLENCA in a Phase 2 trial (CALIBRATE; N=157) through Week 54 (median duration of exposure of 66 weeks). Reference ID: 5485227 8 The most common adverse reactions (all Grades) reported in at least 3% of participants in CAPELLA were nausea and injection site reactions. The proportion of partcipants in CAPELLA who discontinued treatment with SUNLENCA due to adverse events, regardless of severity, was 1% (Grade 1 injection site nodule in 1 participant). Table 3 displays the frequency of adverse reactions (all Grades) greater than or equal to 3% in the SUNLENCA group. Table 3 Adverse Reactions (All Grades) Reported in ≥ 3% a of Heavily Treatment Experienced Adults with HIV-1 Receiving SUNLENCA in CAPELLA (Week 52 Analysis) SUNLENCA + Background Regimen Adverse Reactions (N=72) Injection Site Reactions 65% Nausea 4% a. Frequencies of adverse reactions are based on all adverse events attributed to trial drug by the investigator, based on all participants (cohorts 1 and 2) in CAPELLA. The majority (96%) of all adverse reactions associated with SUNLENCA were mild or moderate in severity. Injection-Associated Adverse Reactions Local Injection Site Reactions (ISRs): The most frequent adverse reactions were ISRs. Of the 72 participants in CAPELLA, 65% had experienced an ISR attributed to study drug through at least the Week 52 visit. Most participants had mild (Grade 1, 44%) or moderate (Grade 2, 17%) ISRs. Four percent of participants experienced a severe (Grade 3) ISR (erythema, pain, swelling) that resolved within 15 days. The ISRs reported in more than 1% of participants were swelling (36%), pain (31%), erythema (31%), nodule (25%), induration (15%), pruritus (6%), extravasation (3%) and mass (3%). ISRs reported in 1% of participants included discomfort, hematoma, edema, and ulcer. Nodules and indurations at the injection site took longer to resolve than other ISRs. The median time to resolution of all ISRs, excluding nodules and indurations, was 5 days (range: 1 to 183). The median time to resolution of nodules and indurations associated with the first injections of SUNLENCA was 148 (range: 41 to 727) and 70 (range: 3 to 252) days, respectively. After a median follow up of 553 days, 30% of nodules and 13% of indurations (in 10% and 1% of participants, respectively) associated with the first injections of SUNLENCA had not fully resolved. Qualitative descriptions of injection site nodules and indurations were not routinely reported, but, where reported, the majority of injection site nodules and indurations were palpable but not visible. Measurements of injection site nodules and indurations were not routinely performed or standardized, but where measurements were reported, the maximum size for the majority of injection site nodules and indurations was approximately 1 to 4 cm [see Warnings and Precautions (5.3)]. Reference ID: 5485227 9 Laboratory Abnormalities The frequency of laboratory abnormalities (Grades 3 to 4) occurring in at least 2% of participants in CAPELLA are presented in Table 4. A causal association between SUNLENCA and these laboratory abnormalities has not been established. Table 4 Selected Laboratory Abnormalities (Grades 3 to 4) Reported in ≥ 2% of Participants Receiving SUNLENCA in CAPELLA (Week 52 Analysis) Laboratory Parameter Abnormality SUNLENCA + Background Regimen (N=72) a Creatinine ( >1.8 x ULN or ≥1.5 x baseline) 13% Glycosuria (>2+) b 6% Hyperglycemia (fasting) (>250 mg/dL) 5% Proteinuria (>2+) b 4% ALT (≥5 x ULN) b 3% AST (≥5 x ULN) 3% Direct Bilirubin (>ULN) b 3% ALT= alanine aminotransferase; AST= aspartate aminotransferase; ULN = upper limit of normal a. Frequencies are based on treatment-emergent laboratory abnormalities in all participants (cohorts 1 and 2) in CAPELLA. Percentages were calculated based on the number of participants with post-baseline toxicity grades for each laboratory parameter (n=72 for all parameters except hyperglycemia fasting n=57). b. Grade 3 only (no Grade 4 values reported). 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General disorders and administration site conditions Injection site necrosis [see Warnings and Precautions (5.3)]. Reference ID: 5485227 10 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on SUNLENCA Lenacapavir is a substrate of P-gp, UGT1A1, and CYP3A. Strong or Moderate CYP3A Inducers Drugs that are strong or moderate inducers of CYP3A may significantly decrease plasma concentrations of lenacapavir [see Clinical Pharmacology (12.3)], which may result in loss of therapeutic effect of SUNLENCA and development of resistance. Concomitant administration of SUNLENCA with strong CYP3A inducers during SUNLENCA treatment is contraindicated [see Contraindications (4)]. Concomitant administration of SUNLENCA with moderate CYP3A inducers during SUNLENCA treatment is not recommended. Combined P-gp, UGT1A1, and Strong CYP3A Inhibitors Combined P-gp, UGT1A1, and strong CYP3A inhibitors may significantly increase plasma concentrations of SUNLENCA. Concomitant administration of SUNLENCA with these inhibitors is not recommended. 7.2 Effect of SUNLENCA on Other Drugs Lenacapavir is a moderate inhibitor of CYP3A. Due to the long half-life of lenacapavir following subcutaneous administration, SUNLENCA may increase the exposure of drugs primarily metabolized by CYP3A [see Clinical Pharmacology (12.3)] initiated within 9 months after the last subcutaneous dose of SUNLENCA, which may increase the potential risk of adverse reactions. See the prescribing information of the sensitive CYP3A substrate for dosing recommendations with moderate inhibitors of CYP3A. 7.3 Established and Other Potentially Significant Drug Interactions Table 5 provides a listing of clinically significant drug interactions with recommended prevention or management strategies, but is not all inclusive. The drug interactions described are based on studies conducted with SUNLENCA or are drug interactions that may occur with SUNLENCA [see Contraindications (4) and Clinical Pharmacology (12.3)]. Table 5 Drug Interactions with SUNLENCA Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Comment Antiarrhythmics: digoxin ↑ digoxin Use with caution and monitor digoxin therapeutic concentration. Anticoagulants: Direct Oral Anticoagulants (DOACs) rivaroxaban dabigatran edoxaban ↑ DOAC Refer to the DOAC prescribing information for concomitant administration with moderate CYP3A inhibitors and/or P-gp inhibitors. Reference ID: 5485227 11 Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Comment Anticonvulsants: ↓ lenacapavir Concomitant administration of carbamazepine carbamazepine, oxcarbazepine, oxcarbazepine phenobarbital, or phenytoin may result in phenobarbital loss of therapeutic effect and development phenytoin of resistance. Concomitant administration of SUNLENCA with carbamazepine or phenytoin is contraindicated. Concomitant administration of SUNLENCA with oxcarbazepine or phenobarbital is not recommended. Consider use of alternative anticonvulsants. Antiretroviral Agents: ↑ lenacapavir Concomitant administration of efavirenz, atazanavir/cobicistat b (atazanavir/cobicistat, nevirapine, or tipranavir/ritonavir may result atazanavir/ritonavir atazanavir/ritonavir) in loss of therapeutic effect and development of resistance. efavirenz b ↓ lenacapavir Concomitant administration with nevirapine tipranavir/ritonavir (efavirenz, nevirapine, tipranavir/ritonavir) atazanavir/cobicistat, atazanavir/ritonavir, efavirenz, nevirapine, or tipranavir/ritonavir is not recommended. Antimycobacterials: ↓ lenacapavir Concomitant administration of rifabutin, rifabutin rifampin and rifapentine may result in loss rifampin b of therapeutic effect and development of rifapentine resistance. Concomitant administration of SUNLENCA with rifampin is contraindicated [see Contraindications (4)]. Concomitant administration of SUNLENCA with rifabutin or rifapentine is not recommended. Corticosteroids (systemic): ↑ corticosteroids Concomitant administration with systemic cortisone/hydrocortisone (systemic) corticosteroids whose exposures are dexamethasone ↓ lenacapavir (dexamethasone) significantly increased by CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression. Initiate with the lowest starting dose and titrate carefully while monitoring for safety. Concomitant administration of systemic dexamethasone may result in loss of therapeutic effect of lenacapavir and development of resistance. Alternative corticosteroids to dexamethasone should be considered, particularly for long-term use. Ergot derivatives: dihydroergotamine ergotamine methylergonovine ↑ dihydroergotamine ↑ ergotamine ↑ methylergonovine Concomitant administration of SUNLENCA with dihydroergotamine, ergotamine or methylergonovine is not recommended. Reference ID: 5485227 12 Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Comment Herbal Products: ↓ lenacapavir Concomitant administration of St. John’s St. John’s wort c wort may result in loss of therapeutic effect (Hypericum perforatum) and development of resistance. Concomitant administration of SUNLENCA with St. John’s wort is contraindicated. HMG-CoA Reductase Inhibitors: lovastatin simvastatin ↑ lovastatin ↑ simvastatin Initiate lovastatin and simvastatin with the lowest starting dose and titrate carefully while monitoring for safety (e.g., myopathy). Narcotic analgesics ↑ fentanyl Careful monitoring of therapeutic effects metabolized by CYP3A: e.g., fentanyl, oxycodone ↑ oxycodone and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co- administration. tramadol ↑ tramadol A decrease in dose may be needed for tramadol with concomitant use. Narcotic analgesic for buprenorphine: Initiation of buprenorphine or methadone in treatment of opioid effects unknown patients taking SUNLENCA: Carefully titrate dependence: the dose of buprenorphine or methadone to buprenorphine, methadone methadone: effects unknown the desired effect; use the lowest feasible initial or maintenance dose. Initiation of SUNLENCA in patients taking buprenorphine or methadone: A dose adjustment for buprenorphine or methadone may be needed. Monitor clinical signs and symptoms. Opioid Antagonist: naloxegol ↑ naloxegol Avoid use with SUNLENCA; if unavoidable, decrease the dosage of naloxegol and monitor for adverse reactions. Phosphodiesterase-5 (PDE-5) ↑ PDE-5 inhibitors Use of PDE-5 inhibitors for pulmonary Inhibitors: arterial hypertension (PAH): sildenafil Concomitant administration of SUNLENCA tadalafil with tadalafil for the treatment of PAH is not vardenafil recommended. Use of PDE-5 inhibitors for erectile dysfunction (ED): Refer to the prescribing information of PDE­ 5 inhibitors for dose recommendations. Sedatives/Hypnotics: midazolam (oral) b triazolam ↑ midazolam (oral) ↑ triazolam Use with caution when midazolam or triazolam is concomitantly administered with SUNLENCA a. ↑ = Increase, ↓ = Decrease. b. Drug-drug interaction study was conducted. c. The induction potency of St. John’s wort may vary widely based on preparation. Reference ID: 5485227 13 7.4 Drugs without Clinically Significant Interactions with SUNLENCA Based on drug interaction studies conducted with SUNLENCA, no clinically significant drug interactions have been observed with: darunavir/cobicistat, cobicistat, famotidine, pitavastatin, rosuvastatin, tenofovir alafenamide, and voriconazole. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SUNLENCA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258­ 4263. Risk Summary There are insufficient human data on the use of SUNLENCA during pregnancy to inform a drug-associated risk of birth defects and miscarriage. In animal reproduction studies, no adverse developmental effects were observed when lenacapavir was administered to rats and rabbits at exposures (AUC) ≥16 times the exposure in humans at the recommended human dose (RHD) of SUNLENCA (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. The background rate of major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. Data Animal Data Lenacapavir was administered intravenously to pregnant rabbits (up to 20 mg/kg/day on gestation days (GD) 7 to 19), orally to rats (up to 300 mg/kg/day on GD 6 to 17), and subcutaneously to rats (up to 300 mg/kg on GD 6). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at exposures (AUC) approximately 16 times (rats) and 39 times (rabbits) the exposure in humans at the RHD of SUNLENCA. 8.2 Lactation Risk Summary It is not known whether SUNLENCA is present in human breast milk, affects human milk production, or has effects on the breastfed infant. After administration to pregnant rats, Reference ID: 5485227 14 --- lenacapavir was detected in the plasma of nursing rat pups, without effects on these nursing pups (see Data). Potential risks of breastfeeding include: (1) HIV-1 transmission (in infants without HIV-1), (2) developing viral resistance (in infants with HIV-1), and (3) adverse reactions in a breastfed infant similar to those seen in adults. Data Lenacapavir was detected at low levels in the plasma of nursing rat pups in the pre/postnatal development study (post-natal day 10). 8.4 Pediatric Use The safety and effectiveness of SUNLENCA have not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of SUNLENCA did not include sufficient numbers of participants aged 65 and over to determine whether they respond differently from younger patients. 8.6 Renal Impairment No dosage adjustment of SUNLENCA is recommended in patients with mild, moderate or severe renal impairment (estimated creatinine clearance greater than or equal to 15 mL per minute). SUNLENCA has not been studied in patients with ESRD (estimated creatinine clearance less than 15 mL per minute) [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustment of SUNLENCA is recommended in patients with mild (Child- Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. SUNLENCA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No data are available on overdose of SUNLENCA in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with SUNLENCA consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. As lenacapavir is highly bound to plasma proteins, it is unlikely to be significantly removed by dialysis. Reference ID: 5485227 15 11 DESCRIPTION SUNLENCA tablets and SUNLENCA injection contain lenacapavir sodium, a capsid inhibitor. The chemical name of lenacapavir sodium is: Sodium (4-chloro-7-(2-((S)-1-(2­ ((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H­ cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6­ (3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol­ 3-yl)(methylsulfonyl)amide. Lenacapavir sodium has a molecular formula of C39H31ClF10N7NaO5S2, a molecular weight of 990.3, and the following structural formula: N S Me H N N N N Cl CF3 O S Me N F F Na+ O O O O N F F F3C Lenacapavir sodium is a light yellow to yellow solid and is practically insoluble in water. SUNLENCA tablets are for oral administration. Each film-coated tablet contains 300 mg of lenacapavir (present as 306.8 mg lenacapavir sodium) and the following inactive ingredients: copovidone, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and poloxamer 407. The tablets are film-coated with a coating material containing iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. SUNLENCA injection is for subcutaneous administration. Each single-dose vial contains 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir (present as 473.1 mg/1.5 mL of lenacapavir sodium) as a sterile, preservative-free, clear, yellow solution and the following inactive ingredients: 896.3 mg of polyethylene glycol 300 (as solvent) and water for injection. The apparent pH range of the injection is 9.0-10.2. The vial stoppers are not made with natural rubber latex. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action SUNLENCA is an HIV-1 antiretroviral agent [see Microbiology (12.4)]. Reference ID: 5485227 16 12.2 Pharmacodynamics Exposure-Response In CAPELLA, oral loading doses (600 mg on Day 1 and Day 2, 300 mg on Day 8) followed by subcutaneous doses (927 mg every 6 months starting on Day 15) of SUNLENCA in heavily treatment-experienced participants with multiclass resistant HIV-1, efficacy outcomes (change in plasma HIV-1 RNA from Day 1 to Day 14, and percentage of participants with HIV-1 RNA less than 50 copies/mL at Week 26) were similar across the range of observed lenacapavir exposures. Cardiac Electrophysiology At supratherapeutic exposures of lenacapavir (9-fold higher than the therapeutic exposures of SUNLENCA), SUNLENCA does not prolong the QTcF interval to any clinically relevant extent. 12.3 Pharmacokinetics The pharmacokinetic (PK) properties of lenacapavir are provided in Table 6 and Table 7. The estimated lenacapavir exposures are comparable between the two recommended dosing regimens. Reference ID: 5485227 17 Table 6 Pharmacokinetic Properties of Lenacapavir Oral Subcutaneous Absorption % Absolute bioavailability 6 to 10 100 a b Tmax 4 hours 77 to 84 days c Effect of Food Effect of low- fat meal (relative to fasting) d AUCinf ratio 98.6 (58.2,167.2) - Cmax ratio 115.8 (55.4, 242.1) - Effect of high- fat meal (relative to fasting) e AUCinf ratio 115.2 (72.0, 184.5) - Cmax ratio 145.2 (77.9, 270.5) - Distribution Apparent volume of distribution (Vd/F, L) 19240 9500 to 11700 % bound to human plasma proteins >98.5 Blood-to-plasma ratio 0.5 to 0.7 f Elimination t1/2 10 to 12 days 8 to 12 weeks Clearance (mean apparent clearance, L/h) 55 4.2 % of dose of unchanged drug in plasma g 69 Metabolism Metabolic pathway(s) CYP3A (minor) UGT1A1 (minor) Excretion Major routes of elimination Excretion of unchanged drug into feces h % of dose excreted in urine g <1 % of dose excreted in feces (% unchanged) h 76 (33) a. Values reflect absolute bioavailability following subcutaneous administration of the 927 mg dose. b. Values reflect administration of lenacapavir with or without food. c. Due to slow release from the site of subcutaneous administration, the absorption profile of subcutaneously administered lenacapavir is complex. d. Values refer to geometric mean ratio [low-fat meal/fasting] in PK parameters and (90% confidence interval). Low fat meal is approximately 400 kcal, 25% fat. e. Values refer to geometric mean ratio [high-fat meal/fasting] in PK parameters and (90% confidence interval). High fat meal is approximately 1000 kcal, 50% fat. f. Values reflect the blood-to-plasma ratio of lenacapavir following a single dose intravenous administration of [14C] lenacapavir through 336 hours postdose. g. Dosing in mass balance studies: single dose intravenous administration of [14C] lenacapair to participants without HIV-1. Reference ID: 5485227 18 h. Metabolized via oxidation, N-dealkylation, hydrogenation, amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathione conjugation; primarily via CYP3A and UGT1A1 and no single circulating metabolite accounted for >10% of plasma drug-related exposure. Table 7 Lenacapavir Exposures Following Oral and Subcutaneous Administration of SUNLENCA in Heavily Treatment Experienced Participants with HIV Parameter Mean (%CV) Recommended Dosing Regimen, Option 1 a Recommended Dosing Regimen, Option 2 a Day 1: 600 mg (oral) + 927 mg (SC) Day 2: 600 mg (oral) Days 1 and 2: 600 mg (oral), Day 8: 300 mg (oral), Day 15: 927 mg (SC) Day 1 to end of Month 6 Days 1 to 15 Day 15 to end of Month 6 Cmax (ng/mL) 101.4 (53.1) 88.0 (72.4) 86.5 (51.7) AUCtau (h•ng/mL) 242266 (46.0) 19496 (72.6) 239163 (47.2) Ctrough (ng/mL) 32.5 (57.2) 46.9 (72.3) 32.5 (57.5) CV = coefficient of variation; NA = not applicable; SC = subcutaneous a. Predicted exposures utilizing population PK analysis. Lenacapavir exposures after subcutaneous administration were similar between heavily treatment experienced participants with HIV-1 and participants without HIV-1 based on population pharmacokinetics analysis. Lenacapavir exposures (AUCtau, Cmax and Ctrough) after oral administration were 28% to 43% higher in participants with HIV-1 who were heavily treatment experienced, compared to participants without HIV-1 based on population PK analysis. These differences were not considered clinically relevant. Specific Populations There were no clinically significant differences in the pharmacokinetics of lenacapavir based on age (18 to 78 years), sex, ethnicity (hispanic or non-hispanic), race (white, black, asian or other), body weight (41.4 to 164 kg), severe renal impairment (creatinine clearance of 15 to less than 30 mL per minute, estimated by Cockroft-Gault method), or moderate hepatic impairment (Child-Pugh Class B). The effect of end-stage renal disease (including dialysis), or severe hepatic impairment (Child-Pugh Class C), on the pharmacokinetics of lenacapavir is unknown. As lenacapavir is greater than 98.5% protein bound, dialysis is not expected to alter exposures of lenacapavir [see Use in Specific Populations (8.6)]. 19 Reference ID: 5485227 Drug Interaction Studies Clinical Studies Clinical drug-drug interaction study indicated that lenacapavir is a substrate of CYP3A, P-gp, and UGT1A1. Table 8 summarizes the pharmacokinetic effects of other drugs on lenacapavir. Lenacapavir is a moderate inhibitor of CYP3A. Lenacapavir is an inhibitor of P-gp and BCRP but does not inhibit OATP. Table 9 summarizes the pharmacokinetic effects of lenacapavir on other drugs. Table 8 Effect of Other Drugs on Lenacapavir a,b Coadministered Drug Dose of Coadministered Drug (mg) Mean Ratio of Lenacapavir Pharmacokinetic Parameters (90% CI); No effect = 1.00 Cmax AUC Cobicistat (fed) (Inhibitor of CYP3A [strong] and P-gp) 150 once daily 2.10 (1.62, 2.72) 2.28 (1.75, 2.96) Darunavir / cobicistat (fed) (Inhibitor of CYP3A [strong] and inhibitor and inducer of P-gp) 800/150 once daily 2.30 (1.79, 2.95) 1.94 (1.50, 2.52) Voriconazole (fasted) (Inhibitor of CYP3A [strong]) 400 twice daily, 200 twice daily c 1.09 (0.81, 1.47) 1.41 (1.10, 1.81) Atazanavir / cobicistat (fed) (Inhibitor of CYP3A [strong] and UGT1A1 and P-gp) 300/150 once daily 6.60 (4.99, 8.73) 4.21 (3.19, 5.57) Rifampin (fasted) (Inducer of CYP3A [strong] and P-gp and UGT) 600 once daily 0.45 (0.34, 0.60) 0.16 (0.12, 0.20) Efavirenz (fasted) (Inducer of CYP3A [moderate] and P-gp) 600 once daily 0.64 (0.45, 0.92) 0.44 (0.32, 0.59) Famotidine (2 hours before, fasted) 40 once daily 1.01 (0.75, 1.34) 1.28 (1.00, 1.63) a. Single dose of lenacapavir 300 mg administered orally. b. All interaction studies conducted in participants without HIV-1. c. 400 mg loading dose twice daily for a day, followed by 200 mg maintenance dose twice daily. Reference ID: 5485227 20 Table 9 Effect of Lenacapavir on Other Drugs a,b Coadministered Drug Dose of Coadministered Drug (mg) Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI) c; No effect = 1.00 Cmax AUC Tenofovir alafenamide (fed) (substrate of P-gp) 25 single dose 1.24 (0.98, 1.58) 1.32 (1.09, 1.59) Tenofovir d (substrate of P-gp) 1.23 (1.05, 1.44) 1.47 (1.27, 1.71) Pitavastatin (simultaneous administration, fed) (substrate of OATP) 2 single dose 1.00 (0.84, 1.19) 1.11 (1.00, 1.25) Pitavastatin (3 days after lenacapavir, fed) (substrate of OATP) 2 single dose 0.85 (0.69, 1.05) 0.96 (0.87, 1.07) Rosuvastatin (fed) (substrate of BCRP and OATP) 5 single dose 1.57 (1.38, 1.80) 1.31 (1.19, 1.43) Midazolam (simultaneous administration, fed) (substrate of CYP3A) 2.5 single dose 1.94 (1.81, 2.08) 3.59 (3.30, 3.91) 1-hydroxymidazolam e (substrate of CYP3A) 0.54 (0.50, 0.59) 0.76 (0.72, 0.80) Midazolam (1 day after lenacapavir, fed) (substrate of CYP3A) 2.5 single dose 2.16 (2.02, 2.30) 4.08 (3.77, 4.41) 1-hydroxymidazolam e (substrate of CYP3A) 0.52 (0.48, 0.57) 0.84 (0.80, 0.88) a. All interaction studies conducted in participants without HIV-1. b. Following 600 mg twice daily for 2 days, single 600 mg doses of lenacapavir were administered with each coadministered drug, resulting in lenacapavir exposures similar to or higher than those at the recommended dosage regimen. c. All No Effect Boundaries are 70% to 143%. d. Tenofovir alafenamide is converted to tenofovir in vivo. e. Major active metabolite of midazolam. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Lenacapavir is not a substrate, inducer, or inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Lenacapavir is not an inducer of CYP3A4. Reference ID: 5485227 21 Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Lenacapavir is not an inhibitor of UGT1A1. Transporter Systems: Lenacapavir is not an inhibitor of organic anion transporter 1 (OAT1), OAT3, organic cation transporter (OCT)1, OCT2, multidrug and toxin extrusion transporter (MATE) 1, or MATE 2-K. Lenacapavir is not a substrate of BCRP, OATP1B1, or OATP1B3. 12.4 Microbiology Mechanism of Action Lenacapavir is a multistage, selective inhibitor of HIV-1 capsid function that directly binds to the interface between capsid protein (p24) subunits in hexamers. Surface plasmon resonance sensorgrams showed dose-dependent and saturable binding of lenacapavir to cross-linked wild-type capsid hexamer with an equilibrium binding constant (KD) of 1.4 nM. Lenacapavir inhibits HIV-1 replication by interfering with multiple essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1 proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (by interfering with Gag/Gag-Pol functioning, reducing production of capsid protein subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to malformed capsids). Antiviral Activity in Cell Culture Lenacapavir has antiviral activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2). The antiviral activity of lenacapavir against laboratory and clinical isolates of HIV-1 was assessed in T-lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes with EC50 values ranging from 30 to 190 pM. Lenacapavir displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including subtypes A, A1, AE, AG, B, BF, C, D, E, F, G with EC50 values ranging from 20 and 160 pM. The median EC50 value for subtype B isolates (n=8) was 40 pM. Lenacapavir was 15- to 25-fold less active against HIV-2 isolates relative to HIV-1. In a study of lenacapavir in combination with representatives from the major classes of anti-retroviral agents (INSTIs, NNRTIs, NRTIs, and PIs), no antagonism of antiviral activity was observed. Resistance In Cell Culture HIV-1 variants with reduced susceptibility to lenacapavir have been selected in cell culture. Resistance selections with lenacapavir identified 7 substitutions in capsid: L56I, M66I, Q67H, K70N, N74D/S, and T107N singly or in dual combination that conferred 4­ to >3,226-fold reduced phenotypic susceptibility to lenacapavir relative to wild-type (WT) virus. The M66I substitution alone or in combination conferred >3,226-fold decreased Reference ID: 5485227 22 susceptibility to lenacapavir in a single-cycle infectivity assay; substitutions Q67H and T107N, conferred 4- to 6.3-fold decreased susceptibility; K70N, N74D and Q67H/N74S conferred 22- to 32-fold decreased susceptibility; and L56I conferred 239-fold decreased susceptibility. In Clinical Trials In CAPELLA, 31% (22/72) of heavily treatment-experienced participants met the criteria for resistance analyses through Week 52 (HIV-1 RNA ≥ 50 copies/mL at confirmed virologic failure [suboptimal virologic response at Week 4, virologic rebound, or viremia at last visit]) and were analyzed for lenacapavir resistance-associated substitution emergence. Lenacapavir resistance-associated capsid substitutions were found in 41% (n=9) of participants with confirmed virologic failure who had post-baseline capsid genotypic resistance data (n=22). The M66I capsid substitution was observed in 27% (6/22) of participants, alone or in combination with other lenacapavir resistance- associated capsid substitutions including Q67Q/H, Q67Q/H/K/N, K70K/R, K70N/S, N74D, N74N/H, A105T, and T107A. The other 3 participants with virologic failure had emergent lenacapavir resistance-associated capsid substitutions Q67K+K70H, Q67H+K70R+T107S, and Q67Q/H. Phenotypic analyses of the confirmed virologic failure isolates with emergent lenacapavir resistance-associated substitutions showed 6- to >1428-fold decreases in lenacapavir susceptibility when compared to WT. Among the 9 participants with virologic failure who developed lenacapavir resistance- associated substitutions in capsid, 4 received SUNLENCA in combination with a background regimen with no fully active antiretrovirals based on the baseline genotypic and/or phenotypic resistance. Therefore, given the risk of developing resistance in situations of functional monotherapy, careful consideration should be given to having active drugs in addition to SUNLENCA in the treatment regimen. Four participants with virologic failure had emergent resistance substitutions to components of the optimized background regimen (OBR): emergent NRTI substitution M184I/V and NNRTI substitution K103N/Y with emtricitabine and doravirine plus atazanavir, bictegravir, and tenofovir alafenamide in OBR; emergent NNRTI substitution V106M from a mixture at baseline (in addition to lenacapavir resistance-associated substitutions M66I + T107A) with doravirine plus emtricitabine and ibalizumab in OBR; emergent NRTI substitutions K65R and S68N from mixtures at baseline (in addition to lenacapavir resistance-associated substitution M66I) with tenofovir alafenamide, plus emtricitabine, dolutegravir, darunavir/cobicistat, and rilpivirine in OBR; and emergent NRTI substitution K65K/R with tenofovir disoproxil fumarate plus darunavir/cobicistat, dolutegravir, and emtricitabine in OBR. Oral Maintenance for Missed Injections Of the 57 participants who received oral maintenance, 9 participants (5 participants in Cohort 1 and 4 participants in Cohort 2) met the criteria for resistance analysis. Six of these 9 participants had emergent lenacapavir resistance substitutions in capsid (Q67H [n=4], K70R or N [n=2], N74D or K [n=2], T107N [n=1]) with 4.5- to 393-fold decreased Reference ID: 5485227 23 lenacapavir susceptibility. In addition, 2 participants had emergent resistance substitutions to darunavir in their optimized background regimen. Lenacapavir Resistance with Suboptimal Adherence to Other Antiretroviral Drugs in the Regimen The development of lenacapavir-associated capsid resistance substitutions in 6 participants during the oral maintenance period was likely due to suboptimal adherence to the optimized background oral regimens that included dolutegravir and/or darunavir. After developing lenacapavir resistance, 5 of the 6 participants achieved HIV-1 RNA resuppression (HIV-1 RNA < 50 copies/mL) while maintaining SUNLENCA treatment. With the emergence of lenacapavir resistance substitutions and decreased susceptibility to lenacapavir, it is unclear how much antiviral activity lenacapavir is contributing to the resuppression of HIV-1 RNA in these 5 participants. Thus, adherence to other antiretroviral drugs in the regimen should be optimized while the patient is receiving SUNLENCA. During SUNLENCA treatment, if suboptimal adherence to the oral antiretroviral regimen occurs with concurrent HIV-1 RNA viral load increases (i.e., virologic failure), lenacapavir resistance should be assessed, and if detected, consideration should be given to discontinuing SUNLENCA treatment [see Dosage and Administration (2.1), Warnings and Precautions (5.2)]. Cross-Resistance The antiviral activity in cell culture of lenacapavir was determined against a broad spectrum of HIV-1 site-directed mutants and patient-derived HIV-1 isolates with resistance to the four main classes of anti-retroviral agents (INSTI, NNRTI, NRTI, and PI; n=58), as well as to viruses resistant to the gp120-directed attachment inhibitor fostemsavir, the CD4+-directed post-attachment inhibitor ibalizumab, the CCR5 co- receptor antagonist maraviroc, and the gp41 fusion inhibitor enfuvirtide (n=42). These data indicated that lenacapavir remained fully active against all variants tested, thereby demonstrating a non-overlapping resistance profile. In addition, the antiviral activity of lenacapavir in patient isolates was unaffected by the presence of naturally occurring Gag polymorphisms and substitutions at protease cleavage sites. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Lenacapavir was not carcinogenic in a 6-month rasH2 transgenic mouse study in males or females at doses of up to 300 mg/kg/dose once every 13 weeks. A 104-week carcinogenicity study was conducted in male and female rats at lenacapavir doses of 0, 102, 309, or 927 mg/kg by subcutaneous injection once every 13-weeks. A treatment-related increase in the incidence of malignant sarcoma at the injection site was observed in males and a treatment-related increase in combined benign fibroma Reference ID: 5485227 24 and malignant fibrosarcoma at the injection site was observed in females, at the highest dose (927 mg/kg). This dose in rats resulted in an exposure approximately 34-times the human exposure at the RHD, based on AUC. These tumors are considered to be a secondary response to chronic tissue irritation and granulomatous inflammation, due to the depot effect of lenacapavir following subcutaneous injection. The clinical relevance of these findings are unknown. Mutagenesis Lenacapavir was not mutagenic in a battery of in vitro and in vivo genotoxicity assays, including microbial mutagenesis, chromosome aberration in human peripheral blood lymphocytes, and in in vivo rat micronucleus assays. Impairment of Fertility There were no effects on fertility, mating performance or early embryonic development when lenacapavir was administered to rats at systemic exposures (AUC) 5 times the exposure to humans at the RHD of SUNLENCA. 14 CLINICAL STUDIES The efficacy and safety of SUNLENCA in heavily treatment-experienced participants with multidrug resistant HIV-1 is based on 52-week data from CAPELLA, a randomized, placebo-controlled, double-blind, multicenter trial (NCT 04150068). CAPELLA was conducted in 72 heavily treatment-experienced participants with multiclass resistant HIV-1. Participants were required to have a viral load ≥ 400 copies/mL, documented resistance to at least two antiretroviral medications from each of at least 3 of the 4 classes of antiretroviral medications (NRTI, NNRTI, PI and INSTI), and ≤ 2 fully active antiretroviral medications from the 4 classes of antiretroviral medications remaining at baseline due to resistance, intolerability, drug access, contraindication, or other safety concerns. The trial was composed of two cohorts. Participants were enrolled into the randomized cohort (cohort 1, N=36) if they had a < 0.5 log10 HIV-1 RNA decline compared to the screening visit. Participants were enrolled into the non-randomized cohort (cohort 2, N=36) if they had a ≥ 0.5 log10 HIV-1 RNA decline compared to the screening visit or after cohort 1 reached its planned sample size. In the 14-day functional monotherapy period, participants in cohort 1 were randomized in a 2:1 ratio in a blinded fashion to receive either SUNLENCA or placebo, while continuing their failing regimen. This period was to establish the virologic activity of SUNLENCA. After the functional monotherapy period, participants who had received SUNLENCA continued on SUNLENCA along with an optimized background regimen (OBR); participants who had received placebo during this period initiated SUNLENCA along with an OBR. Participants in cohort 1 had a mean age of 52 years (range: 24 to 71), 72% were male, Reference ID: 5485227 25     46% were White, 46% were Black, and 9% were Asian. 29% percent of participants identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.3 log10 copies/mL (range: 2.3 to 5.4). 19% of participants had baseline viral loads greater than 100,000 copies/mL. The mean baseline CD4+ cell count was 161 cells/mm3 (range: 6 to 827). 75% of participants had CD4+ cell counts below 200 cells/mm3. The mean number of years since participants first started HIV treatment was 24 years (range: 7 to 33); the mean number of antiretroviral agents in failing regimens at baseline was 4 (range: 1 to 7). The percentage of participants in the randomized cohort with known resistance to at least 2 agents from the NRTI, NNRTI, PI and INSTI classes was 97%, 94%, 78% and 75%, respectively. In cohort 1, 53% of participants had no fully active agents, 31% had 1 fully active agent, and 17% had 2 or more fully active agents within their initial failing regimen, including 6% of participants were who were receiving fostemsavir, which was an investigational agent at the start of the CAPELLA trial. Participants in cohort 2 initiated SUNLENCA and an OBR on Day 1. Participants in cohort 2 had a mean age of 48 years (range: 23 to 78), 78% were male, 36% were White, 31% were Black, 33% were Asian, and 14% of participants identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.1 log10 copies/mL (range: 1.3 to 5.7). 19% of participants had baseline viral loads greater than 100,000 copies/mL. The mean baseline CD4+ cell count was 258 cells/mm3 (range: 3 to 1296). 53% of participants had CD4+ cell counts below 200 cells/mm3. The mean number of years since participants first started HIV treatment was 19 years (range: 3 to 35); the mean number of antiretroviral agents in failing regimens at baseline was 4 (range: 2 to 7). The percentage of participants in the non-randomized cohort with known resistance to at least 2 agents from the NRTI, NNRTI, PI and INSTI classes was 100%, 100%, 83% and 64%, respectively. In cohort 2, 31% of participants had no fully active agents, 42% had 1 fully active agent, and 28% had 2 or more fully active agents within their initial failing regimen, including 6% of participants who were receiving fostemsavir, which was an investigational agent at the start of the CAPELLA trial. The primary efficacy endpoint was the proportion of participants in cohort 1 achieving ≥ 0.5 log10 copies/mL reduction from baseline in HIV-1 RNA at the end of the functional monotherapy period. The results of the primary endpoint analysis are shown in Table 10. Table 10 Proportion of Participants Achieving a ≥ 0.5 log10 Decrease in Viral Load at the End of the Functional Monotherapy Period in the CAPELLA Trial (Cohort 1) SUNLENCA (N=24) Placebo (N=12) Proportion of Participants Achieving a ≥ 0.5 log10 Decrease in Viral Load 87.5% 16.7% Treatment Difference (95% CI) 70.8% (34.9% to 90.0%) a a. p < 0.0001 Reference ID: 5485227 26 The results at Weeks 26 and 52 are provided in Table 11 and Table 12. Table 11 Virologic Outcomes (HIV-1 RNA < 50 copies/mL) at Weeks 26 a and 52 b with SUNLENCA plus OBR in the CAPELLA Trial (Cohort 1) SUNLENCA plus OBR (N=36) Week 26 Week 52 HIV-1 RNA < 50 copies/mL 81% 83% HIV-1 RNA ≥ 50 copies/mLc 19% 14% No virologic data in Week 26 or 52 Window 0 3% Discontinued Study Drug Due to AE or Death d 0 0 Discontinued Study Drug Due to Other Reasons e and Last Available HIV-1 RNA < 50 copies/mL 0 3% Missing Data During Window but on Study Drug 0 0 OBR = optimized background regimen a. Week 26 window was between Days 184 and 232 (inclusive). b. Week 52 window was between Days 324 and 414 (inclusive). c. Includes participants who had ≥ 50 copies/mL in the Week 26 or 52 window; participant who discontinued early due to lack or loss of efficacy; participants who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL. d. Includes participants who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. e. Includes participants who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. Reference ID: 5485227 27 Table 12 Virologic Outcomes (HIV-1 RNA < 50 copies/mL) by Baseline Covariates at Weeks 26 a and 52 b with SUNLENCA plus OBR in the CAPELLA trial (Cohort 1) SUNLENCA plus OBR (N=36) Week 26 Week 52 Age (Years) < 50 100% (9/9) 89% (8/9) ≥ 50 74% (20/27) 81% (22/27) Gender Male 77% (20/26) 77% (20/26) Female 90% (9/10) 100% (10/10) Race Black 81% (13/16) 75% (12/16) Non-Black 84% (16/19) 89% (17/19) Baseline plasma viral load (copies/mL) ≤ 100,000 86% (25/29) 86% (25/29) > 100,000 57% (4/7) 71% (5/7) Baseline CD4+ (cells/mm3) < 200 78% (21/27) 78% (21/27) ≥ 200 89% (8/9) 100% (9/9) Baseline INSTI resistance profile With INSTI resistance 85% (23/27) 81% (22/27) Without INSTI resistance 63% (5/8) 88% (7/8) Number of fully active ARV agents in the OBR 0 67% (4/6) 67% (4/6) 1 86% (12/14) 79% (11/14) ≥ 2 81% (13/16) 94% (15/16) Use of DTG and/or DRV in the OBR With DTG and DRV 83% (10/12) 83% (10/12) With DTG, without DRV 83% (5/6) 83% (5/6) Without DTG, with DRV 78% (7/9) 89% (8/9) Without DTG or DRV 78% (7/9) 78% (7/9) ARV = antiretroviral; DRV=darunavir; DTG=dolutegravir; INSTI = integrase strand-transfer inhibitor; OBR = optimized background regimen; a. Week 26 window was between Days 184 and 232 (inclusive). b. Week 52 window was between Days 324 and 414 (inclusive). Reference ID: 5485227 28 In cohort 1, at Weeks 26 and 52, the mean change from baseline in CD4+ cell count was 81 cells/mm3 (range: -101 to 522) and 82 cells/mm3 (range: -194 to 467), respectively. In cohort 2, at Weeks 26 and 52, 81% (29/36) and 72% (26/36) of participants achieved HIV-1 RNA < 50 copies/mL, respectively, and the mean change from baseline in CD4+ cell count was 97 cells/mm3 (range: -103 to 459) and 113 cells/mm3 (range: -124 to 405), respectively. Oral bridging In CAPELLA across cohorts 1 and 2, 79% of participants (57/72) received SUNLENCA 300 mg once every 7 days as oral bridging. A total of 13, 29, and 15 participants started oral bridging following Weeks 26, 52, and 78 injections, respectively. The median (Q1, Q3) duration of oral bridging was 19 weeks (11, 22), and 12% (7/57) received oral bridging for at least 28 weeks. In a post-hoc analysis, rates of virologic suppression and change from baseline in CD4+ cell counts in the subset of patients who received oral bridging were consistent before and during the oral bridging period. 16 HOW SUPPLIED/STORAGE AND HANDLING SUNLENCA tablets, 300 mg are beige, capsule-shaped, and film-coated with “GSI” debossed on one side and “62L” on the other side. SUNLENCA tablets are available in a bottle and blister packs, packaged as follows: Bottle • SUNLENCA bottle contains 4 tablets (NDC 61958-3001-3). The bottle also contains a silica gel desiccant and polyester coil, and is closed with a child-resistant closure. Do not remove the desiccant packet. Keep bottle tightly closed. Blister Packs • SUNLENCA 4-Tablets™ blister pack contains 4 tablets (NDC 61958-3001-1) • SUNLENCA 5-Tablets™ blister pack contains 5 tablets (NDC 61958-3001-2) Within the blister packs, tablets are packaged in a clear blister film sealed to a foil lidding material. The blister card is fitted between two paperboard cards, and packaged with silica gel desiccant in a sealed child-resistant flexible laminated pouch. Store bottle and blister packs at 20 °C – 25 °C (68 °F – 77 °F), excursions permitted to 15 °C – 30 °C (59 °F – 86 °F) (see USP Controlled Room Temperature). Reference ID: 5485227 29 Dispense and store only in original bottle or blister pack. SUNLENCA injection is packaged in one of two different injection kits containing the following: Vial access device injection kit (NDC 61958-3002-1): • 2 single-dose clear glass vials, each containing sufficient volume to allow withdrawal of 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir. The injection solution is sterile, preservative-free, clear, and yellow with no visible particles. Vials are sealed with a stopper and aluminium overseal with flip-off cap. • 2 vial access devices, 2 disposable syringes, and 2 injection safety needles for subcutaneous injection (22-gauge, ½ inch). Withdrawal needle injection kit (NDC 61958-3005-1): • 2 single-dose clear glass vials, each containing sufficient volume to allow withdrawal of 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir. The injection solution is sterile, preservative-free, clear, and yellow with no visible particles. Vials are sealed with a stopper and aluminium overseal with flip-off cap. • 2 disposable syringes, 2 withdrawal needles (18-gauge, 1.5 inch), and 2 injection safety needles for subcutaneous injection (22-gauge, ½ inch). The vial stoppers are not made with natural rubber latex. Store at 20 °C – 25 °C (68 °F – 77 °F), excursions permitted to 15 °C – 30 °C (59 °F – 86 °F). Keep the vials in the original carton until just prior to preparation of the injections in order to protect from light. Once the solution has been drawn into the syringes, the injections should be administered as soon as possible. Discard any unused portion of the solution. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Drug Interactions SUNLENCA may interact with certain drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products, including St. John’s wort, during treatment with SUNLENCA [see Contraindications (4) and Drug Interactions (7)]. Reference ID: 5485227 30 If SUNLENCA is discontinued, advise patients that SUNLENCA may remain in the body and affect certain other drugs for up to 9 months after receiving their last injection [see Drug Interactions (7.2, 7.3)]. Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.1)]. Adherence to SUNLENCA Counsel patients about the importance of continued medication adherence and scheduled visits to maintain viral suppression and to reduce risk of loss of virologic response and development of resistance. Advise patients to contact their healthcare provider immediately if they stop taking SUNLENCA or any other drug in their antiretroviral regimen [see Dosage and Administration (2.1) and Warnings and Precautions (5.2)]. Missed Dose Inform patients that SUNLENCA can remain in the body for up to 12 months or longer after receiving their last injection. Advise patients to contact their healthcare provider if they miss or plan to miss a scheduled injection visit and that oral SUNLENCA therapy may be used for up to 6 months to replace missed injections. Advise patients that oral dosing should be used on an interim basis only and that the maintenance injection dosage should be resumed at the earliest possible opportunity [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. Injection Site Reactions Inform patients that injection site reactions (ISRs), such as swelling, pain, erythema, nodule, induration, pruritus, extravasation or mass, may occur. Nodules and indurations at the injection site may take longer to resolve than other ISRs and may be persistent. Instruct patients when to contact their healthcare provider about these reactions [see Warnings and Precautions (5.3)]. Pregnancy Registry Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to SUNLENCA [see Use in Specific Populations (8.1)]. Lactation Inform individuals with HIV-1 that the potential risks of breastfeeding include: (1) HIV-1 transmission (in infants without HIV-1), (2) developing viral resistance (in infants with HIV), and (3) adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)]. Reference ID: 5485227 31 SUNLENCA is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners. © 2024 Gilead Sciences, Inc. All rights reserved. Reference ID: 5485227 32 PATIENT INFORMATION SUNLENCA® (sun-LEN-kuh) SUNLENCA® (sun-LEN-kuh) (lenacapavir) (lenacapavir) tablets injection What is SUNLENCA? SUNLENCA is a prescription medicine that is used with other human immunodeficiency virus-1 (HIV-1) medicines to treat HIV-1 infection in adults: • who have received HIV-1 medicines in the past, and • who have HIV-1 virus that is resistant to many HIV-1 medicines, and • whose current HIV-1 medicines are failing. Your HIV-1 medicines may be failing because the HIV-1 medicines are not working or no longer work, you are not able to tolerate the side effects, or there are safety reasons why you cannot take them. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). It is not known if SUNLENCA is safe and effective in children. Do not receive or take SUNLENCA if you also take certain other medicines called strong CYP3A inducers. Ask your healthcare provider if you are not sure. Before receiving or taking SUNLENCA, tell your healthcare provider about all your medical conditions, including if you: • are pregnant or plan to become pregnant. It is not known if SUNLENCA can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with SUNLENCA. Pregnancy Registry: There is a pregnancy registry for women who take SUNLENCA during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry. • are breastfeeding or plan to breastfeed. It is not known whether SUNLENCA will pass to your baby in your breast milk. Talk with your healthcare provider about the following risks to your baby from breastfeeding during treatment with SUNLENCA: o The HIV-1 virus may pass to your baby if your baby does not have HIV-1. o The HIV-1 virus may become harder to treat if your baby has HIV-1. o Your baby may get side effects from SUNLENCA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements, including St. John’s wort. Some medicines may interact with SUNLENCA. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. • You can ask your healthcare provider or pharmacist for a list of medicines that interact with SUNLENCA. • Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take SUNLENCA with other medicines. • SUNLENCA may affect certain other medicines for up to 9 months after your last injection. How should I receive and take SUNLENCA? • Your SUNLENCA treatment will consist of injections and tablets. o SUNLENCA injections will be given to you by your healthcare provider under the skin (subcutaneous injection) in your stomach-area (abdomen). o Take SUNLENCA tablets by mouth, with or without food. • There are two options (Option 1 and Option 2) to start treatment with SUNLENCA. Your healthcare provider will decide which starting option is for you. o If Option 1 is chosen: • On Day 1, you will receive 2 SUNLENCA injections and take 2 SUNLENCA tablets. • On Day 2, you will take 2 SUNLENCA tablets. o If Option 2 is chosen: • On Day 1 and Day 2, you will take 2 SUNLENCA tablets each day. • On Day 8, you will take 1 SUNLENCA tablet. • On Day 15, you will receive 2 SUNLENCA injections. • After completing Option 1 or Option 2, you will receive 2 SUNLENCA injections every 6 months (26 weeks) from the date of your last injection. 1 Reference ID: 5485227 • Stay under the care of a healthcare provider during treatment with SUNLENCA. It is important that you attend your planned appointments to receive your injections of SUNLENCA. • If you miss or plan to miss your scheduled every 6 months injection of SUNLENCA, call your healthcare provider right away to discuss your treatment options. o If you plan to miss a scheduled SUNLENCA injection, there is the option to temporarily take SUNLENCA tablets. You will take 1 SUNLENCA tablet by mouth 1 time every 7 days, until your injections resume. o It is important to continue SUNLENCA treatment as your healthcare provider tells you. Missing SUNLENCA treatment may cause the HIV-1 virus to change (mutate) and become harder to treat (resistant). • Tell your healthcare provider right away if you stop treatment with SUNLENCA or stop treatment with any other HIV-1 medicines. If you stop treatment with SUNLENCA you will need other medicines to treat your HIV-1 infection. If you do not take other HIV-1 medicines, the amount of virus in your blood may increase and the virus may become harder to treat. Call your healthcare provider right away to discuss your treatment options. • If you take too many SUNLENCA tablets, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of SUNLENCA? SUNLENCA may cause serious side effects, including: • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine. • Injection site reactions may happen when you receive SUNLENCA injections and may include swelling, pain, redness, skin hardening, small mass or lump, and itching. Hardened skin or lumps at the injection site usually can be felt but not seen. If you develop hardened skin or a lump, it may take longer than other reactions at the injection site to go away, and the injection site may not completely heal on its own. Tell your healthcare provider if you have any injection site reactions. The most common side effects of SUNLENCA are nausea and injection site reactions. These are not all of the possible side effects of SUNLENCA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store SUNLENCA tablets? • Store SUNLENCA tablets at room temperature between 68 °F to 77 °F (20 °C to 25 °C). • SUNLENCA bottle contains a desiccant packet to help keep your medicine dry (protect it from moisture). Keep the desiccant packet in the bottle. Do not eat the desiccant packet. • Keep SUNLENCA tablets in their original bottle or blister pack. • Keep the bottle tightly closed. Keep SUNLENCA and all medicines out of reach of children. General information about the safe and effective use of SUNLENCA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SUNLENCA for a condition for which it was not prescribed. Do not give SUNLENCA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about SUNLENCA that is written for health professionals. What are the ingredients in SUNLENCA? Active ingredient: lenacapavir Inactive ingredients: SUNLENCA tablets: copovidone, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and poloxamer 407. The tablets are film-coated with a coating material containing iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. SUNLENCA injection: polyethylene glycol 300 and water for injection. Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404 SUNLENCA is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners. © 2024 Gilead Sciences, Inc. All rights reserved. 215973-GS-004/IFU-001/IFU-WD-000 For more information, call 1-800-445-3235 or go to www.SUNLENCA.com. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 2 Reference ID: 5485227
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2025-02-12T15:47:17.576320
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SUNLENCA safely and effectively. See full prescribing information for SUNLENCA. SUNLENCA® (lenacapavir) tablets, for oral use SUNLENCA® (lenacapavir) injection, for subcutaneous use Initial U.S. Approval: 2022 ----------------------------RECENT MAJOR CHANGES-------------------------­ Dosage and Administration (2.1, 2.3, 2.4) 11/2024 Warnings and Precautions (5.3) 11/2024 ----------------------------INDICATIONS AND USAGE---------------------------­ SUNLENCA, a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor, in combination with other antiretroviral(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 whose current antiretroviral regimen is failing due to resistance, intolerance, or safety considerations. (1) ------------------------DOSAGE AND ADMINISTRATION----------------------­ • Recommended dosage – Initiation with one of two options followed by once every 6 months maintenance injection dosing. Tablets may be taken without regard to food. (2.2) Initiation Option 1 Day 1 927 mg by subcutaneous injection (2 x 1.5 mL injections) 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Initiation Option 2 Day 1 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Day 8 300 mg orally (1 x 300 mg tablet) Day 15 927 mg by subcutaneous injection (2 x 1.5 mL injections) Maintenance 927 mg by subcutaneous injection (2 x 1.5 mL injections) every 6 months (26 weeks) from the date of the last injection +/-2 weeks. • Planned missed injections: If scheduled injection is to be missed by more than 2 weeks, SUNLENCA tablets may be used for oral bridging for up to 6 months until injections resume. Recommended dosage is 300 mg orally once every 7 days. (2.3) • Unplanned missed injections: If more than 28 weeks since last injection and tablets have not been taken for oral bridging, restart initiation from Day 1 (using Option 1 or Option 2) if clinically appropriate. (2.3) • SUNLENCA injection is for subcutaneous administration only. Two 1.5 mL injections are required for complete dose. (2.4) ----------------------DOSAGE FORMS AND STRENGTHS--------------------­ Tablets: 300 mg Injection: 463.5 mg/1.5 mL (309 mg/mL) in single-dose vials. (3) -------------------------------CONTRAINDICATIONS------------------------------­ Concomitant administration of SUNLENCA is contraindicated with strong CYP3A inducers. (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ • Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.1) • Residual concentrations of lenacapavir may remain in systemic circulation for up to 12 months or longer. Counsel patients regarding the dosing schedule; non-adherence could lead to loss of virologic response and development of resistance. (5.2) • May increase exposure and risk of adverse reactions to drugs primarily metabolized by CYP3A initiated within 9 months after the last subcutaneous dose of SUNLENCA. (5.2) • If discontinued, initiate an alternative, fully suppressive antiretroviral regimen where possible no later than 28 weeks after the final injection of SUNLENCA. If virologic failure occurs, switch to an alternative regimen if possible. (5.2) • Injection site reactions may occur, and nodules and indurations may be persistent. Improper administration (intradermal injection) has been associated with serious injection site reactions. (5.3) -------------------------------ADVERSE REACTIONS-----------------------------­ Most common adverse reactions (incidence greater than or equal to 3%, all grades) are nausea and injection site reactions. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------­ • Consult the Full Prescribing Information prior to and during treatment for important drug interactions. (4, 7, 12.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Adherence to Treatment Regimen 2.2 Recommended Dosage 2.3 Recommended Dosing Schedule for Missed Dose 2.4 Preparation and Administration of Subcutaneous Injection 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Immune Reconstitution Syndrome 5.2 Long-Acting Properties and Potential Associated Risks with SUNLENCA 5.3 Injection Site Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on SUNLENCA 7.2 Effect of SUNLENCA on Other Drugs 7.3 Established and Other Potentially Significant Drug Interactions 7.4 Drugs without Clinically Significant Interactions with SUNLENCA 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 5485227 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE SUNLENCA, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 whose current antiretroviral regimen is failing due to resistance, intolerance, or safety considerations. 2 DOSAGE AND ADMINISTRATION 2.1 Adherence to Treatment Regimen Prior to starting SUNLECA, healthcare providers should carefully select patients who agree to the required every 6 month injection dosing schedule and counsel patients about the importance of adherence to scheduled SUNLENCA dosing visits and concomitant oral antiretroviral therapy to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance with missed doses [see Warnings and Precautions (5.2), Microbiology (12.4)]. 2.2 Recommended Dosage SUNLENCA can be initiated using one of the two recommended dosage regimens in Table 1 and Table 2 below. Maintenance dosing is administered by subcutaneous injection every 6 months regardless of the initiation regimen. Healthcare providers should determine the appropriate initiation regimen for the patient. SUNLENCA oral tablets may be taken with or without food [see Clinical Pharmacology (12.3)]. Table 1 Recommended Treatment Regimen for SUNLENCA Initiation and Maintenance, Option 1 Treatment Time Dosage of SUNLENCA: Initiation Day 1 927 mg by subcutaneous injection (2 x 1.5 mL injections) 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Dosage of SUNLENCA: Maintenance Every 6 months (26 weeks) a +/-2 weeks 927 mg by subcutaneous injection (2 x 1.5 mL injections) a. From the date of the last injection. Reference ID: 5485227 2 Table 2 Recommended Treatment Regimen for SUNLENCA Initiation and Maintenance, Option 2 Treatment Time Dosage of SUNLENCA: Initiation Day 1 600 mg orally (2 x 300 mg tablets) Day 2 600 mg orally (2 x 300 mg tablets) Day 8 300 mg orally (1 x 300 mg tablet) Day 15 927 mg by subcutaneous injection (2 x 1.5 mL injections) Dosage of SUNLENCA: Maintenance Every 6 months (26 weeks) a +/-2 weeks 927 mg by subcutaneous injection (2 x 1.5 mL injections) a. From the date of the last injection. 2.3 Recommended Dosing Schedule for Missed Dose Planned Missed Injections During the maintenance period, if a patient plans to miss a scheduled 6-month injection visit by more than 2 weeks, SUNLENCA tablets may be taken for up to 6 months until injections resume. Refer to Table 3 below for the recommended dosage after planned missed injections. Table 3 Recommended Dosage after Planned Missed Injections: Weekly Oral Maintenance Time since Last Injection Recommendation 26 to 28 weeks Maintenance oral dosage of 300 mg taken once every 7 days for up to 6 months. Resume the maintenance injection dosage within 7 days after the last oral dose. Unplanned Missed Injections Patients who miss a scheduled injection visit should be clinically reassessed, including consideration of lenacapavir resistance testing, to ensure resumption of therapy remains appropriate. During the maintenance period, if more than 28 weeks have elapsed since the last injection and SUNLENCA tablets have not been taken, see Table 4 below for the recommended dosage after unplanned missed injections. Adherence to the injection dosing schedule is strongly recommended [see Dosage and Administration (2.1) and Microbiology (12.4)]. Reference ID: 5485227 3 Table 4 Recommended Dosage after Unplanned Missed Injections Time since Last Injection Recommendation More than 28 weeks Reinitiate with Option 1 (Table 1) or Option 2 (Table 2) and then continue with maintenance injection dosing. 2.4 Preparation and Administration of Subcutaneous Injection SUNLENCA injection is only for subcutaneous administration into the abdomen by a healthcare provider. Do NOT administer intradermally due to risk of serious injection site reactions [see Warnings and Precautions (5.3)]. Use aseptic technique. Visually inspect the solution in the vials and prepared syringe for particulate matter and discoloration prior to administration. SUNLENCA injection is a yellow solution. Do not use SUNLENCA injection if the solution is discolored or if it contains particulate matter. Once the solution is withdrawn from the vials, the subcutaneous injections should be administered as soon as possible [see How Supplied/Storage and Handling (16)]. There are two available injection kits, which differ only in how SUNLENCA injection is prepared (the components and associated method for withdrawal of the solution from the vials) [see How Supplied/Storage and Handling (16)]. Refer to the figures below for the relevant injection kit. The injection kit components are for single use only. Two 1.5 mL injections are required for a complete dose. Reference ID: 5485227 4 VIAL x2 VIAL ACCESS DEVICE x2 SYRINGE x2 NOTE: all components are for single use Prepare Vial Prepare Vial Access Device Make sure that: • Vial and prepared syringe contain a yellow solution with no particles • Contents are not damaged • Product is not expired Attach 22G Injection Needle to Syringe, Expel Air Bubbles, and Prime to 1.5 ml Clean an Injection Site on Patient's Abdomen e = Injection site options (at least 2 inches from navel) Push down Inject 1.5 ml ofSunlenca Subcutaneously Insert fully 22G, ½inch INJECTION NEEDLE x2 Attach and Fill Syringe Flip upside down and withdraw all contents Administer 2nd Injection Vial access device injection kit Figure 1 identifies the components for use in the administration steps for the vial access device injection kit, and the administration steps are provided in Figure 2. Use of a vial access device is required in this kit. Figure 1 SUNLENCA Vial Access Device Injection Kit Components Figure 2 SUNLENCA Injection Steps for Vial Access Device Injection Kit Reference ID: 5485227 5 VIAL x2 El SYRINGE ; 18G, 1½inch , llllJli x 2 WITHDRAWAL NEEDLE x2 NOTE: all components are for single use. 22G, ½ inch INJECTION NEEDLE x2 Prepare Vial Make sure that: Attach 18G Withdrawal Needle to Syringe Fill Syringe ~ ,-,----,----._ ----- Remove18G Withdrawal Needle from Syringe • Vial and prepared syringe contain a yellow solution with no particles • Contents are not damaged • Product is not expired Attach 22G Injection Needle to Syringe, Expel Air Bubbles, and Prime to 1.5 ml • Clean an Injection Site on Patient's Abdomen e = Injection site options (at least 2 inches from navel) Inject 1.5 ml of air into vial Inject 1.5 ml ofSunlenca Subcutaneously Administer 2nd Injection Withdrawal needle injection kit Figure 3 identifies the components for use in the administration steps for the withdrawal needle injection kit, and the administration steps are provided in Figure 4. The 18-gauge needle is for withdrawal only in this kit. Figure 3 SUNLENCA Withdrawal Needle Injection Kit Components Figure 4 SUNLENCA Injection Steps for Withdrawal Needle Injection Kit 3 DOSAGE FORMS AND STRENGTHS SUNLENCA tablets: Each tablet contains 300 mg of lenacapavir (present as 306.8 mg of lenacapavir sodium). The tablets are beige, capsule-shaped, film-coated, and debossed with ‘GSI’ on one side of the tablet and ‘62L’ on the other side of the tablet. Reference ID: 5485227 6 SUNLENCA injection: Each single-dose vial contains 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir (present as 473.1 mg/1.5 mL of lenacapavir sodium). The lenacapavir injectable solution is sterile, preservative-free, clear, and yellow with no visible particles. 4 CONTRAINDICATIONS Concomitant administration of SUNLENCA with strong CYP3A inducers is contraindicated due to decreased lenacapavir plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to SUNLENCA [see Drug Interactions (7.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.2 Long-Acting Properties and Potential Associated Risks with SUNLENCA Residual concentrations of lenacapavir may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer after the last subcutaneous dose). It is important to counsel patients that maintenance dosing by injection is required every 6 months, because missed doses or non-adherence to injections could lead to loss of virologic response and development of resistance [see Dosage and Administration (2.1)]. Lenacapavir, a moderate CYP3A inhibitor, may increase the exposure to, and therefore potential risk of adverse reactions from, drugs primarily metabolized by CYP3A initiated within 9 months after the last subcutaneous dose of SUNLENCA [see Drug Interactions and Clinical Pharmacology (7.2, 12.3)]. If SUNLENCA is discontinued, to minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen where possible no later than 28 weeks after the final injection of SUNLENCA. If virologic failure occurs during treatment, switch the patient to an alternative regimen if possible [see Dosage and Administration (2.1)]. Reference ID: 5485227 7 5.3 Injection Site Reactions Administration of SUNLENCA may result in local injection site reactions (ISRs). If clinically significant ISRs occur, evaluate and institute appropriate therapy and follow­ up. Manifestations of ISRs may include swelling, pain, erythema, nodule, induration, pruritus, extravasation or mass. Nodules and indurations at the injection site may take longer to resolve than other ISRs. In clinical studies, after a median follow-up of 553 days, 30% of nodules and 13% of indurations (in 10% and 1% of participants, respectively) associated with the first injections of SUNLENCA had not fully resolved. Measurements and qualitative assessments of ISRs were not routinely reported. Where described, the majority of the injection site nodules and indurations were palpable but not visible, and had a maximum size of approximately 1 to 4 cm [see Adverse Reactions (6.1)]. The mechanism driving the persistence of injection site nodules and indurations in some patients is not fully understood, but based on available data, they may be related to the presence of the subcutaneous drug depot. In some patients who had a skin biopsy performed of an injection site nodule or induration, dermatopathology revealed foreign body inflammation or granulomatous response. Improper administration (intradermal injection) has been associated with serious injection site reactions, including necrosis and ulcer [see Adverse Reactions (6)]. Ensure SUNLENCA is only administered subcutaneously in the abdomen [see Dosage and Administration (2.4)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Immune Reconstitution Syndrome [see Warnings and Precautions (5.1)] • Injection Site Reactions [see Warnings and Precautions (5.3)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The primary safety assessment of SUNLENCA was based on data from heavily treatment-experienced adult participants with HIV who received SUNLENCA in a Phase 2/3 trial (CAPELLA; N=72) through Week 52 (median duration on study of 71 weeks) [see Clinical Studies (14)], as well as supportive data in treatment-naïve adult participants with HIV who received SUNLENCA in a Phase 2 trial (CALIBRATE; N=157) through Week 54 (median duration of exposure of 66 weeks). Reference ID: 5485227 8 The most common adverse reactions (all Grades) reported in at least 3% of participants in CAPELLA were nausea and injection site reactions. The proportion of partcipants in CAPELLA who discontinued treatment with SUNLENCA due to adverse events, regardless of severity, was 1% (Grade 1 injection site nodule in 1 participant). Table 3 displays the frequency of adverse reactions (all Grades) greater than or equal to 3% in the SUNLENCA group. Table 3 Adverse Reactions (All Grades) Reported in ≥ 3% a of Heavily Treatment Experienced Adults with HIV-1 Receiving SUNLENCA in CAPELLA (Week 52 Analysis) SUNLENCA + Background Regimen Adverse Reactions (N=72) Injection Site Reactions 65% Nausea 4% a. Frequencies of adverse reactions are based on all adverse events attributed to trial drug by the investigator, based on all participants (cohorts 1 and 2) in CAPELLA. The majority (96%) of all adverse reactions associated with SUNLENCA were mild or moderate in severity. Injection-Associated Adverse Reactions Local Injection Site Reactions (ISRs): The most frequent adverse reactions were ISRs. Of the 72 participants in CAPELLA, 65% had experienced an ISR attributed to study drug through at least the Week 52 visit. Most participants had mild (Grade 1, 44%) or moderate (Grade 2, 17%) ISRs. Four percent of participants experienced a severe (Grade 3) ISR (erythema, pain, swelling) that resolved within 15 days. The ISRs reported in more than 1% of participants were swelling (36%), pain (31%), erythema (31%), nodule (25%), induration (15%), pruritus (6%), extravasation (3%) and mass (3%). ISRs reported in 1% of participants included discomfort, hematoma, edema, and ulcer. Nodules and indurations at the injection site took longer to resolve than other ISRs. The median time to resolution of all ISRs, excluding nodules and indurations, was 5 days (range: 1 to 183). The median time to resolution of nodules and indurations associated with the first injections of SUNLENCA was 148 (range: 41 to 727) and 70 (range: 3 to 252) days, respectively. After a median follow up of 553 days, 30% of nodules and 13% of indurations (in 10% and 1% of participants, respectively) associated with the first injections of SUNLENCA had not fully resolved. Qualitative descriptions of injection site nodules and indurations were not routinely reported, but, where reported, the majority of injection site nodules and indurations were palpable but not visible. Measurements of injection site nodules and indurations were not routinely performed or standardized, but where measurements were reported, the maximum size for the majority of injection site nodules and indurations was approximately 1 to 4 cm [see Warnings and Precautions (5.3)]. Reference ID: 5485227 9 Laboratory Abnormalities The frequency of laboratory abnormalities (Grades 3 to 4) occurring in at least 2% of participants in CAPELLA are presented in Table 4. A causal association between SUNLENCA and these laboratory abnormalities has not been established. Table 4 Selected Laboratory Abnormalities (Grades 3 to 4) Reported in ≥ 2% of Participants Receiving SUNLENCA in CAPELLA (Week 52 Analysis) Laboratory Parameter Abnormality SUNLENCA + Background Regimen (N=72) a Creatinine ( >1.8 x ULN or ≥1.5 x baseline) 13% Glycosuria (>2+) b 6% Hyperglycemia (fasting) (>250 mg/dL) 5% Proteinuria (>2+) b 4% ALT (≥5 x ULN) b 3% AST (≥5 x ULN) 3% Direct Bilirubin (>ULN) b 3% ALT= alanine aminotransferase; AST= aspartate aminotransferase; ULN = upper limit of normal a. Frequencies are based on treatment-emergent laboratory abnormalities in all participants (cohorts 1 and 2) in CAPELLA. Percentages were calculated based on the number of participants with post-baseline toxicity grades for each laboratory parameter (n=72 for all parameters except hyperglycemia fasting n=57). b. Grade 3 only (no Grade 4 values reported). 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General disorders and administration site conditions Injection site necrosis [see Warnings and Precautions (5.3)]. Reference ID: 5485227 10 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on SUNLENCA Lenacapavir is a substrate of P-gp, UGT1A1, and CYP3A. Strong or Moderate CYP3A Inducers Drugs that are strong or moderate inducers of CYP3A may significantly decrease plasma concentrations of lenacapavir [see Clinical Pharmacology (12.3)], which may result in loss of therapeutic effect of SUNLENCA and development of resistance. Concomitant administration of SUNLENCA with strong CYP3A inducers during SUNLENCA treatment is contraindicated [see Contraindications (4)]. Concomitant administration of SUNLENCA with moderate CYP3A inducers during SUNLENCA treatment is not recommended. Combined P-gp, UGT1A1, and Strong CYP3A Inhibitors Combined P-gp, UGT1A1, and strong CYP3A inhibitors may significantly increase plasma concentrations of SUNLENCA. Concomitant administration of SUNLENCA with these inhibitors is not recommended. 7.2 Effect of SUNLENCA on Other Drugs Lenacapavir is a moderate inhibitor of CYP3A. Due to the long half-life of lenacapavir following subcutaneous administration, SUNLENCA may increase the exposure of drugs primarily metabolized by CYP3A [see Clinical Pharmacology (12.3)] initiated within 9 months after the last subcutaneous dose of SUNLENCA, which may increase the potential risk of adverse reactions. See the prescribing information of the sensitive CYP3A substrate for dosing recommendations with moderate inhibitors of CYP3A. 7.3 Established and Other Potentially Significant Drug Interactions Table 5 provides a listing of clinically significant drug interactions with recommended prevention or management strategies, but is not all inclusive. The drug interactions described are based on studies conducted with SUNLENCA or are drug interactions that may occur with SUNLENCA [see Contraindications (4) and Clinical Pharmacology (12.3)]. Table 5 Drug Interactions with SUNLENCA Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Comment Antiarrhythmics: digoxin ↑ digoxin Use with caution and monitor digoxin therapeutic concentration. Anticoagulants: Direct Oral Anticoagulants (DOACs) rivaroxaban dabigatran edoxaban ↑ DOAC Refer to the DOAC prescribing information for concomitant administration with moderate CYP3A inhibitors and/or P-gp inhibitors. Reference ID: 5485227 11 Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Comment Anticonvulsants: ↓ lenacapavir Concomitant administration of carbamazepine carbamazepine, oxcarbazepine, oxcarbazepine phenobarbital, or phenytoin may result in phenobarbital loss of therapeutic effect and development phenytoin of resistance. Concomitant administration of SUNLENCA with carbamazepine or phenytoin is contraindicated. Concomitant administration of SUNLENCA with oxcarbazepine or phenobarbital is not recommended. Consider use of alternative anticonvulsants. Antiretroviral Agents: ↑ lenacapavir Concomitant administration of efavirenz, atazanavir/cobicistat b (atazanavir/cobicistat, nevirapine, or tipranavir/ritonavir may result atazanavir/ritonavir atazanavir/ritonavir) in loss of therapeutic effect and development of resistance. efavirenz b ↓ lenacapavir Concomitant administration with nevirapine tipranavir/ritonavir (efavirenz, nevirapine, tipranavir/ritonavir) atazanavir/cobicistat, atazanavir/ritonavir, efavirenz, nevirapine, or tipranavir/ritonavir is not recommended. Antimycobacterials: ↓ lenacapavir Concomitant administration of rifabutin, rifabutin rifampin and rifapentine may result in loss rifampin b of therapeutic effect and development of rifapentine resistance. Concomitant administration of SUNLENCA with rifampin is contraindicated [see Contraindications (4)]. Concomitant administration of SUNLENCA with rifabutin or rifapentine is not recommended. Corticosteroids (systemic): ↑ corticosteroids Concomitant administration with systemic cortisone/hydrocortisone (systemic) corticosteroids whose exposures are dexamethasone ↓ lenacapavir (dexamethasone) significantly increased by CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression. Initiate with the lowest starting dose and titrate carefully while monitoring for safety. Concomitant administration of systemic dexamethasone may result in loss of therapeutic effect of lenacapavir and development of resistance. Alternative corticosteroids to dexamethasone should be considered, particularly for long-term use. Ergot derivatives: dihydroergotamine ergotamine methylergonovine ↑ dihydroergotamine ↑ ergotamine ↑ methylergonovine Concomitant administration of SUNLENCA with dihydroergotamine, ergotamine or methylergonovine is not recommended. Reference ID: 5485227 12 Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Comment Herbal Products: ↓ lenacapavir Concomitant administration of St. John’s St. John’s wort c wort may result in loss of therapeutic effect (Hypericum perforatum) and development of resistance. Concomitant administration of SUNLENCA with St. John’s wort is contraindicated. HMG-CoA Reductase Inhibitors: lovastatin simvastatin ↑ lovastatin ↑ simvastatin Initiate lovastatin and simvastatin with the lowest starting dose and titrate carefully while monitoring for safety (e.g., myopathy). Narcotic analgesics ↑ fentanyl Careful monitoring of therapeutic effects metabolized by CYP3A: e.g., fentanyl, oxycodone ↑ oxycodone and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co- administration. tramadol ↑ tramadol A decrease in dose may be needed for tramadol with concomitant use. Narcotic analgesic for buprenorphine: Initiation of buprenorphine or methadone in treatment of opioid effects unknown patients taking SUNLENCA: Carefully titrate dependence: the dose of buprenorphine or methadone to buprenorphine, methadone methadone: effects unknown the desired effect; use the lowest feasible initial or maintenance dose. Initiation of SUNLENCA in patients taking buprenorphine or methadone: A dose adjustment for buprenorphine or methadone may be needed. Monitor clinical signs and symptoms. Opioid Antagonist: naloxegol ↑ naloxegol Avoid use with SUNLENCA; if unavoidable, decrease the dosage of naloxegol and monitor for adverse reactions. Phosphodiesterase-5 (PDE-5) ↑ PDE-5 inhibitors Use of PDE-5 inhibitors for pulmonary Inhibitors: arterial hypertension (PAH): sildenafil Concomitant administration of SUNLENCA tadalafil with tadalafil for the treatment of PAH is not vardenafil recommended. Use of PDE-5 inhibitors for erectile dysfunction (ED): Refer to the prescribing information of PDE­ 5 inhibitors for dose recommendations. Sedatives/Hypnotics: midazolam (oral) b triazolam ↑ midazolam (oral) ↑ triazolam Use with caution when midazolam or triazolam is concomitantly administered with SUNLENCA a. ↑ = Increase, ↓ = Decrease. b. Drug-drug interaction study was conducted. c. The induction potency of St. John’s wort may vary widely based on preparation. Reference ID: 5485227 13 7.4 Drugs without Clinically Significant Interactions with SUNLENCA Based on drug interaction studies conducted with SUNLENCA, no clinically significant drug interactions have been observed with: darunavir/cobicistat, cobicistat, famotidine, pitavastatin, rosuvastatin, tenofovir alafenamide, and voriconazole. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SUNLENCA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258­ 4263. Risk Summary There are insufficient human data on the use of SUNLENCA during pregnancy to inform a drug-associated risk of birth defects and miscarriage. In animal reproduction studies, no adverse developmental effects were observed when lenacapavir was administered to rats and rabbits at exposures (AUC) ≥16 times the exposure in humans at the recommended human dose (RHD) of SUNLENCA (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. The background rate of major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. Data Animal Data Lenacapavir was administered intravenously to pregnant rabbits (up to 20 mg/kg/day on gestation days (GD) 7 to 19), orally to rats (up to 300 mg/kg/day on GD 6 to 17), and subcutaneously to rats (up to 300 mg/kg on GD 6). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at exposures (AUC) approximately 16 times (rats) and 39 times (rabbits) the exposure in humans at the RHD of SUNLENCA. 8.2 Lactation Risk Summary It is not known whether SUNLENCA is present in human breast milk, affects human milk production, or has effects on the breastfed infant. After administration to pregnant rats, Reference ID: 5485227 14 --- lenacapavir was detected in the plasma of nursing rat pups, without effects on these nursing pups (see Data). Potential risks of breastfeeding include: (1) HIV-1 transmission (in infants without HIV-1), (2) developing viral resistance (in infants with HIV-1), and (3) adverse reactions in a breastfed infant similar to those seen in adults. Data Lenacapavir was detected at low levels in the plasma of nursing rat pups in the pre/postnatal development study (post-natal day 10). 8.4 Pediatric Use The safety and effectiveness of SUNLENCA have not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of SUNLENCA did not include sufficient numbers of participants aged 65 and over to determine whether they respond differently from younger patients. 8.6 Renal Impairment No dosage adjustment of SUNLENCA is recommended in patients with mild, moderate or severe renal impairment (estimated creatinine clearance greater than or equal to 15 mL per minute). SUNLENCA has not been studied in patients with ESRD (estimated creatinine clearance less than 15 mL per minute) [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustment of SUNLENCA is recommended in patients with mild (Child- Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. SUNLENCA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No data are available on overdose of SUNLENCA in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with SUNLENCA consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. As lenacapavir is highly bound to plasma proteins, it is unlikely to be significantly removed by dialysis. Reference ID: 5485227 15 11 DESCRIPTION SUNLENCA tablets and SUNLENCA injection contain lenacapavir sodium, a capsid inhibitor. The chemical name of lenacapavir sodium is: Sodium (4-chloro-7-(2-((S)-1-(2­ ((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H­ cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6­ (3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol­ 3-yl)(methylsulfonyl)amide. Lenacapavir sodium has a molecular formula of C39H31ClF10N7NaO5S2, a molecular weight of 990.3, and the following structural formula: N S Me H N N N N Cl CF3 O S Me N F F Na+ O O O O N F F F3C Lenacapavir sodium is a light yellow to yellow solid and is practically insoluble in water. SUNLENCA tablets are for oral administration. Each film-coated tablet contains 300 mg of lenacapavir (present as 306.8 mg lenacapavir sodium) and the following inactive ingredients: copovidone, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and poloxamer 407. The tablets are film-coated with a coating material containing iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. SUNLENCA injection is for subcutaneous administration. Each single-dose vial contains 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir (present as 473.1 mg/1.5 mL of lenacapavir sodium) as a sterile, preservative-free, clear, yellow solution and the following inactive ingredients: 896.3 mg of polyethylene glycol 300 (as solvent) and water for injection. The apparent pH range of the injection is 9.0-10.2. The vial stoppers are not made with natural rubber latex. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action SUNLENCA is an HIV-1 antiretroviral agent [see Microbiology (12.4)]. Reference ID: 5485227 16 12.2 Pharmacodynamics Exposure-Response In CAPELLA, oral loading doses (600 mg on Day 1 and Day 2, 300 mg on Day 8) followed by subcutaneous doses (927 mg every 6 months starting on Day 15) of SUNLENCA in heavily treatment-experienced participants with multiclass resistant HIV-1, efficacy outcomes (change in plasma HIV-1 RNA from Day 1 to Day 14, and percentage of participants with HIV-1 RNA less than 50 copies/mL at Week 26) were similar across the range of observed lenacapavir exposures. Cardiac Electrophysiology At supratherapeutic exposures of lenacapavir (9-fold higher than the therapeutic exposures of SUNLENCA), SUNLENCA does not prolong the QTcF interval to any clinically relevant extent. 12.3 Pharmacokinetics The pharmacokinetic (PK) properties of lenacapavir are provided in Table 6 and Table 7. The estimated lenacapavir exposures are comparable between the two recommended dosing regimens. Reference ID: 5485227 17 Table 6 Pharmacokinetic Properties of Lenacapavir Oral Subcutaneous Absorption % Absolute bioavailability 6 to 10 100 a b Tmax 4 hours 77 to 84 days c Effect of Food Effect of low- fat meal (relative to fasting) d AUCinf ratio 98.6 (58.2,167.2) - Cmax ratio 115.8 (55.4, 242.1) - Effect of high- fat meal (relative to fasting) e AUCinf ratio 115.2 (72.0, 184.5) - Cmax ratio 145.2 (77.9, 270.5) - Distribution Apparent volume of distribution (Vd/F, L) 19240 9500 to 11700 % bound to human plasma proteins >98.5 Blood-to-plasma ratio 0.5 to 0.7 f Elimination t1/2 10 to 12 days 8 to 12 weeks Clearance (mean apparent clearance, L/h) 55 4.2 % of dose of unchanged drug in plasma g 69 Metabolism Metabolic pathway(s) CYP3A (minor) UGT1A1 (minor) Excretion Major routes of elimination Excretion of unchanged drug into feces h % of dose excreted in urine g <1 % of dose excreted in feces (% unchanged) h 76 (33) a. Values reflect absolute bioavailability following subcutaneous administration of the 927 mg dose. b. Values reflect administration of lenacapavir with or without food. c. Due to slow release from the site of subcutaneous administration, the absorption profile of subcutaneously administered lenacapavir is complex. d. Values refer to geometric mean ratio [low-fat meal/fasting] in PK parameters and (90% confidence interval). Low fat meal is approximately 400 kcal, 25% fat. e. Values refer to geometric mean ratio [high-fat meal/fasting] in PK parameters and (90% confidence interval). High fat meal is approximately 1000 kcal, 50% fat. f. Values reflect the blood-to-plasma ratio of lenacapavir following a single dose intravenous administration of [14C] lenacapavir through 336 hours postdose. g. Dosing in mass balance studies: single dose intravenous administration of [14C] lenacapair to participants without HIV-1. Reference ID: 5485227 18 h. Metabolized via oxidation, N-dealkylation, hydrogenation, amide hydrolysis, glucuronidation, hexose conjugation, pentose conjugation, and glutathione conjugation; primarily via CYP3A and UGT1A1 and no single circulating metabolite accounted for >10% of plasma drug-related exposure. Table 7 Lenacapavir Exposures Following Oral and Subcutaneous Administration of SUNLENCA in Heavily Treatment Experienced Participants with HIV Parameter Mean (%CV) Recommended Dosing Regimen, Option 1 a Recommended Dosing Regimen, Option 2 a Day 1: 600 mg (oral) + 927 mg (SC) Day 2: 600 mg (oral) Days 1 and 2: 600 mg (oral), Day 8: 300 mg (oral), Day 15: 927 mg (SC) Day 1 to end of Month 6 Days 1 to 15 Day 15 to end of Month 6 Cmax (ng/mL) 101.4 (53.1) 88.0 (72.4) 86.5 (51.7) AUCtau (h•ng/mL) 242266 (46.0) 19496 (72.6) 239163 (47.2) Ctrough (ng/mL) 32.5 (57.2) 46.9 (72.3) 32.5 (57.5) CV = coefficient of variation; NA = not applicable; SC = subcutaneous a. Predicted exposures utilizing population PK analysis. Lenacapavir exposures after subcutaneous administration were similar between heavily treatment experienced participants with HIV-1 and participants without HIV-1 based on population pharmacokinetics analysis. Lenacapavir exposures (AUCtau, Cmax and Ctrough) after oral administration were 28% to 43% higher in participants with HIV-1 who were heavily treatment experienced, compared to participants without HIV-1 based on population PK analysis. These differences were not considered clinically relevant. Specific Populations There were no clinically significant differences in the pharmacokinetics of lenacapavir based on age (18 to 78 years), sex, ethnicity (hispanic or non-hispanic), race (white, black, asian or other), body weight (41.4 to 164 kg), severe renal impairment (creatinine clearance of 15 to less than 30 mL per minute, estimated by Cockroft-Gault method), or moderate hepatic impairment (Child-Pugh Class B). The effect of end-stage renal disease (including dialysis), or severe hepatic impairment (Child-Pugh Class C), on the pharmacokinetics of lenacapavir is unknown. As lenacapavir is greater than 98.5% protein bound, dialysis is not expected to alter exposures of lenacapavir [see Use in Specific Populations (8.6)]. 19 Reference ID: 5485227 Drug Interaction Studies Clinical Studies Clinical drug-drug interaction study indicated that lenacapavir is a substrate of CYP3A, P-gp, and UGT1A1. Table 8 summarizes the pharmacokinetic effects of other drugs on lenacapavir. Lenacapavir is a moderate inhibitor of CYP3A. Lenacapavir is an inhibitor of P-gp and BCRP but does not inhibit OATP. Table 9 summarizes the pharmacokinetic effects of lenacapavir on other drugs. Table 8 Effect of Other Drugs on Lenacapavir a,b Coadministered Drug Dose of Coadministered Drug (mg) Mean Ratio of Lenacapavir Pharmacokinetic Parameters (90% CI); No effect = 1.00 Cmax AUC Cobicistat (fed) (Inhibitor of CYP3A [strong] and P-gp) 150 once daily 2.10 (1.62, 2.72) 2.28 (1.75, 2.96) Darunavir / cobicistat (fed) (Inhibitor of CYP3A [strong] and inhibitor and inducer of P-gp) 800/150 once daily 2.30 (1.79, 2.95) 1.94 (1.50, 2.52) Voriconazole (fasted) (Inhibitor of CYP3A [strong]) 400 twice daily, 200 twice daily c 1.09 (0.81, 1.47) 1.41 (1.10, 1.81) Atazanavir / cobicistat (fed) (Inhibitor of CYP3A [strong] and UGT1A1 and P-gp) 300/150 once daily 6.60 (4.99, 8.73) 4.21 (3.19, 5.57) Rifampin (fasted) (Inducer of CYP3A [strong] and P-gp and UGT) 600 once daily 0.45 (0.34, 0.60) 0.16 (0.12, 0.20) Efavirenz (fasted) (Inducer of CYP3A [moderate] and P-gp) 600 once daily 0.64 (0.45, 0.92) 0.44 (0.32, 0.59) Famotidine (2 hours before, fasted) 40 once daily 1.01 (0.75, 1.34) 1.28 (1.00, 1.63) a. Single dose of lenacapavir 300 mg administered orally. b. All interaction studies conducted in participants without HIV-1. c. 400 mg loading dose twice daily for a day, followed by 200 mg maintenance dose twice daily. Reference ID: 5485227 20 Table 9 Effect of Lenacapavir on Other Drugs a,b Coadministered Drug Dose of Coadministered Drug (mg) Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI) c; No effect = 1.00 Cmax AUC Tenofovir alafenamide (fed) (substrate of P-gp) 25 single dose 1.24 (0.98, 1.58) 1.32 (1.09, 1.59) Tenofovir d (substrate of P-gp) 1.23 (1.05, 1.44) 1.47 (1.27, 1.71) Pitavastatin (simultaneous administration, fed) (substrate of OATP) 2 single dose 1.00 (0.84, 1.19) 1.11 (1.00, 1.25) Pitavastatin (3 days after lenacapavir, fed) (substrate of OATP) 2 single dose 0.85 (0.69, 1.05) 0.96 (0.87, 1.07) Rosuvastatin (fed) (substrate of BCRP and OATP) 5 single dose 1.57 (1.38, 1.80) 1.31 (1.19, 1.43) Midazolam (simultaneous administration, fed) (substrate of CYP3A) 2.5 single dose 1.94 (1.81, 2.08) 3.59 (3.30, 3.91) 1-hydroxymidazolam e (substrate of CYP3A) 0.54 (0.50, 0.59) 0.76 (0.72, 0.80) Midazolam (1 day after lenacapavir, fed) (substrate of CYP3A) 2.5 single dose 2.16 (2.02, 2.30) 4.08 (3.77, 4.41) 1-hydroxymidazolam e (substrate of CYP3A) 0.52 (0.48, 0.57) 0.84 (0.80, 0.88) a. All interaction studies conducted in participants without HIV-1. b. Following 600 mg twice daily for 2 days, single 600 mg doses of lenacapavir were administered with each coadministered drug, resulting in lenacapavir exposures similar to or higher than those at the recommended dosage regimen. c. All No Effect Boundaries are 70% to 143%. d. Tenofovir alafenamide is converted to tenofovir in vivo. e. Major active metabolite of midazolam. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Lenacapavir is not a substrate, inducer, or inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Lenacapavir is not an inducer of CYP3A4. Reference ID: 5485227 21 Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Lenacapavir is not an inhibitor of UGT1A1. Transporter Systems: Lenacapavir is not an inhibitor of organic anion transporter 1 (OAT1), OAT3, organic cation transporter (OCT)1, OCT2, multidrug and toxin extrusion transporter (MATE) 1, or MATE 2-K. Lenacapavir is not a substrate of BCRP, OATP1B1, or OATP1B3. 12.4 Microbiology Mechanism of Action Lenacapavir is a multistage, selective inhibitor of HIV-1 capsid function that directly binds to the interface between capsid protein (p24) subunits in hexamers. Surface plasmon resonance sensorgrams showed dose-dependent and saturable binding of lenacapavir to cross-linked wild-type capsid hexamer with an equilibrium binding constant (KD) of 1.4 nM. Lenacapavir inhibits HIV-1 replication by interfering with multiple essential steps of the viral lifecycle, including capsid-mediated nuclear uptake of HIV-1 proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (by interfering with Gag/Gag-Pol functioning, reducing production of capsid protein subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to malformed capsids). Antiviral Activity in Cell Culture Lenacapavir has antiviral activity that is specific to human immunodeficiency virus (HIV-1 and HIV-2). The antiviral activity of lenacapavir against laboratory and clinical isolates of HIV-1 was assessed in T-lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes with EC50 values ranging from 30 to 190 pM. Lenacapavir displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including subtypes A, A1, AE, AG, B, BF, C, D, E, F, G with EC50 values ranging from 20 and 160 pM. The median EC50 value for subtype B isolates (n=8) was 40 pM. Lenacapavir was 15- to 25-fold less active against HIV-2 isolates relative to HIV-1. In a study of lenacapavir in combination with representatives from the major classes of anti-retroviral agents (INSTIs, NNRTIs, NRTIs, and PIs), no antagonism of antiviral activity was observed. Resistance In Cell Culture HIV-1 variants with reduced susceptibility to lenacapavir have been selected in cell culture. Resistance selections with lenacapavir identified 7 substitutions in capsid: L56I, M66I, Q67H, K70N, N74D/S, and T107N singly or in dual combination that conferred 4­ to >3,226-fold reduced phenotypic susceptibility to lenacapavir relative to wild-type (WT) virus. The M66I substitution alone or in combination conferred >3,226-fold decreased Reference ID: 5485227 22 susceptibility to lenacapavir in a single-cycle infectivity assay; substitutions Q67H and T107N, conferred 4- to 6.3-fold decreased susceptibility; K70N, N74D and Q67H/N74S conferred 22- to 32-fold decreased susceptibility; and L56I conferred 239-fold decreased susceptibility. In Clinical Trials In CAPELLA, 31% (22/72) of heavily treatment-experienced participants met the criteria for resistance analyses through Week 52 (HIV-1 RNA ≥ 50 copies/mL at confirmed virologic failure [suboptimal virologic response at Week 4, virologic rebound, or viremia at last visit]) and were analyzed for lenacapavir resistance-associated substitution emergence. Lenacapavir resistance-associated capsid substitutions were found in 41% (n=9) of participants with confirmed virologic failure who had post-baseline capsid genotypic resistance data (n=22). The M66I capsid substitution was observed in 27% (6/22) of participants, alone or in combination with other lenacapavir resistance- associated capsid substitutions including Q67Q/H, Q67Q/H/K/N, K70K/R, K70N/S, N74D, N74N/H, A105T, and T107A. The other 3 participants with virologic failure had emergent lenacapavir resistance-associated capsid substitutions Q67K+K70H, Q67H+K70R+T107S, and Q67Q/H. Phenotypic analyses of the confirmed virologic failure isolates with emergent lenacapavir resistance-associated substitutions showed 6- to >1428-fold decreases in lenacapavir susceptibility when compared to WT. Among the 9 participants with virologic failure who developed lenacapavir resistance- associated substitutions in capsid, 4 received SUNLENCA in combination with a background regimen with no fully active antiretrovirals based on the baseline genotypic and/or phenotypic resistance. Therefore, given the risk of developing resistance in situations of functional monotherapy, careful consideration should be given to having active drugs in addition to SUNLENCA in the treatment regimen. Four participants with virologic failure had emergent resistance substitutions to components of the optimized background regimen (OBR): emergent NRTI substitution M184I/V and NNRTI substitution K103N/Y with emtricitabine and doravirine plus atazanavir, bictegravir, and tenofovir alafenamide in OBR; emergent NNRTI substitution V106M from a mixture at baseline (in addition to lenacapavir resistance-associated substitutions M66I + T107A) with doravirine plus emtricitabine and ibalizumab in OBR; emergent NRTI substitutions K65R and S68N from mixtures at baseline (in addition to lenacapavir resistance-associated substitution M66I) with tenofovir alafenamide, plus emtricitabine, dolutegravir, darunavir/cobicistat, and rilpivirine in OBR; and emergent NRTI substitution K65K/R with tenofovir disoproxil fumarate plus darunavir/cobicistat, dolutegravir, and emtricitabine in OBR. Oral Maintenance for Missed Injections Of the 57 participants who received oral maintenance, 9 participants (5 participants in Cohort 1 and 4 participants in Cohort 2) met the criteria for resistance analysis. Six of these 9 participants had emergent lenacapavir resistance substitutions in capsid (Q67H [n=4], K70R or N [n=2], N74D or K [n=2], T107N [n=1]) with 4.5- to 393-fold decreased Reference ID: 5485227 23 lenacapavir susceptibility. In addition, 2 participants had emergent resistance substitutions to darunavir in their optimized background regimen. Lenacapavir Resistance with Suboptimal Adherence to Other Antiretroviral Drugs in the Regimen The development of lenacapavir-associated capsid resistance substitutions in 6 participants during the oral maintenance period was likely due to suboptimal adherence to the optimized background oral regimens that included dolutegravir and/or darunavir. After developing lenacapavir resistance, 5 of the 6 participants achieved HIV-1 RNA resuppression (HIV-1 RNA < 50 copies/mL) while maintaining SUNLENCA treatment. With the emergence of lenacapavir resistance substitutions and decreased susceptibility to lenacapavir, it is unclear how much antiviral activity lenacapavir is contributing to the resuppression of HIV-1 RNA in these 5 participants. Thus, adherence to other antiretroviral drugs in the regimen should be optimized while the patient is receiving SUNLENCA. During SUNLENCA treatment, if suboptimal adherence to the oral antiretroviral regimen occurs with concurrent HIV-1 RNA viral load increases (i.e., virologic failure), lenacapavir resistance should be assessed, and if detected, consideration should be given to discontinuing SUNLENCA treatment [see Dosage and Administration (2.1), Warnings and Precautions (5.2)]. Cross-Resistance The antiviral activity in cell culture of lenacapavir was determined against a broad spectrum of HIV-1 site-directed mutants and patient-derived HIV-1 isolates with resistance to the four main classes of anti-retroviral agents (INSTI, NNRTI, NRTI, and PI; n=58), as well as to viruses resistant to the gp120-directed attachment inhibitor fostemsavir, the CD4+-directed post-attachment inhibitor ibalizumab, the CCR5 co- receptor antagonist maraviroc, and the gp41 fusion inhibitor enfuvirtide (n=42). These data indicated that lenacapavir remained fully active against all variants tested, thereby demonstrating a non-overlapping resistance profile. In addition, the antiviral activity of lenacapavir in patient isolates was unaffected by the presence of naturally occurring Gag polymorphisms and substitutions at protease cleavage sites. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Lenacapavir was not carcinogenic in a 6-month rasH2 transgenic mouse study in males or females at doses of up to 300 mg/kg/dose once every 13 weeks. A 104-week carcinogenicity study was conducted in male and female rats at lenacapavir doses of 0, 102, 309, or 927 mg/kg by subcutaneous injection once every 13-weeks. A treatment-related increase in the incidence of malignant sarcoma at the injection site was observed in males and a treatment-related increase in combined benign fibroma Reference ID: 5485227 24 and malignant fibrosarcoma at the injection site was observed in females, at the highest dose (927 mg/kg). This dose in rats resulted in an exposure approximately 34-times the human exposure at the RHD, based on AUC. These tumors are considered to be a secondary response to chronic tissue irritation and granulomatous inflammation, due to the depot effect of lenacapavir following subcutaneous injection. The clinical relevance of these findings are unknown. Mutagenesis Lenacapavir was not mutagenic in a battery of in vitro and in vivo genotoxicity assays, including microbial mutagenesis, chromosome aberration in human peripheral blood lymphocytes, and in in vivo rat micronucleus assays. Impairment of Fertility There were no effects on fertility, mating performance or early embryonic development when lenacapavir was administered to rats at systemic exposures (AUC) 5 times the exposure to humans at the RHD of SUNLENCA. 14 CLINICAL STUDIES The efficacy and safety of SUNLENCA in heavily treatment-experienced participants with multidrug resistant HIV-1 is based on 52-week data from CAPELLA, a randomized, placebo-controlled, double-blind, multicenter trial (NCT 04150068). CAPELLA was conducted in 72 heavily treatment-experienced participants with multiclass resistant HIV-1. Participants were required to have a viral load ≥ 400 copies/mL, documented resistance to at least two antiretroviral medications from each of at least 3 of the 4 classes of antiretroviral medications (NRTI, NNRTI, PI and INSTI), and ≤ 2 fully active antiretroviral medications from the 4 classes of antiretroviral medications remaining at baseline due to resistance, intolerability, drug access, contraindication, or other safety concerns. The trial was composed of two cohorts. Participants were enrolled into the randomized cohort (cohort 1, N=36) if they had a < 0.5 log10 HIV-1 RNA decline compared to the screening visit. Participants were enrolled into the non-randomized cohort (cohort 2, N=36) if they had a ≥ 0.5 log10 HIV-1 RNA decline compared to the screening visit or after cohort 1 reached its planned sample size. In the 14-day functional monotherapy period, participants in cohort 1 were randomized in a 2:1 ratio in a blinded fashion to receive either SUNLENCA or placebo, while continuing their failing regimen. This period was to establish the virologic activity of SUNLENCA. After the functional monotherapy period, participants who had received SUNLENCA continued on SUNLENCA along with an optimized background regimen (OBR); participants who had received placebo during this period initiated SUNLENCA along with an OBR. Participants in cohort 1 had a mean age of 52 years (range: 24 to 71), 72% were male, Reference ID: 5485227 25     46% were White, 46% were Black, and 9% were Asian. 29% percent of participants identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.3 log10 copies/mL (range: 2.3 to 5.4). 19% of participants had baseline viral loads greater than 100,000 copies/mL. The mean baseline CD4+ cell count was 161 cells/mm3 (range: 6 to 827). 75% of participants had CD4+ cell counts below 200 cells/mm3. The mean number of years since participants first started HIV treatment was 24 years (range: 7 to 33); the mean number of antiretroviral agents in failing regimens at baseline was 4 (range: 1 to 7). The percentage of participants in the randomized cohort with known resistance to at least 2 agents from the NRTI, NNRTI, PI and INSTI classes was 97%, 94%, 78% and 75%, respectively. In cohort 1, 53% of participants had no fully active agents, 31% had 1 fully active agent, and 17% had 2 or more fully active agents within their initial failing regimen, including 6% of participants were who were receiving fostemsavir, which was an investigational agent at the start of the CAPELLA trial. Participants in cohort 2 initiated SUNLENCA and an OBR on Day 1. Participants in cohort 2 had a mean age of 48 years (range: 23 to 78), 78% were male, 36% were White, 31% were Black, 33% were Asian, and 14% of participants identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.1 log10 copies/mL (range: 1.3 to 5.7). 19% of participants had baseline viral loads greater than 100,000 copies/mL. The mean baseline CD4+ cell count was 258 cells/mm3 (range: 3 to 1296). 53% of participants had CD4+ cell counts below 200 cells/mm3. The mean number of years since participants first started HIV treatment was 19 years (range: 3 to 35); the mean number of antiretroviral agents in failing regimens at baseline was 4 (range: 2 to 7). The percentage of participants in the non-randomized cohort with known resistance to at least 2 agents from the NRTI, NNRTI, PI and INSTI classes was 100%, 100%, 83% and 64%, respectively. In cohort 2, 31% of participants had no fully active agents, 42% had 1 fully active agent, and 28% had 2 or more fully active agents within their initial failing regimen, including 6% of participants who were receiving fostemsavir, which was an investigational agent at the start of the CAPELLA trial. The primary efficacy endpoint was the proportion of participants in cohort 1 achieving ≥ 0.5 log10 copies/mL reduction from baseline in HIV-1 RNA at the end of the functional monotherapy period. The results of the primary endpoint analysis are shown in Table 10. Table 10 Proportion of Participants Achieving a ≥ 0.5 log10 Decrease in Viral Load at the End of the Functional Monotherapy Period in the CAPELLA Trial (Cohort 1) SUNLENCA (N=24) Placebo (N=12) Proportion of Participants Achieving a ≥ 0.5 log10 Decrease in Viral Load 87.5% 16.7% Treatment Difference (95% CI) 70.8% (34.9% to 90.0%) a a. p < 0.0001 Reference ID: 5485227 26 The results at Weeks 26 and 52 are provided in Table 11 and Table 12. Table 11 Virologic Outcomes (HIV-1 RNA < 50 copies/mL) at Weeks 26 a and 52 b with SUNLENCA plus OBR in the CAPELLA Trial (Cohort 1) SUNLENCA plus OBR (N=36) Week 26 Week 52 HIV-1 RNA < 50 copies/mL 81% 83% HIV-1 RNA ≥ 50 copies/mLc 19% 14% No virologic data in Week 26 or 52 Window 0 3% Discontinued Study Drug Due to AE or Death d 0 0 Discontinued Study Drug Due to Other Reasons e and Last Available HIV-1 RNA < 50 copies/mL 0 3% Missing Data During Window but on Study Drug 0 0 OBR = optimized background regimen a. Week 26 window was between Days 184 and 232 (inclusive). b. Week 52 window was between Days 324 and 414 (inclusive). c. Includes participants who had ≥ 50 copies/mL in the Week 26 or 52 window; participant who discontinued early due to lack or loss of efficacy; participants who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL. d. Includes participants who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. e. Includes participants who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. Reference ID: 5485227 27 Table 12 Virologic Outcomes (HIV-1 RNA < 50 copies/mL) by Baseline Covariates at Weeks 26 a and 52 b with SUNLENCA plus OBR in the CAPELLA trial (Cohort 1) SUNLENCA plus OBR (N=36) Week 26 Week 52 Age (Years) < 50 100% (9/9) 89% (8/9) ≥ 50 74% (20/27) 81% (22/27) Gender Male 77% (20/26) 77% (20/26) Female 90% (9/10) 100% (10/10) Race Black 81% (13/16) 75% (12/16) Non-Black 84% (16/19) 89% (17/19) Baseline plasma viral load (copies/mL) ≤ 100,000 86% (25/29) 86% (25/29) > 100,000 57% (4/7) 71% (5/7) Baseline CD4+ (cells/mm3) < 200 78% (21/27) 78% (21/27) ≥ 200 89% (8/9) 100% (9/9) Baseline INSTI resistance profile With INSTI resistance 85% (23/27) 81% (22/27) Without INSTI resistance 63% (5/8) 88% (7/8) Number of fully active ARV agents in the OBR 0 67% (4/6) 67% (4/6) 1 86% (12/14) 79% (11/14) ≥ 2 81% (13/16) 94% (15/16) Use of DTG and/or DRV in the OBR With DTG and DRV 83% (10/12) 83% (10/12) With DTG, without DRV 83% (5/6) 83% (5/6) Without DTG, with DRV 78% (7/9) 89% (8/9) Without DTG or DRV 78% (7/9) 78% (7/9) ARV = antiretroviral; DRV=darunavir; DTG=dolutegravir; INSTI = integrase strand-transfer inhibitor; OBR = optimized background regimen; a. Week 26 window was between Days 184 and 232 (inclusive). b. Week 52 window was between Days 324 and 414 (inclusive). Reference ID: 5485227 28 In cohort 1, at Weeks 26 and 52, the mean change from baseline in CD4+ cell count was 81 cells/mm3 (range: -101 to 522) and 82 cells/mm3 (range: -194 to 467), respectively. In cohort 2, at Weeks 26 and 52, 81% (29/36) and 72% (26/36) of participants achieved HIV-1 RNA < 50 copies/mL, respectively, and the mean change from baseline in CD4+ cell count was 97 cells/mm3 (range: -103 to 459) and 113 cells/mm3 (range: -124 to 405), respectively. Oral bridging In CAPELLA across cohorts 1 and 2, 79% of participants (57/72) received SUNLENCA 300 mg once every 7 days as oral bridging. A total of 13, 29, and 15 participants started oral bridging following Weeks 26, 52, and 78 injections, respectively. The median (Q1, Q3) duration of oral bridging was 19 weeks (11, 22), and 12% (7/57) received oral bridging for at least 28 weeks. In a post-hoc analysis, rates of virologic suppression and change from baseline in CD4+ cell counts in the subset of patients who received oral bridging were consistent before and during the oral bridging period. 16 HOW SUPPLIED/STORAGE AND HANDLING SUNLENCA tablets, 300 mg are beige, capsule-shaped, and film-coated with “GSI” debossed on one side and “62L” on the other side. SUNLENCA tablets are available in a bottle and blister packs, packaged as follows: Bottle • SUNLENCA bottle contains 4 tablets (NDC 61958-3001-3). The bottle also contains a silica gel desiccant and polyester coil, and is closed with a child-resistant closure. Do not remove the desiccant packet. Keep bottle tightly closed. Blister Packs • SUNLENCA 4-Tablets™ blister pack contains 4 tablets (NDC 61958-3001-1) • SUNLENCA 5-Tablets™ blister pack contains 5 tablets (NDC 61958-3001-2) Within the blister packs, tablets are packaged in a clear blister film sealed to a foil lidding material. The blister card is fitted between two paperboard cards, and packaged with silica gel desiccant in a sealed child-resistant flexible laminated pouch. Store bottle and blister packs at 20 °C – 25 °C (68 °F – 77 °F), excursions permitted to 15 °C – 30 °C (59 °F – 86 °F) (see USP Controlled Room Temperature). Reference ID: 5485227 29 Dispense and store only in original bottle or blister pack. SUNLENCA injection is packaged in one of two different injection kits containing the following: Vial access device injection kit (NDC 61958-3002-1): • 2 single-dose clear glass vials, each containing sufficient volume to allow withdrawal of 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir. The injection solution is sterile, preservative-free, clear, and yellow with no visible particles. Vials are sealed with a stopper and aluminium overseal with flip-off cap. • 2 vial access devices, 2 disposable syringes, and 2 injection safety needles for subcutaneous injection (22-gauge, ½ inch). Withdrawal needle injection kit (NDC 61958-3005-1): • 2 single-dose clear glass vials, each containing sufficient volume to allow withdrawal of 463.5 mg/1.5 mL (309 mg/mL) of lenacapavir. The injection solution is sterile, preservative-free, clear, and yellow with no visible particles. Vials are sealed with a stopper and aluminium overseal with flip-off cap. • 2 disposable syringes, 2 withdrawal needles (18-gauge, 1.5 inch), and 2 injection safety needles for subcutaneous injection (22-gauge, ½ inch). The vial stoppers are not made with natural rubber latex. Store at 20 °C – 25 °C (68 °F – 77 °F), excursions permitted to 15 °C – 30 °C (59 °F – 86 °F). Keep the vials in the original carton until just prior to preparation of the injections in order to protect from light. Once the solution has been drawn into the syringes, the injections should be administered as soon as possible. Discard any unused portion of the solution. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Drug Interactions SUNLENCA may interact with certain drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products, including St. John’s wort, during treatment with SUNLENCA [see Contraindications (4) and Drug Interactions (7)]. Reference ID: 5485227 30 If SUNLENCA is discontinued, advise patients that SUNLENCA may remain in the body and affect certain other drugs for up to 9 months after receiving their last injection [see Drug Interactions (7.2, 7.3)]. Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.1)]. Adherence to SUNLENCA Counsel patients about the importance of continued medication adherence and scheduled visits to maintain viral suppression and to reduce risk of loss of virologic response and development of resistance. Advise patients to contact their healthcare provider immediately if they stop taking SUNLENCA or any other drug in their antiretroviral regimen [see Dosage and Administration (2.1) and Warnings and Precautions (5.2)]. Missed Dose Inform patients that SUNLENCA can remain in the body for up to 12 months or longer after receiving their last injection. Advise patients to contact their healthcare provider if they miss or plan to miss a scheduled injection visit and that oral SUNLENCA therapy may be used for up to 6 months to replace missed injections. Advise patients that oral dosing should be used on an interim basis only and that the maintenance injection dosage should be resumed at the earliest possible opportunity [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. Injection Site Reactions Inform patients that injection site reactions (ISRs), such as swelling, pain, erythema, nodule, induration, pruritus, extravasation or mass, may occur. Nodules and indurations at the injection site may take longer to resolve than other ISRs and may be persistent. Instruct patients when to contact their healthcare provider about these reactions [see Warnings and Precautions (5.3)]. Pregnancy Registry Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to SUNLENCA [see Use in Specific Populations (8.1)]. Lactation Inform individuals with HIV-1 that the potential risks of breastfeeding include: (1) HIV-1 transmission (in infants without HIV-1), (2) developing viral resistance (in infants with HIV), and (3) adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)]. Reference ID: 5485227 31 SUNLENCA is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners. © 2024 Gilead Sciences, Inc. All rights reserved. Reference ID: 5485227 32 PATIENT INFORMATION SUNLENCA® (sun-LEN-kuh) SUNLENCA® (sun-LEN-kuh) (lenacapavir) (lenacapavir) tablets injection What is SUNLENCA? SUNLENCA is a prescription medicine that is used with other human immunodeficiency virus-1 (HIV-1) medicines to treat HIV-1 infection in adults: • who have received HIV-1 medicines in the past, and • who have HIV-1 virus that is resistant to many HIV-1 medicines, and • whose current HIV-1 medicines are failing. Your HIV-1 medicines may be failing because the HIV-1 medicines are not working or no longer work, you are not able to tolerate the side effects, or there are safety reasons why you cannot take them. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). It is not known if SUNLENCA is safe and effective in children. Do not receive or take SUNLENCA if you also take certain other medicines called strong CYP3A inducers. Ask your healthcare provider if you are not sure. Before receiving or taking SUNLENCA, tell your healthcare provider about all your medical conditions, including if you: • are pregnant or plan to become pregnant. It is not known if SUNLENCA can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with SUNLENCA. Pregnancy Registry: There is a pregnancy registry for women who take SUNLENCA during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry. • are breastfeeding or plan to breastfeed. It is not known whether SUNLENCA will pass to your baby in your breast milk. Talk with your healthcare provider about the following risks to your baby from breastfeeding during treatment with SUNLENCA: o The HIV-1 virus may pass to your baby if your baby does not have HIV-1. o The HIV-1 virus may become harder to treat if your baby has HIV-1. o Your baby may get side effects from SUNLENCA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements, including St. John’s wort. Some medicines may interact with SUNLENCA. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. • You can ask your healthcare provider or pharmacist for a list of medicines that interact with SUNLENCA. • Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take SUNLENCA with other medicines. • SUNLENCA may affect certain other medicines for up to 9 months after your last injection. How should I receive and take SUNLENCA? • Your SUNLENCA treatment will consist of injections and tablets. o SUNLENCA injections will be given to you by your healthcare provider under the skin (subcutaneous injection) in your stomach-area (abdomen). o Take SUNLENCA tablets by mouth, with or without food. • There are two options (Option 1 and Option 2) to start treatment with SUNLENCA. Your healthcare provider will decide which starting option is for you. o If Option 1 is chosen: • On Day 1, you will receive 2 SUNLENCA injections and take 2 SUNLENCA tablets. • On Day 2, you will take 2 SUNLENCA tablets. o If Option 2 is chosen: • On Day 1 and Day 2, you will take 2 SUNLENCA tablets each day. • On Day 8, you will take 1 SUNLENCA tablet. • On Day 15, you will receive 2 SUNLENCA injections. • After completing Option 1 or Option 2, you will receive 2 SUNLENCA injections every 6 months (26 weeks) from the date of your last injection. 1 Reference ID: 5485227 • Stay under the care of a healthcare provider during treatment with SUNLENCA. It is important that you attend your planned appointments to receive your injections of SUNLENCA. • If you miss or plan to miss your scheduled every 6 months injection of SUNLENCA, call your healthcare provider right away to discuss your treatment options. o If you plan to miss a scheduled SUNLENCA injection, there is the option to temporarily take SUNLENCA tablets. You will take 1 SUNLENCA tablet by mouth 1 time every 7 days, until your injections resume. o It is important to continue SUNLENCA treatment as your healthcare provider tells you. Missing SUNLENCA treatment may cause the HIV-1 virus to change (mutate) and become harder to treat (resistant). • Tell your healthcare provider right away if you stop treatment with SUNLENCA or stop treatment with any other HIV-1 medicines. If you stop treatment with SUNLENCA you will need other medicines to treat your HIV-1 infection. If you do not take other HIV-1 medicines, the amount of virus in your blood may increase and the virus may become harder to treat. Call your healthcare provider right away to discuss your treatment options. • If you take too many SUNLENCA tablets, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of SUNLENCA? SUNLENCA may cause serious side effects, including: • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having any new symptoms after starting your HIV-1 medicine. • Injection site reactions may happen when you receive SUNLENCA injections and may include swelling, pain, redness, skin hardening, small mass or lump, and itching. Hardened skin or lumps at the injection site usually can be felt but not seen. If you develop hardened skin or a lump, it may take longer than other reactions at the injection site to go away, and the injection site may not completely heal on its own. Tell your healthcare provider if you have any injection site reactions. The most common side effects of SUNLENCA are nausea and injection site reactions. These are not all of the possible side effects of SUNLENCA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store SUNLENCA tablets? • Store SUNLENCA tablets at room temperature between 68 °F to 77 °F (20 °C to 25 °C). • SUNLENCA bottle contains a desiccant packet to help keep your medicine dry (protect it from moisture). Keep the desiccant packet in the bottle. Do not eat the desiccant packet. • Keep SUNLENCA tablets in their original bottle or blister pack. • Keep the bottle tightly closed. Keep SUNLENCA and all medicines out of reach of children. General information about the safe and effective use of SUNLENCA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SUNLENCA for a condition for which it was not prescribed. Do not give SUNLENCA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about SUNLENCA that is written for health professionals. What are the ingredients in SUNLENCA? Active ingredient: lenacapavir Inactive ingredients: SUNLENCA tablets: copovidone, croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and poloxamer 407. The tablets are film-coated with a coating material containing iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. SUNLENCA injection: polyethylene glycol 300 and water for injection. Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404 SUNLENCA is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners. © 2024 Gilead Sciences, Inc. All rights reserved. 215973-GS-004/IFU-001/IFU-WD-000 For more information, call 1-800-445-3235 or go to www.SUNLENCA.com. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 2 Reference ID: 5485227
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2025-02-12T15:47:17.952927
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use SEMGLEE safely and effectively. See full prescribing information for SEMGLEE. SEMGLEE® (insulin glargine-yfgn) injection, for subcutaneous use Initial U.S. Approval: 2021 SEMGLEE® (insulin glargine-yfgn) is biosimilar* to LANTUS (insulin glargine). ----------------------------INDICATIONS AND USAGE--------------------------­ SEMGLEE is a long-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. (1) Limitations of Use Not recommended for the treatment of diabetic ketoacidosis. (1) ----------------------DOSAGE AND ADMINISTRATION----------------------­ • Individualize dosage based on metabolic needs, blood glucose monitoring, glycemic control, type of diabetes, and prior insulin use. (2.2) • Administer subcutaneously into the abdominal area, thigh, or deltoid once daily at any time of day, but at the same time every day. (2.1) • Do not dilute or mix with any other insulin or solution. (2.1) • Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. (2.1) • See Full Prescribing Information for the recommended starting dosage in patients with type 2 diabetes (2.3) and how to change to SEMGLEE from other insulins. (2.4) • Closely monitor glucose when switching to SEMGLEE and during initial weeks thereafter. (2.4) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ Injection: 100 units/mL (U-100) available as: • 10 mL multiple-dose vial (3) • 3 mL single-patient-use prefilled pen (3) ---------------------------CONTRAINDICATIONS---------------------------------­ • During episodes of hypoglycemia (4) • Hypersensitivity to insulin glargine products or any excipient in SEMGLEE (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ • Never share a SEMGLEE prefilled pen, insulin syringe or needle between patients, even if the needle is changed. (5.1) • Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to a patient’s insulin regimen (e.g., insulin strength, FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions 2.2 General Dosing Instructions 2.3 Initiation of SEMGLEE Therapy 2.4 Switching to SEMGLEE from Other Insulin Therapies 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Never Share a SEMGLEE Prefilled Pen, Insulin Syringe, or Needle Between Patients 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen 5.3 Hypoglycemia 5.4 Hypoglycemia due to Medication Errors 5.5 Hypersensitivity Reactions 5.6 Hypokalemia 5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. (5.2) • Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, concomitant drugs , meal pattern, physical activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness. (5.3) • Hypoglycemia due to Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. (5.4) • Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue SEMGLEE. Monitor and treat if indicated. (5.5) • Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. (5.6) • Fluid retention and heart failure with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation of TZD if heart failure occurs. (5.7) ------------------------------ADVERSE REACTIONS------------------------------­ Adverse reactions commonly associated with insulin glargine products include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema and weight gain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Biologics at 1-833-986-1468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------­ • Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. (7) • Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. (7) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of SEMGLEE has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information Revised: 11/2023 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use Renal 8.6 Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE DESCRIPTION 11 CLINICAL PHARMACOLOGY 12 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies 14.2 Clinical Studies in Adult and Pediatric Patients with Type 1 Diabetes 14.3 Clinical Studies in Adults with Type 2 Diabetes 14.4 Additional Clinical Studies in Adults with Diabetes Type 1 and Type 2 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage PATIENT COUNSELING INFORMATION 17 *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5485379 1 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE SEMGLEE is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. Limitations of Use SEMGLEE is not recommended for the treatment of diabetic ketoacidosis. 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions • Always check insulin labels before administration [see Warnings and Precautions (5.4)] • Visually inspect SEMGLEE vials and prefilled pens for particulate matter and discoloration prior to administration. Only use if the solution is clear and colorless with no visible particles. • Administer SEMGLEE subcutaneously into the abdominal area, thigh, or deltoid, and rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2), and Adverse Reactions (6)]. • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)]. • Do not administer intravenously or via an insulin pump. • Do not dilute or mix SEMGLEE with any other insulin or solution. • The SEMGLEE prefilled pen dials in 1-unit increments. • Use SEMGLEE prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose. 2.2 General Dosing Instructions • Administer SEMGLEE subcutaneously once daily at any time of day but at the same time every day. • Individualize and adjust the dosage of SEMGLEE based on the patient’s metabolic needs, blood glucose monitoring results and glycemic control goal. • Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), during acute illness, or changes in renal or hepatic function. Dosage adjustments should only be made under medical supervision with appropriate glucose monitoring [see Warnings and Precautions (5.2)]. • In patients with type 1 diabetes, SEMGLEE must be used concomitantly with short- acting insulin. 2.3 Initiation of SEMGLEE Therapy Recommended Starting Dosage in Patients with Type 1 Diabetes The recommended starting dosage of SEMGLEE in patients with type 1 diabetes is approximately one-third of the total daily insulin requirements. Use short-acting, premeal insulin to satisfy the remainder of the daily insulin requirements. Reference ID: 5485379 2 Recommended Starting Dosage in Patients with Type 2 Diabetes The recommended starting dosage of SEMGLEE in patients with type 2 diabetes who are not currently treated with insulin is 0.2 units/kg or up to 10 units once daily. 2.4 Switching to SEMGLEE from Other Insulin Therapies Dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to SEMGLEE from other insulin therapies [see Warnings and Precautions (5.3)]. When switching from: • Once-daily insulin glargine 300 units/mL to once-daily SEMGLEE (100 units/mL), the recommended starting SEMGLEE dosage is 80% of the insulin glargine 300 units/mL dosage that is being discontinued. • Once-daily NPH insulin to once-daily SEMGLEE, the recommended starting SEMGLEE dosage is the same as the dosage of NPH that is being discontinued. • Twice-daily NPH insulin to once-daily SEMGLEE, the recommended starting SEMGLEE dosage is 80% of the total NPH dosage that is being discontinued. 3 DOSAGE FORMS AND STRENGTHS Injection: 100 units/mL (U-100) a clear and colorless solution available as: • 10 mL multiple-dose vial • 3 mL single-patient-use prefilled pen 4 CONTRAINDICATIONS SEMGLEE is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions (5.3)]. • In patients with hypersensitivity to insulin glargine products or any of the excipients in SEMGLEE [see Warnings and Precautions (5.5)]. 5 WARNINGS AND PRECAUTIONS 5.1 Never Share a SEMGLEE Prefilled Pen, Insulin Syringe, or Needle Between Patients SEMGLEE prefilled pens must never be shared between patients, even if the needle is changed. Patients using SEMGLEE vials must never re-use or share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6)]. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas Reference ID: 5485379 3 of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant oral and antidiabetic products may be needed. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction associated with insulins, including insulin glargine products. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Hypoglycemia can happen suddenly, and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy using drugs that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or who experience recurrent hypoglycemia. The long-acting effect of insulin glargine products may delay recovery from hypoglycemia. Risk Factors for Hypoglycemia The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins, the glucose lowering effect time course of insulin glargine products may vary in different patients or at different times in the same patient and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2)]. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitant drugs [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)]. Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self- monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. 5.4 Hypoglycemia Due to Medication Errors Accidental mix-ups among insulin products have been reported. To avoid medication errors between SEMGLEE and other insulins, instruct patients to always check the insulin label before each injection [see Adverse Reactions (6.3)]. Reference ID: 5485379 4 5.5 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including insulin glargine products [see Adverse Reactions (6.1)]. If hypersensitivity reactions occur, discontinue SEMGLEE; treat per standard of care and monitor until symptoms and signs resolve . SEMGLEE is contraindicated in patients who have had hypersensitivity reactions to insulin glargine products or one of the excipients. 5.6 Hypokalemia All insulins, including insulin glargine products, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia, if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations). 5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)­ gamma agonists, can cause dose-related fluid retention, when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin including SEMGLEE, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered. 6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: • Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen [see Warnings and Precautions (5.2)] • Hypoglycemia [see Warnings and Precautions (5.3)] • Hypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Hypokalemia [see Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. The data in Table 1 reflect the exposure of 2,327 patients with type 1 diabetes to insulin glargine or NPH in Studies A, B, C, and D [see Clinical Studies (14.2)]. The type 1 diabetes population had the following characteristics: the mean age was 39 years. 54% were male, and mean body mass index (BMI) was 25.1 kg/m2. Ninety-seven percent were White, 2% were Black or African American and less than 1% were Asian. Approximately 3% of the patients in studies B and C were Hispanic. The data in Table 2 reflect the exposure of 1,563 patients with type 2 diabetes to insulin glargine or NPH in Studies E, F, and G [see Clinical Studies (14.3)]. The type 2 diabetes population had the following characteristics: the mean age was 59 years, 58% were male, and mean BMI was Reference ID: 5485379 5 29.2 kg/m2. Eighty-seven percent were White, 8% were Black or African American and 3% were Asian. Approximately 9% of patients in Study F were Hispanic. The frequencies of adverse reactions during insulin glargine clinical studies in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below (Tables 1, 2, 3, and 4). Table 1: Adverse Reactions Occurring ≥5% in Pooled Clinical Studies up to 28 Weeks Duration in Adults with Type 1 Diabetes Insulin Glargine, % (n = 1,257) NPH,% (n = 1,070) Upper respiratory tract infection 22.4 23.1 Infection* 9.4 10.3 Accidental injury 5.7 6.4 Headache 5.5 4.7 * Body system not specified Table 2: Adverse Reactions Occurring ≥5% in Pooled Clinical Studies up to 1 Year Duration in Adults with Type 2 Diabetes Insulin Glargine, % (n = 849) NPH,% (n = 714) Upper respiratory tract infection 11.4 13.3 Infection* 10.4 11.6 Retinal vascular disorder 5.8 7.4 * Body system not specified Table 3: Adverse Reactions Occurring ≥10% in a 5-Year Study of Adults with Type 2 Diabetes Insulin Glargine, % (n = 514) NPH,% (n = 503) Upper respiratory tract infection 29.0 33.6 Edema peripheral 20.0 22.7 Hypertension 19.6 18.9 Influenza 18.7 19.5 Sinusitis 18.5 17.9 Cataract 18.1 15.9 Bronchitis 15.2 14.1 Arthralgia 14.2 16.1 Pain in extremity 13.0 13.1 Back pain 12.8 12.3 Cough 12.1 7.4 Urinary tract infection 10.7 10.1 Diarrhea 10.7 10.3 Depression 10.5 9.7 Headache 10.3 9.3 Reference ID: 5485379 6 Table 4: Adverse Reactions Occurring ≥ 5% in a 28-Week Clinical Study in Pediatric Patients with Type 1 Diabetes Insulin Glargine, % (n = 174) NPH,% (n = 175) Infection* 13.8 17.7 Upper respiratory tract infection 13.8 16.0 Pharyngitis 7.5 8.6 Rhinitis 5.2 5.1 * Body system not specified Severe Hypoglycemia Hypoglycemia was the most commonly observed adverse reaction in patients treated with insulin glargine. Tables 5, 6, and 7 summarize the incidence of severe hypoglycemia in the insulin glargine clinical studies. Severe symptomatic hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose below 50 mg/dL (≤ 56 mg/dL in the 5-year study and ≤ 36 mg/dL in the ORIGIN study) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. Percentages of insulin glargine-treated adult patients who experienced severe symptomatic hypoglycemia in the insulin glargine clinical studies [see Clinical Studies (14)] were comparable to percentages of NPH-treated patients for all treatment regimens (see Tables 5 and 6). In the pediatric clinical study, pediatric patients with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult studies with type 1 diabetes. Table 5: Severe Symptomatic Hypoglycemia in Patients with Type 1 Diabetes Study A Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study B Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study C Type 1 Diabetes Adults 16 weeks In combination with insulin lispro Study D Type 1 Diabetes Pediatrics 26 weeks In combination with regular insulin Insulin Glargine n = 292 NPH n = 293 Insulin Glargine n = 264 NPH n = 270 Insulin Glargine n = 310 NPH n = 309 Insulin Glargine n = 174 NPH n = 175 Percent of patients 10.6 15.0 8.7 10.4 6.5 5.2 23.0 28.6 7 Reference ID: 5485379 Table 6: Severe Symptomatic Hypoglycemia in Patients with Type 2 Diabetes Study E Type 2 Diabetes Adults 52 weeks In combination with oral agents Study F Type 2 Diabetes Adults 28 weeks In combination with regular insulin Study G Type 2 Diabetes Adults 5 years In combination with regular insulin Insulin Glargine n = 289 NPH n = 281 Insulin Glargine n = 259 NPH n = 259 Insulin Glargine n = 513 NPH n = 504 Percent of patients 1.7 1.1 0.4 2.3 7.8 11.9 Table 7 displays the proportion of patients who experienced severe symptomatic hypoglycemia in the insulin glargine and Standard Care groups in the ORIGIN study [see Clinical Studies (14)]. Table 7: Severe Symptomatic Hypoglycemia in the ORIGIN Study ORIGIN Study Median duration of follow-up: 6.2 years Insulin Glargine n = 6231 Standard Care n = 6273 Percent of patients 5.6 1.8 Peripheral Edema Some patients taking insulin glargine products have experienced sodium retention and edema, particularly if previously poor metabolic control was improved by intensified insulin therapy. Lipodystrophy Administration of insulin subcutaneously, including insulin glargine products, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients [see Dosage and Administration (2.2)]. Insulin Initiation and Intensification of Glucose Control Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Weight Gain Weight gain has occurred with insulin including insulin glargine products and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Hypersensitivity Reactions Local Reactions 8 Reference ID: 5485379 Patients taking insulin glargine experienced injection site reactions, including redness, pain, itching, urticaria, edema, and inflammation. In clinical studies in adult patients, there was a higher incidence of injection site pain in insulin glargine-treated patients (2.7%) compared to NPH insulin-treated patients (0.7%). The reports of pain at the injection site did not result in discontinuation of therapy. Systemic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occurred with insulin, including insulin glargine products and may be life threatening. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other insulin glargine products may be misleading. All insulin products can elicit the formation of insulin antibodies. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In clinical studies of insulin glargine, increases in titers of antibodies to insulin were observed in NPH insulin and insulin glargine treatment groups with similar incidences. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of insulin glargine products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Medication errors have been reported in which rapid-acting insulins and other insulins have been accidentally administered instead of insulin glargine products. Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site. 7 DRUG INTERACTIONS Table 8 includes clinically significant drug interactions with SEMGLEE. Table 8: Clinically Significant Drug Interactions with SEMGLEE Drugs that May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs Reference ID: 5485379 9 (e.g., octreotide), sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors. Intervention: Dosage reductions and increased frequency of glucose monitoring may be required when SEMGLEE is coadministered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of SEMGLEE Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dosage increases and increased frequency of glucose monitoring may be required when SEMGLEE is coadministered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of SEMGLEE Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dosage adjustment and increased frequency of glucose monitoring may be required when SEMGLEE is coadministered with these drugs. Drugs that May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when SEMGLEE is coadministered with these drugs. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Published studies with use of insulin glargine products during pregnancy have not reported a clear association with insulin glargine products and adverse developmental outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Rats and rabbits were exposed to insulin glargine in animal reproduction studies during organogenesis, respectively 50 times and 10 times the human subcutaneous dosageof 0.2 units/kg/day. Overall, the effects of insulin glargine did not generally differ from those observed with regular human insulin (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20% to 25% in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal and/or Embryo-fetal Risk Reference ID: 5485379 10 Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre­ gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Data Human Data Published data do not report a clear association with insulin glargine products and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups. Animal Data Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 50 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day (0.007 mg/kg/day), on a mg/kg basis. In rabbits, doses of 0.072 mg/kg/day, which is approximately 10 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day on a mg/kg basis, were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal. 8.2 Lactation Risk Summary There are either no or only limited data on the presence of insulin glargine products in human milk, the effects on breastfed infant, or the effects on milk production. Endogenous insulin is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SEMGLEE, and any potential adverse effects on the breastfed child from SEMGLEE or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of SEMGLEE to improve glycemic control in pediatric patients with diabetes mellitus have been established. Use of SEMGLEE for this indication is supported by SEMGLEE’s approval as a biosimilar to insulin glargine and evidence from an adequate and well-controlled study (Study D) in 174 insulin glargine-treated pediatric patients aged 6 to 15 years with type 1 diabetes mellitus and from adequate and well-controlled studies of insulin glargine in adults with diabetes mellitus [see Clinical Pharmacology (12.3), Clinical Studies (14.2)]. In the pediatric clinical study, pediatric patients with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia compared to the adults in studies with type 1 diabetes [see Adverse Reactions (6.1)]. Reference ID: 5485379 11 8.5 Geriatric Use Of the total number of subjects in controlled clinical studies of patients with type 1 and type 2 diabetes who were treated with insulin glargine, 15% (n=316) were ≥ 65 years of age and 2% (n=42) were ≥ 75 years of age. No overall differences in safety or effectiveness of insulin glargine have been observed between patients 65 years of age and older and younger adult patients. Nevertheless, caution should be exercised when SEMGLEE is administered to geriatric patients. In geriatric patients with diabetes, the initial dosing, dosage increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in geriatric patients. 8.6 Renal Impairment The effect of kidney impairment on the pharmacokinetics of insulin glargine products has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with kidney failure. Frequent glucose monitoring and dosage adjustment may be necessary for SEMGLEE in patients with kidney impairment [see Warnings and Precautions (5.3)]. 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of insulin glargine products has not been studied. Frequent glucose monitoring and dosage adjustment may be necessary for SEMGLEE in patients with hepatic impairment [see Warnings and Precautions (5.3)]. 10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6)]. Mild episodes of hypoglycemia can usually be treated with oral carbohydrates. Lowering the insulin dosage, and adjustments in meal patterns, or exercise may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with glucagon for emergency use or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia must be corrected appropriately. 11 DESCRIPTION Insulin glargine-yfgn is a long-acting human insulin analog produced by recombinant DNA technology utilizing a recombinant yeast strain, Pichia pastoris. Insulin glargine-yfgn differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Insulin glargine-yfgn has a molecular weight of 6063 Da. Reference ID: 5485379 12 6 '2 5 t t 4 i:: .-:, * '-l , .. .... , \ ~ 3 \ 0:: I I C: I 0 -~ , a 2 , C: I - I '-l , "' 0 lj 1 ::::, 5 0 0 ' \ \ \ \ .. \ \ ' ... 10 ... \ ' .. __ 20 --Insulin glargine (N=20) - - - - -NPH insulin (N=20) "- End of observation period 30 Time (h) after s.c. injection SEMGLEE (insulin glargine-yfgn) injection is a sterile, clear and colorless solution for subcutaneous use in a 10 mL multiple-dose vial and a 3 mL single-patient-use prefilled pen. Prefilled Pen and Vial: Each mL contains 100 units of insulin glargine-yfgn and the inactive ingredients: glycerol (20 mg), metacresol (2.7 mg), zinc chloride (content adjusted to provide 30 mcg zinc ion), and Water for Injection, USP. The vial also contains polysorbate 20 (20 mcg). The pH is adjusted by addition of aqueous solutions of hydrochloric acid and/or sodium hydroxide. SEMGLEE has a pH of approximately 4. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The primary activity of insulin, including insulin glargine products, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis and enhances protein synthesis. 12.2 Pharmacodynamics In clinical studies, the glucose-lowering effect on a molar basis (i.e., when given at the same doses) of intravenous insulin glargine is approximately the same as that for human insulin. Figure 1 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24 hours after subcutaneous injection of insulin glargine or NPH insulin. The median time between subcutaneous injection and the end of pharmacological effect was 14.5 hours (range: 9.5 to 19.3 hours) for NPH insulin, and 24 hours (range: 10.8 to > 24 hours) (24 hours was the end of the observation period) for insulin glargine. Figure 1: Glucose-Lowering Effect Over 24 Hours in Patients with Type 1 Diabetes * Determined as amount of glucose infused to maintain constant plasma glucose levels Reference ID: 5485379 13 The duration of action after abdominal, deltoid, or thigh subcutaneous administration of insulin glargine was similar. The time course of action of insulins, including insulin glargine products, may vary between patients and within the same patient. 12.3 Pharmacokinetics Absorption After subcutaneous injection of insulin glargine in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH insulin. Elimination Metabolism A metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of human insulin, M1 (21A-Gly-insulin) and M2 (21A-Gly-des­ 30B-Thr-insulin). Unchanged drug and these degradation products are also present in the circulation. Specific Populations Age, Race, Body Mass Index and Gender Effect of age, race, body mass index (BMI) and gender on the pharmacokinetics of insulin glargine products has not been evaluated. However, in controlled clinical studies in adults (n = 3890) and a controlled clinical study in pediatric patients (n = 349), subgroup analyses based on age, race, BMI and gender did not show differences in safety and efficacy between insulin glargine and NPH insulin [see Clinical Studies (14)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which was for the rat approximately 65 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day (0.007 mg/kg/day) on a mg/kg basis. Histiocytomas were found at injection sites in male rats and mice in acid vehicle containing groups and are considered a response to chronic tissue irritation and inflammation in rodents. These tumors were not found in female animals, in saline control, or insulin comparator groups using a different vehicle. Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters). In a combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 50 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day (0.007 mg/kg/day) maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, a reduction Reference ID: 5485379 14 of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin. 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies The safety and effectiveness of insulin glargine given once-daily at bedtime was compared to that of once-daily and twice-daily NPH insulin in open-label, randomized, active-controlled, parallel studies of 2,327 adult patients and 349 pediatric patients with type 1 diabetes mellitus and 1,563 adult patients with type 2 diabetes mellitus (see Tables 9-11). In general, the reduction in glycated hemoglobin (HbA1c) with insulin glargine was similar to that with NPH insulin. 14.2 Clinical Studies in Adult and Pediatric Patients with Type 1 Diabetes Adult Patients with Type 1 Diabetes In two clinical studies (Studies A and B), adult patients with type 1 diabetes (Study A; n = 585, Study B n = 534) were randomized to 28 weeks of basal-bolus treatment with insulin glargine or NPH insulin. Regular human insulin was administered before each meal. Insulin glargine was administered at bedtime. NPH insulin was administered either as once daily at bedtime or in the morning and at bedtime when used twice daily. In Study A, the average age was 39 years. The majority of patients were White (99%) and 56% were male. The mean BMI was approximately 24.9 kg/m2. The mean duration of diabetes was 16 years. In Study B, the average age was 39 years. The majority of patients were White (95%) and 51% were male. The mean BMI was approximately 25.8 kg/m2. The mean duration of diabetes was 17 years. In another clinical study (Study C), patients with type 1 diabetes (n = 619) were randomized to 16 weeks of basal-bolus treatment with insulin glargine or NPH insulin. Insulin lispro was used before each meal. Insulin glargine was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 39 years. The majority of patients were White (97%) and 51% were male. The mean BMI was approximately 25.6 kg/m2. The mean duration of diabetes was 19 years. In these 3 adult studies, insulin glargine and NPH insulin had similar effects on HbA1c (Table 9) with a similar overall rate of severe symptomatic hypoglycemia [see Adverse Reactions (6.1)]. Table 9: Type 1 Diabetes Mellitus – Adults Treatment duration Treatment in combination with Study A 28 weeks Regular insulin Study B 28 weeks Regular insulin Study C 16 weeks Insulin lispro Insulin Glargine NPH Insulin Glargine NPH Insulin Glargine NPH Number of subjects treated 292 293 264 270 310 309 HbA1c Reference ID: 5485379 15 Baseline HbA1c 8.0 8.0 7.7 7.7 7.6 7.7 Adjusted mean change at study end +0.2 +0.1 -0.2 -0.2 -0.1 -0.1 Treatment Difference (95% CI) +0.1 (0.0; +0.2) +0.1 (-0.1; +0.2) 0.0 (-0.1; +0.1) Basal insulin dose Baseline mean 21 23 29 29 28 28 Mean change from baseline -2 0 -4 +2 -5 +1 Total insulin dose Baseline mean 48 52 50 51 50 50 Mean change from baseline -1 0 0 +4 -3 0 Fasting blood glucose (mg/dL) Baseline mean 167 166 166 175 175 173 Adj. mean change from baseline -21 -16 -20 -17 -29 -12 Body weight (kg) Baseline mean 73.2 74.8 75.5 75.0 74.8 75.6 Mean change from baseline 0.1 -0.0 0.7 1.0 0.1 0.5 Pediatric Patients with Type 1 Diabetes In a randomized, controlled clinical study (Study D), pediatric patients (age range 6 to 15 years) with type 1 diabetes (n = 349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. Insulin glargine was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 11.7 years. The majority of patients were White (97%) and 52% were male. The mean BMI was approximately 18.9 kg/m2. The mean duration of diabetes was 5 years. Similar effects on HbA1c (Table 10) were observed in both treatment groups [see Adverse Reactions (6.1)]. Table 10: Type 1 Diabetes Mellitus – Pediatric Patients Treatment duration Treatment in combination with Study D 28 weeks Regular insulin Insulin Glargine + Regular insulin NPH+ Regular insulin Number of subjects treated 174 175 HbA1c Baseline mean 8.5 8.8 Change from baseline (adjusted mean) +0.3 +0.3 Difference from NPH (adjusted mean) 0.0 (95% CI) (-0.2; +0.3) Basal insulin dose Baseline mean 19 19 Mean change from baseline -1 +2 Total insulin dose Baseline mean 43 43 Mean change from baseline +2 +3 Reference ID: 5485379 16 Fasting blood glucose (mg/dL) Baseline mean 194 191 Mean change from baseline -23 -12 Body weight (kg) Baseline mean 45.5 44.6 Mean change from baseline 2.2 2.5 14.3 Clinical Studies in Adults with Type 2 Diabetes In a randomized, controlled clinical study (Study E) in 570 adults with type 2 diabetes, insulin glargine was evaluated for 52 weeks in combination with oral antidiabetic medications (a sulfonylurea, metformin, acarbose, or combinations of these drugs). The average age was 60 years old. The majority of patients were White (93%) and 54% were male. The mean BMI was approximately 29.1 kg/m2. The mean duration of diabetes was 10 years. Insulin glargine administered once daily at bedtime was as effective as NPH insulin administered once daily at bedtime in reducing HbA1c and fasting glucose (Table 11). The rate of severe symptomatic hypoglycemia was similar in insulin glargine and NPH insulin treated patients [see Adverse Reactions (6.1)]. In a randomized, controlled clinical study (Study F), in adult patients with type 2 diabetes not using oral antidiabetic medications (n = 518), a basal-bolus regimen of insulin glargine once daily at bedtime or NPH insulin administered once or twice daily was evaluated for 28 weeks. Regular human insulin was used before meals, as needed. The average age was 59 years. The majority of patients were White (81%) and 60% were male. The mean BMI was approximately 30.5 kg/m2. The mean duration of diabetes was 14 years. Insulin glargine had similar effectiveness as either once- or twice-daily NPH insulin in reducing HbA1c and fasting glucose (Table 11) with a similar incidence of hypoglycemia [see Adverse Reactions (6.1)]. In a randomized, controlled clinical study (Study G), adult patients with type 2 diabetes were randomized to 5 years of treatment with once-daily insulin glargine or twice-daily NPH insulin. For patients not previously treated with insulin, the starting dosage of insulin glargine or NPH insulin was 10 units daily. Patients who were already treated with NPH insulin either continued on the same total daily NPH insulin dose or started insulin glargine at a dosage that was 80% of the total previous NPH insulin dosage. The primary endpoint for this study was a comparison of the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. HbA1c change from baseline was a secondary endpoint. Similar glycemic control in the 2 treatment groups was desired in order to not confound the interpretation of the retinal data. Patients or study personnel used an algorithm to adjust the insulin glargine and NPH insulin dosages to a target fasting plasma glucose ≤ 100 mg/dL. After the insulin glargine or NPH insulin dosage was adjusted, other antidiabetic agents, including premeal insulin were to be adjusted or added. The average age was 55 years. The majority of patients were White (85%) and 54% were male. The mean BMI was approximately 34.3 kg/m2. The mean duration of diabetes was 11 years. The insulin glargine group had a smaller mean reduction from baseline in HbA1c compared to the NPH insulin group, which may be explained by the lower daily basal insulin doses in the insulin glargine group (Table 11). The incidences of severe symptomatic hypoglycemia were similar between groups [see Adverse Reactions (6.1)]. Reference ID: 5485379 17 Table 11: Type 2 Diabetes Mellitus – Adults Treatment duration Treatment in combination with Study E 52 weeks Oral agents Study F 28 weeks Regular insulin Study G 5 years Regular insulin Insulin Glargine NPH Insulin Glargine NPH Insulin Glargine NPH Number of subjects treated 289 281 259 259 513 504 HbA1c Baseline mean 9.0 8.9 8.6 8.5 8.4 8.3 Adjusted mean change from baseline -0.5 -0.4 -0.4 -0.6 -0.6 -0.8 Insulin Glargine ‒ NPH -0.1 +0.2 +0.2 95% CI for Treatment difference (-0.3; +0.1) (0.0; +0.4) (+0.1; +0.4) Basal insulin dose* Baseline mean 14 15 44.1 45.5 39 44 Mean change from baseline +12 +9 -1 +7 +23 +30 Total insulin dose* Baseline mean 14 15 64 67 48 53 Mean change from baseline +12 +9 +10 +13 +41 +40 Fasting blood glucose (mg/dL) Baseline mean 179 180 164 166 190 180 Adj. mean change from baseline -49 -46 -24 -22 -45 -44 Body weight (kg) Baseline mean 83.5 82.1 89.6 90.7 100 99 Adj. mean change from baseline 2.0 1.9 0.4 1.4 3.7 4.8 * In Study G, the baseline dose of basal or total insulin was the first available on-treatment dose prescribed during the study (on visit month 1.5) 14.4 Additional Clinical Studies in Adults with Diabetes Type 1 and Type 2 Different Timing of Insulin Glargine Administration in Diabetes Type 1 and Diabetes Type 2 The safety and efficacy of once daily insulin glargine administered either at pre-breakfast, pre­ dinner, or at bedtime were evaluated in a randomized, controlled clinical study in adult patients with type 1 diabetes (Study H, n = 378). Patients were also treated with insulin lispro at mealtime. The average age was 41 years. All patients were White (100%) and 54% were male. The mean BMI was approximately 25.3 kg/m2. The mean duration of diabetes was 17 years. Insulin glargine administered at pre-breakfast or at pre-dinner (both once daily) resulted in similar reductions in HbA1c compared to that with bedtime administration (see Table 12). In these patients, data are available from 8-point home glucose monitoring. The maximum mean blood glucose was observed just prior to insulin glargine injection regardless of time of administration. In this study, 5% of patients in the insulin glargine-breakfast group discontinued treatment because of lack of efficacy. No patients in the other two groups (pre-dinner, bedtime) discontinued for this reason. Reference ID: 5485379 18 The safety and efficacy of once daily insulin glargine administered pre-breakfast or at bedtime were also evaluated in a randomized, active-controlled clinical study (Study I, n = 697) in patients with type 2 diabetes not adequately controlled on oral antidiabetic therapy. All patients in this study also received glimepiride 3 mg daily. The average age was 61 years. The majority of patients were White (97%) and 54% were male. The mean BMI was approximately 28.7 kg/m2. The mean duration of diabetes was 10 years. Insulin glargine given before breakfast was at least as effective in lowering HbA1c as insulin glargine given at bedtime or NPH insulin given at bedtime (see Table 12). Table 12: Study of Different Times of Once Daily Insulin Glargine Dosing in Type 1 (Study H) and Type 2 (Study I) Diabetes Mellitus Treatment duration Treatment in combination with Study H 24 weeks Insulin lispro Study I 24 weeks Glimepiride Insulin Glargine Before Breakfast Insulin Glargine Before Dinner Insulin Glargine Bedtime Insulin Glargine Before Breakfast Insulin Glargine Bedtime NPH Bedtime Number of subjects treated* 112 124 128 234 226 227 HbA1c Baseline mean 7.6 7.5 7.6 9.1 9.1 9.1 Mean change from baseline -0.2 -0.1 0.0 -1.3 -1.0 -0.8 Basal insulin dose (Units) Baseline mean 22 23 21 19 20 19 Mean change from baseline 5 2 2 11 18 18 Total insulin dose (Units) - - - NA† NA† NA† Baseline mean 52 52 49 - - - Mean change from baseline 2 3 2 - - - Body weight (kg) Baseline mean 77.1 77.8 74.5 80.7 82 81 Mean change from baseline 0.7 0.1 0.4 3.9 3.7 2.9 * Intent-to-treat †Not applicable Progression of Retinopathy Evaluation in adults with Diabetes Type 1 and Diabetes Type 2 Insulin glargine was compared to NPH insulin in a 5-year randomized clinical study that evaluated the progression of retinopathy as assessed with fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS). Patients had 19 Reference ID: 5485379 type 2 diabetes (mean age 55 years) with no (86%) or mild (14%) retinopathy at baseline. Mean baseline HbA1c was 8.4%. The primary outcome was progression by 3 or more steps on the ETDRS scale at study endpoint. Patients with prespecified postbaseline eye procedures (pan­ retinal photocoagulation for proliferative or severe nonproliferative diabetic retinopathy, local photocoagulation for new vessels, and vitrectomy for diabetic retinopathy) were also considered as 3-step progressors regardless of actual change in ETDRS score from baseline. Retinopathy graders were blinded to treatment group assignment. The results for the primary endpoint are shown in Table 13 for both the per-protocol and intent- to-treat populations and indicate similarity of insulin glargine to NPH in the progression of diabetic retinopathy as assessed by this outcome. In this study, the numbers of retinal adverse events reported for insulin glargine and NPH insulin treatment groups were similar for adult patients with type 1 and type 2 diabetes. Table 13: Number (%) of Patients with 3 or More Step Progression on ETDRS Scale at Endpoint Insulin Glargine (%) NPH (%) Difference*,† (SE) 95% CI for difference Per-protocol 53/374 (14.2%) 57/363 (15.7%) -2.0% (2.6%) -7.0% to +3.1% Intent-to-Treat 63/502 (12.5%) 71/487 (14.6%) -2.1% (2.1%) -6.3% to +2.1% * Difference = Insulin Glargine – NPH † Using a generalized linear model (SAS GENMOD) with treatment and baseline HbA1c strata (cutoff 9.0%) as the classified independent variables, and with binomial distribution and identity link function The ORIGIN Study of Major Cardiovascular Outcomes in Patients with Established CV Disease or CV Risk Factors The Outcome Reduction with Initial Glargine Intervention study (i.e., ORIGIN) was an open- label, randomized, 2-by-2, factorial design study. One intervention in ORIGIN compared the effect of insulin glargine to standard care on major adverse cardiovascular (CV) outcomes in 12,537 adults ≥ 50 years of age with; • Abnormal glucose levels (i.e., impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) or early type 2 diabetes mellitus and • Established CV disease or CV risk factors at baseline. The objective of the study was to demonstrate that insulin glargine use could significantly lower the risk of major CV outcomes compared to standard care. There were two coprimary composite CV endpoints. • The first coprimary endpoint was the time to first occurrence of a major adverse CV event defined as the composite of CV death, nonfatal myocardial infarction and nonfatal stroke. • The second coprimary endpoint was the time to the first occurrence of CV death or nonfatal myocardial infarction or nonfatal stroke or revascularization procedure or hospitalization for heart failure. Reference ID: 5485379 20 Patients were randomized to either insulin glargine (N = 6,264) titrated to a goal fasting plasma glucose of ≤ 95 mg/dL or to standard care (N = 6,273). Anthropometric and disease characteristics were balanced at baseline. The mean age was 64 years and 8% of patients were 75 years of age or older. The majority of patients were male (65%). Fifty nine percent were White, 25% were Latin, 10% were Asian and 3% were Black or African American. The median baseline BMI was 29 kg/m2. Approximately 12% of patients had abnormal glucose levels (IGT and/or IFG) at baseline and 88% had type 2 diabetes. For patients with type 2 diabetes, 59% were treated with a single oral antidiabetic drug, 23% had known diabetes but were on no antidiabetic drug and 6% were newly diagnosed during the screening procedure. The mean HbA1c (SD) at baseline was 6.5% (1.0). Fifty-nine percent of the patients had a prior CV event and 39% had documented coronary artery disease or other CV risk factors. Vital status was available for 99.9% and 99.8% of patients randomized to insulin glargine and standard care respectively at end of study. The median duration of follow-up was 6.2 years (range: 8 days to 7.9 years). The mean HbA1c (SD) at the end of the study was 6.5% (1.1) and 6.8% (1.2) in the insulin glargine and standard care group respectively. The median dose of insulin glargine at end of study was 0.45 U/kg. Eighty-one percent of patients randomized to insulin glargine were using insulin glargine at end of the study. The mean change in body weight from baseline to the last treatment visit was 2.2 kg greater in the insulin glargine group than in the standard care group. Overall, the incidence of major adverse CV outcomes was similar between groups (see Table 14). All-cause mortality was also similar between groups. Table 14: Cardiovascular Outcomes in ORIGIN in Patients with Established CV Disease or CV Risk Factors – Time to First Event Analyses Insulin Glargine N = 6,264 Standard Care N = 6,273 Insulin Glargine vs Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Coprimary endpoints CV death, nonfatal myocardial infarction, or nonfatal stroke 1041 (2.9) 1013 (2.9) 1.02 (0.94, 1.11) CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure or revascularization procedure 1792 (5.5) 1727 (5.3) 1.04 (0.97, 1.11) Components of coprimary endpoints CV death 580 576 1.00 (0.89, 1.13) Myocardial Infarction (fatal or nonfatal) 336 326 1.03 (0.88, 1.19) Stroke (fatal or nonfatal) 331 319 1.03 (0.89, 1.21) Reference ID: 5485379 21 Revascularizations 908 860 1.06 (0.96, 1.16) Hospitalization for heart failure 310 343 0.90 (0.77, 1.05) In the ORIGIN study, the overall incidence of cancer (all types combined) or death from cancer (Table 15) was similar between treatment groups. Table 15: Cancer Outcomes in ORIGIN – Time to First Event Analyses Insulin Glargine N = 6,264 Standard Care N = 6,273 Insulin Glargine vs Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Cancer endpoints Any cancer event (new or recurrent) 559 (1.56) 561 (1.56) 0.99 (0.88, 1.11) New cancer events 524 (1.46) 535 (1.49) 0.96 (0.85, 1.09) Death due to Cancer 189 (0.51) 201 (0.54) 0.94 (0.77, 1.15) 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied SEMGLEE (insulin glargine-yfgn) injection is supplied as a clear and colorless solution containing 100 units/mL (U-100) available as follows: SEMGLEE NDC Number Package Size 10 mL multiple-dose vial 83257-011-11 1 vial per carton 3 mL single-patient-use prefilled pen 83257-012-31 1 pen per carton 83257-012-32 3 pens per carton 83257-012-33 5 pens per carton Additional Information about SEMGLEE: • The SEMGLEE prefilled pen dials in 1-unit increments. • Needles are not included in the packs. BD® Ultra-Fine needles are compatible with this pen. 16.2 Storage Dispense in the original sealed carton with the enclosed Instructions for Use. Store unused SEMGLEE in a refrigerator between 2° to 8°C (36° to 46°F). Do not freeze. Discard SEMGLEE if it has been frozen. Protect SEMGLEE from direct heat and light. Reference ID: 5485379 22 Storage conditions are summarized in the following table: Not in-use (unopened) Refrigerated (2° to 8°C [36° to 46°F]) Not in-use (unopened) Room Temperature (up to 30°C [86°F]) In-use (opened) (see temperature below) 10 mL multiple- dose vial Until expiration date 28 days 28 days Refrigerated or room temperature 3 mL single­ patient-use prefilled pen Until expiration date 28 days 28 days Room temperature only (Do not refrigerate) 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). There are separate Instructions for Use for the vial and prefilled pen. Never Share a SEMGLEE Prefilled Pen or Insulin Syringe Between Patients Advise patients that they must never share a SEMGLEE prefilled pen with another person, even if the needle is changed. Advise patients using SEMGLEE vials not to re-use or share needles or insulin syringes with another person. Sharing carries a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)]. Hyperglycemia or Hypoglycemia Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia (e.g., impaired ability to concentrate and react). This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see Warnings and Precautions (5.3)]. Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.2)]. Hypoglycemia Due to Medication Errors Instruct patients to always check the insulin label before each injection to reduce the risk of a medication error [see Warnings and Precautions (5.4)]. Hypersensitivity Reactions Advise patients that hypersensitivity reactions have occurred with insulin glargine products. Inform patients about the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)]. BD is a registered trademark of Becton, Dickinson, and Company. Reference ID: 5485379 23 Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor, Cambridge, MA 02142 U.S.A U.S. License No. 2324 Product of Malaysia Reference ID: 5485379 24 PATIENT INFORMATION SEMGLEE® (Sehm-GLEE) (insulin glargine-yfgn) injection for subcutaneous use VIAL:100 units/mL (U-100) Do not share your syringes with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. What is SEMGLEE? SEMGLEE is a long-acting man-made-insulin used to control high blood sugar in adults and children with diabetes mellitus. SEMGLEE is not for use to treat diabetic ketoacidosis. Who should not use SEMGLEE? Do not use SEMGLEE if you: • are having an episode of low blood sugar (hypoglycemia). • have an allergy to insulin glargine products or any of the ingredients in SEMGLEE. See the end of this Patient Information leaflet for a complete list of ingredients in SEMGLEE. What should I tell my healthcare provider before using SEMGLEE? Before using SEMGLEE, tell your healthcare provider about all your medical conditions including if you: • have liver or kidney problems. • take other medicines, especially ones called TZDs (thiazolidinediones). • have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with SEMGLEE. • are pregnant, planning to become pregnant, or are breastfeeding. It is not known if SEMGLEE may harm your unborn baby or breastfeeding baby. Tell your healthcare provider about all the medicines you take including prescription and over­ the-counter medicines, vitamins, and herbal supplements. Before you start using SEMGLEE, talk to your healthcare provider about low blood sugar and how to manage it. How should I use SEMGLEE? • Read the detailed Instructions for Use that come with your SEMGLEE insulin. • Use SEMGLEE exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much SEMGLEE to use and when to use it. • Know the amount of SEMGLEE you use. Do not change the amount of SEMGLEE you use unless your healthcare provider tells you to. • Check your insulin label each time you give your injection to make sure you are using the correct insulin. • Do not re-use needles. Always use a new needle for each injection. Re-use of needles increases your risk of having blocked needles, which may cause you to get the wrong dose of SEMGLEE. Using a new needle for each injection lowers your risk of getting an infection. • You may take SEMGLEE at any time during the day but you must take it at the same time every day. • Only use SEMGLEE that is clear and colorless. If your SEMGLEE is cloudy or slightly colored, return it to your pharmacy for a replacement. Reference ID: 5485379 • SEMGLEE is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen). • Do not use SEMGLEE in an insulin pump or inject SEMGLEE into your vein (intravenously). • Change (rotate) injection sites within the area you chose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. o Do not use the exact same spot for each injection. o Do not inject where the skin has pits, is thickened or has lumps. o Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. • Do not mix SEMGLEE with any other type of insulin or liquid medicine. Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels. Keep SEMGLEE and all medicines out of the reach of children. Your dose of SEMGLEE may need to change because of: • a change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of the medicines you take. What should I avoid while using SEMGLEE? While using SEMGLEE do not: • drive or operate heavy machinery, until you know how SEMGLEE affects you. • drink alcohol or use over-the counter medicines that contain alcohol. What are the possible side effects of SEMGLEE and other insulins? SEMGLEE may cause serious side effects that can lead to death, including: • low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include: o dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger. • severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of a severe allergic reaction: o a rash over your whole body, trouble breathing, a fast heartbeat, or sweating. • low potassium in your blood (hypokalemia). • heart failure. Taking certain diabetes pills called TZDs (thiazolidinediones) with SEMGLEE may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with SEMGLEE. Your healthcare provider should monitor you closely while you are taking TZDs with SEMGLEE. Tell your healthcare provider if you have any new or worse symptoms of heart failure including: o shortness of breath, swelling of your ankles or feet, sudden weight gain. Treatment with TZDs and SEMGLEE may need to be changed or stopped by your healthcare provider if you have new or worse heart failure. Get emergency medical help if you have: • trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion. The most common side effects of SEMGLEE include: Reference ID: 5485379 • low blood sugar (hypoglycemia); weight gain; allergic reactions, including reactions at your injection site; skin thickening or pits at the injection site (lipodystrophy). These are not all the possible side effects of SEMGLEE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of SEMGLEE. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SEMGLEE for a condition for which it was not prescribed. Do not give SEMGLEE to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about SEMGLEE. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about SEMGLEE that is written for healthcare professionals. What are the ingredients in SEMGLEE? • Active ingredient: insulin glargine-yfgn • 10 mL vial inactive ingredients: glycerol, metacresol, polysorbate-20, zinc chloride, and Water for Injection. Hydrochloric acid and sodium hydroxide may be added to adjust the pH. For more information, call Biocon Biologics at 1-833-986-1468. Manufactured by: Biocon Biologics Inc., 245 Main St, 2nd Floor, Cambridge, MA 02142, U.S.A. U.S. License No. 2324 Product of Malaysia This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 11/2023 Reference ID: 5485379 Patient Information SEMGLEE® (Sehm-GLEE) (insulin glargine-yfgn) injection for subcutaneous use 100 units/mL (U-100) Do not share your SEMGLEE pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. What is SEMGLEE? SEMGLEE is a long-acting man-made insulin used to control high blood sugar in adults and children with diabetes mellitus. SEMGLEE is not for use to treat diabetic ketoacidosis Who should not use SEMGLEE? Do not use SEMGLEE if you: • are having an episode of low blood sugar (hypoglycemia). • have an allergy to insulin glargine products or any of the ingredients in SEMGLEE. See the end of this Patient Information leaflet for a complete list of ingredients in SEMGLEE. What should I tell my healthcare provider before using SEMGLEE? Before using SEMGLEE, tell your healthcare provider about all your medical conditions including if you: • have liver or kidney problems. • take other medicines, especially ones called TZDs (thiazolidinediones). • have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with SEMGLEE. • are pregnant, planning to become pregnant, or are breastfeeding. It is not known if SEMGLEE may harm your unborn baby or breastfeeding baby. Tell your healthcare provider about all the medicines you take including prescription and over­ the-counter medicines, vitamins, and herbal supplements. Before you start using SEMGLEE, talk to your healthcare provider about low blood sugar and how to manage it. How should I use SEMGLEE? • Read the detailed Instructions for Use that come with your SEMGLEE single-patient-use prefilled pen. • Use SEMGLEE exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much SEMGLEE to use and when to use it. • Know the amount of SEMGLEE you use. Do not change the amount of SEMGLEE you use unless your healthcare provider tells you to. • Check your insulin label each time you give your injection to make sure you are using the correct insulin. • The dose counter on your pen shows your dose of SEMGLEE. Do not make any dose changes unless your healthcare provider tells you to. • Do not use a syringe to remove SEMGLEE from your disposable prefilled pen. • Do not re-use needles. Always use a new needle for each injection. Re-use of needles increases your risk of having blocked needles, which may cause you to get the wrong dose of SEMGLEE. Using a new needle for each injection lowers your risk of getting an Reference ID: 5485379 infection. If your needle is blocked, follow the instructions in Step 3 of the Instructions for Use. • You may take SEMGLEE at any time during the day but you must take it at the same time every day. • SEMGLEE is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen). • Do not use SEMGLEE in an insulin pump or inject SEMGLEE into your vein (intravenously). • Change (rotate) your injection sites within area you chose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. o Do not use the exact same spot for each injection. o Do not inject where the skin has pits, is thickened, or has lumps. o Do not inject where skin is tender, bruised, scaly or hard, or into scars or damaged skin. • Do not mix SEMGLEE with any other type of insulin or liquid medicine. • Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels. Keep SEMGLEE and all medicines out of the reach of children. Your dose of SEMGLEE may need to change because of: • a change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of the medicines you take. What should I avoid while using SEMGLEE? While using SEMGLEE do not: • drive or operate heavy machinery, until you know how SEMGLEE affects you. • drink alcohol or use over-the-counter medicines that contain alcohol. What are the possible side effects of SEMGLEE and other insulins? SEMGLEE may cause serious side effects that can lead to death, including: • low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include: o dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger. • severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of a severe allergic reaction: o a rash over your whole body, trouble breathing, a fast heartbeat, or sweating. • low potassium in your blood (hypokalemia). • heart failure. Taking certain diabetes pills called TZDs (thiazolidinediones) with SEMGLEE may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with SEMGLEE. Your healthcare provider should monitor you closely while you are taking TZDs with SEMGLEE. Tell your healthcare provider if you have any new or worse symptoms of heart failure including: o shortness of breath, swelling of your ankles or feet, sudden weight gain. Treatment with TZDs and SEMGLEE may need to be changed or stopped by your healthcare provider if you have new or worse heart failure. Reference ID: 5485379 <$ Biocon Biologics - Get emergency medical help if you have: • trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion. The most common side effects of SEMGLEE include: • low blood sugar (hypoglycemia); weight gain; allergic reactions, including reactions at your injection site; skin thickening or pits at the injection site (lipodystrophy). These are not all the possible side effects of SEMGLEE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of SEMGLEE. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SEMGLEE for a condition for which it was not prescribed. Do not give SEMGLEE to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about SEMGLEE. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about SEMGLEE that is written for healthcare professionals. What are the ingredients in SEMGLEE? • Active ingredient: insulin glargine-yfgn • 3 mL prefilled pen inactive ingredients: glycerol, metacresol, zinc chloride and Water for Injection. Hydrochloric acid and sodium hydroxide may be added to adjust the pH. For more information, call Biocon Biologics at 1-833-986-1468. Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor, Cambridge, MA 02142, U.S.A. U.S. License No. 2324 Product of Malaysia This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 11/2023 SEMGLEE is a registered trademark of Biosimilars New Co Ltd; a Biocon Biologics Company. Copyright © 2023 Biocon Biologics Inc. All rights reserved. Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor, Cambridge, MA 02142 U.S.A. U.S. License No. 2324 Product of Malaysia Reference ID: 5485379 INSTRUCTIONS FOR USE SEMGLEE® (Sehm-GLEE) (insulin glargine-yfgn) injection, for subcutaneous use 3 mL Single-Patient-Use PREFILLED PEN: 100 units/mL (U-100) Read these Instructions for Use before you start using the SEMGLEE pen and each time you get a new SEMGLEE pen. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Do not share your SEMGLEE pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. People who are blind or have vision problems should not use the SEMGLEE prefilled pen without help from a person trained to use the SEMGLEE prefilled pen. SEMGLEE is a disposable prefilled pen used to inject SEMGLEE. Each SEMGLEE pen has 300 units of insulin which can be used for multiple injections. You can select doses from 1 to 80 units in steps of 1 unit. The pen plunger moves with each dose. The plunger will only move to the end of the cartridge when 300 units of SEMGLEE have been given. Important Information You Need to Know Before Injecting SEMGLEE: • Do not use your pen if it is damaged or if you are not sure that it is working properly. • Do not use a syringe to remove SEMGLEE from your pen. • Do not reuse needles. If you do, you might get the wrong dose of SEMGLEE or you may increase the chances of getting an infection. • Always perform a safety test (see Step 3). • Always carry a spare pen and spare needles in case they get lost or stop working. • Change (rotate) your injection sites within the area you choose for each dose (see Places to Inject). Learn to Inject • Talk with your healthcare provider about how to inject before using your pen. • Ask for help if you have problems handling the pen, for example if you have problems with your sight. • Read all these instructions before using your pen. If you do not follow all these instructions, you may get too much or too little insulin. Need Help? If you have any questions about your pen or about diabetes, ask your healthcare provider, or call Biocon Biologics at 1-833-986-1468. Extra Items You Will Need • A new sterile needle (see Step 2). • An alcohol swab. • A puncture-resistant container for used needles and pens. (See Throwing your pen away) Places to inject • Inject your insulin exactly as your healthcare provider has shown you. • Inject your insulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen). Reference ID: 5485379 Upperanns Front and--­ side of thigh ( Cartridge hOlder I . . r Pen Expiration Dose Injection body dale pooter button Rubber seal 0 I • • 1~~_-: ,.._, j Cartridge Insulin Dose Dose Typo Window selectO< Pan nelldta (not lncludad) I • Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. • Do not inject where the skin has pits, is thickened, or has lumps. • Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Get to know your pen Step 1: Check your pen Take a new pen out of the refrigerator at least 1 hour before you inject. Cold insulin is more painful to inject. 1A Check the name and expiration date on the label of your pen. • Make sure you have the correct insulin (See Figure a). Reference ID: 5485379 • • L01. »xt.WWX 8P. Y'l'll•NII -o..-70l2-'1 ,"_..,, ... i.,y, Semglee· i~suli1 g<'lrgine-y'g~ injeclioo r«Sqlt Patent Ult Olly • Do not use your pen after the expiration date (See Figure b). 1B Pull off the pen cap (See Figure c). 1C Check that the insulin is clear (See Figure d). • Do not use the pen if the insulin looks cloudy, colored or contains particles. Reference ID: 5485379 1D Wipe the rubber seal with an alcohol swab (See Figure e). If you have other injector pens: • Making sure you have the correct medicine is especially important if you have other injector pens. Step 2: Attach a new needle • Do not reuse needles. Always use a new sterile needle for each injection. This helps stop blocked needles, contamination, and infection. Only use needles that are compatible for use with SEMGLEE, such as BD Ultra Fine® 2A Take a new needle and peel off the protective seal (See Figure f). 2B Keep the needle straight and screw it onto the pen until fixed. Do not over-tighten (See Figure g). Reference ID: 5485379 Keep outer cap 2C Pull off the outer needle cap (See Figure h). Keep this for later. 2D Pull off the inner needle cap and throw away (See Figure i). Handling needles • Take care when handling needles to prevent needle-stick injury and cross-infection. Step 3: Do a safety test Always do a safety test before each injection to: • Check your pen and the needle to make sure they are working properly. • Make sure that you get the correct SEMGLEE dose. 3A Select 2 units by turning the dose selector until the dose pointer is at the 2 mark (See Figure j). 3B Press the injection button all the way in (See Figure k). When insulin comes out of the needle tip, your pen is working correctly. Reference ID: 5485379 If no insulin appears: • You may need to repeat this step up to 3 times before seeing insulin. • If no insulin comes out after the third time, the needle may be blocked. If this happens: o change the needle (see Step 6 and Step 2), o then repeat the safety test (Step 3). • Do not use your pen if there is still no insulin coming out of the needle tip. Use a new pen. • Do not use a syringe to remove insulin from your pen. If you see air bubbles: • You may see air bubbles in the insulin. This is normal, they will not harm you. Step 4: Select the dose Do not select a dose or press the injection button without a needle attached. This may damage your pen. 4A Make sure a needle is attached and the dose is set to “0” (See Figure l). 4B Turn the dose selector until the dose pointer lines up with your dose (See Figure m). • If you turn past your dose, you can turn back down. • If there are not enough units left in your pen for your dose, the dose selector will stop at the number of units left. • If you cannot select your full prescribed dose, use a new pen or inject the remaining units and use a new pen to complete your dose. Reference ID: 5485379 48 How to read the dose window Even numbers are shown in line with dose pointer (See Figure n). Odd numbers are shown as a line between even numbers (See Figure o). Units of SEMGLEE in your pen: • Your pen contains a total of 300 units of SEMGLEE. You can select doses from 1 to 80 units in steps of 1 unit. Each pen contains more than 1 dose. • You can see roughly how many units of insulin are left by looking at where the plunger is on the insulin scale. Step 5: Injecting Your SEMGLEE Dose If you find it hard to press the injection button in, do not force it as this may break your pen. See the section below for help. 5A Choose a place to inject as shown in the section Places to Inject 5B Push the needle into your skin as shown by your healthcare provider (See Figure p). Do not touch the injection button yet. Reference ID: 5485379 5C Place your thumb on the injection button. Slowly press all the way in and hold (see Figure q). Do not press hard. • Do not press at an angle. Your thumb could block the dose selector from turning. 5D Keep the injection button held in and when you see 0 in the dose window, slowly count to 10 (See Figure r). • This will make sure you get your full dose. 5E After holding and slowly counting to 10, release the injection button. Then remove the needle from your skin. If you find it hard to press the button in: • Change the needle (see Step 6 and Step 2) then do a safety test (see Step 3). • If you still find it hard to press in, get a new pen. • Do not use a syringe to remove insulin from your pen. Step 6: Remove the needle • Take care when handling needles to prevent needle-stick injury and cross-infection. • Do not put the inner needle cap back on. 6A Grip the widest part of the outer needle cap. Keep the needle straight and guide it into the outer needle cap. Then push firmly on (See Figure s). • The needle can puncture the cap if it is recapped at an angle. Reference ID: 5485379 6B Grip and squeeze the widest part of the outer needle cap. Turn your pen several times with your other hand to remove the needle (See Figure t). • Try again if the needle does not come off the first time. 6C Throw away the used needle in a puncture-resistant container (see Throwing your pen away at the end of this Instructions for Use). (See Figure u). 6D Put your pen cap back on (See Figure v). • Do not put the pen back in the refrigerator. Reference ID: 5485379 Storing the SEMGLEE Pen Before first use: • Keep new pens in the refrigerator between 36°F to 46°F (2°C to 8°C). • Do not freeze. Do not use SEMGLEE if it has been frozen. After first use: • Keep your pen at room temperature below 86°F (30°C). • Keep your pen away from heat or light. • Store your pen with the pen cap on. • Do not put your pen back in the refrigerator. • Do not store your pen with the needle attached. • Keep out of the reach of children. • Only use your pen for up to 28 days after its first use. Throw away the SEMGLEE pen you are using after 28 days, even if it still has insulin left in it. Caring for Your SEMGLEE Pen Handle your pen with care • Do not drop your pen or knock it against hard surfaces. • If you think that your pen may be damaged, do not try to fix it. Use a new one. Protect your pen from dust and dirt You can clean the outside of your pen by wiping it with a damp cloth (water only). Do not soak, wash or lubricate your pen. This may damage it. Throwing your Pen away • The used SEMGLEE pen may be thrown away in your household trash after you have removed the needle. • Put the used needle in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the used needles in your household trash. • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community Reference ID: 5485379 <$ Biocon Biologics'" guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 BD is a registered trademark of Becton, Dickinson, and Company. SEMGLEE is a registered trademark of Biosimilars New Co Ltd; a Biocon Biologics Company. Copyright © 2023 Biocon Biologics Inc. All rights reserved Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142 U.S.A U.S. License No. 2324 Product of Malaysia Reference ID: 5485379 INSTRUCTIONS FOR USE SEMGLEE® (Sehm-GLEE) (insulin glargine-yfgn) Injection, for subcutaneous use VIAL: 100 units/mL (U-100) These Instructions for Use contain information on how to inject SEMGLEE using the vial. Read these Instructions for Use before you start taking SEMGLEE and each time you get a new SEMGLEE vial. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Do not share your SEMGLEE syringes with other people even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. Supplies needed to give your injection: • a SEMGLEE 10 mL vial • a U-100 insulin syringe and needle • 2 alcohol swabs • 1 sharps container for throwing away used needles and syringes. See “Disposing of used needles and syringes” at the end of these instructions. Preparing to Inject SEMGLEE: • Wash your hands with soap and water or clean your hands with alcohol. • Check the SEMGLEE label to make sure you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin. • Check the SEMGLEE in the vial to make sure it is clear and colorless. Do not use SEMGLEE if it is colored or cloudy, or if you see particles in the solution. • Do not use SEMGLEE after the expiration date stamped on the label or 28 days after you first use it. • Always use a syringe that is marked for U-100 insulin. If you use a syringe other than a U­ 100 insulin syringe, you may get the wrong dose of SEMGLEE. Always use a new syringe and a new needle for each injection to help prevent infections and prevent blocked needles. Step 1: If you are using a new SEMGLEE vial, remove the protective cap. Do not remove the rubber stopper. Reference ID: 5485379 Step 2: Wipe the top of the vial with an alcohol swab. You do not have to shake the vial of SEMGLEE before use. Step 3: Draw air into the syringe equal to your SEMGLEE dose. Put the needle through the rubber top of the vial and push the plunger to inject the air into the vial. Step 4: Leave the syringe in the vial and turn both upside down. Hold the syringe and vial firmly in one hand. Make sure the tip of the needle is in the SEMGLEE solution. With your free hand, pull the plunger to withdraw the correct dose into the syringe. Step 5: Before you take the needle out of the vial, check the syringe for air bubbles. If bubbles are in the syringe, hold the syringe straight up and tap the side of the syringe until the bubbles float to the Reference ID: 5485379 Upper arms Front and --­ side of thigh top. Push the bubbles out with the plunger and draw insulin back in until you have the correct dose. Step 6: Remove the needle from the vial. Do not let the needle touch anything. You are now ready to inject. Injecting SEMGLEE: • Inject your SEMGLEE (with a syringe) exactly as your healthcare provider has shown you. • Inject SEMGLEE 1 time per day. Inject at any time of the day but at the same time every day. Step 7: Choose your injection site: • SEMGLEE is injected under the skin (subcutaneously) of your upper arms, thighs, or stomach area (abdomen). • Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in the skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. • Do not inject where the skin has pits, is thickened, or has lumps. • Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Reference ID: 5485379 • Wipe the skin with an alcohol swab to clean the injection site. Let the injection site dry before you inject your dose. Step 8: • Pinch the skin. • Insert the needle under the skin in the way your healthcare provider showed you. • Release the skin. • Slowly push in the plunger of the syringe all the way, making sure you have injected all the SEMGLEE. • Leave the needle in the skin for about 10 seconds. Step 9: • Pull the needle straight out of your skin. • Gently press the injection site for several seconds. Do not rub the area. • Do not recap the used needle. Recapping the needle can lead to a needle stick injury. Disposing of used needles and syringes: • Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. • If you do not have a FDA-cleared sharps container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, Reference ID: 5485379 o leak resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Storing and Disposing SEMGLEE? Unopened (not in-use) SEMGLEE vials • Store unused SEMGLEE vials in the refrigerator at 36° to 46°F (2° to 8°C). • Do not freeze SEMGLEE. • Keep SEMGLEE out of direct heat and light. • If a vial has been frozen or overheated, throw it away. • Unopened vials can be used until the expiration date on the carton and vial label if they have been stored in the refrigerator (they can be stored past 28 days in the refrigerator). • Unopened vials should be thrown away after 28 days if they are stored at room temperature. After SEMGLEE vials have been opened (in-use) • Store in-use (opened) SEMGLEE vials in a refrigerator from 36°F to 46°F (2°C to 8°C) or at room temperature below 86°F (30°C) for up to 28 days. • Do not freeze SEMGLEE. If a vial has been frozen, throw it away. • Keep SEMGLEE out of direct heat and light. • The SEMGLEE vial you are using should be thrown away after 28 days or if the expiration date has passed, even if it still has insulin left in it. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 11/2023 SEMGLEE is a registered trademark of Biosimilars New Co Ltd; a Biocon Biologics Company. Copyright © 2023 Biocon Biologics Inc. All rights reserved. Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor, Cambridge, MA 02142 U.S.A. U.S. License No. 2324 Product of Malaysia Reference ID: 5485379 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INSULIN GLARGINE-YFGN safely and effectively. See full prescribing information for INSULIN GLARGINE-YFGN . INSULIN GLARGINE-YFGN injection, for subcutaneous use Initial U.S. Approval: 2021 This product is SEMGLEE (insulin glargine-yfgn). SEMGLEE (insulin glargine-yfgn) is biosimilar* to LANTUS (insulin glargine). ----------------------------INDICATIONS AND USAGE--------------------------­ Insulin Glargine-yfgn is a long-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. (1) Limitations of Use Not recommended for the treatment of diabetic ketoacidosis. (1) ----------------------DOSAGE AND ADMINISTRATION----------------------­ • Individualize dosage based on metabolic needs, blood glucose monitoring, glycemic control, type of diabetes, and prior insulin use. (2.2) • Administer subcutaneously into the abdominal area, thigh, or deltoid once daily at any time of day, but at the same time every day. (2.1) • Do not dilute or mix with any other insulin or solution. (2.1) • Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. (2.1) • See Full Prescribing Information for the recommended starting dosage in patients with type 2 diabetes (2.3) and how to change to Insulin Glargine-yfgn from other insulins. (2.4) • Closely monitor glucose when switching to Insulin Glargine-yfgn and during initial weeks thereafter. (2.4) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ Injection: 100 units/mL (U-100) available as: • 10 mL multiple-dose vial (3) • 3 mL single-patient-use prefilled pen (3) ---------------------------CONTRAINDICATIONS---------------------------------­ • During episodes of hypoglycemia (4) • Hypersensitivity to insulin glargine products or any excipient in Insulin Glargine-yfgn (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ • Never share an Insulin Glargine-yfgn prefilled pen, insulin syringe, or needle between patients, even if the needle is changed. (5.1) • Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to a patient’s insulin regimen (e.g., insulin strength, FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions 2.2 General Dosing Instructions 2.3 Initiation of Insulin Glargine-yfgn Therapy 2.4 Switching to Insulin Glargine-yfgn from Other Insulin Therapies 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Never Share an Insulin Glargine-yfgn Prefilled Pen, Insulin Syringe, or Needle Between Patients 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen 5.3 Hypoglycemia 5.4 Hypoglycemia Due to Medication Errors 5.5 Hypersensitivity Reactions 5.6 Hypokalemia 5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. (5.2) • Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, concomitant drugs, meal pattern, physical activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness. (5.3) • Hypoglycemia due to medication errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. (5.4) • Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue Insulin Glargine-yfgn. Monitor and treat if indicated. (5.5) • Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. (5.6) • Fluid retention and heart failure with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation of TZD if heart failure occurs. (5.7) ------------------------------ADVERSE REACTIONS------------------------------­ Adverse reactions commonly associated with insulin glargine products include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Biologics at 1-833-986-1468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------­ • Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. (7) • Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. (7) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of Insulin Glargine-yfgn has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. Revised: 11/2023 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies 14.2 Clinical Studies in Adult and Pediatric Patients with Type 1 Diabetes 14.3 Clinical Studies in Adults with Type 2 Diabetes 14.4 Additional Clinical Studies in Adults with Diabetes Type 1 and Type 2 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed Reference ID: 5485379 1 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Insulin Glargine-yfgn is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. Limitations of Use Insulin Glargine-yfgn is not recommended for the treatment of diabetic ketoacidosis. 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions • Always check insulin labels before administration. This product is SEMGLEE (insulin glargine-yfgn) [see Warnings and Precautions (5.4)]. • Visually inspect Insulin Glargine-yfgn vials and prefilled pens for particulate matter and discoloration prior to administration. Only use if the solution is clear and colorless with no visible particles. • Administer Insulin Glargine-yfgn subcutaneously into the abdominal area, thigh, or deltoid, and rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6)]. • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)]. • Do not administer intravenously or via an insulin pump. • Do not dilute or mix Insulin Glargine-yfgn with any other insulin or solution. • The Insulin Glargine-yfgn prefilled pen dials in 1-unit increments. • Use the Insulin Glargine-yfgn prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose. 2.2 General Dosing Instructions • Administer Insulin Glargine-yfgn subcutaneously once daily at any time of day but at the same time every day. • Individualize and adjust the dosage of Insulin Glargine-yfgn based on the patient’s metabolic needs, blood glucose monitoring results and glycemic control goal. • Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), during acute illness, or changes in renal or hepatic function. Dosage adjustments should only be made under medical supervision with appropriate glucose monitoring [see Warnings and Precautions (5.2)]. • In patients with type 1 diabetes, Insulin Glargine-yfgn must be used concomitantly with short-acting insulin. 2.3 Initiation of Insulin Glargine-yfgn Therapy Recommended Starting Dosage in Patients with Type 1 Diabetes Reference ID: 5485379 2 The recommended starting dosage of Insulin Glargine-yfgn in patients with type 1 diabetes is approximately one-third of the total daily insulin requirements. Use short-acting, premeal insulin to satisfy the remainder of the daily insulin requirements. Recommended Starting Dosage in Patients with Type 2 Diabetes The recommended starting dosage of Insulin Glargine-yfgn in patients with type 2 diabetes who are not currently treated with insulin is 0.2 units/kg or up to 10 units once daily. 2.4 Switching to Insulin Glargine-yfgn from Other Insulin Therapies Dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to Insulin Glargine-yfgn from other insulin therapies [see Warnings and Precautions (5.3)]. When switching from: • Once-daily insulin glargine 300 units/mL to once-daily Insulin Glargine-yfgn (100 units/mL), the recommended starting Insulin Glargine-yfgn dosage is 80% of the insulin glargine 300 units/mL dosage that is being discontinued. • Once-daily NPH insulin to once-daily Insulin Glargine-yfgn, the recommended starting Insulin Glargine-yfgn dosage is the same as the dosage of NPH that is being discontinued. • Twice-daily NPH insulin to once-daily Insulin Glargine-yfgn, the recommended starting Insulin Glargine-yfgn dosage is 80% of the total NPH dosage that is being discontinued. 3 DOSAGE FORMS AND STRENGTHS Injection: 100 units/mL (U-100) a clear and colorless solution available as: • 10 mL multiple-dose vial • 3 mL single-patient-use prefilled pen 4 CONTRAINDICATIONS Insulin Glargine-yfgn is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions (5.3)] • In patients with hypersensitivity to insulin glargine products or any of the excipients in Insulin Glargine-yfgn [see Warnings and Precautions (5.5)] 5 WARNINGS AND PRECAUTIONS 5.1 Never Share an Insulin Glargine-yfgn Prefilled Pen, Insulin Syringe, or Needle Between Patients Insulin Glargine-yfgn prefilled pens must never be shared between patients, even if the needle is changed. Patients using Insulin Glargine-yfgn vials must never re-use or share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden Reference ID: 5485379 3 change in the injection site (to unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6)]. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant oral and antidiabetic products may be needed. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction associated with insulins, including insulin glargine products. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Hypoglycemia can happen suddenly, and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, using drugs that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or who experience recurrent hypoglycemia. The long-acting effect of insulin glargine products may delay recovery from hypoglycemia. Risk Factors for Hypoglycemia The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins, the glucose lowering effect time course of insulin glargine products may vary in different patients or at different times in the same patient and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2)]. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitant drugs [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)]. Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self- monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. Reference ID: 5485379 4 5.4 Hypoglycemia Due to Medication Errors Accidental mix-ups among insulin products have been reported. To avoid medication errors between Insulin Glargine-yfgn and other insulins, instruct patients to always check the insulin label before each injection [see Adverse Reactions (6.3)]. 5.5 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including insulin glargine products [see Adverse Reactions (6.1)]. If hypersensitivity reactions occur, discontinue Insulin Glargine-yfgn; treat per standard of care and monitor until symptoms and signs resolve. Insulin Glargine-yfgn is contraindicated in patients who have had hypersensitivity reactions to insulin glargine products or one of the excipients. 5.6 Hypokalemia All insulins, including insulin glargine products, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia, if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations). 5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)­ gamma agonists, can cause dose-related fluid retention, when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including Insulin Glargine-yfgn, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered. 6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: • Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen [see Warnings and Precautions (5.2)] • Hypoglycemia [see Warnings and Precautions (5.3)] • Hypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Hypokalemia [see Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. The data in Table 1 reflect the exposure of 2,327 patients with type 1 diabetes to insulin glargine or NPH in Studies A, B, C, and D [see Clinical Studies (14.2)]. The type 1 diabetes population had the following characteristics: the mean age was 39 years, 54% were male and the mean body mass index (BMI) was 25.1 kg/m2. Ninety-seven percent were White, 2% were Black or Reference ID: 5485379 5 African American and less than 1% were Asian. Approximately 3% of the patients in studies B and C were Hispanic. The data in Table 2 reflect the exposure of 1,563 patients with type 2 diabetes to insulin glargine or NPH in Studies E, F, and G [see Clinical Studies (14.3)]. The type 2 diabetes population had the following characteristics: the mean age was 59 years, 58% were male, and the mean BMI was 29.2 kg/m2. Eighty-seven percent were White, 8% were Black or African American, and 3% were Asian. Approximately 9% of patients in Study F were Hispanic. The frequencies of adverse reactions during insulin glargine clinical studies in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below (Tables 1, 2, 3, and 4). Table 1: Adverse Reactions Occurring ≥ 5% in Pooled Clinical Studies up to 28 Weeks Duration in Adults with Type 1 Diabetes Insulin Glargine, % (n = 1,257) NPH,% (n = 1,070) Upper respiratory tract infection 22.4 23.1 Infection* 9.4 10.3 Accidental injury 5.7 6.4 Headache 5.5 4.7 * Body system not specified Table 2: Adverse Reactions Occurring ≥ 5% in Pooled Clinical Studies up to 1 Year Duration in Adults with Type 2 Diabetes Insulin Glargine, % (n = 849) NPH,% (n = 714) Upper respiratory tract infection 11.4 13.3 Infection* 10.4 11.6 Retinal vascular disorder 5.8 7.4 * Body system not specified Table 3: Adverse Reactions Occurring ≥ 10% in a 5-Year Study of Adults with Type 2 Diabetes Insulin Glargine, % (n = 514) NPH,% (n = 503) Upper respiratory tract infection 29.0 33.6 Edema peripheral 20.0 22.7 Hypertension 19.6 18.9 Influenza 18.7 19.5 Sinusitis 18.5 17.9 Cataract 18.1 15.9 Bronchitis 15.2 14.1 Arthralgia 14.2 16.1 Pain in extremity 13.0 13.1 Reference ID: 5485379 6 Back pain 12.8 12.3 Cough 12.1 7.4 Urinary tract infection 10.7 10.1 Diarrhea 10.7 10.3 Depression 10.5 9.7 Headache 10.3 9.3 Table 4: Adverse Reactions Occurring ≥ 5% in a 28-Week Clinical Study in Pediatric Patients with Type 1 Diabetes Insulin Glargine, % (n = 174) NPH,% (n = 175) Infection* 13.8 17.7 Upper respiratory tract infection 13.8 16.0 Pharyngitis 7.5 8.6 Rhinitis 5.2 5.1 * Body system not specified Severe Hypoglycemia Hypoglycemia was the most commonly observed adverse reaction in patients treated with insulin glargine. Tables 5, 6, and 7 summarize the incidence of severe hypoglycemia in the insulin glargine clinical studies. Severe symptomatic hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose below 50 mg/dL (≤ 56 mg/dL in the 5-year study and ≤ 36 mg/dL in the ORIGIN study) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration. Percentages of insulin glargine-treated adult patients who experienced severe symptomatic hypoglycemia in the insulin glargine clinical studies [see Clinical Studies (14)] were comparable to percentages of NPH-treated patients for all treatment regimens (see Tables 5 and 6). In the pediatric clinical study, pediatric patients with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult studies with type 1 diabetes. Table 5: Severe Symptomatic Hypoglycemia in Patients with Type 1 Diabetes Study A Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study B Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study C Type 1 Diabetes Adults 16 weeks In combination with insulin lispro Study D Type 1 Diabetes Pediatrics 26 weeks In combination with regular insulin Insulin Glargine n = 292 NPH n = 293 Insulin Glargine n= 264 NPH n = 270 Insulin Glargine n = 310 NPH n = 309 Insulin Glargine n = 174 NPH n = 175 Percent of patients 10.6 15.0 8.7 10.4 6.5 5.2 23.0 28.6 7 Reference ID: 5485379 Table 6: Severe Symptomatic Hypoglycemia in Patients with Type 2 Diabetes Study E Type 2 Diabetes Adults 52 weeks In combination with oral agents Study F Type 2 Diabetes Adults 28 weeks In combination with regular insulin Study G Type 2 Diabetes Adults 5 years In combination with regular insulin Insulin Glargine n = 289 NPH n = 281 Insulin Glargine n = 259 NPH n = 259 Insulin Glargine n = 513 NPH n = 504 Percent of patients 1.7 1.1 0.4 2.3 7.8 11.9 Table 7 displays the proportion of patients who experienced severe symptomatic hypoglycemia in the insulin glargine and Standard Care groups in the ORIGIN study [see Clinical Studies (14)]. Table 7: Severe Symptomatic Hypoglycemia in the ORIGIN Study ORIGIN Study Median duration of follow-up: 6.2 years Insulin Glargine n = 6231 Standard Care n = 6273 Percent of patients 5.6 1.8 Peripheral Edema Some patients taking insulin glargine products have experienced sodium retention and edema, particularly if previously poor metabolic control was improved by intensified insulin therapy. Lipodystrophy Administration of insulin subcutaneously, including insulin glargine products, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients [see Dosage and Administration (2.2)]. Insulin Initiation and Intensification of Glucose Control Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Weight Gain Weight gain has occurred with insulin including insulin glargine products and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Hypersensitivity Reactions 8 Reference ID: 5485379 Local Reactions Patients taking insulin glargine experienced injection site reactions, including redness, pain, itching, urticaria, edema, and inflammation. In clinical studies in adult patients, there was a higher incidence of injection site pain in insulin glargine-treated patients (2.7%) compared to NPH insulin-treated patients (0.7%). The reports of pain at the injection site did not result in discontinuation of therapy. Systemic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occurred with insulin, including insulin glargine products and may be life threatening. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other insulin glargine products may be misleading. All insulin products can elicit the formation of insulin antibodies. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In clinical studies of insulin glargine, increases in titers of antibodies to insulin were observed in NPH insulin and insulin glargine treatment groups with similar incidences. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of insulin glargine products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Medication errors have been reported in which rapid-acting insulins and other insulins, have been accidentally administered instead of insulin glargine products. Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site. 7 DRUG INTERACTIONS Table 8 includes clinically significant drug interactions with Insulin Glargine-yfgn. Table 8: Clinically Significant Drug Interactions with Insulin Glargine-yfgn Drugs that May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase Reference ID: 5485379 9 inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors. Intervention: Dosage reductions and increased frequency of glucose monitoring may be required when Insulin Glargine-yfgn is coadministered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of Insulin Glargine-yfgn Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dosage increases and increased frequency of glucose monitoring may be required when Insulin Glargine-yfgn is coadministered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Glargine-yfgn Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dosage adjustment and increased frequency of glucose monitoring may be required when Insulin Glargine-yfgn is coadministered with these drugs. Drugs that May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine. Intervention: Increased frequency of glucose monitoring may be required when Insulin Glargine-yfgn is coadministered with these drugs. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Published studies with use of insulin glargine products during pregnancy have not reported a clear association with insulin glargine products and adverse developmental outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Rats and rabbits were exposed to insulin glargine in animal reproduction studies during organogenesis, respectively 50 times and 10 times the human subcutaneous dosage of 0.2 units/kg/day. Overall, the effects of insulin glargine did not generally differ from those observed with regular human insulin (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20% to 25% Reference ID: 5485379 10 in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal and/or Embryo-fetal Risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre­ gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Data Human Data Published data do not report a clear association with insulin glargine products and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups. Animal Data Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 50 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day (0.007 mg/kg/day), on a mg/kg basis. In rabbits, doses of 0.072 mg/kg/day, which is approximately 10 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day on a mg/kg basis, were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal. 8.2 Lactation Risk Summary There are either no or only limited data on the presence of insulin glargine products in human milk, the effects on breastfed infant, or the effects on milk production. Endogenous insulin is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Insulin Glargine-yfgn, and any potential adverse effects on the breastfed child from Insulin Glargine-yfgn or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Insulin Glargine-yfgn to improve glycemic control in pediatric patients with diabetes mellitus have been established. Use of Insulin Glargine-yfgn for this indication is supported by Insulin Glargine-yfgn’s approval as a biosimilar to insulin glargine and evidence from an adequate and well-controlled study (Study D) in 174 insulin glargine­ treated pediatric patients aged 6 to 15 years with type 1 diabetes mellitus, and from adequate and Reference ID: 5485379 11 well-controlled studies of insulin glargine in adults with diabetes mellitus [see Clinical Pharmacology (12.3), Clinical Studies (14.2)]. In the pediatric clinical study, pediatric patients with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia compared to the adults in studies with type 1 diabetes [see Adverse Reactions (6.1)]. 8.5 Geriatric Use Of the total number of subjects in controlled clinical studies of patients with type 1 and type 2 diabetes who were treated with insulin glargine, 15% (n = 316) were ≥ 65 years of age and 2% (n = 42) were ≥ 75 years of age. No overall differences in safety or effectiveness of insulin glargine have been observed between patients 65 years of age and older and younger adult patients. Nevertheless, caution should be exercised when Insulin Glargine-yfgn is administered to geriatric patients. In geriatric patients with diabetes, the initial dosing, dosage increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in geriatric patients. 8.6 Renal Impairment The effect of kidney impairment on the pharmacokinetics of insulin glargine products has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with kidney failure. Frequent glucose monitoring and dosage adjustment may be necessary for Insulin Glargine-yfgn in patients with kidney impairment [see Warnings and Precautions (5.3)]. 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of insulin glargine products has not been studied. Frequent glucose monitoring and dosage adjustment may be necessary for Insulin Glargine-yfgn in patients with hepatic impairment [see Warnings and Precautions (5.3)]. 10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6)]. Mild episodes of hypoglycemia can usually be treated with oral carbohydrates. Lowering the insulin dosage, and adjustments in meal patterns or exercise may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with glucagon for emergency use or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia must be corrected appropriately. Reference ID: 5485379 12 11 DESCRIPTION Insulin glargine-yfgn is a long-acting human insulin analog produced by recombinant DNA technology utilizing a recombinant yeast strain, Pichia pastoris. Insulin glargine-yfgn differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Insulin glargine-yfgn has a molecular weight of 6063 Da. Insulin Glargine-yfgn is a sterile, clear and colorless solution for subcutaneous use in a 10 mL multiple-dose vial and a 3 mL single-patient-use prefilled pen. Prefilled Pen and Vial: Each mL contains 100 units of insulin glargine-yfgn and the inactive ingredients: glycerol (20 mg), metacresol (2.7 mg), zinc chloride (content adjusted to provide 30 mcg zinc ion), and Water for Injection, USP. The vial also contains polysorbate 20 (20 mcg). The pH is adjusted by addition of aqueous solutions of hydrochloric acid and/or sodium hydroxide. Insulin Glargine-yfgn has a pH of approximately 4. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The primary activity of insulin, including insulin glargine products, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis. 12.2 Pharmacodynamics In clinical studies, the glucose-lowering effect on a molar basis (i.e., when given at the same doses) of intravenous insulin glargine is approximately the same as that for human insulin. Figure 1 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24 hours after subcutaneous injection of insulin glargine or NPH insulin. The median time between subcutaneous injection and the end of pharmacological effect was 14.5 hours (range: 9.5 to 19.3 hours) for NPH insulin, and 24 hours (range: 10.8 to > 24 hours) (24 hours was the end of the observation period) for insulin glargine. Figure 1: Glucose-Lowering Effect Over 24 Hours in Patients with Type 1 Diabetes Reference ID: 5485379 13 6 = 5 t t 4 i:: ,:, *~ , .. .... , \ e.: 3 \ ~ ' ' .. C: ' \ 0 ' -~ , a 2 , C: ' - ' ~ , ,,., 0 ~ 1 ::::, 5 0 0 \ \ \ .. .. \ \ ' ' 10 .. \ ' .. __ 20 --Insulin glargine (N=20) -----r PH insulin (N=20) "- End of observation period 30 Time (h) after s.c. injection * Determined as amount of glucose infused to maintain constant plasma glucose levels The duration of action after abdominal, deltoid, or thigh subcutaneous administration of insulin glargine was similar. The time course of action of insulins, including insulin glargine products, may vary between patients and within the same patient. 12.3 Pharmacokinetics Absorption After subcutaneous injection of insulin glargine in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH insulin. Elimination Metabolism A metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of human insulin, M1 (21A-Gly-insulin) and M2 (21A-Gly-des­ 30B-Thr-insulin). Unchanged drug and these degradation products are also present in the circulation. Specific Populations Age, Race, Body Mass Index, and Gender Effect of age, race, body mass index (BMI), and gender on the pharmacokinetics of insulin glargine products has not been evaluated. However, in controlled clinical studies in adults (n = 3,890) and a controlled clinical study in pediatric patients (n = 349), subgroup analyses based on age, race, BMI, and gender did not show differences in safety and efficacy between insulin glargine and NPH insulin [see Clinical Studies (14)]. Reference ID: 5485379 14 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which was for the rat approximately 65 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day (0.007 mg/kg/day) on a mg/kg basis. Histiocytomas were found at injection sites in male rats and mice in acid vehicle containing groups and are considered a response to chronic tissue irritation and inflammation in rodents. These tumors were not found in female animals, in saline control, or insulin comparator groups using a different vehicle. Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters). In a combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 50 times the recommended human subcutaneous starting dosage of 0.2 units/kg/day (0.007 mg/kg/day) maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, a reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin. 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies The safety and effectiveness of insulin glargine given once-daily at bedtime was compared to that of once-daily and twice-daily NPH insulin in open-label, randomized, active-controlled, parallel studies of 2,327 adult patients and 349 pediatric patients with type 1 diabetes mellitus and 1,563 adult patients with type 2 diabetes mellitus (see Tables 9-11). In general, the reduction in glycated hemoglobin (HbA1c) with insulin glargine was similar to that with NPH insulin. 14.2 Clinical Studies in Adult and Pediatric Patients with Type 1 Diabetes Adult Patients with Type 1 Diabetes In two clinical studies (Studies A and B), adult patients with type 1 diabetes (Study A, n = 585, Study B n = 534) were randomized to 28 weeks of basal-bolus treatment with insulin glargine or NPH insulin. Regular human insulin was administered before each meal. Insulin glargine was administered at bedtime. NPH insulin was administered either as once daily at bedtime or in the morning and at bedtime when used twice daily. In Study A, the average age was 39 years. The majority of patients were White (99%) and 56% were male. The mean BMI was approximately 24.9 kg/m2. The mean duration of diabetes was 16 years. In Study B, the average age was 39 years. The majority of patients were White (95%) and 51% were male. The mean BMI was approximately 25.8 kg/m2. The mean duration of diabetes was 17 years. Reference ID: 5485379 15 In another clinical study (Study C), patients with type 1 diabetes (n = 619) were randomized to 16 weeks of basal-bolus treatment with insulin glargine or NPH insulin. Insulin lispro was used before each meal. Insulin glargine was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 39 years. The majority of patients were White (97%) and 51% were male. The mean BMI was approximately 25.6 kg/m2. The mean duration of diabetes was 19 years. In these 3 adult studies, insulin glargine and NPH insulin had similar effects on HbA1c (Table 9) with a similar overall rate of severe symptomatic hypoglycemia [see Adverse Reactions (6.1)]. Table 9: Type 1 Diabetes Mellitus – Adults Treatment duration Treatment in combination with Study A 28 weeks Regular insulin Study B 28 weeks Regular insulin Study C 16 weeks Insulin lispro Insulin Glargine NPH Insulin Glargine NPH Insulin Glargine NPH Number of subjects treated 292 293 264 270 310 309 HbA1c Baseline HbA1c 8.0 8.0 7.7 7.7 7.6 7.7 Adjusted mean change at study end +0.2 +0.1 -0.2 -0.2 -0.1 -0.1 Treatment Difference (95% CI) +0.1 (0.0; +0.2) +0.1 (-0.1; +0.2) 0.0 (-0.1; +0.1) Basal insulin dose Baseline mean 21 23 29 29 28 28 Mean change from baseline -2 0 -4 +2 -5 +1 Total insulin dose Baseline mean 48 52 50 51 50 50 Mean change from baseline -1 0 0 +4 -3 0 Fasting blood glucose (mg/dL) Baseline mean 167 166 166 175 175 173 Adj. mean change from baseline -21 -16 -20 -17 -29 -12 Body weight (kg) Baseline mean 73.2 74.8 75.5 75.0 74.8 75.6 Mean change from baseline 0.1 -0.0 0.7 1.0 0.1 0.5 Pediatric Patients with Type 1 Diabetes In a randomized, controlled clinical study (Study D), pediatric patients (age range 6 to 15 years) with type 1 diabetes (n = 349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. Insulin glargine was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 11.7 years. The majority of patients were White (97%) and 52% were male. The mean BMI was approximately 18.9 kg/m2. The mean duration of diabetes was 5 years. Similar effects on HbA1c (Table 10) were observed in both treatment groups [see Adverse Reactions (6.1)]. Reference ID: 5485379 16 Table 10: Type 1 Diabetes Mellitus – Pediatric Patients Treatment duration Treatment in combination with Study D 28 weeks Regular insulin Insulin Glargine + Regular insulin NPH+ Regular insulin Number of subjects treated 174 175 HbA1c Baseline mean 8.5 8.8 Change from baseline (adjusted mean) +0.3 +0.3 Difference from NPH (adjusted mean) 0.0 (95% CI) (-0.2; +0.3) Basal insulin dose Baseline mean 19 19 Mean change from baseline -1 +2 Total insulin dose Baseline mean 43 43 Mean change from baseline +2 +3 Fasting blood glucose (mg/dL) Baseline mean 194 191 Mean change from baseline -23 -12 Body weight (kg) Baseline mean 45.5 44.6 Mean change from baseline 2.2 2.5 14.3 Clinical Studies in Adults with Type 2 Diabetes In a randomized, controlled clinical study (Study E) in 570 adults with type 2 diabetes, insulin glargine was evaluated for 52 weeks in combination with oral antidiabetic medications (a sulfonylurea, metformin, acarbose, or combinations of these drugs). The average age was 60 years old. The majority of patients were White (93%) and 54% were male. The mean BMI was approximately 29.1 kg/m2. The mean duration of diabetes was 10 years. Insulin glargine administered once daily at bedtime was as effective as NPH insulin administered once daily at bedtime in reducing HbA1c and fasting glucose (Table 11). The rate of severe symptomatic hypoglycemia was similar in insulin glargine and NPH insulin treated patients [see Adverse Reactions (6.1)]. In a randomized, controlled clinical study (Study F), in adult patients with type 2 diabetes not using oral antidiabetic medications (n = 518), a basal-bolus regimen of insulin glargine once daily at bedtime or NPH insulin administered once or twice daily was evaluated for 28 weeks. Regular human insulin was used before meals, as needed. The average age was 59 years. The majority of patients were White (81%) and 60% were male. The mean BMI was approximately 30.5 kg/m2. The mean duration of diabetes was 14 years. Insulin glargine had similar effectiveness as either once- or twice-daily NPH insulin in reducing HbA1c and fasting glucose (Table 11) with a similar incidence of hypoglycemia [see Adverse Reactions (6.1)]. Reference ID: 5485379 17 In a randomized, controlled clinical study (Study G), adult patients with type 2 diabetes were randomized to 5 years of treatment with once-daily insulin glargine or twice-daily NPH insulin. For patients not previously treated with insulin, the starting dosage of insulin glargine or NPH insulin was 10 units daily. Patients who were already treated with NPH insulin either continued on the same total daily NPH insulin dose or started insulin glargine at a dosage that was 80% of the total previous NPH insulin dosage. The primary endpoint for this study was a comparison of the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. HbA1c change from baseline was a secondary endpoint. Similar glycemic control in the 2 treatment groups was desired in order to not confound the interpretation of the retinal data. Patients or study personnel used an algorithm to adjust the insulin glargine and NPH insulin dosages to a target fasting plasma glucose ≤ 100 mg/dL. After the insulin glargine or NPH insulin dosage was adjusted, other antidiabetic agents, including premeal insulin were to be adjusted or added. The average age was 55 years. The majority of patients were White (85%) and 54% were male. The mean BMI was approximately 34.3 kg/m2. The mean duration of diabetes was 11 years. The insulin glargine group had a smaller mean reduction from baseline in HbA1c compared to the NPH insulin group, which may be explained by the lower daily basal insulin doses in the insulin glargine group (Table 11). The incidences of severe symptomatic hypoglycemia were similar between groups [see Adverse Reactions (6.1)]. Table 11: Type 2 Diabetes Mellitus – Adults Treatment duration Treatment in combination with Study E 52 weeks Oral agents Study F 28 weeks Regular insulin Study G 5 years Regular insulin Insulin Glargine NPH Insulin Glargine NPH Insulin Glargine NPH Number of subjects treated 289 281 259 259 513 504 HbA1c Baseline mean 9.0 8.9 8.6 8.5 8.4 8.3 Adjusted mean change from baseline -0.5 -0.4 -0.4 -0.6 -0.6 -0.8 Insulin Glargine ‒ NPH -0.1 +0.2 +0.2 95% CI for Treatment difference (-0.3; +0.1) (0.0; +0.4) (+0.1; +0.4) Basal insulin dose* Baseline mean 14 15 44.1 45.5 39 44 Mean change from baseline +12 +9 -1 +7 +23 +30 Total insulin dose* Baseline mean 14 15 64 67 48 53 Mean change from baseline +12 +9 +10 +13 +41 +40 Fasting blood glucose (mg/dL) Baseline mean 179 180 164 166 190 180 Adj. mean change from baseline -49 -46 -24 -22 -45 -44 Body weight (kg) Baseline mean 83.5 82.1 89.6 90.7 100 99 Adj. mean change from baseline 2.0 1.9 0.4 1.4 3.7 4.8 * In Study G, the baseline dose of basal or total insulin was the first available on-treatment dose prescribed during Reference ID: 5485379 18 the study (on visit month 1.5). 14.4 Additional Clinical Studies in Adults with Diabetes Type 1 and Type 2 Different Timing of Insulin Glargine Administration in Diabetes Type 1 and Diabetes Type 2 The safety and efficacy of once daily insulin glargine administered either at pre-breakfast, pre­ dinner, or at bedtime were evaluated in a randomized, controlled clinical study in adult patients with type 1 diabetes (Study H, n = 378). Patients were also treated with insulin lispro at mealtime. The average age was 41 years. All patients were White (100%) and 54% were male. The mean BMI was approximately 25.3 kg/m2. The mean duration of diabetes was 17 years. Insulin glargine administered at pre-breakfast or at pre-dinner (both once daily) resulted in similar reductions in HbA1c compared to that with bedtime administration (see Table 12). In these patients, data are available from 8-point home glucose monitoring. The maximum mean blood glucose was observed just prior to insulin glargine injection regardless of time of administration. In this study, 5% of patients in the insulin glargine-breakfast group discontinued treatment because of lack of efficacy. No patients in the other two groups (pre-dinner, bedtime) discontinued for this reason. The safety and efficacy of once daily insulin glargine administered pre-breakfast or at bedtime were also evaluated in a randomized, active-controlled clinical study (Study I, n = 697) in patients with type 2 diabetes not adequately controlled on oral antidiabetic therapy. All patients in this study also received glimepiride 3 mg daily. The average age was 61 years. The majority of patients were White (97%) and 54% were male. The mean BMI was approximately 28.7 kg/m2. The mean duration of diabetes was 10 years. Insulin glargine given before breakfast was at least as effective in lowering HbA1c as insulin glargine given at bedtime or NPH insulin given at bedtime (see Table 12). Table 12: Study of Different Times of Once Daily Insulin Glargine Dosing in Type 1 (Study H) and Type 2 (Study I) Diabetes Mellitus Treatment duration Treatment in combination with Study H 24 weeks Insulin lispro Study I 24 weeks Glimepiride Insulin Glargine Before Breakfast Insulin Glargine Before Dinner Insulin Glargine Bedtime Insulin Glargine Before Breakfast Insulin Glargine Bedtime NPH Bedtime Number of subjects treated* 112 124 128 234 226 227 HbA1c Baseline mean 7.6 7.5 7.6 9.1 9.1 9.1 Mean change from baseline -0.2 -0.1 0.0 -1.3 -1.0 -0.8 Basal insulin dose (Units) Baseline mean 22 23 21 19 20 19 19 Reference ID: 5485379 Mean change from baseline 5 2 2 11 18 18 Total insulin dose (Units) - - - NA† NA† NA† Baseline mean 52 52 49 - - - Mean change from baseline 2 3 2 - - - Body weight (kg) Baseline mean 77.1 77.8 74.5 80.7 82 81 Mean change from baseline 0.7 0.1 0.4 3.9 3.7 2.9 * Intent-to-treat †Not applicable Progression of Retinopathy Evaluation in Adults with Diabetes Type 1 and Diabetes Type 2 Insulin glargine was compared to NPH insulin in a 5-year randomized clinical study that evaluated the progression of retinopathy as assessed with fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS). Patients had type 2 diabetes (mean age 55 years) with no (86%) or mild (14%) retinopathy at baseline. Mean baseline HbA1c was 8.4%. The primary outcome was progression by 3 or more steps on the ETDRS scale at study endpoint. Patients with prespecified postbaseline eye procedures (pan­ retinal photocoagulation for proliferative or severe nonproliferative diabetic retinopathy, local photocoagulation for new vessels, and vitrectomy for diabetic retinopathy) were also considered as 3-step progressors regardless of actual change in ETDRS score from baseline. Retinopathy graders were blinded to treatment group assignment. The results for the primary endpoint are shown in Table 13 for both the per-protocol and intent- to-treat populations, and indicate similarity of insulin glargine to NPH in the progression of diabetic retinopathy as assessed by this outcome. In this study, the numbers of retinal adverse events reported for insulin glargine and NPH insulin treatment groups were similar for adult patients with type 1 and type 2 diabetes. Table 13: Number (%) of Patients with 3 or More Step Progression on ETDRS Scale at Endpoint Insulin Glargine (%) NPH (%) Difference*,† (SE) 95% CI for difference Per-protocol 53/374 (14.2%) 57/363 (15.7%) -2.0% (2.6%) -7.0% to +3.1% Intent-to-Treat 63/502 (12.5%) 71/487 (14.6%) -2.1% (2.1%) -6.3% to +2.1% * Difference = Insulin Glargine – NPH † Using a generalized linear model (SAS GENMOD) with treatment and baseline HbA1c strata (cutoff 9.0%) as the classified independent variables, and with binomial distribution and identity link function The ORIGIN Study of Major Cardiovascular Outcomes in Patients with Established CV Disease or CV Risk Factors The Outcome Reduction with Initial Glargine Intervention study (i.e., ORIGIN) was an open- label, randomized, 2-by-2, factorial design study. One intervention in ORIGIN compared the effect of insulin glargine to standard care on major adverse cardiovascular (CV) outcomes in 12,537 adults ≥ 50 years of age with: 20 Reference ID: 5485379 • Abnormal glucose levels (i.e., impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) or early type 2 diabetes mellitus and • Established CV disease or CV risk factors at baseline. The objective of the study was to demonstrate that insulin glargine use could significantly lower the risk of major CV outcomes compared to standard care. There were two coprimary composite CV endpoints: • The first coprimary endpoint was the time to first occurrence of a major adverse CV event defined as the composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. • The second coprimary endpoint was the time to the first occurrence of CV death or nonfatal myocardial infarction or nonfatal stroke or revascularization procedure or hospitalization for heart failure. Patients were randomized to either insulin glargine (N = 6,264) titrated to a goal fasting plasma glucose of ≤ 95 mg/dL or to standard care (N = 6,273). Anthropometric and disease characteristics were balanced at baseline. The mean age was 64 years and 8% of patients were 75 years of age or older. The majority of patients were male (65%). Fifty nine percent were White, 25% were Latin, 10% were Asian and 3% were Black or African American. The median baseline BMI was 29 kg/m2. Approximately 12% of patients had abnormal glucose levels (IGT and/or IFG) at baseline and 88% had type 2 diabetes. For patients with type 2 diabetes, 59% were treated with a single oral antidiabetic drug, 23% had known diabetes but were on no antidiabetic drug and 6% were newly diagnosed during the screening procedure. The mean HbA1c (SD) at baseline was 6.5% (1.0). Fifty-nine percent of the patients had a prior CV event and 39% had documented coronary artery disease or other CV risk factors. Vital status was available for 99.9% and 99.8% of patients randomized to insulin glargine and standard care respectively at end of study. The median duration of follow-up was 6.2 years (range: 8 days to 7.9 years). The mean HbA1c (SD) at the end of the study was 6.5% (1.1) and 6.8% (1.2) in the insulin glargine and standard care group respectively. The median dose of insulin glargine at end of study was 0.45 U/kg. Eighty-one percent of patients randomized to insulin glargine were using insulin glargine at end of the study. The mean change in body weight from baseline to the last treatment visit was 2.2 kg greater in the insulin glargine group than in the standard care group. Overall, the incidence of major adverse CV outcomes was similar between groups (see Table 14). All-cause mortality was also similar between groups. Table 14: Cardiovascular Outcomes in ORIGIN in Patients with Established CV Disease or CV Risk Factors – Time to First Event Analyses Insulin Glargine N = 6,264 Standard Care N = 6,273 Insulin Glargine vs Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Coprimary endpoints 21 Reference ID: 5485379 CV death, nonfatal myocardial infarction, or nonfatal stroke 1041 (2.9) 1013 (2.9) 1.02 (0.94, 1.11) CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure or revascularization procedure 1792 (5.5) 1727 (5.3) 1.04 (0.97, 1.11) Components of coprimary endpoints CV death 580 576 1.00 (0.89, 1.13) Myocardial Infarction (fatal or nonfatal) 336 326 1.03 (0.88, 1.19) Stroke (fatal or nonfatal) 331 319 1.03 (0.89, 1.21) Revascularizations 908 860 1.06 (0.96, 1.16) Hospitalization for heart failure 310 343 0.90 (0.77, 1.05) In the ORIGIN study, the overall incidence of cancer (all types combined) or death from cancer (Table 15) was similar between treatment groups. Table 15: Cancer Outcomes in ORIGIN – Time to First Event Analyses Insulin Glargine N = 6,264 Standard Care N = 6,273 Insulin Glargine vs Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Cancer endpoints Any cancer event (new or recurrent) 559 (1.56) 561 (1.56) 0.99 (0.88, 1.11) New cancer events 524 (1.46) 535 (1.49) 0.96 (0.85, 1.09) Death due to Cancer 189 (0.51) 201 (0.54) 0.94 (0.77, 1.15) 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Insulin Glargine-yfgn injection is supplied as a clear and colorless solution containing 100 units/mL (U-100) available as follows: Insulin Glargine-yfgn NDC Number Package Size 10 mL multiple-dose vial 83257-014-11 1 vial per carton 3 mL single-patient-use prefilled pen 83257-015-31 1 pen per carton 83257-015-32 5 pens per carton Additional Information about Insulin Glargine-yfgn: • The Insulin Glargine-yfgn prefilled pen dials in 1-unit increments. Reference ID: 5485379 22 • Needles are not included in the packs. BD® Ultra-Fine needles are compatible with this pen. 16.2 Storage Dispense in the original sealed carton with the enclosed Instructions for Use. Store unused Insulin Glargine-yfgn in a refrigerator between 2° to 8°C (36° to 46°F). Do not freeze. Discard Insulin Glargine-yfgn if it has been frozen. Protect Insulin Glargine-yfgn from direct heat and light. Storage conditions are summarized in the following table: Not in-use (unopened) Refrigerated (2° to 8°C [36° to 46°F]) Not in-use (unopened) Room Temperature (up to 30°C [86°F]) In-use (opened) (see temperature below) 10 mL multiple-dose vial Until expiration date 28 days 28 days Refrigerated or room temperature 3 mL single-patient­ use prefilled pen Until expiration date 28 days 28 days Room temperature only (Do not refrigerate) 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). There are separate Instructions for Use for the vial and prefilled pen. Never Share an Insulin Glargine-yfgn Prefilled Pen or Insulin Syringe Between Patients Advise patients that they must never share a Insulin Glargine-yfgn prefilled pen with another person, even if the needle is changed. Advise patients using Insulin Glargine-yfgn vials not to re­ use or share needles or insulin syringes with another person. Sharing carries a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)]. Hyperglycemia or Hypoglycemia Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia (e.g., impaired ability to concentrate and react). This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see Warnings and Precautions (5.3)]. Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.2)]. Reference ID: 5485379 23 Hypoglycemia Due to Medication Errors Instruct patients to always check the insulin label before each injection to reduce the risk of a medication error [see Warnings and Precautions (5.4)]. Hypersensitivity Reactions Advise patients that hypersensitivity reactions have occurred with insulin glargine products. Inform patients about the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)]. BD is a registered trademark of Becton, Dickinson, and Company. Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142 U.S.A U.S. License No. 2324 Product of Malaysia Reference ID: 5485379 24 PATIENT INFORMATION Insulin Glargine-yfgn (in′ su lin glar′ jeen) injection for subcutaneous use VIAL: 100 units/mL (U-100) This product is SEMGLEE (insulin glargine-yfgn). Do not share your syringes with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. What is Insulin Glargine-yfgn? Insulin Glargine-yfgn is a long-acting man-made-insulin used to control high blood sugar in adults and children with diabetes mellitus. Insulin Glargine-yfgn is not for use to treat diabetic ketoacidosis. Who should not use Insulin Glargine-yfgn? Do not use Insulin Glargine-yfgn if you: • are having an episode of low blood sugar (hypoglycemia). • have an allergy to insulin glargine products or any of the ingredients in Insulin Glargine­ yfgn. See the end of this Patient Information leaflet for a complete list of ingredients in Insulin Glargine-yfgn. What should I tell my healthcare provider before using Insulin Glargine-yfgn? Before using Insulin Glargine-yfgn, tell your healthcare provider about all your medical conditions including if you: • have liver or kidney problems. • take other medicines, especially ones called TZDs (thiazolidinediones). • have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with Insulin Glargine-yfgn. • are pregnant, planning to become pregnant, or are breastfeeding. It is not known if Insulin Glargine-yfgn may harm your unborn baby or breastfeeding baby. Tell your healthcare provider about all the medicines you take including prescription and over­ the-counter medicines, vitamins, and herbal supplements. Before you start using Insulin Glargine-yfgn, talk to your healthcare provider about low blood sugar and how to manage it. How should I use Insulin Glargine-yfgn? • Read the detailed Instructions for Use that come with your Insulin Glargine-yfgn. • Use Insulin Glargine-yfgn exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much Insulin Glargine-yfgn to use and when to use it. • Know the amount of Insulin Glargine-yfgn you use. Do not change the amount of Insulin Glargine-yfgn you use unless your healthcare provider tells you to. • Check your insulin label each time you give your injection to make sure you are using the correct insulin. • Do not re-use needles. Always use a new needle for each injection. Re-use of needles increases your risk of having blocked needles, which may cause you to get the wrong dose of Insulin Glargine-yfgn. Using a new needle for each injection lowers your risk of getting an infection. • You may take Insulin Glargine-yfgn at any time during the day but you must take it at the same time every day. Reference ID: 5485379 • Only use Insulin Glargine-yfgn that is clear and colorless. If your Insulin Glargine-yfgn is cloudy or slightly colored, return it to your pharmacy for a replacement. • Insulin Glargine-yfgn is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen). • Do not use Insulin Glargine-yfgn in an insulin pump or inject Insulin Glargine-yfgn into your vein (intravenously). • Change (rotate) injection sites within the area you chose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. o Do not use the exact same spot for each injection. o Do not inject where the skin has pits, is thickened, or has lumps. o Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. • Do not mix Insulin Glargine-yfgn with any other type of insulin or liquid medicine. • Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels. Keep Insulin Glargine-yfgn and all medicines out of the reach of children. Your dose of Insulin Glargine-yfgn may need to change because of: • a change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of the medicines you take. What should I avoid while using Insulin Glargine-yfgn? While using Insulin Glargine-yfgn do not: • drive or operate heavy machinery, until you know how Insulin Glargine-yfgn affects you. • drink alcohol or use over-the-counter medicines that contain alcohol. What are the possible side effects of Insulin Glargine-yfgn and other insulins? Insulin Glargine-yfgn may cause serious side effects that can lead to death, including: • low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include: o dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger. • severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of a severe allergic reaction: o a rash over your whole body, trouble breathing, a fast heartbeat, or sweating. • low potassium in your blood (hypokalemia). • heart failure. Taking certain diabetes pills called TZDs (thiazolidinediones) with Insulin Glargine-yfgn may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with Insulin Glargine-yfgn. Your healthcare provider should monitor you closely while you are taking TZDs with Insulin Glargine-yfgn. Tell your healthcare provider if you have any new or worse symptoms of heart failure including: o shortness of breath, swelling of your ankles or feet, sudden weight gain. Treatment with TZDs and Insulin Glargine-yfgn may need to be changed or stopped by your healthcare provider if you have new or worse heart failure. Get emergency medical help if you have: Reference ID: 5485379 • trouble breathing; shortness of breath; fast heartbeat; swelling of your face, tongue, or throat; sweating; extreme drowsiness; dizziness; confusion. The most common side effects of Insulin Glargine-yfgn include: • low blood sugar (hypoglycemia); weight gain; allergic reactions, including reactions at your injection site; skin thickening or pits at the injection site (lipodystrophy). These are not all the possible side effects of Insulin Glargine-yfgn. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Insulin Glargine-yfgn. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Insulin Glargine-yfgn for a condition for which it was not prescribed. Do not give Insulin Glargine-yfgn to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about Insulin Glargine-yfgn. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Insulin Glargine-yfgn that is written for healthcare professionals. What are the ingredients in Insulin Glargine-yfgn? • Active ingredient: insulin glargine-yfgn • 10 mL vial inactive ingredients: glycerol, metacresol, polysorbate-20, zinc chloride, and Water for Injection. Hydrochloric acid and sodium hydroxide may be added to adjust the pH. For more information, call Biocon Biologics at 1-833-986-1468 Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142 U.S.A U.S. License No. 2324 Product of Malaysia This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2023 Reference ID: 5485379 PATIENT INFORMATION Insulin Glargine-yfgn (in′ su lin glar′ jeen) injection, for subcutaneous use 100 units/mL (U-100) This product is SEMGLEE (insulin glargine-yfgn). Do not share your Insulin Glargine-yfgn pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. What is Insulin Glargine-yfgn? Insulin Glargine-yfgn is a long-acting man-made insulin used to control high blood sugar in adults and children with diabetes mellitus. Insulin Glargine-yfgn is not for use to treat diabetic ketoacidosis. Who should not use Insulin Glargine-yfgn? Do not use Insulin Glargine-yfgn if you: • are having an episode of low blood sugar (hypoglycemia). • have an allergy to insulin glargine products or any of the ingredients in Insulin Glargine­ yfgn. See the end of this Patient Information leaflet for a complete list of ingredients in Insulin Glargine-yfgn. What should I tell my healthcare provider before using Insulin Glargine-yfgn? Before using Insulin Glargine-yfgn, tell your healthcare provider about all your medical conditions including if you: • have liver or kidney problems. • take other medicines, especially ones called TZDs (thiazolidinediones). • have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with Insulin Glargine-yfgn. • are pregnant, planning to become pregnant, or are breastfeeding. It is not known if Insulin Glargine-yfgn may harm your unborn baby or breastfeeding baby. Tell your healthcare provider about all the medicines you take including prescription and over­ the-counter medicines, vitamins, and herbal supplements. Before you start using Insulin Glargine-yfgn, talk to your healthcare provider about low blood sugar and how to manage it. How should I use Insulin Glargine-yfgn? • Read the detailed Instructions for Use that come with your Insulin Glargine-yfgn single­ patient-use prefilled pen. • Use Insulin Glargine-yfgn exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much Insulin Glargine-yfgn to use and when to use it. • Know the amount of Insulin Glargine-yfgn you use. Do not change the amount of Insulin Glargine-yfgn you use unless your healthcare provider tells you to. • Check your insulin label each time you give your injection to make sure you are using the correct insulin. • The dose counter on your pen shows your dose of Insulin Glargine-yfgn. Do not make any dose changes unless your healthcare provider tells you to. • Do not use a syringe to remove Insulin Glargine-yfgn from your disposable prefilled pen. • Do not re-use needles. Always use a new needle for each injection. Re-use of needles increases your risk of having blocked needles, which may cause you to get the wrong dose Reference ID: 5485379 of Insulin Glargine-yfgn. Using a new needle for each injection lowers your risk of getting an infection. If your needle is blocked, follow the instructions in Step 3 of the Instructions for Use. • You may take Insulin Glargine-yfgn at any time during the day but you must take it at the same time every day. • Insulin Glargine-yfgn is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen). • Do not use Insulin Glargine-yfgn in an insulin pump or inject Insulin Glargine-yfgn into your vein (intravenously). • Change (rotate) your injection sites within area you chose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. o Do not use the exact same spot for each injection. o Do not inject where the skin has pits, is thickened, or has lumps. o Do not inject where skin is tender, bruised, scaly or hard, or into scars or damaged skin. • Do not mix Insulin Glargine-yfgn with any other type of insulin or liquid medicine. • Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels. Keep Insulin Glargine-yfgn and all medicines out of the reach of children. Your dose of Insulin Glargine-yfgn may need to change because of: • a change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of the medicines you take. What should I avoid while using Insulin Glargine-yfgn? While using Insulin Glargine-yfgn do not: • drive or operate heavy machinery, until you know how Insulin Glargine-yfgn affects you. • drink alcohol or use over-the-counter medicines that contain alcohol. What are the possible side effects of Insulin Glargine-yfgn and other insulins? Insulin Glargine-yfgn may cause serious side effects that can lead to death, including: • low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include: o dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger. • severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of a severe allergic reaction: o a rash over your whole body, trouble breathing, a fast heartbeat, or sweating. • low potassium in your blood (hypokalemia). • heart failure. Taking certain diabetes pills called TZDs (thiazolidinediones) with Insulin Glargine-yfgn may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with Insulin Glargine-yfgn. Your healthcare provider should monitor you closely while you are taking TZDs with Insulin Glargine-yfgn. Tell your healthcare provider if you have any new or worse symptoms of heart failure including: o shortness of breath, swelling of your ankles or feet, sudden weight gain. Reference ID: 5485379 Treatment with TZDs and Insulin Glargine-yfgn may need to be changed or stopped by your healthcare provider if you have new or worse heart failure. Get emergency medical help if you have: • trouble breathing; shortness of breath; fast heartbeat; swelling of your face, tongue, or throat; sweating; extreme drowsiness; dizziness; confusion. The most common side effects of Insulin Glargine-yfgn include: • low blood sugar (hypoglycemia); weight gain; allergic reactions, including reactions at your injection site; skin thickening or pits at the injection site (lipodystrophy). These are not all the possible side effects of Insulin Glargine-yfgn. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Insulin Glargine-yfgn. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Insulin Glargine-yfgn for a condition for which it was not prescribed. Do not give Insulin Glargine-yfgn to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about Insulin Glargine-yfgn. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Insulin Glargine-yfgn that is written for healthcare professionals. What are the ingredients in Insulin Glargine-yfgn? • Active ingredient: insulin glargine-yfgn • 3 mL prefilled pen inactive ingredients: glycerol, metacresol, zinc chloride and Water for Injection. Hydrochloric acid and sodium hydroxide may be added to adjust the pH. For more information, call Biocon Biologics at 1-833-986-1468 Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142 U.S.A U.S. License No. 2324 Product of Malaysia This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2023 Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142 U.S.A U.S. License No. 2324 Product of Malaysia ©2023 Biocon Biologics Inc. Reference ID: 5485379 INSTRUCTIONS FOR USE Insulin Glargine-yfgn (in′ su lin glar′ jeen) injection, for subcutaneous use 3 mL Single-Patient-Use PREFILLED PEN: 100 units/mL (U-100) This product is SEMGLEE (insulin glargine-yfgn). Read these Instructions for Use before you start using the Insulin Glargine-yfgn pen and each time you get a new Insulin Glargine-yfgn pen. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Do not share your Insulin Glargine-yfgn pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. People who are blind or have vision problems should not use the Insulin Glargine-yfgn prefilled pen without help from a person trained to use the Insulin Glargine-yfgn prefilled pen. Insulin Glargine-yfgn is a disposable prefilled pen used to inject Insulin Glargine-yfgn. Each Insulin Glargine-yfgn pen has 300 units of insulin which can be used for multiple injections. You can select doses from 1 to 80 units in steps of 1 unit. The pen plunger moves with each dose. The plunger will only move to the end of the cartridge when 300 units of Insulin Glargine-yfgn have been given. Important Information You Need to Know Before Injecting Insulin Glargine-yfgn: • Do not use your pen if it is damaged or if you are not sure that it is working properly. • Do not use a syringe to remove Insulin Glargine-yfgn from your pen. • Do not reuse needles. If you do, you might get the wrong dose of Insulin Glargine­ yfgn or you may increase the chances of getting an infection. • Always perform a safety test (see Step 3). • Always carry a spare pen and spare needles in case they get lost or stop working. • Change (rotate) your injection sites within the area you choose for each dose (see Places to Inject) Learn to Inject • Talk with your healthcare provider about how to inject before using your pen. • Ask for help if you have problems handling the pen, for example if you have problems with your sight. • Read all these instructions before using your pen. If you do not follow all these instructions, you may get too much or too little insulin. Reference ID: 5485379 Upperanns Front and--­ side of thigh Need Help? If you have any questions about your pen or about diabetes, ask your healthcare provider, or call Biocon Biologics at 1-833-986-1468 Extra Items You Will Need • A new sterile needle (see Step 2). • An alcohol swab. • A puncture-resistant container for used needles and pens. (See Throwing your pen away) Places to inject • Inject your insulin exactly as your healthcare provider has shown you. • Inject your insulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen). • Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. • Do not inject where the skin has pits, is thickened, or has lumps. • Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Reference ID: 5485379 Cartridge Pen Expiration Dose Injection holde, • " b~ _"j' •- p. ointer bujtton \!J ~ msulnG- I ... . .. 0 I ~--~... a 1r.aaa I Cartridge Insulin Dose Dose seal Type window setector Pen needle (not included) ( I • I Get to know your pen Step 1: Check your pen Take a new pen out of the refrigerator at least 1 hour before you inject. Cold insulin is more painful to inject. 1A Check the name and expiration date on the label of your pen. • Make sure you have the correct insulin (See Figure a). • Do not use your pen after the expiration date (See Figure b). Reference ID: 5485379 • 111Kam-O'IS-i1 , - Insulin Glargine-yfgn Injection for,,..f>M11r .-.»r1, 1B Pull off the pen cap (See Figure c). 1C Check that the insulin is clear (See Figure d). • Do not use the pen if the insulin looks cloudy, colored or contains particles. 1D Wipe the rubber seal with an alcohol swab (See Figure e). If you have other injector pens: • Making sure you have the correct medicine is especially important if you have other injector pens. Step 2: Attach a new needle • Do not reuse needles. Always use a new sterile needle for each injection. This helps stop blocked needles, contamination, and infection. Reference ID: 5485379 Only use needles that are compatible for use with Insulin Glargine-yfgn, such as BD Ultra Fine®. 2A Take a new needle and peel off the protective seal (See Figure f). 2B Keep the needle straight and screw it onto the pen until fixed. Do not over- tighten (See Figure g). 2C Pull off the outer needle cap (See Figure h). Keep this for later. Reference ID: 5485379 2D Pull off the inner needle cap and throw away (See Figure i). Handling needles • Take care when handling needles to prevent needle-stick injury and cross-infection. Step 3: Do a safety test Always do a safety test before each injection to: • Check your pen and the needle to make sure they are working properly. • Make sure that you get the correct Insulin Glargine-yfgn dose. 3A Select 2 units by turning the dose selector until the dose pointer is at the 2 mark (See Figure j). 3B Press the injection button all the way in (See Figure k). When insulin comes out of the needle tip, your pen is working correctly. Reference ID: 5485379 If no insulin appears: • You may need to repeat this step up to 3 times before seeing insulin. • If no insulin comes out after the third time, the needle may be blocked. If this happens: o change the needle (see Step 6 and Step 2), o then repeat the safety test (Step 3). • Do not use your pen if there is still no insulin coming out of the needle tip. Use a new pen. • Do not use a syringe to remove insulin from your pen. If you see air bubbles: • You may see air bubbles in the insulin. This is normal, they will not harm you. Step 4: Select the dose Do not select a dose or press the injection button without a needle attached. This may damage your pen. 4A Make sure a needle is attached and the dose is set to “0” (See Figure l). 4B Turn the dose selector until the dose pointer lines up with your dose (See Figure m). • If you turn past your dose, you can turn back down. • If there are not enough units left in your pen for your dose, the dose selector will stop at the number of units left. Reference ID: 5485379 • If you cannot select your full prescribed dose, use a new pen or inject the remaining units and use a new pen to complete your dose. How to read the dose window Even numbers are shown in line with dose pointer (See Figure n). Odd numbers are shown as a line between even numbers (See Figure o). Units of Insulin Glargine-yfgn in your pen: • Your pen contains a total of 300 units of Insulin Glargine-yfgn. You can select doses from 1 to 80 units in steps of 1 unit. Each pen contains more than 1 dose. • You can see roughly how many units of insulin are left by looking at where the plunger is on the insulin scale. Reference ID: 5485379 Step 5: Injecting Your Insulin Glargine-yfgn Dose If you find it hard to press the injection button in, do not force it as this may break your pen. See the section below for help. 5A Choose a place to inject as shown in the section “Places to Inject” 5B Push the needle into your skin as shown by your healthcare provider (See Figure p). Do not touch the injection button yet. 5C Place your thumb on the injection button. . Slowly press all the way in and hold (see Figure q). Do not press hard. • Do not press at an angle. Your thumb could block the dose selector from turning. 5D Keep the injection button held in and when you see “0” in the dose window, slowly count to 10 (See Figure r). • This will make sure you get your full dose. Reference ID: 5485379 5E After holding and slowly counting to 10, release the injection button. Then remove the needle from your skin. If you find it hard to press the button in: • Change the needle (see Step 6 and Step 2) then do a safety test (see Step 3). • If you still find it hard to press in, get a new pen. • Do not use a syringe to remove insulin from your pen. Step 6: Remove the needle • Take care when handling needles to prevent needle-stick injury and cross-infection. • Do not put the inner needle cap back on. 6A Grip the widest part of the outer needle cap. Keep the needle straight and guide it into the outer needle cap. Then push firmly on (See Figure s). • The needle can puncture the cap if it is recapped at an angle. 6B Grip and squeeze the widest part of the outer needle cap. Turn your pen several times with your other hand to remove the needle (See Figure t). • Try again if the needle does not come off the first time. Reference ID: 5485379 6C Throw away the used needle in a puncture-resistant container (see Throwing your pen away at the end of this Instructions for Use). (See Figure u). 6D Put your pen cap back on (See Figure v). • Do not put the pen back in the refrigerator. Storing the Insulin Glargine-yfgn Pen Before first use: • Keep new pens in the refrigerator between 36°F to 46°F (2°C to 8°C). • Do not freeze. Do not use Insulin Glargine-yfgn if it has been frozen. After first use: • Keep your pen at room temperature below 86°F (30°C). • Keep your pen away from heat or light. Reference ID: 5485379 • Store your pen with the pen cap on. • Do not put your pen back in the refrigerator. • Do not store your pen with the needle attached. • Keep out of the reach of children. • Only use your pen for up to 28 days after its first use. Throw away the Insulin Glargine-yfgn pen you are using after 28 days, even if it still has insulin left in it. Caring for Your Insulin Glargine-yfgn Pen Handle your pen with care • Do not drop your pen or knock it against hard surfaces. • If you think that your pen may be damaged, do not try to fix it. Use a new one. Protect your pen from dust and dirt You can clean the outside of your pen by wiping it with a damp cloth (water only). Do not soak, wash or lubricate your pen. This may damage it. Throwing your Pen away • The used Insulin Glargine-yfgn pen may be thrown away in your household trash after you have removed the needle. • Put the used needle in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the used needles in your household trash. • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Reference ID: 5485379 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142 U.S.A U.S. License No. 2324 Product of Malaysia BD is a registered trademark of Becton, Dickinson, and Company. © 2023 Biocon Biologics Inc. Reference ID: 5485379 INSTRUCTIONS FOR USE Insulin Glargine-yfgn (in′ su lin glar′ jeen) injection, for subcutaneous use VIAL: 100 units/mL (U-100) This product is SEMGLEE (insulin glargine-yfgn). These Instructions for Use contain information on how to inject Insulin Glargine-yfgn using the vial. Read these Instructions for Use before you start taking Insulin Glargine-yfgn and each time you get a new Insulin Glargine-yfgn vial. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Do not share your Insulin Glargine-yfgn syringes with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them. Supplies Needed to Give Your Injection: • an Insulin Glargine-yfgn 10 mL vial • a U-100 insulin syringe and needle • 2 alcohol swabs • 1 sharps container for throwing away used needles and syringes. See “Disposing of used needles and syringes” at the end of these instructions. Preparing to Inject Insulin Glargine-yfgn: • Wash your hands with soap and water or clean your hands with alcohol. • Check the Insulin Glargine-yfgn label to make sure you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin. • Check the Insulin Glargine-yfgn in the vial to make sure it is clear and colorless. Do not use Insulin Glargine-yfgn if it is colored or cloudy, or if you see particles in the solution. • Do not use Insulin Glargine-yfgn after the expiration date stamped on the label or 28 days after you first use it. • Always use a syringe that is marked for U-100 insulin. If you use a syringe other than a U­ 100 insulin syringe, you may get the wrong dose of Insulin Glargine-yfgn. • Always use a new syringe and a new needle for each injection to help prevent infections and prevent blocked needles. Step 1: If you are using a new Insulin Glargine-yfgn vial, remove the protective cap. Do not remove the rubber stopper. Reference ID: 5485379 Step 2: Wipe the top of the vial with an alcohol swab. You do not have to shake the vial of Insulin Glargine-yfgn before use. Step 3: Draw air into the syringe equal to your Insulin Glargine-yfgn dose. Put the needle through the rubber top of the vial and push the plunger to inject the air into the vial. Step 4: Leave the syringe in the vial and turn both upside down. Hold the syringe and vial firmly in one hand. Make sure the tip of the needle is in the Insulin Glargine-yfgn solution. With your free hand, pull the plunger to withdraw the correct dose into the syringe. Reference ID: 5485379 Step 5: Before you take the needle out of the vial, check the syringe for air bubbles. If bubbles are in the syringe, hold the syringe straight up and tap the side of the syringe until the bubbles float to the top. Push the bubbles out with the plunger and draw insulin back in until you have the correct dose. Step 6: Remove the needle from the vial. Do not let the needle touch anything. You are now ready to inject. Injecting Insulin Glargine-yfgn: • Inject your Insulin Glargine-yfgn (with a syringe) exactly as your healthcare provider has shown you. • Inject Insulin Glargine-yfgn 1 time per day. Inject at any time of the day but at the same time every day. Step 7: Choose your injection site: • Insulin Glargine-yfgn is injected under the skin (subcutaneously) of your upper arms, thighs, or stomach area (abdomen). • Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in the skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. • Do not inject where the skin has pits, is thickened, or has lumps. • Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Reference ID: 5485379 Upper arms Front and--­ side of thigh • Wipe the skin with an alcohol swab to clean the injection site. Let the injection site dry before you inject your dose. Step 8: • Pinch the skin. • Insert the needle under the skin in the way your healthcare provider showed you. • Release the skin. • Slowly push in the plunger of the syringe all the way, making sure you have injected all the Insulin Glargine-yfgn. • Leave the needle in the skin for about 10 seconds. Reference ID: 5485379 Step 9: • Pull the needle straight out of your skin. • Gently press the injection site for several seconds. Do not rub the area. • Do not recap the used needle. Recapping the needle can lead to a needle-stick injury. Disposing of Used Needles and Syringes • Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. • If you do not have a FDA-cleared sharps container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Storing and Disposing Insulin Glargine-yfgn? Unopened (not in-use) Insulin Glargine-yfgn vials • Store unused Insulin Glargine-yfgn vials in the refrigerator from 36°F to 46°F (2°C to 8°C). • Do not freeze Insulin Glargine-yfgn. • Keep Insulin Glargine-yfgn away from direct heat and light. • If a vial has been frozen or overheated, throw it away. • Unopened vials can be used until the expiration date on the carton and vial label if they have been stored in the refrigerator (they can be stored past 28 days in the refrigerator). • Unopened vials should be thrown away after 28 days if they are stored at room temperature. After Insulin Glargine-yfgn vials have been opened (in-use) • Store in-use (opened) Insulin Glargine-yfgn vials in a refrigerator from 36°F to 46°F (2°C to 8°C) or at room temperature below 86°F (30°C) for up to 28 days. • Do not freeze Insulin Glargine-yfgn. If a vial has been frozen, throw it away. • Keep Insulin Glargine-yfgn out of direct heat and light. • The Insulin Glargine-yfgn vial you are using should be thrown away after 28 days or if the expiration date has passed, even if it still has insulin left in it. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Reference ID: 5485379 Revised: 11/2023 Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142 U.S.A. U.S. License No. 2324 Product of Malaysia © 2023 Biocon Biologics Inc. Reference ID: 5485379
custom-source
2025-02-12T15:47:18.830126
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Diastat® C-IV (diazepam rectal gel) Rectal Delivery System Diastat® AcuDial™ Rectal Delivery System (diazepam rectal gel) DESCRIPTION Diazepam rectal gel rectal delivery system is a non-sterile diazepam gel provided in a prefilled, unit-dose, rectal delivery system. Diazepam rectal gel contains 5 mg/mL diazepam, benzoic acid, benzyl alcohol (1.5%), ethyl alcohol (10%), hydroxypropyl methylcellulose, propylene glycol, purified water, and sodium benzoate. Diazepam rectal gel is clear to slightly yellow and has a pH between 6.5-7.5. Diazepam, the active ingredient of diazepam rectal gel, is a benzodiazepine anticonvulsant with the chemical name 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. The structural formula is as follows: WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS • Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS). • The use of benzodiazepines, including DIASTAT, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing DIASTAT and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS). • The continued use of benzodiazepines may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although DIASTAT is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of DIASTAT may precipitate acute withdrawal reactions, which can be life-threatening. For patients using DIASTAT more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue DIASTAT (see WARNINGS). CLINICAL PHARMACOLOGY Mechanism of Action Although the precise mechanism by which diazepam exerts its antiseizure effects is unknown, animal and in vitro studies suggest that diazepam acts to suppress seizures through an interaction with γ-aminobutyric acid (GABA) receptors of the A-type (GABAA). GABA, the major inhibitory neurotransmitter in the central nervous system (CNS), acts at this receptor to open the membrane channel allowing chloride ions to flow into neurons. Entry of chloride ions causes an inhibitory potential that reduces the ability of neurons to depolarize to the threshold potential necessary to produce action potentials. Excessive depolarization of neurons is implicated in the generation and spread of seizures. It is believed that diazepam enhances the actions of GABA by causing GABA to bind more tightly to the GABAA receptor. Pharmacokinetics Pharmacokinetic information of diazepam following rectal administration was obtained from studies conducted in healthy adult subjects. No pharmacokinetic studies were conducted in pediatric patients. Therefore, information from the literature is used to define pharmacokinetic labeling in the pediatric population. Diazepam rectal gel is well absorbed following rectal administration, reaching peak plasma concentrations in 1.5 hours. The absolute bioavailability of diazepam rectal gel relative to Valium injectable is 90%. The volume of distribution of diazepam rectal gel is calculated to be approximately 1 L/kg. The mean elimination half-life of diazepam and desmethyldiazepam following administration of a 15 mg dose of diazepam rectal gel was found to be about 46 hours (CV=43%) and 71 hours (CV=37%), respectively. Both diazepam and its major active metabolite desmethyldiazepam bind extensively to plasma proteins (95-98%). FIGURE 1: Plasma Concentrations of Diazepam and Desmethyldiazepam Following DIASTAT or IV Diazepam Metabolism and Elimination: It has been reported in the literature that diazepam is extensively metabolized to one major active metabolite (desmethyldiazepam) and two minor active metabolites, 3- hydroxydiazepam (temazepam) and 3-hydroxy-N-diazepam (oxazepam) in plasma. At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam while oxazepam and temazepam are not usually detectable. The metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. The marked inter-individual variability in the clearance of diazepam reported in the literature is probably attributable to variability of CYP2C19 (which is known to exhibit genetic polymorphism; about 3-5% of Caucasians have little or no activity and are “poor metabolizers”) and CYP3A4. No inhibition was demonstrated in the presence of inhibitors selective for CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP1A2, indicating that these enzymes are not significantly involved in metabolism of diazepam. Special Populations Hepatic Impairment: No pharmacokinetic studies were conducted with diazepam rectal gel in hepatically impaired subjects. Literature review indicates that following administration of 0.1 to 0.15 mg/kg of diazepam intravenously, the half-life of diazepam was prolonged by two to five-fold in subjects with alcoholic cirrhosis (n=24) compared to age-matched control subjects (n=37) with a corresponding decrease in clearance by half: however, the exact degree of hepatic impairment in these subjects was not characterized in this literature (see PRECAUTIONS). Renal Impairment: The pharmacokinetics of diazepam have not been studied in renally impaired subjects (see PRECAUTIONS). Pediatrics: No pharmacokinetic studies were conducted with diazepam rectal gel in the pediatric population. However, literature review indicates that following IV administration (0.33 mg/kg), diazepam has a longer half-life in neonates (birth up to one month; approximately 50-95 hours) and infants (one month up to two years; about 40-50 hours), whereas it has a shorter half-life in children (two to 12 years; approximately 15-21 hours) and adolescents (12 to 16 years; about 18-20 hours) (see PRECAUTIONS). Elderly: A study of single dose IV administration of diazepam (0.1 mg/kg) indicates that the elimination half-life of diazepam increases linearly with age, ranging from about 15 hours at 18 years (healthy young adults) to about 100 hours at 95 years (healthy elderly) with a corresponding decrease in clearance of free diazepam (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Effect of Gender, Race, and Cigarette Smoking: No targeted pharmacokinetic studies have been conducted to evaluate the effect of gender, race, and cigarette smoking on the pharmacokinetics of diazepam. However, covariate analysis of a population of treated patients following administration of diazepam rectal gel, indicated that neither gender nor cigarette smoking had any effect on the pharmacokinetics of diazepam. Clinical Studies The effectiveness of diazepam rectal gel has been established in two adequate and well controlled clinical studies in children and adults exhibiting the seizure pattern described below under INDICATIONS AND USAGE. A randomized, double-blind study compared sequential doses of diazepam rectal gel and placebo in 91 patients (47 children, 44 adults) exhibiting the appropriate seizure profile. The first dose was given at the onset of an identified episode. Children were dosed again four hours after the first dose and were observed for a total of 12 hours. Adults were dosed at four and 12 hours after the first dose and were observed for a total of 24 hours. Primary outcomes for this study were seizure frequency during the period of observation and a global assessment that took into account the severity and nature of the seizures as well as their frequency. The median seizure frequency for the diazepam rectal gel treated group was zero seizures per hour, compared to a median seizure frequency of 0.3 seizures per hour for the placebo group, a difference that was statistically significant (p <0.0001). All three categories of the global assessment (seizure frequency, seizure severity, and “overall”) were also found to be statistically significant in favor of diazepam rectal gel (p < 0.0001). The following histogram displays the results for the “overall” category of the global assessment. FIGURE 2: Caregiver Overall Global Assessment of the Efficacy of DIASTAT Patients treated with diazepam rectal gel experienced prolonged time-to-next-seizure compared to placebo (p = 0.0002) as shown in the following graph. FIGURE 3: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure – First Study In addition, 62% of patients treated with diazepam rectal gel were seizure-free during the observation period compared to 20% of placebo patients. Analysis of response by gender and age revealed no substantial differences between treatment in either of these subgroups. Analysis of response by race was considered unreliable, due to the small percentage of non-Caucasians. A second double-blind study compared single doses of diazepam rectal gel and placebo in 114 patients (53 children, 61 adults). The dose was given at the onset of the identified episode and patients were observed for a total of 12 hours. The primary outcome in this study was seizure frequency. The median seizure frequency for the diazepam rectal gel-treated group was zero seizures per 12 hours, compared to a median seizure frequency of 2.0 seizures per 12 hours for the placebo group, a difference that was statistically significant (p < 0.03). Patients treated with diazepam rectal gel experienced prolonged time- to-next-seizure compared to placebo (p = 0.0072) as shown in the following graph. FIGURE 4: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure – Second Study In addition, 55% of patients treated with diazepam rectal gel were seizure-free during the observation period compared to 34% of patients receiving placebo. Overall, caregivers judged diazepam rectal gel to be more effective than placebo (p = 0.018), based on a 10 centimeter visual analog scale. In addition, investigators also evaluated the effectiveness of diazepam rectal gel and judged diazepam rectal gel to be more effective than placebo (p < 0.001). An analysis of response by gender revealed a statistically significant difference between treatments in females but not in males in this study, and the difference between the 2 genders in response to the treatments reached borderline statistical significance. Analysis of response by race was considered unreliable, due to the small percentage of non-Caucasians. INDICATIONS AND USAGE Diazepam rectal gel is intended for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 2 years of age and older. CONTRAINDICATIONS Diazepam rectal gel is contraindicated in patients with a known hypersensitivity to diazepam. Diazepam rectal gel may be used in patients with open angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow angle glaucoma. WARNINGS General Diazepam rectal gel should only be administered by caregivers who in the opinion of the prescribing physician 1) are able to distinguish the distinct cluster of seizures (and/or the events presumed to herald their onset) from the patient’s ordinary seizure activity, 2) have been instructed and judged to be competent to administer the treatment rectally, 3) understand explicitly which seizure manifestations may or may not be treated with diazepam rectal gel, and 4) are able to monitor the clinical response and recognize when that response is such that immediate professional medical evaluation is required. Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including DIASTAT and DIASTAT ACUDIAL, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe DIASTAT or DIASTAT ACUDIAL concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when DIASTAT or DIASTAT ACUDIAL is used with opioids (see PRECAUTIONS). Abuse, Misuse, and Addiction The use of benzodiazepines, including DIASTAT, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE: Abuse). Before prescribing DIASTAT and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. Use of DIASTAT, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of DIASTAT along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. Dependence and Withdrawal Reactions After Use of DIASTAT More Frequently Than Recommended For patients using DIASTAT more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue DIASTAT (a patient-specific plan should be used to taper the dose). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines may lead to clinically significant physical dependence. Although DIASTAT is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of DIASTAT, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE: Dependence). Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE: Dependence). CNS Depression Because diazepam rectal gel produces CNS depression, patients receiving this drug who are otherwise capable and qualified to do so should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery, driving a motor vehicle, or riding a bicycle until they have completely returned to their level of baseline functioning. Although diazepam rectal gel is indicated for use solely on an intermittent basis, the potential for a synergistic CNS-depressant effect when used simultaneously with alcohol or other CNS depressants must be considered by the prescribing physician, and appropriate recommendations made to the patient and/or caregiver. Prolonged CNS depression has been observed in neonates treated with diazepam. Therefore, diazepam rectal gel is not recommended for use in children under six months of age. Neonatal Sedation and Withdrawal Syndrome Use of DIASTAT late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see PRECAUTIONS: Pregnancy). Monitor neonates exposed to DIASTAT during pregnancy or labor for signs of sedation and monitor neonates exposed to DIASTAT during pregnancy for signs of withdrawal; manage these neonates accordingly. Chronic Use Diazepam rectal gel is not recommended for chronic, daily use as an anticonvulsant because of the potential for development of tolerance to diazepam. Chronic daily use of diazepam may increase the frequency and/or severity of tonic clonic seizures, requiring an increase in the dosage of standard anticonvulsant medication. In such cases, abrupt withdrawal of chronic diazepam may also be associated with a temporary increase in the frequency and/or severity of seizures. Use in Patients with Petit Mal Status Tonic status epilepticus has been precipitated in patients treated with IV diazepam for petit mal status or petit mal variant status. PRECAUTIONS Information for Patients Risks from Concomitant Use with Opioids: Inform patients and caregivers that potentially fatal additive effects may occur if DIASTAT or DIASTAT ACUDIAL is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider (see WARNINGS and PRECAUTIONS: Drug Interactions). Abuse, Misuse, and Addiction: Inform patients that the use of DIASTAT more frequently than recommended, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug (see WARNINGS: Abuse, Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE). Withdrawal Reactions: Inform patients that use of DIASTAT more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of DIASTAT may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE). Administration: Prescribers are strongly advised to take all reasonable steps to ensure that caregivers fully understand their role and obligations vis a vis the administration of diazepam rectal gel to individuals in their care. Prescribers should routinely discuss the steps in the Patient/Caregiver Package Insert (see Patient/Caregiver Insert printed at the end of the product labeling and also included in the product carton). The successful and safe use of diazepam rectal gel depends in large measure on the competence and performance of the caregiver. Prescribers should advise caregivers that they expect to be informed immediately if a patient develops any new findings which are not typical of the patient’s characteristic seizure episode. Interference With Cognitive and Motor Performance: Because benzodiazepines have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that diazepam rectal gel therapy does not affect them adversely. Pregnancy Advise pregnant females that use of DIASTAT late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy). Instruct patients to inform their healthcare provider if they are pregnant. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant while taking DIASTAT. The registry is collecting information about the safety of antiepileptic drugs during pregnancy (see PRECAUTIONS: Pregnancy). Lactation Counsel patients that diazepam, the active ingredient in DIASTAT, is present in breast milk. Instruct patients to inform their healthcare provider if they are breastfeeding or plan to breastfeed. Instruct breastfeeding patients who take DIASTAT to monitor their infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs (see PRECAUTIONS: Nursing Mothers). Concomitant Medication Although diazepam rectal gel is indicated for use solely on an intermittent basis, the potential for a synergistic CNS-depressant effect when used simultaneously with alcohol or other CNS-depressants must be considered by the prescribing physician, and appropriate recommendations made to the patient and/or caregiver. Drug Interactions There have been no clinical studies or reports in literature to evaluate the interaction of rectally administered diazepam with other drugs. As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Effect of Concomitant Use of Benzodiazepines and Opioids: The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation. Other Psychotropic Agents or Other CNS Depressants: If diazepam rectal gel is to be combined with other psychotropic agents or other CNS depressants, careful consideration should be given to the pharmacology of the agents to be employed particularly with known compounds which may potentiate the action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO inhibitors and other antidepressants. Cimetidine: The clearance of diazepam and certain other benzodiazepines can be delayed in association with cimetidine administration. The clinical significance of this is unclear. Valproate: Valproate may potentiate the CNS-depressant effects of diazepam. Effect of Other Drugs on Diazepam Metabolism: In vitro studies using human liver preparations suggest that CYP2C19 and CYP3A4 are the principal isozymes involved in the initial oxidative metabolism of diazepam. Therefore, potential interactions may occur when diazepam is given concurrently with agents that affect CYP2C19 and CYP3A4 activity. Potential inhibitors of CYP2C19 (e.g., cimetidine, quinidine, and tranylcypromine) and CYP3A4 (e.g., ketoconazole, troleandomycin, and clotrimazole) could decrease the rate of diazepam elimination, while inducers of CYP2C19 (e.g., rifampin) and CYP3A4 (e.g., carbamazepine, phenytoin, dexamethasone, and phenobarbital) could increase the rate of elimination of diazepam. Effect of Diazepam on the Metabolism of Other Drugs: There are no reports as to which isozymes could be inhibited or induced by diazepam. But, based on the fact that diazepam is a substrate for CYP2C19 and CYP3A4, it is possible that diazepam may interfere with the metabolism of drugs which are substrates for CYP2C19, (e.g. omeprazole, propranolol, and imipramine) and CYP3A4 (e.g. cyclosporine, paclitaxel, terfenadine, theophylline, and warfarin) leading to a potential drug-drug interaction. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of rectal diazepam has not been evaluated. In studies in which mice and rats were administered diazepam in the diet at a dose of 75 mg/kg/day (approximately six and 12 times, respectively, the maximum recommended human dose [MRHD=1 mg/kg/day] on a mg/m2 basis) for 80 and 104 weeks, respectively, an increased incidence of liver tumors was observed in males of both species. The data currently available are inadequate to determine the mutagenic potential of diazepam. Reproduction studies in rats showed decreases in the number of pregnancies and in the number of surviving offspring following administration of an oral dose of 100 mg/kg/day (approximately 16 times the MRHD on a mg/m2 basis) prior to and during mating and throughout gestation and lactation. No adverse effects on fertility or offspring viability were noted at a dose of 80 mg/kg/day (approximately 13 times the MRHD on a mg/m2 basis). Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as DIASTAT, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking DIASTAT enroll in the NAAED Pregnancy Registry by calling 1-888- 233-2334 or online at http://www.aedpregnancyregistry.org/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy, Clinical Considerations). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Human Data). In animal studies, administration of diazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for diazepam and other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals following prenatal or early postnatal exposure at clinically relevant doses (see Animal Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to DIASTAT during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to DIASTAT during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome). Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. Animal Data Diazepam has been shown to produce increased incidences of fetal malformations in mice and hamsters when given orally at single doses of 100 mg/kg or greater (approximately 20 times the maximum recommended adult human dose [0.4 mg/kg/day] or greater on a mg/m2 basis). Cleft palate and exencephaly are the most common and consistently reported malformations produced in these species by administration of high, maternally-toxic doses of diazepam during organogenesis. In published animal studies, administration of benzodiazepines or other drugs that enhance GABAergic neurotransmission to neonatal rats has been reported to result in widespread apoptotic neurodegeneration in the developing brain at plasma concentrations relevant for seizure control in humans. The window of vulnerability to these changes in rats (postnatal days 0-14) includes a period of brain development that takes place during the third trimester of pregnancy in humans. Nursing Mothers Risk Summary Diazepam is present in breastmilk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the effects of diazepam on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DIASTAT and any potential adverse effects on the breastfed infant from DIASTAT or from the underlying maternal condition. Clinical Considerations Infants exposed to DIASTAT through breast milk should be monitored for sedation, poor feeding and poor weight gain. Because diazepam and its metabolites may be present in human breast milk for prolonged periods of time after acute use of diazepam rectal gel, patients should be advised not to breastfeed for an appropriate period of time after receiving treatment with diazepam rectal gel. Caution in Renally Impaired Patients Metabolites of diazepam rectal gel are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function. Caution in Hepatically Impaired Patients Concomitant liver disease is known to decrease the clearance of diazepam (see CLINICAL PHARMACOLOGY: Special Populations, Hepatic Impairment). Therefore, diazepam rectal gel should be used with caution in patients with liver disease. Use in Pediatrics The controlled trials demonstrating the effectiveness of diazepam rectal gel included children two years of age and older. Clinical studies have not been conducted to establish the efficacy and safety of diazepam rectal gel in children under two years of age. Use in Patients with Compromised Respiratory Function Diazepam rectal gel should be used with caution in patients with compromised respiratory function related to a concurrent disease process (e.g., asthma, pneumonia) or neurologic damage. Use in Elderly In elderly patients diazepam rectal gel should be used with caution due to an increase in half-life with a corresponding decrease in the clearance of free diazepam. It is also recommended that the dosage be decreased to reduce the likelihood of ataxia or oversedation. ADVERSE REACTIONS Diazepam rectal gel adverse event data were collected from double-blind, placebo-controlled studies and open-label studies. The majority of adverse events were mild to moderate in severity and transient in nature. Two patients who received diazepam rectal gel died seven to 15 weeks following treatment; neither of these deaths was deemed related to diazepam rectal gel. The most frequent adverse event reported to be related to diazepam rectal gel in the two double-blind, placebo-controlled studies was somnolence (23%). Less frequent adverse events were dizziness, headache, pain, abdominal pain, nervousness, vasodilatation, diarrhea, ataxia, euphoria, incoordination, asthma, rhinitis, and rash, which occurred in approximately 2-5% of patients. Approximately 1.4% of the 573 patients who received diazepam rectal gel in clinical trials of epilepsy discontinued treatment because of an adverse event. The adverse event most frequently associated with discontinuation (occurring in three patients) was somnolence. Other adverse events most commonly associated with discontinuation and occurring in two patients were hypoventilation and rash. Adverse events occurring in one patient were asthenia, hyperkinesia, incoordination, vasodilatation and urticaria. These events were judged to be related to diazepam rectal gel. In the two domestic double-blind, placebo-controlled, parallel-group studies, the proportion of patients who discontinued treatment because of adverse events was 2% for the group treated with diazepam rectal gel, versus 2% for the placebo group. In the diazepam rectal gel group, the adverse events considered the primary reason for discontinuation were different in the two patients who discontinued treatment; one discontinued due to rash and one discontinued due to lethargy. The primary reason for discontinuation in the patients treated with placebo was lack of effect. Adverse Event Incidence in Controlled Clinical Trials Table 1 lists treatment-emergent signs and symptoms that occurred in > 1% of patients enrolled in parallel-group, placebo-controlled trials and were numerically more common in the diazepam rectal gel group. Adverse events were usually mild or moderate in intensity. The prescriber should be aware that these figures, obtained when diazepam rectal gel was added to concurrent antiepileptic drug therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied. TABLE 1: Treatment-Emergent Signs and Symptoms That Occurred in > 1% Of Patients Enrolled in Parallel-Group, Placebo-Controlled Trials and Were Numerically More Common in the Diazepam Rectal Gel Group DIASTAT Placebo Body System COSTART Term N = 101 % N = 104 % Body As A Whole Headache 5% 4% Cardiovascular Vasodilatation 2% 0% Digestive Diarrhea 4% <1% Nervous Ataxia 3% <1% Dizziness 3% 2% Euphoria 3% 0% Incoordination 3% 0% Somnolence 23% 8% Respiratory Asthma 2% 0% Skin and Appendages Rash 3% 0% Other events reported by 1% or more of patients treated in controlled trials but equally or more frequent in the placebo group than in the diazepam rectal gel group were abdominal pain, pain, nervousness, and rhinitis. Other events reported by fewer than 1% of patients were infection, anorexia, vomiting, anemia, lymphadenopathy, grand mal convulsion, hyperkinesia, cough increased, pruritus, sweating, mydriasis, and urinary tract infection. The pattern of adverse events was similar for different age, race and gender groups. Other Adverse Events Observed During All Clinical Trials Diazepam rectal gel has been administered to 573 patients with epilepsy during all clinical trials, only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below. All of the events listed below occurred in at least 1% of the 573 individuals exposed to diazepam rectal gel. All reported events are included except those already listed above, events unlikely to be drug-related, and those too general to be informative. Events are included without regard to determination of a causal relationship to diazepam. BODY AS A WHOLE: Asthenia CARDIOVASCULAR: Hypotension, vasodilatation NERVOUS: Agitation, confusion, convulsion, dysarthria, emotional lability, speech disorder, thinking abnormal, vertigo RESPIRATORY: Hiccup The following infrequent adverse events were not seen with diazepam rectal gel but have been reported previously with diazepam use: depression, slurred speech, syncope, constipation, changes in libido, urinary retention, bradycardia, cardiovascular collapse, nystagmus, urticaria, neutropenia and jaundice. Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, sleep disturbances and stimulation have been reported with diazepam; should these occur, use of diazepam rectal gel should be discontinued. To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321- 4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG ABUSE AND DEPENDENCE Controlled Substance: DIASTAT contains diazepam, a Schedule IV controlled substance. Abuse: DIASTAT is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see WARNINGS, Abuse, Misuse, and Addiction). The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol). Dependence: Physical Dependence After Use of DIASTAT More Frequently Than Recommended DIASTAT may produce physical dependence if used more frequently than recommended. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Although DIASTAT is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use (see WARNINGS, Dependence and Withdrawal Reactions). For patients using DIASTAT more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue DIASTAT (see WARNINGS, Dependence and Withdrawal Reactions). Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to DIASTAT may develop after use more frequently than recommended. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of benzodiazepines may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines. OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Abuse, Misuse, and Addiction). Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help line (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations. DOSAGE AND ADMINISTRATION (see also Patient/Caregiver Package Insert) This section is intended primarily for the prescriber; however, the prescriber should also be aware of the dosing information and directions for use provided in the patient package insert. A decision to prescribe diazepam rectal gel involves more than the diagnosis and the selection of the correct dose for the patient. First, the prescriber must be convinced from historical reports and/or personal observations that the patient exhibits the characteristic identifiable seizure cluster that can be distinguished from the patient’s usual seizure activity by the caregiver who will be responsible for administering diazepam rectal gel. Second, because diazepam rectal gel is only intended for adjunctive use, the prescriber must ensure that the patient is receiving an optimal regimen of standard anti-epileptic drug treatment and is, nevertheless, continuing to experience these characteristic episodes. Third, because a non-health professional will be obliged to identify episodes suitable for treatment, make the decision to administer treatment upon that identification, administer the drug, monitor the patient, and assess the adequacy of the response to treatment, a major component of the prescribing process involves the necessary instruction of this individual. Fourth, the prescriber and caregiver must have a common understanding of what is and is not an episode of seizures that is appropriate for treatment, the timing of administration in relation to the onset of the episode, the mechanics of administering the drug, how and what to observe following administration, and what would constitute an outcome requiring immediate and direct medical attention. Calculating Prescribed Dose The diazepam rectal gel dose should be individualized for maximum beneficial effect. The recommended dose of diazepam rectal gel is 0.2-0.5 mg/kg depending on age. See the dosing table for specific recommendations. Age (years) Recommended Dose 2 through 5 0.5 mg/kg 6 through 11 0.3 mg/kg 12 and older 0.2 mg/kg Because diazepam rectal gel is provided as unit doses of 2.5, 5, 7.5, 10, 12.5, 15, 17.5, and 20 mg, the prescribed dose is obtained by rounding upward to the next available dose. The following table provides acceptable weight ranges for each dose and age category, such that patients will receive between 90% and 180% of the calculated recommended dose. The safety of this strategy has been established in clinical trials. 2 - 5 Years 6 - 11 Years 12+ Years 0.5 mg/kg 0.3 mg/kg 0.2 mg/kg Weight Dose Weight Dose Weight Dose (kg) (mg) (kg) (mg) (kg) (mg) 6 to 10 5 10 to 16 5 14 to 25 5 11 to 15 7.5 17 to 25 7.5 26 to 37 7.5 16 to 20 10 26 to 33 10 38 to 50 10 21 to 25 12.5 34 to 41 12.5 51 to 62 12.5 26 to 30 15 42 to 50 15 63 to 75 15 31 to 35 17.5 51 to 58 17.5 76 to 87 17.5 36 to 44 20 59 to 74 20 88 to 111 20 DIASTAT® Rectal Tip Size NDC 2.5 mg Twin Pack 4.4 cm 66490-650-20 DIASTAT® ACUDIAL™ Rectal Tip Size NDC 10 mg Delivery System Twin Pack 4.4 cm 0187-0658-20 20 mg Delivery System Twin Pack 6.0 cm 0187-0659-20 Each Twin Pack contains two diazepam rectal gel delivery systems, two packets of lubricating jelly, and administration and disposal Instructions available on the bottom of the package. DIASTAT ACUDIAL is also packed with Instructions for Caregivers upon receipt from pharmacy. Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. DIASTAT® ACUDIAL™ INSTRUCTIONS FOR CAREGIVERS UPON RECEIPT FROM PHARMACY • Remove the syringe from the case. • Confirm the dose prescribed by your doctor is visible and if known, is correct. FOR EACH SYRINGE: • Confirm that the prescribed dose is visible in the dose display window. • Confirm that the green “READY” band is visible. • Return the syringe to the case. SEE PHARMACIST IF YOU HAVE ANY QUESTIONS ABOUT THESE INSTRUCTIONS. The Instructions are also available on the bottom of each drug product package. CAUTION: Federal law prohibits the transfer of this drug to any person other than the patient for whom it was prescribed. Distributed by: Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: DPT Laboratories, Ltd. San Antonio, TX 78215 USA ®/™ are trademarks of Bausch Health Companies Inc. or its affiliates. © 2023 Bausch Health Companies Inc. or its affiliates Rev. XX/2023
custom-source
2025-02-12T15:47:18.950090
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IOMERVU safely and effectively. See full prescribing information for IOMERVU. IOMERVUTM (iomeprol) injection, for intra-arterial or intravenous use Initial U.S. Approval: 2024 WARNING: RISKS ASSOCIATED WITH INTRATHECAL ADMINISTRATION Intrathecal administration, even if inadvertent, may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. IOMERVU is for intra-arterial or intravenous use only. (2.1, 5.1) ----------------------------INDICATIONS AND USAGE--------------------------­ IOMERVU is a radiographic contrast agent indicated for: Intra-arterial Procedures† (1.1) • Cerebral arteriography, including intra-arterial digital subtraction angiography (IA-DSA), in adults and pediatric patients • Visceral and peripheral arteriography and aortography, including IA-DSA, in adults and pediatric patients • Coronary arteriography and cardiac ventriculography in adults • Radiographic evaluation of cardiac chambers and related arteries in pediatric patients Intravenous Procedures† (1.2) • Computed tomography (CT) of the head and body in adults and pediatric patients • CT angiography of intracranial, visceral, and lower extremity arteries in adults and pediatric patients • Coronary CT angiography in adults and pediatric patients • CT urography in adults and pediatric patients †Specific concentrations are recommended for each type of imaging procedure. (2.2, 2.3, 2.4, 2.5) ----------------------DOSAGE AND ADMINISTRATION----------------------­ • Individualize the volume and concentration according to the specific dosing tables accounting for factors such as age, body weight, vessel size, rate of blood flow within the vessel, and structures or areas to be examined. (2.2, 2.3, 2.4, 2.5) • See full prescribing information for complete dosage and administration information. (2) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ Injection: 250 mg Iodine/mL, 300 mg Iodine/mL, 350 mg Iodine/mL, and 400 mg Iodine/mL in single-dose vials or bottles (3) -------------------------------CONTRAINDICATIONS-----------------------------­ None (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ • Hypersensitivity Reactions: Life-threatening or fatal reactions can occur. Always have emergency resuscitation equipment and trained personnel available. (5.2) • Acute Kidney Injury: Acute injury including renal failure can occur. Minimize dose and maintain adequate hydration to minimize risk. (5.3) • Cardiovascular Adverse Reactions: Hemodynamic disturbances including shock and cardiac arrest may occur during or after administration. (5.4) • Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age: Individualize thyroid function monitoring based on risk factors such as prematurity. (5.8) ------------------------------ADVERSE REACTIONS------------------------------­ Most common adverse reactions (incidence ≥0.5%) are feeling hot, headache, nausea, chest pain, back pain, and vomiting. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------USE IN SPECIFIC POPULATIONS-----------------------­ Lactation: A lactating woman may pump and discard breast milk for 10 hours after IOMERVU administration. (8.2) See 17 for PATIENT COUNSELING INFORMATION Date: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISKS ASSOCIATED WITH INTRATHECAL ADMINISTRATION 1 INDICATIONS AND USAGE 1.1 Intra-arterial Procedures 1.2 Intravenous Procedures 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information 2.2 Recommended Dosage for Intra-arterial Procedures in Adults 2.3 Recommended Dosage for Intra-arterial Procedures in Pediatric Patients 2.4 Recommended Dosage for Intravenous Procedures in Adults 2.5 Recommended Dosage for Intravenous Procedures in Pediatric Patients 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risks Associated with Intrathecal Administration 5.2 Hypersensitivity Reactions 5.3 Acute Kidney Injury 5.4 Cardiovascular Adverse Reactions 5.5 Thromboembolic Events 5.6 Extravasation and Injection Site Reactions 5.7 Thyroid Storm in Patients with Hyperthyroidism 5.8 Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age 5.9 Hypertensive Crisis in Patients with Pheochromocytoma 5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease 5.11 Severe Cutaneous Adverse Reactions 5.12 Interference with Laboratory Tests 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions 7.2 Drug-Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Intra-arterial Studies 14.2 Intravenous Studies 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 of 20 Reference ID: 5486655 FULL PRESCRIBING INFORMATION WARNING: RISKS ASSOCIATED WITH INTRATHECAL ADMINISTRATION Intrathecal administration, even if inadvertent, may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. IOMERVU is for intra-arterial or intravenous use only [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE 1.1 Intra-arterial Procedures† IOMERVU is indicated for: • Cerebral arteriography, including intra-arterial digital subtraction angiography (IA-DSA), in adults and pediatric patients • Visceral and peripheral arteriography and aortography, including IA-DSA, in adults and pediatric patients • Coronary arteriography and cardiac ventriculography in adults • Radiographic evaluation of cardiac chambers and related arteries in pediatric patients 1.2 Intravenous Procedures† IOMERVU is indicated for: • Computed tomography (CT) of the head and body in adults and pediatric patients • CT angiography of intracranial, visceral, and lower extremity arteries in adults and pediatric patients • Coronary CT angiography in adults and pediatric patients • CT urography in adults and pediatric patients †Specific concentrations of IOMERVU are recommended for each type of imaging procedure [see Dosage and Administration (2.2, 2.3, 2.4, 2.5)]. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information • IOMERVU is for intra-arterial or intravenous use only and must not be administered intrathecally [see Warnings and Precautions (5.1)]. • Specific concentrations of IOMERVU are recommended for each type of imaging procedure [see Dosage and Administration (2.2, 2.3, 2.4, 2.5)]. • Individualize the volume, concentration, and injection rate of IOMERVU within the specified ranges [see Dosage and Administration (2.2, 2.3, 2.4, 2.5)]. Consider factors such as age, body weight, vessel size, rate of blood flow within the vessel, anticipated pathology, 2 of 20 Reference ID: 5486655 degree and extent of opacification required, structures or area to be examined, disease processes affecting the patient, and equipment and technique to be employed. • Hydrate patients before and after IOMERVU administration [see Warnings and Precautions (5.3)]. • Use aseptic technique for all handling and administration of IOMERVU. • IOMERVU may be administered at either body temperature (37°C, 98.6°F) or room temperature (20°C to 25°C, 68°F to 77°F). • Visually inspect IOMERVU for particulate matter or discoloration before administration, whenever the solution and container permit. Do not administer IOMERVU if particulate matter or discoloration is observed. • Do not mix IOMERVU with, or inject in intravenous lines containing, other drugs or total nutritional admixtures. • Each single-dose container of IOMERVU injection is intended for one procedure only. Discard any unused portion. 2.2 Recommended Dosage for Intra-arterial Procedures in Adults • Recommended doses of IOMERVU in adults for intra-arterial procedures are shown in Table 1. • Inject at rates approximately equal to the flow rate in the vessel being injected. 3 of 20 Reference ID: 5486655 Table 1. Recommended Concentrations and Volumes of IOMERVU to Administer per Single Injection into Selected Arteries for Intra-arterial Procedures in Adults Imaging Procedure Concentration (mg Iodine/mL) Volume (mL) Maximum Total Dose (mL) Cerebral arteriography 300 • Carotid, subclavian, and vertebral arteries: 6 mL to 12 mL • Aortic arch: 30 mL to 50 mL 200 mL Visceral and peripheral arteriography; aortography 300 • Aortography: 30 mL to 70 mL • Renal arteries: 10 mL to 12 mL • Other major branches of aorta: 20 mL to 60 mL 200 mL Intra-arterial digital subtraction angiography 300 • Carotid, subclavian, and vertebral arteries: 4 mL to 12 mL • Aortic arch: 20 mL to 25 mL • Aortography: 15 mL to 40 mL • Renal arteries: 6 mL to 16 mL • Other major branches of aorta: 10 mL to 40 mL • Ilio-femoral runoff: 8 mL to 40 mL 200 mL Coronary arteriography and cardiac ventriculography 300 • Coronary arteries: 3 mL to 7 mL • Cardiac ventriculography: 30 mL to 45 mL 286 mL 350 245 mL 400 215 mL 4 of 20 Reference ID: 5486655 2.3 Recommended Dosage for Intra-arterial Procedures in Pediatric Patients • Recommended doses of IOMERVU in pediatric patients for intra-arterial procedures are shown in Table 2. • Inject at rates approximately equal to the flow rate in the vessel being injected. Table 2. Recommended Concentrations and Volumes per Body Weight of IOMERVU to Administer per Single Injection for Intra-arterial Procedures in Pediatric Patients Imaging Procedure Concentration (mg Iodine/mL) Volume (mL/kg body weight) Maximum Total Dose (mL/kg) Cerebral arteriography 300 0.5 mL/kg to 2 mL/kg • 5 mL/kg • Do not exceed adult maximum dose (see Table 1) Visceral and peripheral arteriography; aortography 300 0.5 mL/kg to 2 mL/kg Intra-arterial digital subtraction angiography 300 0.3 mL/kg to 1 mL/kg Radiographic evaluation of cardiac chambers and related arteries 300, 350, or 400 0.5 mL/kg to 2 mL/kg 2.4 Recommended Dosage for Intravenous Procedures in Adults Recommended doses of IOMERVU in adults for intravenous procedures are shown in Table 3. Table 3. Recommended Concentrations, Volumes, and Injection Rates of IOMERVU for Intravenous Procedures in Adults Imaging Procedure Concentration (mg Iodine/mL) Volume (mL) Injection Rate3 (mL/s) CT of Head and Body 250 or 300 100 mL to 190 mL 2 mL/s to 4 mL/s 350 or 400 75 mL to 150 mL CT Angiography1 300, 350, or 400 80 mL to 130 mL 4 mL/s to 6 mL/s Coronary CT Angiography1 400 50 mL to 90 mL 4 mL/s to 6 mL/s CT Urography2 350 90 mL to 120 mL 2.5 mL/s 1 The IOMERVU volume may be immediately followed by a 40 mL to 50 mL 0.9% sodium chloride injection flush at the same flow rate as the contrast volume. 2 The IOMERVU volume may be administered either as a single bolus, or for dual-phase protocols as divided doses. 3 The injection rate of IOMERVU should be determined according to the clinical indication and the location, size, and type of the intravenous access. 5 of 20 Reference ID: 5486655 2.5 Recommended Dosage for Intravenous Procedures in Pediatric Patients Recommended doses of IOMERVU in pediatric patients for intravenous procedures are shown in Table 4. Table 4. Recommended Concentrations, Volumes per Body Weight, and Injection Rates of IOMERVU for Intravenous Procedures in Pediatric Patients Imaging Procedure Concentration (mg Iodine/mL) Volume (mL/kg body weight) Injection Rate (mL/s)* CT of Head and Body 250 or 300 1.5 mL/kg to 2.5 mL/kg 1 mL/s to 2 mL/s 350 or 400 1 mL/kg to 2 mL/kg CT Angiography 300, 350, or 400 1 mL/kg to 2 mL/kg 2 mL/s to 3 mL/s Coronary CT Angiography 300 or 400 1 mL/kg to 2 mL/kg 2 mL/s to 3 mL/s CT Urography 300 1 mL/kg to 2 mL/kg 1 mL/s to 2 mL/s * The injection rate of IOMERVU should be determined according to the clinical indication and the location, size, and type of the intravenous access. In neonates and patients <15 kg in whom a 24-gauge angiocatheter is the only option, an injection rate of 1 mL/s is recommended. 3 DOSAGE FORMS AND STRENGTHS Injection: clear, colorless to pale yellow solution available in the following iodine concentrations and configurations: Concentration (mg Iodine/mL) Package Size Package Type 250 100 mL Single-dose bottles 300 50 mL Single-dose vials 100 mL, 150 mL, and 200 mL Single-dose bottles 350 50 mL Single-dose vials 100 mL, 150 mL, and 200 mL Single-dose bottles 400 50 mL Single-dose vials 100 mL, 150 mL, and 200 mL Single-dose bottles 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Risks Associated with Intrathecal Administration IOMERVU is for intra-arterial or intravenous use only and must not be administered intrathecally [see Dosage and Administration (2.1)]. Intrathecal administration, even if inadvertent, can cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. 6 of 20 Reference ID: 5486655 5.2 Hypersensitivity Reactions IOMERVU can cause life-threatening or fatal hypersensitivity reactions including anaphylaxis. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock [see Adverse Reactions (6.2)]. Most severe reactions develop shortly after the start of injection (e.g., within 1 to 3 minutes), but delayed reactions can occur. There is an increased risk in patients with a history of a previous reaction to contrast agents, and known allergic disorders (i.e., bronchial asthma, drug, or food allergies) or other hypersensitivities. Premedication with antihistamines or corticosteroids to minimize possible allergic reactions does not prevent serious life-threatening reactions, but may reduce their incidence and severity. Obtain a history of allergy, hypersensitivity, and hypersensitivity reactions to iodinated contrast agents. Always have emergency resuscitation equipment and trained personnel available before use of IOMERVU. Monitor all patients for hypersensitivity reactions. 5.3 Acute Kidney Injury Acute kidney injury, including renal failure, may occur after IOMERVU administration. Risk factors include pre-existing renal impairment, dehydration, diabetes mellitus, heart failure, advanced vascular disease, advanced age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma or other paraproteinemia, and repetitive or large doses of IOMERVU. Use the lowest necessary dose of IOMERVU in patients with renal impairment. Adequately hydrate patients prior to and following IOMERVU administration. Do not use laxatives, diuretics, or preparatory dehydration prior to IOMERVU administration. 5.4 Cardiovascular Adverse Reactions IOMERVU increases the circulatory osmotic load and may induce acute or delayed hemodynamic disturbances in patients with heart failure, severely impaired renal function, combined renal and hepatic disease, or combined renal and cardiac disease, particularly when repetitive or large doses are administered. Life-threatening or fatal cardiovascular reactions including hypotension, shock, and cardiac arrest have occurred with the use of IOMERVU. Most deaths occur within 10 minutes of injection, with cardiovascular disease as the main underlying factor. Cardiac decompensation, serious arrhythmias, and myocardial ischemia or infarction can occur during coronary arteriography and ventriculography. Based upon literature reports, deaths from the administration of iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Use the lowest necessary dose of IOMERVU in patients with heart failure and always have emergency resuscitation equipment and trained personnel available. Monitor all patients for severe cardiovascular reactions. 5.5 Thromboembolic Events Serious, in some cases fatal, thromboembolic events including myocardial infarction and stroke can occur during angiographic procedures with iodinated contrast agents including IOMERVU. During these procedures, increased thrombosis and activation of the complement system can occur. Risk factors for developing thromboembolic events include length of procedure, catheter and syringe material, underlying disease state, and concomitant medications. 7 of 20 Reference ID: 5486655 To reduce risk of thromboembolic events, use meticulous angiographic techniques and minimize the length of the procedure. Avoid blood remaining in contact with syringes containing IOMERVU, which increases the risk of clotting. Avoid angiocardiography in patients with homocystinuria because of the risk of inducing thrombosis and embolism. 5.6 Extravasation and Injection Site Reactions Extravasation can occur with IOMERVU administration, particularly in patients with severe arterial or venous disease. Inflammation, blistering, skin necrosis, and compartment syndrome have been reported following extravasation. In addition, injection site reactions such as pain and swelling at the injection site can also occur [see Adverse Reactions (6.1, 6.2)]. Ensure intravascular placement of catheters prior to injection. Monitor patients for extravasation and advise patients to seek medical care for progression of symptoms. 5.7 Thyroid Storm in Patients with Hyperthyroidism Thyroid storm has occurred after the intravascular use of iodinated contrast agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of IOMERVU. 5.8 Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age Thyroid dysfunction characterized by hypothyroidism or transient thyroid suppression has been reported after both single exposure and multiple exposures to iodinated contrast agents in pediatric patients 0 years to 3 years of age. Younger age, very low birth weight, prematurity, underlying medical conditions affecting thyroid function, admission to neonatal or pediatric intensive care units, and congenital cardiac conditions are associated with an increased risk of hypothyroidism after iodinated contrast agent exposure. Pediatric patients with congenital cardiac conditions may be at greatest risk given that they often require high doses of contrast during invasive cardiac procedures. An underactive thyroid during early life may be harmful for cognitive and neurological development and may require thyroid hormone replacement therapy. After exposure to IOMERVU, individualize thyroid function monitoring based on underlying risk factors, especially in term and preterm neonates. 5.9 Hypertensive Crisis in Patients with Pheochromocytoma Hypertensive crisis has occurred after the use of iodinated contrast agents in patients with pheochromocytoma. Closely monitor patients when administering IOMERVU if pheochromocytoma or catecholamine-secreting paragangliomas are suspected. Inject the minimum amount of IOMERVU necessary, assess blood pressure throughout the procedure, and have measures for treatment of a hypertensive crisis readily available. 5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease Iodinated contrast agents when administered intravascularly may promote sickling in individuals who are homozygous for sickle cell disease. Hydrate patients prior to and following IOMERVU 8 of 20 Reference ID: 5486655 administration and use IOMERVU only if the necessary imaging information cannot be obtained with alternative imaging modalities. 5.11 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR) may develop from 1 hour to several weeks after intravascular contrast agent administration. These reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). Reaction severity may increase and time to onset may decrease with repeat administration of a contrast agent; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering IOMERVU to patients with a history of a severe cutaneous adverse reaction to IOMERVU. 5.12 Interference with Laboratory Tests IOMERVU can interfere with protein-bound iodine tests [see Drug Interactions (7.2)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Risks Associated with Intrathecal Administration [see Warnings and Precautions (5.1)] • Hypersensitivity Reactions [see Warnings and Precautions (5.2)] • Acute Kidney Injury [see Warnings and Precautions (5.3)] • Cardiovascular Adverse Reactions [see Warnings and Precautions (5.4)] • Thromboembolic Events [see Warnings and Precautions (5.5)] • Extravasation and Injection Site Reactions [see Warnings and Precautions (5.6)] • Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age [see Warnings and Precautions (5.8)] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adult Patients The safety of IOMERVU was evaluated in 4,621 adult patients who received 1,500 mg to 86,000 mg iodine doses of IOMERVU intra-arterially or intravenously in clinical trials. The average age was 60 years (range 18 years to 99 years), and 34% were female. The racial and ethnic distribution was 83% White, 10% Asian, 1% Black, 1% Hispanic, and 5% patients of other or unspecified groups. Table 5 provides a summary of the adverse reactions reported in ≥0.5% of adult patients. 9 of 20 Reference ID: 5486655 Table 5: Adverse Reactions Reported in ≥0.5% of 4,621 Adult Patients Receiving Intra-arterial or Intravenous Administration of IOMERVU in Clinical Trials Adverse Reaction Incidence (%) Feeling hot 2 Headache 1.2 Nausea 1 Chest pain 0.6 Back pain 0.5 Vomiting 0.5 The following adverse reactions were observed in <0.5% of the adult patients receiving IOMERVU: Blood and lymphatic system disorders: activated partial thromboplastin time prolonged, prothrombin time prolonged Cardiovascular disorders: ventricular fibrillation, hypertensive crisis, coronary arteriospasm, congestive cardiac failure, cardiac flutter, atrioventricular block, right bundle branch block, hypotension, arrhythmia, bradycardia, supraventricular extrasystoles, ventricular extrasystoles, increased blood pressure, flushing Ear and labyrinth disorders: vertigo, ear discomfort Eye disorder: vision blurred, periorbital edema, photopsia Gastrointestinal: esophageal varices hemorrhage, abdominal pain, abdominal distension, alanine aminotransferase (ALT) increased, constipation, diarrhea, dry mouth, salivary hypersecretion, oral paresthesia General disorders: pain, injection site reactions (pain, discomfort, or warmth), peripheral edema, chills, asthenia, malaise Musculoskeletal and connective tissue disorders: arthralgia, pain in jaw Nervous system disorders: cerebrovascular disorder, dysarthria, visual field defect, burning sensation, presyncope, dizziness, dysgeusia, paresthesia Psychiatric disorders: delirium, anxiety, insomnia Renal and urinary disorders: acute kidney injury, increased blood creatinine, urinary urgency Respiratory, thoracic, and mediastinal disorders: respiratory arrest, pulmonary edema, bronchospasm, dyspnea, cough, rhinitis, throat irritation or tightness, sneezing Skin and subcutaneous tissue disorders: urticaria, blister, purpura, ecchymosis, rash, pruritus, erythema Adverse Reactions in Pediatric Patients The safety of IOMERVU was evaluated in 184 pediatric patients who received 1,800 mg to 76,000 mg iodine doses of IOMERVU intra-arterially or intravenously in clinical trials. The average age was 6 years (range 11 days to 17 years), and 47% were female. The racial distribution was 98% White, 1% Black, and 1% patients of other or unspecified groups. The overall character, quality, and severity of adverse reactions reported in pediatric patients were similar to those reported in adult patients. 10 of 20 Reference ID: 5486655 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of IOMERVU outside the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: thrombocytopenia, leukopenia, leukocytosis Cardiovascular disorders: cardio-respiratory arrest, circulatory collapse or shock, myocardial infarction, atrial fibrillation, cyanosis, pallor Endocrine disorders: hyperthyroidism, hypothyroidism Eye disorders: transient blindness, conjunctivitis, increased lacrimation Gastrointestinal disorders: salivary gland enlargement, increased aspartate aminotransferase (AST), dysphagia General disorders and administration site conditions: injection site swelling (usually due to extravasation) Immune system disorders: hypersensitivity reactions including fatal anaphylaxis Nervous system disorders: coma, loss of consciousness, encephalopathy, transient ischemic attack, paralysis, convulsion, syncope, amnesia, somnolence Psychiatric disorders: confusional state Respiratory, thoracic, and mediastinal disorders: acute respiratory distress syndrome (ARDS), laryngeal edema, pharyngeal edema, dysphonia Skin and subcutaneous tissue disorders: severe reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS)) and mild reactions (rash, erythema, pruritus, urticaria, and skin discoloration) 7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions Metformin Stop metformin at the time of, or prior to, IOMERVU administration in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast agents. Re­ evaluate eGFR 48 hours after the imaging procedure, and reinstitute metformin only after renal function is stable. Metformin can cause lactic acidosis in patients with renal impairment. Iodinated contrast agents appear to increase the risk of metformin-induced lactic acidosis, possibly as a result of worsening renal function. 11 of 20 Reference ID: 5486655 Radioactive Iodine Avoid thyroid therapy or testing using radioactive iodine for up to 6 weeks post IOMERVU. Administration of IOMERVU may interfere with thyroid uptake of radioactive iodine (I-131 and I­ 123) and decrease therapeutic and diagnostic efficacy. 7.2 Drug-Laboratory Test Interactions Protein-Bound Iodine Test Do not perform a protein-bound iodine test for at least 16 days following administration of IOMERVU. Iodinated contrast agents, including IOMERVU, will temporarily increase protein-bound iodine in blood. However, thyroid function tests that do not depend on iodine estimations, e.g., triiodothyronine (T3) resin uptake and total or free thyroxine (T4) assays, are not affected. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from literature and postmarketing reports on iomeprol use in pregnant women over decades have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental outcomes were observed with intravenous administration of iomeprol to pregnant rats and rabbits at doses up to 0.45-times the maximum recommended human dose of 86,000 mg iodine. Animal studies show that iomeprol crosses the placenta (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Embryo-fetal developmental toxicity studies were performed with intravenous administration of iomeprol in rats at daily doses of 600 mg, 1,500 mg, or 4,000 mg iodine/kg (0.07-, 0.17- or 0.45-fold the human equivalent dose (HED, mg/m2) using the maximum human dose of 86,000 mg iodine per administration) from gestation days (GD) 6 to 15 and in rabbits at daily doses of 300 mg, 800 mg, or 2,000 mg iodine/kg (0.07-, 0.18- or 0.45-fold the HED using the maximum human dose of 86,000 mg iodine per administration) from GD 6 to 18. Iomeprol did not result in fetal harm at the highest doses evaluated, 0.45-times the maximum recommended human dose of 86,000 mg iodine. A biodistribution study with a single intravenous administration of 1,000 mg iodine/kg (0.11-fold the HED using the maximum human dose of 86,000 mg iodine per administration) of radiolabeled iomeprol to pregnant rats showed that iomeprol crosses the placenta. No accumulation of radioactivity in fetal tissues was observed. 12 of 20 Reference ID: 5486655 8.2 Lactation Risk Summary There are no data on the presence of iomeprol in human milk, the effects on the breastfed infant, or the effects on milk production. Iomeprol is present in animal milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Iodinated contrast agents are excreted unchanged in human milk in very low amounts, with poor absorption from the gastrointestinal tract of a breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for IOMERVU and any potential adverse effects on the breastfed infant from IOMERVU or from the underlying maternal condition. Clinical Considerations Interruption of breastfeeding after exposure to iodinated contrast agents is not necessary because the potential exposure of the breastfed infant to iodine is small. However, a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 10 hours (approximately 5 elimination half-lives) after IOMERVU administration to minimize any potential drug exposure to a breastfed infant. Data An animal study with a single intravenous administration of 500 mg iodine/kg (0.06-fold the HED using the maximum human dose of 86,000 mg iodine per administration) of radiolabeled iomeprol to lactating rats showed that iomeprol rapidly distributed into the milk. 8.4 Pediatric Use Intra-arterial Use The safety and effectiveness of IOMERVU have been established in pediatric patients for cerebral, visceral, and peripheral arteriography, aortography including intra-arterial digital subtraction angiography, and radiographic evaluation of cardiac chambers and related arteries. Use of IOMERVU is supported by evidence from adequate and well-controlled studies of IOMERVU in adults, pharmacokinetic data in pediatric patients aged 3 years to 17 years, pharmacokinetic simulation in pediatric patients younger than 3 years of age, and safety data obtained in 44 pediatric patients including 29 who were < 2 years of age, 14 children (2 years to 11 years), and 1 adolescent (12 years to 17 years). In general, adverse reactions reported in pediatric patients were similar to those in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. Intravenous Use The safety and effectiveness of IOMERVU have been established in pediatric patients for CT of the head and body, CT angiography of intracranial, visceral, and lower extremity arteries, coronary CT angiography, and CT urography. Use of IOMERVU is supported by evidence from adequate and well-controlled studies of IOMERVU in adults, pharmacokinetic data in pediatric patients aged 3 years to 17 years, pharmacokinetic simulation in pediatric patients younger than 3 years of age, and safety data obtained in 140 pediatric patients including 22 who were < 2 years of age, 92 children (2 years to 11 years), and 26 adolescents (12 years to 17 years). In general, adverse reactions reported in pediatric patients were similar to those in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. 13 of 20 Reference ID: 5486655 Intra-arterial and Intravenous Use Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent may include those with asthma, sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, heart failure, or serum creatinine greater than 1.5 mg/dL, or those less than 12 months of age. Pediatric patients with immature renal function or dehydration may be at increased risk for adverse events due to slower elimination of iodinated contrast agents [See Clinical Pharmacology (12.3)]. Thyroid function tests indicative of thyroid dysfunction, characterized by hypothyroidism or transient thyroid suppression have been reported following iodinated contrast agent administration in pediatric patients, including term and preterm neonates. Some patients were treated for hypothyroidism. After exposure to iodinated contrast agents, individualize thyroid function monitoring in pediatric patients 0 years to 3 years of age based on underlying risk factors, especially in term and preterm neonates [See Warnings and Precautions (5.8) and Adverse Reactions (6.2)]. 8.5 Geriatric Use Of the total number of subjects in clinical studies of IOMERVU, 1,977 (43%) patients were 65 years and older, while 629 (14%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Iomeprol is excreted by the kidneys, and the risk of adverse reactions to IOMERVU is greater in patients with renal impairment. Because elderly patients are more likely to have renal impairment, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. 8.6 Renal Impairment Preexisting renal impairment increases the risk for acute kidney injury. Renal impairment reduces the rate of elimination of iomeprol. Iomeprol can be removed by dialysis [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems. Treatment of an overdosage is directed toward the support of all vital functions and prompt institution of symptomatic therapy. Iomeprol can be removed by dialysis [see Clinical Pharmacology (12.3)]. 11 DESCRIPTION IOMERVU (iomeprol) injection is a tri-iodinated, non-ionic radiographic contrast agent for intra- arterial or intravenous use. It is provided as a sterile, nonpyrogenic, clear, colorless to pale yellow solution. The chemical name for iomeprol is N,N’-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)­ methylamino]-2,4,6-tri-iodo-1,3-benzenedicarboxamide. Iomeprol has a molecular formula of C17H22I3N3O8, a molecular weight of 777.09 (iodine content of 49%), and the following structural formula: 14 of 20 Reference ID: 5486655 CONHCH2 I I CH3 OH CHCH2OH I OH HOCH2CO-N CONHCH2CHCH2OH IOMERVU injection is available in four iodine concentrations: • IOMERVU 250 mg Iodine/mL: Each mL contains 510 mg iomeprol (providing 250 mg bound iodine) and 1 mg tromethamine. • IOMERVU 300 mg Iodine/mL: Each mL contains 612 mg iomeprol (providing 300 mg bound iodine) and 1 mg tromethamine. • IOMERVU 350 mg Iodine/mL: Each mL contains 714 mg iomeprol (providing 350 mg bound iodine) and 1 mg tromethamine. • IOMERVU 400 mg Iodine/mL: Each mL contains 816 mg iomeprol (providing 400 mg bound iodine) and 1 mg tromethamine. The pH of IOMERVU has been adjusted to 6.5 to 7.2 with hydrochloric acid. Physical characteristics are noted in Table 6. IOMERVU has osmolalities approximately 1.5 to 2.5 times that of plasma (285 mOsm/kg water) as shown in the table below and are hypertonic under conditions of use. Table 6. Physical Characteristics of IOMERVU Concentration (mg Iodine/mL) Density (d204 ± 0.0002) Osmolality (mOsmol/kg) Viscosity (mPa·s) 37°C 20°C 37°C 250 1.278 435 4.9 2.9 300 1.334 521 8.1 4.5 350 1.390 618 14.5 7.5 400 1.446 726 27.5 12.6 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Iomeprol is a radiographic iodinated contrast agent that opacifies the vessels and body structures where the contrast agent is present following intravenous or intra-arterial administration, permitting radiographic visualization of the internal structures through attenuation of X-ray photons. In imaging of the body, iodinated contrast agents diffuse from the vessels into the extravascular space. In normal brain with an intact blood-brain barrier, the contrast agent does not diffuse into the extravascular space and contrast enhancement is generally due to the presence of contrast within the 15 of 20 Reference ID: 5486655 vascular space. In patients with a disrupted blood-brain barrier, the contrast agent accumulates in the extravascular space in the region of disruption. 12.2 Pharmacodynamics The degree of radiographic enhancement by iomeprol is related to the iodine concentration in the tissue of interest following the administration of IOMERVU. However, the exposure-response relationships and time course of pharmacodynamic response of iomeprol have not been fully characterized. 12.3 Pharmacokinetics The pharmacokinetic parameters of iomeprol are presented as mean (standard deviation, SD) unless otherwise specified. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) are dose- proportional across the dose range of 250 mg iodine/kg to 1,250 mg iodine/kg body weight. Distribution The volume of distribution of iomeprol is 0.28 (0.05) L/kg. Iomeprol does not bind to plasma proteins. Elimination The elimination half-life of iomeprol is 1.8 (0.33) hours and the total body clearance is 0.10 (0.01) L/hr/kg. Metabolism Iomeprol does not undergo significant metabolism. Excretion Approximately 90% of the iomeprol dose is excreted unchanged in urine within 24 hours. Specific Populations Pediatric Patients No clinically significant differences in the pharmacokinetics of iomeprol were observed in pediatric patients aged 3 years to 17 years compared to adult patients who received IOMERVU. No clinically significant differences in Cmax and concentration of iomeprol within 5 minutes after IOMERVU administration between pediatric patients younger than 3 years of age and adults are expected based on pharmacokinetic simulations. Patients with Renal Impairment The renal clearance of iomeprol decreased by 28% in patients with mild (GFR 51 − 75 mL/min, estimated by inulin clearance (CLinulin)), 66% with moderate (GFR 26 − 50 mL/min, by CLinulin), and 84% with severe (GFR ≤ 25 mL/min, by CLinulin) renal impairment. Similarly, mean half-life increased 1.6-fold in mild, 2.9-fold in moderate, and 6.4-fold in severe renal impairment. Iomeprol is dialyzable. Iomeprol plasma concentrations decreased by 83% in patients with severe renal impairment who underwent hemodialysis 2 hours after a single administration of a 20,000 mg iodine dose of IOMERVU by intravenous route. 16 of 20 Reference ID: 5486655 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies of iomeprol have been conducted. Mutagenesis Iomeprol did not demonstrate mutagenic or clastogenic potential in an in vitro bacterial reverse mutation assay (Ames test) or in an in vivo rat bone marrow micronucleus assay. Impairment of Fertility Iomeprol did not impair the fertility of male or female rats when intravenously administered at doses up to 0.45-times the maximum recommended human dose. 14 CLINICAL STUDIES 14.1 Intra-arterial Studies Cerebral arteriography was evaluated in one blinded read study incorporating two prospective, randomized, double-blind, multi-center clinical studies of 61 adult patients (35 male, 26 female) who were administered IOMERVU 300 mg Iodine/mL by intra-arterial route. The mean age was 52 years (range 17 years to 86 years), and 23% of patients were ≥65 years old. The mean total iodine dose administered was 29,000 mg. The racial and ethnic representations were 62% White, 15% Black, 20% Hispanic, and 3% Asian. Visualization was independently assessed as adequate or inadequate by three blinded readers. Visualization was rated as adequate in 100% of patients. Visceral and peripheral arteriography were evaluated in one blinded read study incorporating two prospective, randomized, double-blind, multi-center clinical studies of 60 adult patients (36 male, 24 female) who were administered IOMERVU 300 mg Iodine/mL by intra-arterial route. The mean age was 67 years (range 29 years to 95 years) and 62% of patients were ≥65 years old. The mean total iodine dose administered was 48,000 mg. The racial and ethnic representations were 92% White, 7% Black, and 1% Hispanic. Visualization was independently assessed as adequate or inadequate by three blinded readers. Visualization was rated as adequate in 98% of patients. Similar cerebral arteriography, visceral arteriography, and peripheral arteriography studies with digital subtraction angiography (DSA) were completed with comparable findings. Coronary arteriography and cardiac ventriculography were evaluated in one blinded read study incorporating four prospective, randomized, double-blind, multi-center clinical studies of 59 adult patients (41 male, 18 female) who were administered IOMERVU 400 mg Iodine/mL, and 59 adult patients (43 male, 16 female) who were administered IOMERVU 300 mg Iodine/mL by intra-arterial route. The mean age was 60 years (range 22 years to 85 years), and 42% of patients were ≥65 years old. The mean total iodine dose administered was 45,000 mg. The racial and ethnic representations were 75% White, 15% Black, 6% Hispanic, 1% Asian, and 3% other racial or ethnic groups. Visualization was independently assessed as adequate or inadequate by three blinded readers. Visualization was rated as adequate in 93% - 100% of patients for both concentrations. 14.2 Intravenous Studies CT of the head and body was evaluated in one blinded read study incorporating four prospective, randomized, double-blind, multi-center clinical studies of 59 adult patients (22 male, 37 female) who 17 of 20 Reference ID: 5486655 were administered IOMERVU 400 mg Iodine/mL and 59 adult patients (26 male, 33 female) who were administered IOMERVU 250 mg Iodine/mL by intravenous route. The mean age was 55 years (range 19 years to 80 years), and 30% of patients were ≥65 years old. The mean total iodine dose administered was 41,000 mg. The racial and ethnic representations were 78% White, 16% Black, 4% Hispanic, 1% Asian, and 1% other racial or ethnic groups. Visualization was independently assessed as adequate or inadequate by three blinded readers. Visualization was rated as adequate in 98% ­ 100% of patients for both concentrations. CT angiography was evaluated in two prospective, single-center clinical studies enrolling a total of 262 adult patients (202 male, 60 female) with suspected or known peripheral arterial disease who were administered IOMERVU 400 mg Iodine/mL by intravenous route. The mean age was 62 years (range 36 years to 88 years). Both studies assessed the diagnostic performance for detection of significant stenosis at the arterial segment level using digital subtraction angiography as the reference standard. In the first study, 212 patients (7,392 segments, 42% positive by reference standard) were independently evaluated by three blinded readers. The reported segment-level sensitivity and specificity (95% confidence interval) for the detection of ≥70% stenosis were 99% (98%, 99%) and 97% (96%, 97%), respectively. In the second study, 50 patients (929 to 933 lesions, 34% positive by reference standard) were evaluated by two blinded readers. The reported lesion- level sensitivity and specificity (95% confidence interval) for the detection of >50% stenosis were 93% (91%, 96%) and 97% (95%, 98%), respectively, for reader 1 and 90% (87%, 93%) and 96% (94%, 97%), respectively, for reader 2. Coronary CT angiography was evaluated in two prospective, single-center clinical studies enrolling a total of 301 adult patients (259 male, 42 female) with suspected coronary artery disease who were administered IOMERVU 400 mg Iodine/mL by intravenous route. The mean age was 64 years. Both studies assessed the diagnostic performance for detection of ≥50% stenosis at the coronary artery segment level using invasive coronary angiography as the reference standard. In the first study, 210 patients (2,532 segments, 22% positive by reference standard) were independently evaluated by two blinded readers with discrepancies resolved by consensus. The segment-level sensitivity and specificity (95% confidence interval) were 84% (81%, 87%) and 94% (92%, 95%), respectively. In the second study, 91 patients (1,456 segments, 18% positive by reference standard) were independently evaluated by two blinded readers with discrepancies resolved by a third reader. The segment-level sensitivity and specificity (95% confidence interval) were 97% (95%, 99%) and 91% (89%, 92%), respectively. CT urography was evaluated in two retrospective, single-center clinical studies of 185 adult patients (130 male, 55 female) who were administered IOMERVU 350 mg Iodine/mL by intravenous route. The mean age was 55 years (range 20 years to 89 years). In the first study, two readers assessed parenchymal image quality on a 3-point scale (inadequate, diagnostic, or very good or excellent) as very good or excellent in 64% to 98% of the patients depending on scan protocol. In the second study, two blinded readers assessed visualization quality for the urinary system overall (calyces, renal pelvis, ureter, and bladder), on a scale of 0 (absence of visualization) to 5 (excellent visualization), with the mean score (SD) for reader 1 being 4.2 (1.4) and for reader 2 being 4.1 (1.5). 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied IOMERVU (iomeprol) injection is a clear, colorless to pale yellow solution supplied in clear glass single-dose vials or bottles in the following configurations: 18 of 20 Reference ID: 5486655 Concentration (mg Iodine/mL) Package Size Package Type Sale Unit NDC 250 100 mL Single-dose bottles Carton of 10 0270-7013-14 300 50 mL Single-dose vials Carton of 10 0270-7016-15 100 mL Single-dose bottles Carton of 10 0270-7016-17 150 mL Carton of 10 0270-7016-18 200 mL Carton of 10 0270-7016-19 350 50 mL Single-dose vials Carton of 10 0270-7017-20 100 mL Single-dose bottles Carton of 10 0270-7017-21 150 mL Carton of 10 0270-7017-24 200 mL Carton of 10 0270-7017-25 400 50 mL Single-dose vials Carton of 10 0270-7018-26 100 mL Single-dose bottles Carton of 10 0270-7018-27 150 mL Carton of 10 0270-7018-28 200 mL Carton of 10 0270-7018-29 Storage and Handling Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Keep in original carton with the cover closed to protect from light. Do not freeze. 17 PATIENT COUNSELING INFORMATION Hypersensitivity Reactions Advise the patient concerning the risk of hypersensitivity reactions that can occur both during and after IOMERVU administration. Advise the patient to report any signs or symptoms of hypersensitivity reactions during the procedure and to seek immediate medical attention for any signs or symptoms experienced after discharge [see Warnings and Precautions (5.2)]. Advise patients to inform their physician if they develop a rash after receiving IOMERVU [see Warnings and Precautions (5.11)]. Acute Kidney Injury Advise the patient concerning appropriate hydration to decrease the risk of kidney injury [see Warnings and Precautions (5.3)]. Extravasation If extravasation occurs during injection, advise patients to seek medical care for progression of symptoms [see Warnings and Precautions (5.6)]. 19 of 20 Reference ID: 5486655 Thyroid Dysfunction Advise parents or caregivers about the risk of developing thyroid dysfunction after IOMERVU administration. Advise parents or caregivers about when to seek medical care for their child to monitor for thyroid dysfunction [see Warnings and Precautions (5.8)]. Lactation Advise a lactating woman that interruption of breastfeeding is not necessary, however, to avoid any exposure a lactating woman may consider pumping and discarding breast milk for 10 hours after IOMERVU administration [see Use in Specific Populations (8.2)]. Manufactured for Bracco Diagnostic Inc. Monroe Township, NJ 08831 Manufactured by BIPSO GmbH 78224 Singen (Germany) 20 of 20 Reference ID: 5486655
custom-source
2025-02-12T15:47:19.536064
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80,449
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IOMERVU safely and effectively. See full prescribing information for IOMERVU. IOMERVUTM (iomeprol) injection, for intra-arterial or intravenous use Initial U.S. Approval: 2024 WARNING: RISKS ASSOCIATED WITH INTRATHECAL ADMINISTRATION Intrathecal administration, even if inadvertent, may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. IOMERVU is for intra-arterial or intravenous use only. (2.1, 5.1) ----------------------------INDICATIONS AND USAGE--------------------------­ IOMERVU is a radiographic contrast agent indicated for: Intra-arterial Procedures† (1.1) • Cerebral arteriography, including intra-arterial digital subtraction angiography (IA-DSA), in adults and pediatric patients • Visceral and peripheral arteriography and aortography, including IA-DSA, in adults and pediatric patients • Coronary arteriography and cardiac ventriculography in adults • Radiographic evaluation of cardiac chambers and related arteries in pediatric patients Intravenous Procedures† (1.2) • Computed tomography (CT) of the head and body in adults and pediatric patients • CT angiography of intracranial, visceral, and lower extremity arteries in adults and pediatric patients • Coronary CT angiography in adults and pediatric patients • CT urography in adults and pediatric patients †Specific concentrations are recommended for each type of imaging procedure. (2.2, 2.3, 2.4, 2.5) ----------------------DOSAGE AND ADMINISTRATION----------------------­ • Individualize the volume and concentration according to the specific dosing tables accounting for factors such as age, body weight, vessel size, rate of blood flow within the vessel, and structures or areas to be examined. (2.2, 2.3, 2.4, 2.5) • See full prescribing information for complete dosage and administration information. (2) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ Injection: 250 mg Iodine/mL, 300 mg Iodine/mL, 350 mg Iodine/mL, and 400 mg Iodine/mL in single-dose vials or bottles (3) -------------------------------CONTRAINDICATIONS-----------------------------­ None (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ • Hypersensitivity Reactions: Life-threatening or fatal reactions can occur. Always have emergency resuscitation equipment and trained personnel available. (5.2) • Acute Kidney Injury: Acute injury including renal failure can occur. Minimize dose and maintain adequate hydration to minimize risk. (5.3) • Cardiovascular Adverse Reactions: Hemodynamic disturbances including shock and cardiac arrest may occur during or after administration. (5.4) • Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age: Individualize thyroid function monitoring based on risk factors such as prematurity. (5.8) ------------------------------ADVERSE REACTIONS------------------------------­ Most common adverse reactions (incidence ≥0.5%) are feeling hot, headache, nausea, chest pain, back pain, and vomiting. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------USE IN SPECIFIC POPULATIONS-----------------------­ Lactation: A lactating woman may pump and discard breast milk for 10 hours after IOMERVU administration. (8.2) See 17 for PATIENT COUNSELING INFORMATION Date: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISKS ASSOCIATED WITH INTRATHECAL ADMINISTRATION 1 INDICATIONS AND USAGE 1.1 Intra-arterial Procedures 1.2 Intravenous Procedures 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information 2.2 Recommended Dosage for Intra-arterial Procedures in Adults 2.3 Recommended Dosage for Intra-arterial Procedures in Pediatric Patients 2.4 Recommended Dosage for Intravenous Procedures in Adults 2.5 Recommended Dosage for Intravenous Procedures in Pediatric Patients 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risks Associated with Intrathecal Administration 5.2 Hypersensitivity Reactions 5.3 Acute Kidney Injury 5.4 Cardiovascular Adverse Reactions 5.5 Thromboembolic Events 5.6 Extravasation and Injection Site Reactions 5.7 Thyroid Storm in Patients with Hyperthyroidism 5.8 Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age 5.9 Hypertensive Crisis in Patients with Pheochromocytoma 5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease 5.11 Severe Cutaneous Adverse Reactions 5.12 Interference with Laboratory Tests 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions 7.2 Drug-Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Intra-arterial Studies 14.2 Intravenous Studies 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 of 20 Reference ID: 5486655 FULL PRESCRIBING INFORMATION WARNING: RISKS ASSOCIATED WITH INTRATHECAL ADMINISTRATION Intrathecal administration, even if inadvertent, may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. IOMERVU is for intra-arterial or intravenous use only [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE 1.1 Intra-arterial Procedures† IOMERVU is indicated for: • Cerebral arteriography, including intra-arterial digital subtraction angiography (IA-DSA), in adults and pediatric patients • Visceral and peripheral arteriography and aortography, including IA-DSA, in adults and pediatric patients • Coronary arteriography and cardiac ventriculography in adults • Radiographic evaluation of cardiac chambers and related arteries in pediatric patients 1.2 Intravenous Procedures† IOMERVU is indicated for: • Computed tomography (CT) of the head and body in adults and pediatric patients • CT angiography of intracranial, visceral, and lower extremity arteries in adults and pediatric patients • Coronary CT angiography in adults and pediatric patients • CT urography in adults and pediatric patients †Specific concentrations of IOMERVU are recommended for each type of imaging procedure [see Dosage and Administration (2.2, 2.3, 2.4, 2.5)]. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information • IOMERVU is for intra-arterial or intravenous use only and must not be administered intrathecally [see Warnings and Precautions (5.1)]. • Specific concentrations of IOMERVU are recommended for each type of imaging procedure [see Dosage and Administration (2.2, 2.3, 2.4, 2.5)]. • Individualize the volume, concentration, and injection rate of IOMERVU within the specified ranges [see Dosage and Administration (2.2, 2.3, 2.4, 2.5)]. Consider factors such as age, body weight, vessel size, rate of blood flow within the vessel, anticipated pathology, 2 of 20 Reference ID: 5486655 degree and extent of opacification required, structures or area to be examined, disease processes affecting the patient, and equipment and technique to be employed. • Hydrate patients before and after IOMERVU administration [see Warnings and Precautions (5.3)]. • Use aseptic technique for all handling and administration of IOMERVU. • IOMERVU may be administered at either body temperature (37°C, 98.6°F) or room temperature (20°C to 25°C, 68°F to 77°F). • Visually inspect IOMERVU for particulate matter or discoloration before administration, whenever the solution and container permit. Do not administer IOMERVU if particulate matter or discoloration is observed. • Do not mix IOMERVU with, or inject in intravenous lines containing, other drugs or total nutritional admixtures. • Each single-dose container of IOMERVU injection is intended for one procedure only. Discard any unused portion. 2.2 Recommended Dosage for Intra-arterial Procedures in Adults • Recommended doses of IOMERVU in adults for intra-arterial procedures are shown in Table 1. • Inject at rates approximately equal to the flow rate in the vessel being injected. 3 of 20 Reference ID: 5486655 Table 1. Recommended Concentrations and Volumes of IOMERVU to Administer per Single Injection into Selected Arteries for Intra-arterial Procedures in Adults Imaging Procedure Concentration (mg Iodine/mL) Volume (mL) Maximum Total Dose (mL) Cerebral arteriography 300 • Carotid, subclavian, and vertebral arteries: 6 mL to 12 mL • Aortic arch: 30 mL to 50 mL 200 mL Visceral and peripheral arteriography; aortography 300 • Aortography: 30 mL to 70 mL • Renal arteries: 10 mL to 12 mL • Other major branches of aorta: 20 mL to 60 mL 200 mL Intra-arterial digital subtraction angiography 300 • Carotid, subclavian, and vertebral arteries: 4 mL to 12 mL • Aortic arch: 20 mL to 25 mL • Aortography: 15 mL to 40 mL • Renal arteries: 6 mL to 16 mL • Other major branches of aorta: 10 mL to 40 mL • Ilio-femoral runoff: 8 mL to 40 mL 200 mL Coronary arteriography and cardiac ventriculography 300 • Coronary arteries: 3 mL to 7 mL • Cardiac ventriculography: 30 mL to 45 mL 286 mL 350 245 mL 400 215 mL 4 of 20 Reference ID: 5486655 2.3 Recommended Dosage for Intra-arterial Procedures in Pediatric Patients • Recommended doses of IOMERVU in pediatric patients for intra-arterial procedures are shown in Table 2. • Inject at rates approximately equal to the flow rate in the vessel being injected. Table 2. Recommended Concentrations and Volumes per Body Weight of IOMERVU to Administer per Single Injection for Intra-arterial Procedures in Pediatric Patients Imaging Procedure Concentration (mg Iodine/mL) Volume (mL/kg body weight) Maximum Total Dose (mL/kg) Cerebral arteriography 300 0.5 mL/kg to 2 mL/kg • 5 mL/kg • Do not exceed adult maximum dose (see Table 1) Visceral and peripheral arteriography; aortography 300 0.5 mL/kg to 2 mL/kg Intra-arterial digital subtraction angiography 300 0.3 mL/kg to 1 mL/kg Radiographic evaluation of cardiac chambers and related arteries 300, 350, or 400 0.5 mL/kg to 2 mL/kg 2.4 Recommended Dosage for Intravenous Procedures in Adults Recommended doses of IOMERVU in adults for intravenous procedures are shown in Table 3. Table 3. Recommended Concentrations, Volumes, and Injection Rates of IOMERVU for Intravenous Procedures in Adults Imaging Procedure Concentration (mg Iodine/mL) Volume (mL) Injection Rate3 (mL/s) CT of Head and Body 250 or 300 100 mL to 190 mL 2 mL/s to 4 mL/s 350 or 400 75 mL to 150 mL CT Angiography1 300, 350, or 400 80 mL to 130 mL 4 mL/s to 6 mL/s Coronary CT Angiography1 400 50 mL to 90 mL 4 mL/s to 6 mL/s CT Urography2 350 90 mL to 120 mL 2.5 mL/s 1 The IOMERVU volume may be immediately followed by a 40 mL to 50 mL 0.9% sodium chloride injection flush at the same flow rate as the contrast volume. 2 The IOMERVU volume may be administered either as a single bolus, or for dual-phase protocols as divided doses. 3 The injection rate of IOMERVU should be determined according to the clinical indication and the location, size, and type of the intravenous access. 5 of 20 Reference ID: 5486655 2.5 Recommended Dosage for Intravenous Procedures in Pediatric Patients Recommended doses of IOMERVU in pediatric patients for intravenous procedures are shown in Table 4. Table 4. Recommended Concentrations, Volumes per Body Weight, and Injection Rates of IOMERVU for Intravenous Procedures in Pediatric Patients Imaging Procedure Concentration (mg Iodine/mL) Volume (mL/kg body weight) Injection Rate (mL/s)* CT of Head and Body 250 or 300 1.5 mL/kg to 2.5 mL/kg 1 mL/s to 2 mL/s 350 or 400 1 mL/kg to 2 mL/kg CT Angiography 300, 350, or 400 1 mL/kg to 2 mL/kg 2 mL/s to 3 mL/s Coronary CT Angiography 300 or 400 1 mL/kg to 2 mL/kg 2 mL/s to 3 mL/s CT Urography 300 1 mL/kg to 2 mL/kg 1 mL/s to 2 mL/s * The injection rate of IOMERVU should be determined according to the clinical indication and the location, size, and type of the intravenous access. In neonates and patients <15 kg in whom a 24-gauge angiocatheter is the only option, an injection rate of 1 mL/s is recommended. 3 DOSAGE FORMS AND STRENGTHS Injection: clear, colorless to pale yellow solution available in the following iodine concentrations and configurations: Concentration (mg Iodine/mL) Package Size Package Type 250 100 mL Single-dose bottles 300 50 mL Single-dose vials 100 mL, 150 mL, and 200 mL Single-dose bottles 350 50 mL Single-dose vials 100 mL, 150 mL, and 200 mL Single-dose bottles 400 50 mL Single-dose vials 100 mL, 150 mL, and 200 mL Single-dose bottles 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Risks Associated with Intrathecal Administration IOMERVU is for intra-arterial or intravenous use only and must not be administered intrathecally [see Dosage and Administration (2.1)]. Intrathecal administration, even if inadvertent, can cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. 6 of 20 Reference ID: 5486655 5.2 Hypersensitivity Reactions IOMERVU can cause life-threatening or fatal hypersensitivity reactions including anaphylaxis. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock [see Adverse Reactions (6.2)]. Most severe reactions develop shortly after the start of injection (e.g., within 1 to 3 minutes), but delayed reactions can occur. There is an increased risk in patients with a history of a previous reaction to contrast agents, and known allergic disorders (i.e., bronchial asthma, drug, or food allergies) or other hypersensitivities. Premedication with antihistamines or corticosteroids to minimize possible allergic reactions does not prevent serious life-threatening reactions, but may reduce their incidence and severity. Obtain a history of allergy, hypersensitivity, and hypersensitivity reactions to iodinated contrast agents. Always have emergency resuscitation equipment and trained personnel available before use of IOMERVU. Monitor all patients for hypersensitivity reactions. 5.3 Acute Kidney Injury Acute kidney injury, including renal failure, may occur after IOMERVU administration. Risk factors include pre-existing renal impairment, dehydration, diabetes mellitus, heart failure, advanced vascular disease, advanced age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma or other paraproteinemia, and repetitive or large doses of IOMERVU. Use the lowest necessary dose of IOMERVU in patients with renal impairment. Adequately hydrate patients prior to and following IOMERVU administration. Do not use laxatives, diuretics, or preparatory dehydration prior to IOMERVU administration. 5.4 Cardiovascular Adverse Reactions IOMERVU increases the circulatory osmotic load and may induce acute or delayed hemodynamic disturbances in patients with heart failure, severely impaired renal function, combined renal and hepatic disease, or combined renal and cardiac disease, particularly when repetitive or large doses are administered. Life-threatening or fatal cardiovascular reactions including hypotension, shock, and cardiac arrest have occurred with the use of IOMERVU. Most deaths occur within 10 minutes of injection, with cardiovascular disease as the main underlying factor. Cardiac decompensation, serious arrhythmias, and myocardial ischemia or infarction can occur during coronary arteriography and ventriculography. Based upon literature reports, deaths from the administration of iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Use the lowest necessary dose of IOMERVU in patients with heart failure and always have emergency resuscitation equipment and trained personnel available. Monitor all patients for severe cardiovascular reactions. 5.5 Thromboembolic Events Serious, in some cases fatal, thromboembolic events including myocardial infarction and stroke can occur during angiographic procedures with iodinated contrast agents including IOMERVU. During these procedures, increased thrombosis and activation of the complement system can occur. Risk factors for developing thromboembolic events include length of procedure, catheter and syringe material, underlying disease state, and concomitant medications. 7 of 20 Reference ID: 5486655 To reduce risk of thromboembolic events, use meticulous angiographic techniques and minimize the length of the procedure. Avoid blood remaining in contact with syringes containing IOMERVU, which increases the risk of clotting. Avoid angiocardiography in patients with homocystinuria because of the risk of inducing thrombosis and embolism. 5.6 Extravasation and Injection Site Reactions Extravasation can occur with IOMERVU administration, particularly in patients with severe arterial or venous disease. Inflammation, blistering, skin necrosis, and compartment syndrome have been reported following extravasation. In addition, injection site reactions such as pain and swelling at the injection site can also occur [see Adverse Reactions (6.1, 6.2)]. Ensure intravascular placement of catheters prior to injection. Monitor patients for extravasation and advise patients to seek medical care for progression of symptoms. 5.7 Thyroid Storm in Patients with Hyperthyroidism Thyroid storm has occurred after the intravascular use of iodinated contrast agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of IOMERVU. 5.8 Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age Thyroid dysfunction characterized by hypothyroidism or transient thyroid suppression has been reported after both single exposure and multiple exposures to iodinated contrast agents in pediatric patients 0 years to 3 years of age. Younger age, very low birth weight, prematurity, underlying medical conditions affecting thyroid function, admission to neonatal or pediatric intensive care units, and congenital cardiac conditions are associated with an increased risk of hypothyroidism after iodinated contrast agent exposure. Pediatric patients with congenital cardiac conditions may be at greatest risk given that they often require high doses of contrast during invasive cardiac procedures. An underactive thyroid during early life may be harmful for cognitive and neurological development and may require thyroid hormone replacement therapy. After exposure to IOMERVU, individualize thyroid function monitoring based on underlying risk factors, especially in term and preterm neonates. 5.9 Hypertensive Crisis in Patients with Pheochromocytoma Hypertensive crisis has occurred after the use of iodinated contrast agents in patients with pheochromocytoma. Closely monitor patients when administering IOMERVU if pheochromocytoma or catecholamine-secreting paragangliomas are suspected. Inject the minimum amount of IOMERVU necessary, assess blood pressure throughout the procedure, and have measures for treatment of a hypertensive crisis readily available. 5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease Iodinated contrast agents when administered intravascularly may promote sickling in individuals who are homozygous for sickle cell disease. Hydrate patients prior to and following IOMERVU 8 of 20 Reference ID: 5486655 administration and use IOMERVU only if the necessary imaging information cannot be obtained with alternative imaging modalities. 5.11 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR) may develop from 1 hour to several weeks after intravascular contrast agent administration. These reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). Reaction severity may increase and time to onset may decrease with repeat administration of a contrast agent; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering IOMERVU to patients with a history of a severe cutaneous adverse reaction to IOMERVU. 5.12 Interference with Laboratory Tests IOMERVU can interfere with protein-bound iodine tests [see Drug Interactions (7.2)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Risks Associated with Intrathecal Administration [see Warnings and Precautions (5.1)] • Hypersensitivity Reactions [see Warnings and Precautions (5.2)] • Acute Kidney Injury [see Warnings and Precautions (5.3)] • Cardiovascular Adverse Reactions [see Warnings and Precautions (5.4)] • Thromboembolic Events [see Warnings and Precautions (5.5)] • Extravasation and Injection Site Reactions [see Warnings and Precautions (5.6)] • Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age [see Warnings and Precautions (5.8)] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adult Patients The safety of IOMERVU was evaluated in 4,621 adult patients who received 1,500 mg to 86,000 mg iodine doses of IOMERVU intra-arterially or intravenously in clinical trials. The average age was 60 years (range 18 years to 99 years), and 34% were female. The racial and ethnic distribution was 83% White, 10% Asian, 1% Black, 1% Hispanic, and 5% patients of other or unspecified groups. Table 5 provides a summary of the adverse reactions reported in ≥0.5% of adult patients. 9 of 20 Reference ID: 5486655 Table 5: Adverse Reactions Reported in ≥0.5% of 4,621 Adult Patients Receiving Intra-arterial or Intravenous Administration of IOMERVU in Clinical Trials Adverse Reaction Incidence (%) Feeling hot 2 Headache 1.2 Nausea 1 Chest pain 0.6 Back pain 0.5 Vomiting 0.5 The following adverse reactions were observed in <0.5% of the adult patients receiving IOMERVU: Blood and lymphatic system disorders: activated partial thromboplastin time prolonged, prothrombin time prolonged Cardiovascular disorders: ventricular fibrillation, hypertensive crisis, coronary arteriospasm, congestive cardiac failure, cardiac flutter, atrioventricular block, right bundle branch block, hypotension, arrhythmia, bradycardia, supraventricular extrasystoles, ventricular extrasystoles, increased blood pressure, flushing Ear and labyrinth disorders: vertigo, ear discomfort Eye disorder: vision blurred, periorbital edema, photopsia Gastrointestinal: esophageal varices hemorrhage, abdominal pain, abdominal distension, alanine aminotransferase (ALT) increased, constipation, diarrhea, dry mouth, salivary hypersecretion, oral paresthesia General disorders: pain, injection site reactions (pain, discomfort, or warmth), peripheral edema, chills, asthenia, malaise Musculoskeletal and connective tissue disorders: arthralgia, pain in jaw Nervous system disorders: cerebrovascular disorder, dysarthria, visual field defect, burning sensation, presyncope, dizziness, dysgeusia, paresthesia Psychiatric disorders: delirium, anxiety, insomnia Renal and urinary disorders: acute kidney injury, increased blood creatinine, urinary urgency Respiratory, thoracic, and mediastinal disorders: respiratory arrest, pulmonary edema, bronchospasm, dyspnea, cough, rhinitis, throat irritation or tightness, sneezing Skin and subcutaneous tissue disorders: urticaria, blister, purpura, ecchymosis, rash, pruritus, erythema Adverse Reactions in Pediatric Patients The safety of IOMERVU was evaluated in 184 pediatric patients who received 1,800 mg to 76,000 mg iodine doses of IOMERVU intra-arterially or intravenously in clinical trials. The average age was 6 years (range 11 days to 17 years), and 47% were female. The racial distribution was 98% White, 1% Black, and 1% patients of other or unspecified groups. The overall character, quality, and severity of adverse reactions reported in pediatric patients were similar to those reported in adult patients. 10 of 20 Reference ID: 5486655 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of IOMERVU outside the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: thrombocytopenia, leukopenia, leukocytosis Cardiovascular disorders: cardio-respiratory arrest, circulatory collapse or shock, myocardial infarction, atrial fibrillation, cyanosis, pallor Endocrine disorders: hyperthyroidism, hypothyroidism Eye disorders: transient blindness, conjunctivitis, increased lacrimation Gastrointestinal disorders: salivary gland enlargement, increased aspartate aminotransferase (AST), dysphagia General disorders and administration site conditions: injection site swelling (usually due to extravasation) Immune system disorders: hypersensitivity reactions including fatal anaphylaxis Nervous system disorders: coma, loss of consciousness, encephalopathy, transient ischemic attack, paralysis, convulsion, syncope, amnesia, somnolence Psychiatric disorders: confusional state Respiratory, thoracic, and mediastinal disorders: acute respiratory distress syndrome (ARDS), laryngeal edema, pharyngeal edema, dysphonia Skin and subcutaneous tissue disorders: severe reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS)) and mild reactions (rash, erythema, pruritus, urticaria, and skin discoloration) 7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions Metformin Stop metformin at the time of, or prior to, IOMERVU administration in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast agents. Re­ evaluate eGFR 48 hours after the imaging procedure, and reinstitute metformin only after renal function is stable. Metformin can cause lactic acidosis in patients with renal impairment. Iodinated contrast agents appear to increase the risk of metformin-induced lactic acidosis, possibly as a result of worsening renal function. 11 of 20 Reference ID: 5486655 Radioactive Iodine Avoid thyroid therapy or testing using radioactive iodine for up to 6 weeks post IOMERVU. Administration of IOMERVU may interfere with thyroid uptake of radioactive iodine (I-131 and I­ 123) and decrease therapeutic and diagnostic efficacy. 7.2 Drug-Laboratory Test Interactions Protein-Bound Iodine Test Do not perform a protein-bound iodine test for at least 16 days following administration of IOMERVU. Iodinated contrast agents, including IOMERVU, will temporarily increase protein-bound iodine in blood. However, thyroid function tests that do not depend on iodine estimations, e.g., triiodothyronine (T3) resin uptake and total or free thyroxine (T4) assays, are not affected. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from literature and postmarketing reports on iomeprol use in pregnant women over decades have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental outcomes were observed with intravenous administration of iomeprol to pregnant rats and rabbits at doses up to 0.45-times the maximum recommended human dose of 86,000 mg iodine. Animal studies show that iomeprol crosses the placenta (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Embryo-fetal developmental toxicity studies were performed with intravenous administration of iomeprol in rats at daily doses of 600 mg, 1,500 mg, or 4,000 mg iodine/kg (0.07-, 0.17- or 0.45-fold the human equivalent dose (HED, mg/m2) using the maximum human dose of 86,000 mg iodine per administration) from gestation days (GD) 6 to 15 and in rabbits at daily doses of 300 mg, 800 mg, or 2,000 mg iodine/kg (0.07-, 0.18- or 0.45-fold the HED using the maximum human dose of 86,000 mg iodine per administration) from GD 6 to 18. Iomeprol did not result in fetal harm at the highest doses evaluated, 0.45-times the maximum recommended human dose of 86,000 mg iodine. A biodistribution study with a single intravenous administration of 1,000 mg iodine/kg (0.11-fold the HED using the maximum human dose of 86,000 mg iodine per administration) of radiolabeled iomeprol to pregnant rats showed that iomeprol crosses the placenta. No accumulation of radioactivity in fetal tissues was observed. 12 of 20 Reference ID: 5486655 8.2 Lactation Risk Summary There are no data on the presence of iomeprol in human milk, the effects on the breastfed infant, or the effects on milk production. Iomeprol is present in animal milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Iodinated contrast agents are excreted unchanged in human milk in very low amounts, with poor absorption from the gastrointestinal tract of a breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for IOMERVU and any potential adverse effects on the breastfed infant from IOMERVU or from the underlying maternal condition. Clinical Considerations Interruption of breastfeeding after exposure to iodinated contrast agents is not necessary because the potential exposure of the breastfed infant to iodine is small. However, a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 10 hours (approximately 5 elimination half-lives) after IOMERVU administration to minimize any potential drug exposure to a breastfed infant. Data An animal study with a single intravenous administration of 500 mg iodine/kg (0.06-fold the HED using the maximum human dose of 86,000 mg iodine per administration) of radiolabeled iomeprol to lactating rats showed that iomeprol rapidly distributed into the milk. 8.4 Pediatric Use Intra-arterial Use The safety and effectiveness of IOMERVU have been established in pediatric patients for cerebral, visceral, and peripheral arteriography, aortography including intra-arterial digital subtraction angiography, and radiographic evaluation of cardiac chambers and related arteries. Use of IOMERVU is supported by evidence from adequate and well-controlled studies of IOMERVU in adults, pharmacokinetic data in pediatric patients aged 3 years to 17 years, pharmacokinetic simulation in pediatric patients younger than 3 years of age, and safety data obtained in 44 pediatric patients including 29 who were < 2 years of age, 14 children (2 years to 11 years), and 1 adolescent (12 years to 17 years). In general, adverse reactions reported in pediatric patients were similar to those in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. Intravenous Use The safety and effectiveness of IOMERVU have been established in pediatric patients for CT of the head and body, CT angiography of intracranial, visceral, and lower extremity arteries, coronary CT angiography, and CT urography. Use of IOMERVU is supported by evidence from adequate and well-controlled studies of IOMERVU in adults, pharmacokinetic data in pediatric patients aged 3 years to 17 years, pharmacokinetic simulation in pediatric patients younger than 3 years of age, and safety data obtained in 140 pediatric patients including 22 who were < 2 years of age, 92 children (2 years to 11 years), and 26 adolescents (12 years to 17 years). In general, adverse reactions reported in pediatric patients were similar to those in adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. 13 of 20 Reference ID: 5486655 Intra-arterial and Intravenous Use Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent may include those with asthma, sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, heart failure, or serum creatinine greater than 1.5 mg/dL, or those less than 12 months of age. Pediatric patients with immature renal function or dehydration may be at increased risk for adverse events due to slower elimination of iodinated contrast agents [See Clinical Pharmacology (12.3)]. Thyroid function tests indicative of thyroid dysfunction, characterized by hypothyroidism or transient thyroid suppression have been reported following iodinated contrast agent administration in pediatric patients, including term and preterm neonates. Some patients were treated for hypothyroidism. After exposure to iodinated contrast agents, individualize thyroid function monitoring in pediatric patients 0 years to 3 years of age based on underlying risk factors, especially in term and preterm neonates [See Warnings and Precautions (5.8) and Adverse Reactions (6.2)]. 8.5 Geriatric Use Of the total number of subjects in clinical studies of IOMERVU, 1,977 (43%) patients were 65 years and older, while 629 (14%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Iomeprol is excreted by the kidneys, and the risk of adverse reactions to IOMERVU is greater in patients with renal impairment. Because elderly patients are more likely to have renal impairment, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. 8.6 Renal Impairment Preexisting renal impairment increases the risk for acute kidney injury. Renal impairment reduces the rate of elimination of iomeprol. Iomeprol can be removed by dialysis [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems. Treatment of an overdosage is directed toward the support of all vital functions and prompt institution of symptomatic therapy. Iomeprol can be removed by dialysis [see Clinical Pharmacology (12.3)]. 11 DESCRIPTION IOMERVU (iomeprol) injection is a tri-iodinated, non-ionic radiographic contrast agent for intra- arterial or intravenous use. It is provided as a sterile, nonpyrogenic, clear, colorless to pale yellow solution. The chemical name for iomeprol is N,N’-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)­ methylamino]-2,4,6-tri-iodo-1,3-benzenedicarboxamide. Iomeprol has a molecular formula of C17H22I3N3O8, a molecular weight of 777.09 (iodine content of 49%), and the following structural formula: 14 of 20 Reference ID: 5486655 CONHCH2 I I CH3 OH CHCH2OH I OH HOCH2CO-N CONHCH2CHCH2OH IOMERVU injection is available in four iodine concentrations: • IOMERVU 250 mg Iodine/mL: Each mL contains 510 mg iomeprol (providing 250 mg bound iodine) and 1 mg tromethamine. • IOMERVU 300 mg Iodine/mL: Each mL contains 612 mg iomeprol (providing 300 mg bound iodine) and 1 mg tromethamine. • IOMERVU 350 mg Iodine/mL: Each mL contains 714 mg iomeprol (providing 350 mg bound iodine) and 1 mg tromethamine. • IOMERVU 400 mg Iodine/mL: Each mL contains 816 mg iomeprol (providing 400 mg bound iodine) and 1 mg tromethamine. The pH of IOMERVU has been adjusted to 6.5 to 7.2 with hydrochloric acid. Physical characteristics are noted in Table 6. IOMERVU has osmolalities approximately 1.5 to 2.5 times that of plasma (285 mOsm/kg water) as shown in the table below and are hypertonic under conditions of use. Table 6. Physical Characteristics of IOMERVU Concentration (mg Iodine/mL) Density (d204 ± 0.0002) Osmolality (mOsmol/kg) Viscosity (mPa·s) 37°C 20°C 37°C 250 1.278 435 4.9 2.9 300 1.334 521 8.1 4.5 350 1.390 618 14.5 7.5 400 1.446 726 27.5 12.6 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Iomeprol is a radiographic iodinated contrast agent that opacifies the vessels and body structures where the contrast agent is present following intravenous or intra-arterial administration, permitting radiographic visualization of the internal structures through attenuation of X-ray photons. In imaging of the body, iodinated contrast agents diffuse from the vessels into the extravascular space. In normal brain with an intact blood-brain barrier, the contrast agent does not diffuse into the extravascular space and contrast enhancement is generally due to the presence of contrast within the 15 of 20 Reference ID: 5486655 vascular space. In patients with a disrupted blood-brain barrier, the contrast agent accumulates in the extravascular space in the region of disruption. 12.2 Pharmacodynamics The degree of radiographic enhancement by iomeprol is related to the iodine concentration in the tissue of interest following the administration of IOMERVU. However, the exposure-response relationships and time course of pharmacodynamic response of iomeprol have not been fully characterized. 12.3 Pharmacokinetics The pharmacokinetic parameters of iomeprol are presented as mean (standard deviation, SD) unless otherwise specified. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) are dose- proportional across the dose range of 250 mg iodine/kg to 1,250 mg iodine/kg body weight. Distribution The volume of distribution of iomeprol is 0.28 (0.05) L/kg. Iomeprol does not bind to plasma proteins. Elimination The elimination half-life of iomeprol is 1.8 (0.33) hours and the total body clearance is 0.10 (0.01) L/hr/kg. Metabolism Iomeprol does not undergo significant metabolism. Excretion Approximately 90% of the iomeprol dose is excreted unchanged in urine within 24 hours. Specific Populations Pediatric Patients No clinically significant differences in the pharmacokinetics of iomeprol were observed in pediatric patients aged 3 years to 17 years compared to adult patients who received IOMERVU. No clinically significant differences in Cmax and concentration of iomeprol within 5 minutes after IOMERVU administration between pediatric patients younger than 3 years of age and adults are expected based on pharmacokinetic simulations. Patients with Renal Impairment The renal clearance of iomeprol decreased by 28% in patients with mild (GFR 51 − 75 mL/min, estimated by inulin clearance (CLinulin)), 66% with moderate (GFR 26 − 50 mL/min, by CLinulin), and 84% with severe (GFR ≤ 25 mL/min, by CLinulin) renal impairment. Similarly, mean half-life increased 1.6-fold in mild, 2.9-fold in moderate, and 6.4-fold in severe renal impairment. Iomeprol is dialyzable. Iomeprol plasma concentrations decreased by 83% in patients with severe renal impairment who underwent hemodialysis 2 hours after a single administration of a 20,000 mg iodine dose of IOMERVU by intravenous route. 16 of 20 Reference ID: 5486655 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies of iomeprol have been conducted. Mutagenesis Iomeprol did not demonstrate mutagenic or clastogenic potential in an in vitro bacterial reverse mutation assay (Ames test) or in an in vivo rat bone marrow micronucleus assay. Impairment of Fertility Iomeprol did not impair the fertility of male or female rats when intravenously administered at doses up to 0.45-times the maximum recommended human dose. 14 CLINICAL STUDIES 14.1 Intra-arterial Studies Cerebral arteriography was evaluated in one blinded read study incorporating two prospective, randomized, double-blind, multi-center clinical studies of 61 adult patients (35 male, 26 female) who were administered IOMERVU 300 mg Iodine/mL by intra-arterial route. The mean age was 52 years (range 17 years to 86 years), and 23% of patients were ≥65 years old. The mean total iodine dose administered was 29,000 mg. The racial and ethnic representations were 62% White, 15% Black, 20% Hispanic, and 3% Asian. Visualization was independently assessed as adequate or inadequate by three blinded readers. Visualization was rated as adequate in 100% of patients. Visceral and peripheral arteriography were evaluated in one blinded read study incorporating two prospective, randomized, double-blind, multi-center clinical studies of 60 adult patients (36 male, 24 female) who were administered IOMERVU 300 mg Iodine/mL by intra-arterial route. The mean age was 67 years (range 29 years to 95 years) and 62% of patients were ≥65 years old. The mean total iodine dose administered was 48,000 mg. The racial and ethnic representations were 92% White, 7% Black, and 1% Hispanic. Visualization was independently assessed as adequate or inadequate by three blinded readers. Visualization was rated as adequate in 98% of patients. Similar cerebral arteriography, visceral arteriography, and peripheral arteriography studies with digital subtraction angiography (DSA) were completed with comparable findings. Coronary arteriography and cardiac ventriculography were evaluated in one blinded read study incorporating four prospective, randomized, double-blind, multi-center clinical studies of 59 adult patients (41 male, 18 female) who were administered IOMERVU 400 mg Iodine/mL, and 59 adult patients (43 male, 16 female) who were administered IOMERVU 300 mg Iodine/mL by intra-arterial route. The mean age was 60 years (range 22 years to 85 years), and 42% of patients were ≥65 years old. The mean total iodine dose administered was 45,000 mg. The racial and ethnic representations were 75% White, 15% Black, 6% Hispanic, 1% Asian, and 3% other racial or ethnic groups. Visualization was independently assessed as adequate or inadequate by three blinded readers. Visualization was rated as adequate in 93% - 100% of patients for both concentrations. 14.2 Intravenous Studies CT of the head and body was evaluated in one blinded read study incorporating four prospective, randomized, double-blind, multi-center clinical studies of 59 adult patients (22 male, 37 female) who 17 of 20 Reference ID: 5486655 were administered IOMERVU 400 mg Iodine/mL and 59 adult patients (26 male, 33 female) who were administered IOMERVU 250 mg Iodine/mL by intravenous route. The mean age was 55 years (range 19 years to 80 years), and 30% of patients were ≥65 years old. The mean total iodine dose administered was 41,000 mg. The racial and ethnic representations were 78% White, 16% Black, 4% Hispanic, 1% Asian, and 1% other racial or ethnic groups. Visualization was independently assessed as adequate or inadequate by three blinded readers. Visualization was rated as adequate in 98% ­ 100% of patients for both concentrations. CT angiography was evaluated in two prospective, single-center clinical studies enrolling a total of 262 adult patients (202 male, 60 female) with suspected or known peripheral arterial disease who were administered IOMERVU 400 mg Iodine/mL by intravenous route. The mean age was 62 years (range 36 years to 88 years). Both studies assessed the diagnostic performance for detection of significant stenosis at the arterial segment level using digital subtraction angiography as the reference standard. In the first study, 212 patients (7,392 segments, 42% positive by reference standard) were independently evaluated by three blinded readers. The reported segment-level sensitivity and specificity (95% confidence interval) for the detection of ≥70% stenosis were 99% (98%, 99%) and 97% (96%, 97%), respectively. In the second study, 50 patients (929 to 933 lesions, 34% positive by reference standard) were evaluated by two blinded readers. The reported lesion- level sensitivity and specificity (95% confidence interval) for the detection of >50% stenosis were 93% (91%, 96%) and 97% (95%, 98%), respectively, for reader 1 and 90% (87%, 93%) and 96% (94%, 97%), respectively, for reader 2. Coronary CT angiography was evaluated in two prospective, single-center clinical studies enrolling a total of 301 adult patients (259 male, 42 female) with suspected coronary artery disease who were administered IOMERVU 400 mg Iodine/mL by intravenous route. The mean age was 64 years. Both studies assessed the diagnostic performance for detection of ≥50% stenosis at the coronary artery segment level using invasive coronary angiography as the reference standard. In the first study, 210 patients (2,532 segments, 22% positive by reference standard) were independently evaluated by two blinded readers with discrepancies resolved by consensus. The segment-level sensitivity and specificity (95% confidence interval) were 84% (81%, 87%) and 94% (92%, 95%), respectively. In the second study, 91 patients (1,456 segments, 18% positive by reference standard) were independently evaluated by two blinded readers with discrepancies resolved by a third reader. The segment-level sensitivity and specificity (95% confidence interval) were 97% (95%, 99%) and 91% (89%, 92%), respectively. CT urography was evaluated in two retrospective, single-center clinical studies of 185 adult patients (130 male, 55 female) who were administered IOMERVU 350 mg Iodine/mL by intravenous route. The mean age was 55 years (range 20 years to 89 years). In the first study, two readers assessed parenchymal image quality on a 3-point scale (inadequate, diagnostic, or very good or excellent) as very good or excellent in 64% to 98% of the patients depending on scan protocol. In the second study, two blinded readers assessed visualization quality for the urinary system overall (calyces, renal pelvis, ureter, and bladder), on a scale of 0 (absence of visualization) to 5 (excellent visualization), with the mean score (SD) for reader 1 being 4.2 (1.4) and for reader 2 being 4.1 (1.5). 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied IOMERVU (iomeprol) injection is a clear, colorless to pale yellow solution supplied in clear glass single-dose vials or bottles in the following configurations: 18 of 20 Reference ID: 5486655 Concentration (mg Iodine/mL) Package Size Package Type Sale Unit NDC 250 100 mL Single-dose bottles Carton of 10 0270-7013-14 300 50 mL Single-dose vials Carton of 10 0270-7016-15 100 mL Single-dose bottles Carton of 10 0270-7016-17 150 mL Carton of 10 0270-7016-18 200 mL Carton of 10 0270-7016-19 350 50 mL Single-dose vials Carton of 10 0270-7017-20 100 mL Single-dose bottles Carton of 10 0270-7017-21 150 mL Carton of 10 0270-7017-24 200 mL Carton of 10 0270-7017-25 400 50 mL Single-dose vials Carton of 10 0270-7018-26 100 mL Single-dose bottles Carton of 10 0270-7018-27 150 mL Carton of 10 0270-7018-28 200 mL Carton of 10 0270-7018-29 Storage and Handling Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Keep in original carton with the cover closed to protect from light. Do not freeze. 17 PATIENT COUNSELING INFORMATION Hypersensitivity Reactions Advise the patient concerning the risk of hypersensitivity reactions that can occur both during and after IOMERVU administration. Advise the patient to report any signs or symptoms of hypersensitivity reactions during the procedure and to seek immediate medical attention for any signs or symptoms experienced after discharge [see Warnings and Precautions (5.2)]. Advise patients to inform their physician if they develop a rash after receiving IOMERVU [see Warnings and Precautions (5.11)]. Acute Kidney Injury Advise the patient concerning appropriate hydration to decrease the risk of kidney injury [see Warnings and Precautions (5.3)]. Extravasation If extravasation occurs during injection, advise patients to seek medical care for progression of symptoms [see Warnings and Precautions (5.6)]. 19 of 20 Reference ID: 5486655 Thyroid Dysfunction Advise parents or caregivers about the risk of developing thyroid dysfunction after IOMERVU administration. Advise parents or caregivers about when to seek medical care for their child to monitor for thyroid dysfunction [see Warnings and Precautions (5.8)]. Lactation Advise a lactating woman that interruption of breastfeeding is not necessary, however, to avoid any exposure a lactating woman may consider pumping and discarding breast milk for 10 hours after IOMERVU administration [see Use in Specific Populations (8.2)]. Manufactured for Bracco Diagnostic Inc. Monroe Township, NJ 08831 Manufactured by BIPSO GmbH 78224 Singen (Germany) 20 of 20 Reference ID: 5486655
custom-source
2025-02-12T15:47:19.675046
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80,445
10 mg each 30 Tab e s 30 TABLETS HIVES RELIEF Actual Size ® HIVES Cetirizine HCl tablets 10mg/antihistamine NDC 50580-116-04 Cetirizine HCl tablets 10 mg/antihistamine The trade dress of this ZYRTEC® package is subject to trademark protection. Active ingredient made in Switzerland HIVES RELIEF 30 Tablets 10 mg each Actual Size relief Hour 24 Reduces Hives Reduces Itching Due to Hives Hives Relief Hives Relief HIVES ® Original Prescription Strength adults and children 6 years and over adults 65 years and over ch ldren under 6 years of age one 10 mg tablet once daily; do not take more than one 10 mg tablet in 24 hours. A 5 mg product may be appropriate for less severe symptoms. ask a doctor ask a doctor consumers with iver or kidney disease ask a doctor Active ingredient (in each tablet) Purpose Cetirizine HCl 10 mg... ........ ....... ....... ....... ....... ........ ....... .....Antihistamine Uses reduces hives and relieves itching due to hives (urticaria). This product will not prevent hives or an allergic skin reaction from occurring. Warnings Severe Allergy Warning: Get emergency help immediately if you have hives along with any of the following symptoms: I trouble swallowing I dizziness or loss of consciousness I swelling of tongue I swel ing in or around mouth I trouble speaking I drooling I wheezing or problems breathing These symptoms may be signs of anaphylactic shock. This condition can be life threatening if not treated by a health professional immediately. Symptoms of anaphylactic shock may occur when hives first appear or up to a few hours later. Not a Substitute for Epinephrine. If your doctor has prescribed an epinephrine injector for “anaphylaxis” or severe a lergy symptoms that could occur with your hives, never use this product as a substitute for the epinephrine injector. If you have been prescribed an epinephrine injector, you should carry it with you at a l times. Drug Facts Drug Facts (continued) Drug Facts (continued) Drug Facts (continued) Do not use I to prevent hives from any known cause such as: I foods I insect stings I medicines I latex or rubber gloves because this product will not stop hives from occurring. Avoiding the cause of your hives is the only way to prevent them. Hives can sometimes be serious. If you do not know the cause of your hives, see your doctor for a medical exam. Your doctor may be able to help you find a cause. I if you have ever had an a lergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have I iver or kidney disease. Your doctor should determine if you need a different dose. I hives that are an unusual color, look bruised or blistered I hives that do not itch Ask a doctor or pharmacist before use if you are taking tranqui izers or sedatives. When using this product I drowsiness may occur I avoid alcoholic drinks I alcohol, sedatives, and tranqu lizers may increase drowsiness I be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if I an allergic reaction to this product occurs. Seek medical help right away. I symptoms do not improve after 3 days of treatment I the hives have lasted more than 6 weeks Other information I store between 20° to 25°C (68° to 77°F) I do not use if foil inner seal imprinted with “Sealed For Your Safety” is broken or missing I meets USP Dissolution Test 2 Inactive ingredients colloidal s licon dioxide, croscarmellose sodium, hyprome lose, lactose monohydrate, magnesium stearate, microcrystalline ce lulose, polyethylene glycol, titanium dioxide Questions? call 1-800-343-7805 (toll-free) or 215-273-8755 (collect). If pregnant or breast-feeding: I if breast-feeding: not recommended I if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) Directions Important: Read all product information before using. Keep this box for important information. Distributed by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 2024 zyrtec.com Pat. www.kenvuepats.com 30056389 20.58 in 0.125” Drug Facts Format Information 79% -25 2.0 0.5 6.00 5.00 6.50 9.00 8.00 8.00 LOT: XXXXXXXX EXP: YYYY/MMM Reference ID: 5486429 (b) (4) Tablets 10 mg each 30 HIVES RELIEF ® HIVES NDC 50580-116-04 Cetirizine HCl tablets 10mg/antihistamine Active ingredient (in each tablet) Purpose Cetirizine HCl 10 mg........................Antihistamine Uses reduces hives and relieves itching due to hives (urticaria). This product will not prevent hives or an allergic skin reaction from occurring. Warnings Severe Allergy Warning: Get emergency help immediately if you have hives along with any of the following symptoms: I trouble swallowing I dizziness or loss of consciousness I swelling of tongue I swelling in or around mouth I trouble speaking I drooling I wheezing or problems breathing These symptoms may be signs of anaphylactic shock. This condition can be life threatening if not treated by a health professional immediately. Symptoms of anaphylactic shock may occur when hives first appear or up to a few hours later. Not a Substitute for Epinephrine. If your doctor has prescribed an epinephrine injector for “anaphylaxis” or severe allergy symptoms that could occur with your hives, never use this product as a substitute for the epinephrine injector. If you have been prescribed an epinephrine injector, you should carry it with you at all times. Do not use I to prevent hives from any known cause such as: I foods I insect stings I medicines I latex or rubber gloves because this product will not stop hives from occurring. Avoiding the cause of your hives is the only way to prevent them. Hives can sometimes be serious. If you do not know the cause of your hives, see your doctor for a medical exam. Your doctor may be able to help you find a cause. I if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have I liver or kidney disease. Your doctor should determine if you need a different dose. I hives that are an unusual color, look bruised or blistered I hives that do not itch Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. When using this product I drowsiness may occur I avoid alcoholic drinks I alcohol, sedatives, and tranquilizers may increase drowsiness I be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if I an allergic reaction to this product occurs. Seek medical help right away. I symptoms do not improve after 3 days of treatment I the hives have lasted more than 6 weeks If pregnant or breast-feeding: I if breast-feeding: not recommended I if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) PEEL HERE Directions Adults and children 6 years and over: one 10 mg tablet once daily; do not take more than one 10 mg tablet in 24 hours. A 5 mg product may be appropriate for less severe symptoms. Adults 65 years and over: ask a doctor Children under 6 years of age: ask a doctor Consumers with liver or kidney disease: ask a doctor Other information I store between 20° to 25°C (68° to 77°F) I do not use if foil inner seal imprinted with “Sealed For Your Safety” is broken or missing I meets USP Dissolution Test 2 Inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide Questions? call 1-800-343-7805 (toll-free) or 215-273-8755 (collect). The trade dress of this ZYRTEC® package is subject to trademark protection. Active ingredient made in Switzerland. Distributed by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division, Fort Washington, PA 19034 USA ©J&JCI 2024 Pat. www.kenvuepats.com zyrtec.com 30056340 Drug Facts Format Information 80% 0 N/A N/A 4.50 3.50 4.70 N/A N/A 4.50 LOT: XXXXXXXX EXP: YYYY/MMM Reference ID: 5486429 (b) (4) ® Cetirizine HCl oral solution 1 mg/ml/ antihistamineHIVES Grape Flavor OPEN HERE ® HIVES Cetirizine HCl oral solution 1 mg/ml/ antihistamine HIVES RELIEF relief Hour 24 Reduces Hives Reduces Itching Due to Hives Grape Flavor Dosing cup included 4 fl oz (118 ml) ® HIVES Cetirizine HCl oral solution 1 mg/ml/ antihistamine yrs & older 6 Hives Relief HIVES RELIEF relief Hour 24 Reduces Hives Reduces Itching Due to Hives Dosing cup included Grape Flavor 4 fl oz (118 ml) Drug Facts (continued) Other information ■ store between 20° to 25°C (68° to 77°F) ■ do not use if carton is opened or if bottle wrap imprinted with “Sealed For Your Safety” is broken or missing Inactive ingredients anhydrous citric acid, flavors, propylene glycol, purified water, sodium benzoate, sorbitol solution, sucralose Questions? call 1-800-343-7805 (toll-free) or 215-273-8755 (collect). 5 mL or 10 mL once daily depending upon severity of symptoms; do not take more than 10 mL in 24 hours. adults and children 6 years and over 5 mL once daily; do not take more than 5 mL in 24 hours. adults 65 years and over children under 6 years of age ask a doctor consumers with liver or kidney disease ask a doctor Drug Facts Active ingredient Purpose (in each 5 mL) Cetirizine HCl 5 mg.......................................Antihistamine Uses reduces hives and relieves itching due to hives (urticaria). This product will not prevent hives or an allergic skin reaction from occurring. Warnings Severe Allergy Warning: Get emergency help immediately if you have hives along with any of the following symptoms: ■ trouble swallowing ■ dizziness or loss of consciousness ■ swelling of tongue ■ swelling in or around mouth ■ trouble speaking ■ drooling ■ wheezing or problems breathing These symptoms may be signs of anaphylactic shock. This condition can be life threatening if not treated by a health professional immediately. Symptoms of anaphylactic shock may occur when hives first appear or up to a few hours later. Not a Substitute for Epinephrine. If your doctor has prescribed an epinephrine injector for “anaphylaxis” or severe allergy symptoms that could occur with your hives, never use this product as a substitute for the epinephrine injector. If you have been prescribed an epinephrine injector, you should carry it with you at all times. Do not use ■ to prevent hives from any known cause such as: ■ foods ■ insect stings ■ medicines ■ latex or rubber gloves because this product will not stop hives from occurring. Avoiding the cause of your hives is the only way to prevent them. Hives can sometimes be serious. If you do not know the cause of your hives, see your doctor for a medical exam. Your doctor may be able to help you find a cause. ■ if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have ■ liver or kidney disease. Your doctor should determine if you need a different dose. ■ hives that are an unusual color, look bruised or blistered ■ hives that do not itch Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. Important: Read all product information before using. Keep this box for important information. When using this product ■ drowsiness may occur ■ avoid alcoholic drinks ■ alcohol, sedatives, and tranquilizers may increase drowsiness ■ be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if ■ an allergic reaction to this product occurs. Seek medical help right away. ■ symptoms do not improve after 3 days of treatment ■ the hives have lasted more than 6 weeks If pregnant or breast-feeding: ■ if breast-feeding: not recommended ■ if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) Directions ■ use only with enclosed dosing cup ■ find right dose on chart below ■ mL = milliliter The trade dress of this ZYRTEC package is subject to trademark protection. Active ingredient made in Switzerland Distributed by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 2024 zyrtec.com Pat. www.kenvuepats.com 30056395 NDC 50580-128-04 LOT XXXXXXXX EXP YYYY/MMM 9.69 in 0.125” Drug Facts Format Information 80% -10 2.5 0.5 6.00 5.00 6.30 10.00 8.00 8.00 (b) (4) ® Cetirizine HCl 1 mg/ml oral solution antihistamine HIVES relief 24 Hour HIVES RELIEF Reduces Hives Reduces Itching Due to Hives Grape Flavor yrs & older 6 Dosing cup should be washed and left to air dry after each use. Active ingredient made in Switzerland The trade dress of this ZYRTEC® package is subject to trademark protection. Distributed by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 2024 zyrtec.com Pat. www.kenvuepats.com 30056339 4 fl oz (118 ml) Active ingredient (in each 5 mL) Purpose Cetirizine HCl 5 mg.............................................................Antihistamine Uses reduces hives and relieves itching due to hives (urticaria). This product will not prevent hives or an allergic skin reaction from occurring. Warnings Severe Allergy Warning: Get emergency help immediately if you have hives along with any of the following symptoms: ■ trouble swallowing ■ dizziness or loss of consciousness ■ swelling of tongue ■ swelling in or around mouth ■ trouble speaking ■ drooling ■ wheezing or problems breathing These symptoms may be signs of anaphylactic shock. This condition can be life threatening if not treated by a health professional immediately. Symptoms of anaphylactic shock may occur when hives first appear or up to a few hours later. Not a Substitute for Epinephrine. If your doctor has prescribed an epinephrine injector for “anaphylaxis” or severe allergy symptoms that could occur with your hives, never use this product as a substitute for the epinephrine injector. If you have been prescribed an epinephrine injector, you should carry it with you at all times. Do not use ■ to prevent hives from any known cause such as: ■ foods ■ insect stings ■ medicines ■ latex or rubber gloves because this product will not stop hives from occurring. Avoiding the cause of your hives is the only way to prevent them. Hives can sometimes be serious. If you do not know the cause of your hives, see your doctor for a medical exam. Your doctor may be able to help you find a cause. ■ if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have ■ liver or kidney disease. Your doctor should determine if you need a different dose. ■ hives that are an unusual color, look bruised or blistered ■ hives that do not itch Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. When using this product ■ drowsiness may occur ■ avoid alcoholic drinks ■ alcohol, sedatives, and tranquilizers may increase drowsiness ■ be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if ■ an allergic reaction to this product occurs. Seek medical help right away. ■ symptoms do not improve after 3 days of treatment ■ the hives have lasted more than 6 weeks If pregnant or breast-feeding: ■ if breast-feeding: not recommended ■ if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222). Directions ■ use only with enclosed dosing cup ■ find right dose on chart below ■ mL = milliliter Adults and children 6 years and over: 5 mL or 10 mL once daily depending upon severity of symptoms; do not take more than 10 mL in 24 hours. Adults 65 years and over: 5 mL once daily; do not take more than 5 mL in 24 hours. Children under 6 years of age: ask a doctor Consumers with liver or kidney disease: ask a doctor Other information ■ store between 20° to 25°C (68° to 77°F) ■ do not use if bottle wrap imprinted with “Sealed For Your Safety” is broken or missing. Inactive ingredients anhydrous citric acid, flavors, propylene glycol, purified water, sodium benzoate, sorbitol solution, sucralose Questions? call 1-800-343-7805 (toll-free) or 215-273-8755 (collect) NDC 50580-128 04 Drug Facts Format Information 90% -20 N/A N/A 5.00 4.00 5.25 N/A N/A 5.00 LOT: XXXXXXXX EXP: YYYY/MMM Reference ID: 5486429 (b) (4) -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ MARTHA K LENHART 11/26/2024 03:45:08 PM Signature Page 1 of 1 Reference ID: 5486429 (b
custom-source
2025-02-12T15:47:20.127646
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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use YESINTEK safely and effectively. See full prescribing information for YESINTEK. YESINTEKTM (ustekinumab-kfce) injection, for subcutaneous or intravenous use Initial U.S. Approval: 2024 YESINTEKTM (ustekinumab-kfce) is biosimilar* to STELARA® (ustekinumab). ----------------------------INDICATIONS AND USAGE--------------------------- YESINTEK is a human interleukin-12 and -23 antagonist indicated for the treatment of: Adult patients with: • moderate to severe plaque psoriasis (PsO) who are candidates for phototherapy or systemic therapy. (1.1) • active psoriatic arthritis (PsA). (1.2) • moderately to severely active Crohn’s disease (CD). (1.3) • moderately to severely active ulcerative colitis. (1.4) Pediatric patients 6 years and older with: • moderate to severe plaque psoriasis, who are candidates for phototherapy or systemic therapy. (1.1) • active psoriatic arthritis (PsA). (1.2) ----------------------DOSAGE AND ADMINISTRATION----------------------- Psoriasis Adult Subcutaneous Recommended Dosage (2.1): Weight Range (kilograms) Recommended Dosage less than or equal to 100 kg 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks greater than 100 kg 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks Psoriasis Pediatric Patients (6 to 17 years old) Subcutaneous Recommended Dosage (2.1): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter. Weight Range (kilograms) Dose less than 60 kg 0.75 mg/kg 60 kg to 100 kg 45 mg greater than 100 kg 90 mg Psoriatic Arthritis Adult Subcutaneous Recommended Dosage (2.2): • The recommended dosage is 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks. • For patients with co-existent moderate-to-severe plaque psoriasis weighing greater than 100 kg, the recommended dosage is 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks. Psoriatic Arthritis Pediatric (6 to 17 years old) Subcutaneous Recommended Dosage (2.2): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter. Weight Range (kilograms) Dose less than 60 kg 0.75 mg/kg 60 kg or more 45 mg greater than 100 kg with co- existent moderate-to-severe plaque psoriasis 90 mg Crohn’s Disease and Ulcerative Colitis Initial Adult Intravenous Recommended Dosage (2.3): A single intravenous infusion using weight- based dosing: Weight Range (kilograms) Dose up to 55 kg 260 mg (2 vials) greater than 55 kg to 85 kg 390 mg (3 vials) greater than 85 kg 520 mg (4 vials) Crohn’s Disease and Ulcerative Colitis Maintenance Adult Subcutaneous Recommended Dosage (2.3): A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. ---------------------DOSAGE FORMS AND STRENGTHS---------------------- Subcutaneous Injection (3) • Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe • Injection: 45 mg/0.5 mL solution in a single-dose vial Intravenous Infusion (3) • Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial (3) ---------------------------CONTRAINDICATIONS---------------------------------- Clinically significant hypersensitivity to ustekinumab products or to any of the excipients in YESINTEK. (4) -----------------------WARNINGS AND PRECAUTIONS------------------------ • Infections: Serious infections have occurred. Avoid starting YESINTEK during any clinically important active infection. If a serious infection or clinically significant infection develops, discontinue YESINTEK until the infection resolves. (5.1) • Theoretical Risk for Particular Infections: Serious infections from mycobacteria, salmonella and Bacillus Calmette-Guerin (BCG) vaccinations have been reported in patients genetically deficient in IL- 12/IL-23. Consider diagnostic tests for these infections as dictated by clinical circumstances. (5.2). • Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with YESINTEK. Initiate treatment of latent TB before administering YESINTEK. (5.3). • Malignancies: Ustekinumab products may increase risk of malignancy. The safety of ustekinumab products in patients with a history of or a known malignancy has not been evaluated. (5.4) • Hypersensitivity Reactions: If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue YESINTEK. (5.5) • Posterior Reversible Encephalopathy Syndrome (PRES): If PRES is suspected, treat promptly and discontinue YESINTEK. (5.6) • Immunizations: Avoid use of live vaccines in patients during treatment with YESINTEK. (5.7) • Noninfectious Pneumonia: Cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. If diagnosis is confirmed, discontinue YESINTEK and institute appropriate treatment. (5.8) ------------------------------ADVERSE REACTIONS------------------------------- Most common adverse reactions are: • Psoriasis (≥3%): nasopharyngitis, upper respiratory tract infection, headache, and fatigue. (6.1) • Crohn’s Disease, induction (≥3%): vomiting. (6.1) • Crohn’s Disease, maintenance (≥3%): nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis. (6.1) • Ulcerative colitis, induction (≥3%): nasopharyngitis (6.1) • Ulcerative colitis, maintenance (≥3%): nasopharyngitis, headache, abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Biocon Biologics at 1-833-986-1468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. *Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of YESINTEK has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. Revised: 11/2024 Reference ID: 5487421 2 FULL PRESCRIBING INFORMATION: CONTENTS* 1. INDICATIONS AND USAGE 1.1. Plaque Psoriasis (PsO) 1.2. Psoriatic Arthritis (PsA) 1.3. Crohn’s Disease (CD) 1.4. Ulcerative Colitis 2. DOSAGE AND ADMINISTRATION 2.1. Recommended Dosage in Plaque Psoriasis 2.2. Recommended Dosage in Psoriatic Arthritis 2.3. Recommended Dosage in Crohn’s Disease and Ulcerative Colitis 2.4. General Considerations for Administration 2.5. Instructions for Administration of YESINTEK Prefilled Syringes Equipped with Needle Safety Guard 2.6. Preparation and Administration of YESINTEK 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion (Crohn’s Disease and Ulcerative Colitis) 3. DOSAGE FORMS AND STRENGTHS 4. CONTRAINDICATIONS 5. WARNINGS AND PRECAUTIONS 5.1. Infections 5.2. Theoretical Risk for Vulnerability to Particular Infections 5.3. Pre-treatment Evaluation for Tuberculosis 5.4. Malignancies 5.5. Hypersensitivity Reactions 5.6. Posterior Reversible Encephalopathy Syndrome (PRES) 5.7. Immunizations 5.8. Noninfectious Pneumonia 6. ADVERSE REACTIONS 6.1. Clinical Trials Experience 6.2. Immunogenicity 6.3. Postmarketing Experience 7. DRUG INTERACTIONS 7.1. Concomitant Therapies 7.2. CYP450 Substrates 7.3. Allergen Immunotherapy 8. USE IN SPECIFIC POPULATIONS 8.1. Pregnancy 8.2. Lactation 8.4. Pediatric Use 8.5 Geriatric Use 10. OVERDOSAGE 11. DESCRIPTION 12. CLINICAL PHARMACOLOGY 12.1. Mechanism of Action 12.2. Pharmacodynamics 12.3. Pharmacokinetics 13. NONCLINICAL TOXICOLOGY 13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2. Animal Toxicology and/or Pharmacology 14. CLINICAL STUDIES 14.1. Adult Plaque Psoriasis 14.2. Pediatric Plaque Psoriasis 14.3. Psoriatic Arthritis 14.4. Crohn’s Disease 14.5. Ulcerative Colitis 15. REFERENCES 16. HOW SUPPLIED/STORAGE AND HANDLING 17. PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5487421 3 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Plaque Psoriasis (PsO) YESINTEK is indicated for the treatment of adults and pediatric patients 6 years of age and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. 1.2 Psoriatic Arthritis (PsA) YESINTEK is indicated for the treatment of adults and pediatric patients 6 years of age and older with active psoriatic arthritis. 1.3 Crohn’s Disease (CD) YESINTEK is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease. 1.4 Ulcerative Colitis YESINTEK is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Plaque Psoriasis Subcutaneous Adult Dosage Regimen • For patients weighing 100 kg or less, the recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. • For patients weighing more than 100 kg, the recommended dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these subjects [see Clinical Studies (14)]. Subcutaneous Pediatric Dosage Regimen Administer YESINTEK subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter. The recommended dose of YESINTEK for pediatric patients (6-17 years old) with plaque psoriasis based on body weight is shown below (Table 1). Table 1: Recommended Dose of YESINTEK for Subcutaneous Injection in Pediatric Patients (6-17 years old) with Plaque Psoriasis Body Weight of Patient at the Time of Dosing Recommended Dose less than 60 kg 0.75 mg/kg 60 kg to 100 kg 45 mg more than 100 kg 90 mg Reference ID: 5487421 4 For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is shown in Table 2; withdraw the appropriate volume from the single-dose vial. Table 2: Injection volumes of YESINTEK 45 mg/0.5 mL single-dose vials for pediatric patients (6-17 years old) with plaque psoriasis and pediatric patients (6-17 years old) with psoriatic arthritis* weighing less than 60 kg Body Weight (kg) at the time of dosing Dose (mg) Volume of injection (mL) 15 11.3 0.12 16 12.0 0.13 17 12.8 0.14 18 13.5 0.15 19 14.3 0.16 20 15.0 0.17 21 15.8 0.17 22 16.5 0.18 23 17.3 0.19 24 18.0 0.20 25 18.8 0.21 26 19.5 0.22 27 20.3 0.22 28 21.0 0.23 29 21.8 0.24 30 22.5 0.25 31 23.3 0.26 32 24 0.27 33 24.8 0.27 34 25.5 0.28 35 26.3 0.29 36 27 0.3 37 27.8 0.31 38 28.5 0.32 39 29.3 0.32 40 30 0.33 41 30.8 0.34 42 31.5 0.35 43 32.3 0.36 44 33 0.37 45 33.8 0.37 46 34.5 0.38 47 35.3 0.39 48 36 0.4 49 36.8 0.41 50 37.5 0.42 51 38.3 0.42 52 39 0.43 53 39.8 0.44 54 40.5 0.45 55 41.3 0.46 56 42 0.46 57 42.8 0.47 58 43.5 0.48 59 44.3 0.49 * Refer to 2.2 Psoriatic Arthritis; Subcutaneous Pediatric Dosage Regimen. Reference ID: 5487421 5 2.2 Recommended Dosage in Psoriatic Arthritis Subcutaneous Adult Dosage Regimen • The recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. • For patients with co-existent moderate-to-severe plaque psoriasis weighing more than 100 kg, the recommended dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. Subcutaneous Pediatric Dosage Regimen Administer YESINTEK subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter. The recommended dose of YESINTEK for pediatric patients (6 to 17 years old) with psoriatic arthritis, based on body weight, is shown below (Table 3). Table 3: Recommended Dose of YESINTEK for Subcutaneous Injection in Pediatric Patients (6 to 17 years old) with Psoriatic Arthritis Body Weight of Patient at the Time of Dosing Recommended Dose less than 60 kg* 0.75 mg/kg 60 kg or more 45 mg greater than 100 kg with co-existent moderate-to- severe plaque psoriasis 90 mg * For pediatric patients weighing less than 60 kg, the administration volume for the recommended dose (0.75 mg/kg) is shown in Table 2; withdraw the appropriate volume from the single-dose vial. 2.3 Recommended Dosage in Crohn’s Disease and Ulcerative Colitis Intravenous Induction Adult Dosage Regimen A single intravenous infusion dose of YESINTEK using the weight-based dosage regimen specified in Table 4 [see Instructions for dilution of YESINTEK 130 mg vial for intravenous infusion (2.6)]. Table 4: Initial Intravenous Dosage of YESINTEK Body Weight of Patient at the time of dosing Dose Number of 130 mg/26 mL (5 mg/mL) YESINTEK vials 55 kg or less 260 mg 2 more than 55 kg to 85 kg 390 mg 3 more than 85 kg 520 mg 4 Subcutaneous Maintenance Adult Dosage Regimen The recommended maintenance dosage is a subcutaneous 90 mg dose administered 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. Reference ID: 5487421 6 2.4 General Considerations for Administration • YESINTEK is intended for use under the guidance and supervision of a healthcare provider. YESINTEK should only be administered to patients who will be closely monitored and have regular follow-up visits with a healthcare provider. The appropriate dose should be determined by a healthcare provider using the patient’s current weight at the time of dosing. In pediatric patients, it is recommended that YESINTEK be administered by a healthcare provider. If a healthcare provider determines that it is appropriate, a patient may self-inject or a caregiver may inject YESINTEK after proper training in subcutaneous injection technique. Instruct patients to follow the directions provided in the Medication Guide [see Medication Guide]. • It is recommended that each injection be administered at a different anatomic location (such as upper arms, gluteal regions, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, or indurated. When using the single-dose vial, a 1 mL syringe with a 27 gauge, ½ inch needle is recommended. • Prior to administration, visually inspect YESINTEK for particulate matter and discoloration. YESINTEK is a clear, colorless to pale yellow solution. Do not use YESINTEK if it is discolored or cloudy, or if other particulate matter is present. YESINTEK does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe. 2.5 Instructions for Administration of YESINTEK Prefilled Syringes Equipped with Needle Safety Guard Refer to the diagram below for the provided instructions. • Hold the BODY and remove the NEEDLE COVER. Do not hold the PLUNGER or PLUNGER HEAD while removing the NEEDLE COVER or the PLUNGER may move. Do not use the prefilled syringe if it is dropped without the NEEDLE COVER in place. Reference ID: 5487421 7 • Inject YESINTEK subcutaneously as recommended [see Dosage and Administration (2.1, 2.2, 2.3)]. • Inject all of the medication by pushing in the PLUNGER until the PLUNGER HEAD is completely between the needle guard wings. Injection of the entire prefilled syringe contents is necessary to activate the needle guard. • After injection, maintain the pressure on the PLUNGER HEAD and remove the needle from the skin. Slowly take your thumb off the PLUNGER HEAD to allow the empty syringe to move up until the entire needle is covered by the needle guard, as shown by the illustration below: • Used syringes should be placed in a puncture-resistant container. 2.6 Preparation and Administration of YESINTEK 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion (Crohn’s Disease and Ulcerative Colitis) YESINTEK solution for intravenous infusion must be diluted, prepared, and infused by a healthcare professional using aseptic technique. 1. Calculate the dose and the number of YESINTEK vials needed based on patient weight (Table 4). Each 26 mL vial of YESINTEK contains 130 mg of ustekinumab-kfce. 2. Withdraw, and then discard a volume of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal to the volume of YESINTEK to be added (discard 26 mL sodium chloride for each vial of YESINTEK needed, for 2 vials- discard 52 mL, for 3 vials- discard 78 mL, 4 vials- discard 104 mL). Alternatively, a 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used. Reference ID: 5487421 8 3. Withdraw 26 mL of YESINTEK from each vial needed and add it to the 250 mL infusion bag. The final volume in the infusion bag should be 250 mL. Gently mix. 4. Visually inspect the diluted solution before infusion. Do not use if visibly opaque particles, discoloration or foreign particles are observed. 5. Infuse the diluted solution over a period of at least one hour. Once diluted, the infusion should be completely administered within four hours of the dilution in the infusion bag. 6. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer). 7. Do not infuse YESINTEK concomitantly in the same intravenous line with other agents. 8. YESINTEK does not contain preservatives. Each vial is for one-time use in only one patient. Discard any remaining solution. Dispose any unused medicinal product in accordance with local requirements. Storage If necessary, the diluted infusion solution may be kept at room temperature up to 25°C (77°F) for up to 4 hours. Storage time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within 4 hours after the dilution in the infusion bag (cumulative time after preparation including the storage and the infusion period). Do not freeze. Discard any unused portion of the infusion solution. 3 DOSAGE FORMS AND STRENGTHS YESINTEK (ustekinumab-kfce) is a clear and colorless to pale yellow solution. Subcutaneous Injection • Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe • Injection: 45 mg/0.5 mL solution in a single-dose vial Intravenous Infusion • Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial 4 CONTRAINDICATIONS YESINTEK is contraindicated in patients with clinically significant hypersensitivity to ustekinumab products or to any of the excipients in YESINTEK [see Warnings and Precautions (5.5)]. Reference ID: 5487421 9 5 WARNINGS AND PRECAUTIONS 5.1 Infections Ustekinumab products may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab products [see Adverse Reactions (6.1, 6.3)]. Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in clinical trials included the following: • Plaque Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis, and urinary tract infections. • Psoriatic arthritis: cholecystitis. • Crohn’s disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis. • Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis. Avoid initiating treatment with YESINTEK in patients with any clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to initiating use of YESINTEK in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while on treatment with YESINTEK and discontinue YESINTEK for serious or clinically significant infections until the infection resolves or is adequately treated. 5.2 Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with ustekinumab products may be susceptible to these types of infections. Consider appropriate diagnostic testing, (e.g., tissue culture, stool culture, as dictated by clinical circumstances). 5.3 Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis infection prior to initiating treatment with YESINTEK. Avoid administering YESINTEK to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis prior to administering YESINTEK. Consider anti-tuberculosis therapy prior to initiation of YESINTEK in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving YESINTEK for signs and symptoms of active tuberculosis during and after treatment. Reference ID: 5487421 10 5.4 Malignancies Ustekinumab products are immunosuppressants and may increase the risk of malignancy. Malignancies were reported among subjects who received ustekinumab in clinical trials [see Adverse Reactions (6.1)]. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical Toxicology (13)]. The safety of ustekinumab products has not been evaluated in patients who have a history of malignancy or who have a known malignancy. There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving ustekinumab products who had pre-existing risk factors for developing non-melanoma skin cancer. Monitor all patients receiving YESINTEK for the appearance of non-melanoma skin cancer. Closely follow patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment [see Adverse Reactions (6.1)]. 5.5 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with ustekinumab products [see Adverse Reactions (6.1, 6.3)]. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue YESINTEK. 5.6 Posterior Reversible Encephalopathy Syndrome (PRES) Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing experience in patients with psoriasis, psoriatic arthritis, and Crohn’s disease. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab product initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab products. Monitor all patients treated with YESINTEK for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue YESINTEK. 5.7 Immunizations Prior to initiating therapy with YESINTEK, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with YESINTEK should avoid receiving live vaccines. Avoid administering BCG vaccines during treatment with YESINTEK or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving YESINTEK because of the potential risk for shedding from the household contact and transmission to patient. Non-live vaccinations received during a course of YESINTEK may not elicit an immune response sufficient to prevent disease. Reference ID: 5487421 11 5.8 Noninfectious Pneumonia Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue YESINTEK and institute appropriate treatment [see Postmarketing Experience (6.3)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the label: • Infections [see Warnings and Precautions (5.1)] • Malignancies [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)] • Noninfectious Pneumonia [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Subjects with Plaque Psoriasis The safety data reflect exposure to ustekinumab in 3117 adult subjects with plaque psoriasis, including 2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at least five years. Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% with higher rates in the ustekinumab groups during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see Clinical Studies (14)]. Table 5: Adverse Reactions Reported by ≥1% of Subjects with Plaque Psoriasis and at Higher Rates in the ustekinumab groups through Week 12 in Ps STUDY 1 and Ps STUDY 2 Ustekinumab Placebo 45 mg 90 mg Subjects treated 665 664 666 Nasopharyngitis 51 (8%) 56 (8%) 49 (7%) Upper respiratory tract infection 30 (5%) 36 (5%) 28 (4%) Reference ID: 5487421 12 Headache 23 (3%) 33 (5%) 32 (5%) Fatigue 14 (2%) 18 (3%) 17 (3%) Back pain 8 (1%) 9 (1%) 14 (2%) Dizziness 8 (1%) 8 (1%) 14 (2%) Pharyngolaryngeal pain 7 (1%) 9 (1%) 12 (2%) Pruritus 9 (1%) 10 (2%) 9 (1%) Injection site erythema 3 (<1%) 6 (1%) 13 (2%) Myalgia 4 (1%) 7 (1%) 8 (1%) Depression 3 (<1%) 8 (1%) 4 (1%) Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 through week 12 included: cellulitis, herpes zoster, diverticulitis, and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation). One case of PRES occurred during adult plaque psoriasis clinical trials [see Warnings and Precautions (5.6)]. Infections In the placebo-controlled period of clinical trials of subjects with plaque psoriasis (average follow- up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for ustekinumab-treated subjects), 27% of ustekinumab-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in 0.3% of ustekinumab-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) [see Warnings and Precautions (5.1)]. In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of ustekinumab-treated subjects reported infections (0.87 per subject-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up). Malignancies In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years, representing 8998 subject-years of exposure), 1.7% of ustekinumab-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of ustekinumab-treated subjects (0.52 per hundred subject-years of follow-up) [see Warnings and Precautions (5.4)]. The most frequently observed malignancies other than non-melanoma skin cancer during the clinical trials were: prostate, melanoma, colorectal and breast. Malignancies other than non-melanoma skin cancer in ustekinumab-treated subjects during the controlled and uncontrolled portions of trials were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).1 Pediatric Subjects with Plaque Psoriasis The safety of ustekinumab was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects 12 to 17 years old. Ps STUDY 4 evaluated safety for up to 56 weeks in 44 pediatric subjects 6 to 11 Reference ID: 5487421 13 years old. The safety profile in pediatric subjects was similar to the safety profile from trials in adults with plaque psoriasis. Psoriatic Arthritis The safety of ustekinumab was assessed in 927 subjects in two randomized, double-blind, placebo- controlled trials in adults with active psoriatic arthritis (PsA). The overall safety profile of ustekinumab in subjects with PsA was consistent with the safety profile seen in adult psoriasis clinical trials. A higher incidence of arthralgia, nausea, and dental infections was observed in ustekinumab-treated subjects when compared with placebo-treated subjects (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical trials. Crohn’s Disease The safety of ustekinumab was assessed in 1407 subjects with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] greater than or equal to 220 and less than or equal to 450) in three randomized, double-blind, placebo-controlled, parallel-group, multicenter trials. These 1407 subjects included 40 subjects who received a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses. In trials CD-1 and CD- 2 there were 470 subjects who received ustekinumab 6 mg/kg as a weight-based single intravenous induction dose and 466 who received placebo [see Dosage and Administration (2.3)]. Subjects who were responders in either trial CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, or placebo for 44 weeks in trial CD-3. Subjects in these 3 trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX)], oral corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn’s disease [see Clinical Studies (14.4)]. The overall safety profile of ustekinumab was consistent with the safety profile seen in the adult psoriasis and psoriatic arthritis clinical trials. Common adverse reactions in trials CD-1 and CD-2 and in trial CD-3 are listed in Tables 6 and 7, respectively. Table 6: Common adverse reactions through Week 8 in Trials CD-1 and CD-2 occurring in ≥3% of Ustekinumab - treated subjects and higher than placebo Placebo N=466 Ustekinumab 6 mg/kg single intravenous induction dose N=470 Vomiting 3% 4% Other less common adverse reactions reported in subjects in trials CD-1 and CD-2 included asthenia (1% vs 0.4%), acne (1% vs 0.4%), and pruritus (2% vs 0.4%). Reference ID: 5487421 14 Table 7: Common adverse reactions through Week 44 in Trial CD-3 occurring in ≥3% of Ustekinumab -treated subjects and higher than placebo Placebo N=133 Ustekinumab 90 mg subcutaneous maintenance dose every 8 weeks N=131 Nasopharyngitis 8% 11% Injection site erythema 0 5% Vulvovaginal candidiasis/mycotic infection 1% 5% Bronchitis 3% 5% Pruritus 2% 4% Urinary tract infection 2% 4% Sinusitis 2% 3% Infections In subjects with Crohn’s disease, serious or other clinically significant infections included anal abscess, gastroenteritis, and pneumonia. In addition, listeria meningitis and ophthalmic herpes zoster were reported in one patient each [see Warnings and Precautions (5.1)]. Malignancies With up to one year of treatment in the Crohn’s disease clinical trials, 0.2% of ustekinumab-treated subjects (0.36 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.58 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non- melanoma skin cancers occurred in 0.2% of ustekinumab-treated subjects (0.27 events per hundred patient-years) and in none of the placebo-treated subjects. Hypersensitivity Reactions Including Anaphylaxis In CD trials, two subjects reported hypersensitivity reactions following ustekinumab administration. One patient experienced signs and symptoms consistent with anaphylaxis (tightness of the throat, shortness of breath, and flushing) after a single subcutaneous administration (0.1% of subjects receiving subcutaneous ustekinumab). In addition, one subject experienced signs and symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body temperature) after the initial intravenous ustekinumab dose (0.08% of subjects receiving intravenous ustekinumab). These subjects were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour. Ulcerative Colitis The safety of ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to severely active ulcerative colitis [see Clinical Studies (14.5)]. The overall safety profile of ustekinumab in subjects with ulcerative colitis was consistent with the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of ustekinumab-treated subjects and at a higher rate than placebo were: Reference ID: 5487421 15 • Induction (UC-1): nasopharyngitis (7% vs 4%). • Maintenance (UC-2): nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs. 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and nausea (3% vs 2%). Infections In subjects with ulcerative colitis, serious or other clinically significant infections included gastroenteritis and pneumonia. In addition, listeriosis and ophthalmic herpes zoster were reported in one subject each [see Warnings and Precautions (5.1)]. Malignancies With up to one year of treatment in the ulcerative colitis clinical trials, 0.4% of ustekinumab- treated subjects (0.48 events per hundred patient-years) and 0.0% of placebo-treated subjects (0.00 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.5% of ustekinumab-treated subjects (0.64 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.40 events per hundred patient- years). 6.2 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ustekinumab or of other ustekinumab products. Approximately 6 to 12.4% of subjects treated with ustekinumab in plaque psoriasis and psoriatic arthritis clinical trials developed antibodies to ustekinumab, which were generally low-titer. In plaque psoriasis clinical trials, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In plaque psoriasis trials, the majority of subjects who were positive for antibodies to ustekinumab had neutralizing antibodies. In Crohn’s disease and ulcerative colitis clinical trials, 2.9% and 4.6% of subjects, respectively, developed antibodies to ustekinumab when treated with ustekinumab for approximately one year. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen. 6.3 Postmarketing Experience The following adverse reactions have been reported during post-approval use of ustekinumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ustekinumab product exposure. Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria). Reference ID: 5487421 16 Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections and tuberculosis). Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES). Respiratory, thoracic, and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia. Skin reactions: Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis. 7 DRUG INTERACTIONS 7.1 Concomitant Therapies In plaque psoriasis trials the safety of ustekinumab products in combination with immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis trials, concomitant MTX use did not appear to influence the safety or efficacy of ustekinumab. In Crohn’s disease and ulcerative colitis induction trials, immunomodulators (6-MP, AZA, MTX) were used concomitantly in approximately 30% of subjects and corticosteroids were used concomitantly in approximately 40% and 50% of Crohn’s disease and ulcerative colitis subjects, respectively. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of ustekinumab. 7.2 CYP450 Substrates The formation of CYP450 enzymes can be suppressed by increased levels of certain cytokines (e.g., IL-1, IL-6, TNFα, IFN) during chronic inflammation. Thus, use of ustekinumab products, antagonists of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of YESINTEK in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and adjust the individual dosage of the CYP substrate as needed. See the prescribing information of specific CYP substrates. A CYP-mediated drug interaction effect was not observed in subjects with Crohn’s disease [see Clinical Pharmacology (12.3)]. 7.3 Allergen Immunotherapy Ustekinumab products have not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab products may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Reference ID: 5487421 17 Limited data from observational studies, published case reports, and postmarketing surveillance on the use of ustekinumab products during pregnancy are insufficient to inform a drug associated risk of major birth defects, miscarriage, and other adverse maternal or fetal outcomes. Transport of human IgG antibody across the placenta increases as pregnancy progresses and peaks during the third trimester; therefore, ustekinumab products may be transferred to the developing fetus (see Clinical Considerations). In animal reproductive and developmental toxicity studies, no adverse developmental effects were observed in offspring after administration of ustekinumab to pregnant monkeys at exposures greater than 100 times the maximum recommended human dose (MRHD). The background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Because ustekinumab products may theoretically interfere with immune response to infections, consider risks and benefits prior to administering live vaccines to infants exposed to YESINTEK in utero. There are insufficient data regarding exposed infant serum levels of ustekinumab products at birth and the duration of persistence of ustekinumab products in infant serum after birth. Although a specific timeframe to delay administration of live attenuated vaccines in infants exposed in utero is unknown, consider the risks and benefits of delaying a minimum of 6 months after birth because of the clearance of the product. Data Animal Data Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys. No teratogenic or other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab subcutaneously twice weekly or intravenously weekly during the period of organogenesis. Serum concentrations of ustekinumab in pregnant monkeys were greater than 100 times the serum concentration in patients treated subcutaneously with 90 mg of ustekinumab weekly for 4 weeks. In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly at exposures greater than 100 times the MRHD from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related-effects on functional, morphological, or immunological development were observed in the neonates from birth through six months of age. Reference ID: 5487421 18 8.2 Lactation Risk Summary Limited data from published literature suggests that ustekinumab is present in human breast milk. There are no available data on the effects of ustekinumab products on milk production. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to ustekinumab products are unknown. No adverse effects on the breastfed infant causally related to ustekinumab products have been identified in the published literature or postmarketing experience. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for YESINTEK and any potential adverse effects on the breastfed child from YESINTEK or from the underlying maternal condition. 8.4 Pediatric Use Plaque Psoriasis The safety and effectiveness of YESINTEK have been established for the treatment of moderate to severe plaque psoriasis in pediatric patients 6 to 17 years of age who are candidates for phototherapy or systemic therapy. Use of YESINTEK in pediatric patients 12 to less than 17 years of age is supported by evidence from a multicenter, randomized, 60-week trial (Ps STUDY 3) of ustekinumab that included a 12- week, double-blind, placebo-controlled, parallel-group portion, in 110 pediatric subjects 12 years of age and older [see Adverse Reactions (6.1), Clinical Studies (14.2)]. Use of YESINTEK in pediatric patients 6 to 11 years of age is supported by evidence from an open-label, single-arm, efficacy, safety, and pharmacokinetics trial (Ps STUDY 4) of ustekinumab in 44 subjects [see Adverse Reactions (6.1), Pharmacokinetics (12.3)]. The safety and effectiveness of YESINTEK have not been established in pediatric patients less than 6 years of age with plaque psoriasis. Psoriatic Arthritis The safety and effectiveness of YESINTEK have been established for treatment of psoriatic arthritis in pediatric patients 6 to 17 years old. Use of YESINTEK in these age groups is supported by evidence from adequate and well controlled trials of ustekinumab in adults with psoriasis and PsA, pharmacokinetic data from adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and safety data of ustekinumab from two clinical trials in 44 pediatric subjects 6 to 11 years old with psoriasis and 110 pediatric subjects 12 to 17 years old with psoriasis. The observed pre-dose (trough) concentrations are generally comparable between adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and the PK exposure is expected to be comparable between adult and pediatric subjects with PsA [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2, 14.3)]. Reference ID: 5487421 19 The safety and effectiveness of YESINTEK have not been established in pediatric patients less than 6 years old with psoriatic arthritis. Crohn’s Disease and Ulcerative Colitis The safety and effectiveness of YESINTEK have not been established in pediatric patients with Crohn’s disease or ulcerative colitis. 8.5 Geriatric Use Of the 6709 subjects exposed to ustekinumab, a total of 340 were 65 years of age or older (183 subjects with plaque psoriasis, 65 subjects with psoriatic arthritis, 58 subjects with Crohn’s disease and 34 subjects with ulcerative colitis), and 40 subjects were 75 years of age or older. Clinical trials of ustekinumab did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects. 10 OVERDOSAGE Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose- limiting toxicity. In case of overdosage, monitor the patient for any signs or symptoms of adverse reactions or effects and institute appropriate symptomatic treatment immediately. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations. 11 DESCRIPTION Ustekinumab-kfce, a human IgG1κ monoclonal antibody, is a human interleukin-12 and -23 antagonist. Using DNA recombinant technology, ustekinumab-kfce is produced in a murine cell line (Sp2/0). The manufacturing process contains steps for the clearance of viruses. Ustekinumab is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons. YESINTEK (ustekinumab-kfce) injection is a sterile, preservative-free, clear and colorless to pale yellow solution with pH of 5.7- 6.3. YESINTEK for Subcutaneous Use Available as 45 mg of ustekinumab-kfce in 0.5 mL and 90 mg of ustekinumab-kfce in 1 mL, supplied as a sterile solution in a single-dose prefilled syringe with a 29 gauge fixed ½ inch needle and as 45 mg of ustekinumab-kfce in 0.5 mL in a single-dose 2 mL Type I glass vial with a coated stopper. The syringe is fitted with a passive needle guard and a needle cover. Each 0.5 mL prefilled syringe or vial delivers 45 mg ustekinumab-kfce, histidine, L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg). Hydrochloric acid and sodium hydroxide are used to adjust pH to 5.7- 6.3 during manufacturing. Each 1 mL prefilled syringe delivers 90 mg ustekinumab-kfce, histidine, L-histidine monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg). Hydrochloric acid and sodium hydroxide are used to adjust pH to 5.7- 6.3 during manufacturing. Reference ID: 5487421 20 YESINTEK for Intravenous Infusion Available as 130 mg of ustekinumab-kfce in 26 mL, supplied as a single-dose 30 mL Type I glass vial with a coated stopper. Each 26 mL vial delivers 130 mg ustekinumab-kfce, edetate disodium (0.47 mg), histidine (20 mg), L-histidine hydrochloride monohydrate (27 mg), methionine (10.4 mg), Polysorbate 80 (10.4 mg), and sucrose (2210 mg). Hydrochloric acid and sodium hydroxide added to adjust the pH to 5.7- 6.3 during manufacturing. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ustekinumab products are human IgG1қ monoclonal antibodies that bind with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab products were shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1. The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn’s disease and ulcerative colitis. In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab products, was shown to be protective. 12.2 Pharmacodynamics Plaque Psoriasis In a small exploratory trial, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in lesional skin biopsies measured at baseline and up to two weeks post- treatment in subjects with plaque psoriasis. Ulcerative Colitis In both trial UC-1 (induction) and trial UC-2 (maintenance), a positive relationship was observed between exposure and rates of clinical remission, clinical response, and endoscopic improvement. The response rate approached a plateau at the ustekinumab exposures associated with the recommended dosing regimen for maintenance treatment [see Clinical Studies (14.5)]. 12.3 Pharmacokinetics Absorption In adult subjects with plaque psoriasis, the median time to reach the maximum serum concentration (Tmax) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of 45 mg (N=22) and 90 mg (N=24) of ustekinumab. In healthy subjects (N=30), the median Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in subjects with plaque psoriasis. Reference ID: 5487421 21 Following multiple subcutaneous doses of ustekinumab in adult subjects with plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state trough serum ustekinumab concentrations were 0.69 ± 0.69 mcg/mL for subjects less than or equal to 100 kg receiving a 45 mg dose and 0.74 ± 0.78 mcg/mL for subjects greater than 100 kg receiving a 90 mg dose. There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks. Following the recommended intravenous induction dose, mean ±SD peak serum ustekinumab concentration was 125.2 ± 33.6 mcg/mL in subjects with Crohn’s disease, and 129.1 ± 27.6 mcg/mL in subjects with ulcerative colitis. Starting at Week 8, the recommended subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 weeks. Steady state ustekinumab concentration was achieved by the start of the second maintenance dose. There was no apparent accumulation in ustekinumab concentration over time when given subcutaneously every 8 weeks. Mean ±SD steady-state trough concentration was 2.5 ± 2.1 mcg/mL in subjects with Crohn’s disease, and 3.3 ± 2.3 mcg/mL in subjects with ulcerative colitis for 90 mg ustekinumab administered every 8 weeks. Distribution Population pharmacokinetic analyses showed that the volume of distribution of ustekinumab in the central compartment was 2.7 L (95% CI: 2.69, 2.78) in subjects with Crohn’s disease and 3.0 L (95% CI: 2.96, 3.07) in subjects with ulcerative colitis. The total volume of distribution at steady- state was 4.6 L in subjects with Crohn’s disease and 4.4 L in subjects with ulcerative colitis. Elimination The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all plaque psoriasis trials following subcutaneous administration. Population pharmacokinetic analyses showed that the clearance of ustekinumab was 0.19 L/day (95% CI: 0.185, 0.197) in subjects with Crohn’s disease and 0.19 L/day (95% CI: 0.179, 0.192) in subjects with ulcerative colitis with an estimated median terminal half-life of approximately 19 days for both IBD (Crohn’s disease and ulcerative colitis) populations. These results indicate the pharmacokinetics of ustekinumab were similar between subjects with Crohn’s disease and ulcerative colitis. Metabolism The metabolic pathway of ustekinumab products has not been characterized. As a human IgG1κ monoclonal antibody, ustekinumab products are expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Specific Populations Weight When given the same dose, subjects with plaque psoriasis or psoriatic arthritis weighing more than 100 kg had lower median serum ustekinumab concentrations compared with those subjects weighing 100 kg or less. The median trough serum concentrations of ustekinumab in subjects of Reference ID: 5487421 22 higher weight (greater than 100 kg) in the 90 mg group were comparable to those in subjects of lower weight (100 kg or less) in the 45 mg group. Age: Geriatric Population A population pharmacokinetic analysis (N=106/1937 subjects with plaque psoriasis greater than or equal to 65 years old) was performed to evaluate the effect of age on the pharmacokinetics of ustekinumab. There were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution) in subjects older than 65 years old. Age: Pediatric Population Following multiple recommended doses of ustekinumab in pediatric subjects 6 to 17 years of age with plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28. At Week 28, the mean ±SD steady-state trough serum ustekinumab concentrations were 0.36 ± 0.26 mcg/mL and 0.54 ± 0.43 mcg/mL, respectively, in pediatric subjects 6 to 11 years of age and pediatric subjects 12 to 17 years of age. Overall, the observed steady-state ustekinumab trough concentrations in pediatric subjects with plaque psoriasis were within the range of those observed for adult subjects with plaque psoriasis and adult subjects with PsA after administration of ustekinumab. Drug Interaction Studies The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4). No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly with ustekinumab at the approved recommended dosage in subjects with Crohn’s disease [see Drug Interactions (7.2)]. Population pharmacokinetic analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to a TNF blocker in subjects with psoriatic arthritis. In subjects with Crohn’s disease and ulcerative colitis, population pharmacokinetic analyses did not indicate changes in ustekinumab clearance with concomitant use of corticosteroids or immunomodulators (AZA, 6-MP, or MTX); and serum ustekinumab concentrations were not impacted by concomitant use of these medications. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of ustekinumab products. Published literature showed that administration of murine IL-12 caused an anti-tumor effect in mice that contained transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice Reference ID: 5487421 23 genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed UV- induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in mouse models for malignancy risk in humans is unknown. No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab at subcutaneous doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and during the mating period. However, fertility and pregnancy outcomes were not evaluated in mated females. No effects on fertility were observed in female mice that were administered an analogous IL-12/IL- 23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and during early pregnancy. 13.2 Animal Toxicology and/or Pharmacology In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly for 26 weeks had a bacterial infection. 14 CLINICAL STUDIES 14.1 Adult Plaque Psoriasis Two multicenter, randomized, double-blind, placebo-controlled trials (Ps STUDY 1 and Ps STUDY 2) enrolled a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded from the trials. Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The trials had the same design through Week 28. In both trials, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of ustekinumab. Subjects randomized to ustekinumab received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo at Weeks 0 and 4 crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16. In both trials, subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline PGA score was marked or severe in 44% of subjects in Ps STUDY 1 and 40% of subjects in Ps STUDY 2. Approximately two-thirds of all subjects had received prior phototherapy, 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis, with 56% receiving prior conventional systemic therapy and 43% receiving prior biologic therapy. A total of 28% of subjects had a history of psoriatic arthritis. In both trials, the endpoints were the proportion of subjects who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the Physician’s Global Assessment (PGA). The PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician’s overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling. Reference ID: 5487421 24 Clinical Response The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 8 below. Table 8: Clinical Outcomes at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2 Examination of age, gender, and race subgroups did not identify differences in response to ustekinumab among these subgroups. In subjects who weighed 100 kg or less, response rates were comparable with both the 45 mg and 90 mg doses; however, in subjects who weighed greater than 100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg dosing (Table 9 below). Table 9: Clinical Outcomes by Weight at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2 * Subjects were dosed with trial medication at Weeks 0 and 4. Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re- randomized at Week 40 to either continued dosing of ustekinumab (ustekinumab at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re- randomized to ustekinumab treatment were PASI 75 responders compared with 63% (100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks. 14.2 Pediatric Plaque Psoriasis A multicenter, randomized, double blind, placebo-controlled trial (Ps STUDY 3) enrolled 110 pediatric subjects 12 to 17 years of age with a minimum BSA involvement of 10%, a PASI score Ps STUDY 1 Ps STUDY 2 Ustekinumab Ustekinumab Placebo 45 mg 90 mg Placebo 45 mg 90 mg Subjects randomized 255 255 256 410 409 411 PASI 75 response 8 (3%) 171 (67%) 170 (66%) 15 (4%) 273 (67%) 311 (76%) PGA of Cleared or Minimal 10 (4%) 151 (59%) 156 (61%) 18 (4%) 277 (68%) 300 (73%) Ps STUDY 1 Ps STUDY 2 Ustekinumab Ustekinumab Placebo 45 mg 90 mg Placebo 45 mg 90 mg Subjects randomized 255 255 256 410 409 411 PASI 75 response * <100 kg 4% 6/166 74% 124/168 65% 107/164 4% 12/290 73% 218/297 78% 225/289 >100 kg 2% 2/89 54% 47/87 68% 63/92 3% 3/120 49% 55/112 71% 86/121 PGA of Cleared or Minimal * <100 kg 4% 7/166 64% 108/168 63% 103/164 5% 14/290 74% 220/297 75% 216/289 >100 kg 3% 3/89 49% 43/87 58% 53/92 3% 4/120 51% 57/112 69% 84/121 Reference ID: 5487421 25 greater than or equal to 12, and a PGA score greater than or equal to 3, who were candidates for phototherapy or systemic therapy and whose disease was inadequately controlled by topical therapy. Subjects were randomized to receive placebo (n = 37), the recommended dose of ustekinumab (n = 36), or one-half the recommended dose of ustekinumab (n = 37) by subcutaneous injection at Weeks 0 and 4 followed by dosing every 12 weeks (q12w). The recommended dose of ustekinumab was 0.75 mg/kg for subjects weighing less than 60 kg, 45 mg for subjects weighing 60 kg to 100 kg, and 90 mg for subjects weighing greater than 100 kg. At Week 12, subjects who received placebo were crossed over to receive ustekinumab at the recommended dose or one-half the recommended dose. Of the pediatric subjects, approximately 63% had prior exposure to phototherapy or conventional systemic therapy and approximately 11% had prior exposure to biologics. The endpoints were the proportion of subjects who achieved a PGA score of cleared (0) or minimal (1), PASI 75, and PASI 90 at Week 12. Subjects were followed for up to 60 weeks following first administration of trial agent. Clinical Response The efficacy results at Week 12 for Ps STUDY 3 are presented in Table 10. Table 10: Efficacy Results at Week 12 in Pediatric Subjects 12 to 17 years with Plaque Psoriasis in Ps STUDY 3 Ps STUDY 3 Placebo n (%) Ustekinumab*n (%) N 37 36 PGA PGA of cleared (0) or minimal (1) 2 (5.4%) 25 (69.4%) PASI PASI 75 responders 4 (10.8%) 29 (80.6%) PASI 90 responders 2 (5.4%) 22 (61.1%) * Using the weight-based dosage regimen specified in Table 1 and Table 2. 14.3 Psoriatic Arthritis The safety and efficacy of ustekinumab was assessed in 927 subjects (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled trials in adult subjects 18 years of age and older with active PsA (≥5 swollen joints and ≥5 tender joints) despite non- steroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Subjects in these trials had a diagnosis of PsA for at least 6 months. Subjects with each subtype of PsA were enrolled, including polyarticular arthritis with the absence of rheumatoid nodules (39%), spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%) and arthritis mutilans (0.5%). Over 70% and 40% of the subjects, respectively, had enthesitis and dactylitis at baseline. Subjects were randomized to receive treatment with ustekinumab 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and 4 followed by every 12 weeks (q12w) dosing. Approximately 50% Reference ID: 5487421 26 of subjects continued on stable doses of MTX (≤25 mg/week). The primary endpoint was the percentage of subjects achieving ACR 20 response at Week 24. In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the subjects, respectively, had been previously treated with DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-α agent was not allowed. In PsA STUDY 2, 58% (n=180) of the subjects had been previously treated with TNF blocker, of whom over 70% had discontinued their TNF blocker treatment for lack of efficacy or intolerance at any time. Clinical Response In both trials, a greater proportion of subjects achieved ACR 20, ACR 50 and PASI 75 response in the ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 11). ACR 70 responses were also higher in the ustekinumab 45 mg and 90 mg groups, although the difference was only numerical (p=NS) in STUDY 2. Responses were consistent in subjects treated with ustekinumab alone or in combination with methotrexate. Responses were similar in subjects regardless of prior TNFα exposure. Table 11: ACR 20, ACR 50, ACR 70 and PASI 75 responses in PsA STUDY 1 and PsA STUDY 2 at Week 24 PsA STUDY 1 PsA STUDY 2 Ustekinumab Ustekinumab Placebo 45 mg 90 mg Placebo 45 mg 90 mg Number of subjects randomized 206 205 204 104 103 105 ACR 20 response, N (%) 47 (23%) 87 (42%) 101 (50%) 21 (20%) 45 (44%) 46 (44%) ACR 50 response, N (%) 18 (9%) 51 (25%) 57 (28%) 7 (7%) 18 (17%) 24 (23%) ACR 70 response, N (%) 5 (2%) 25 (12%) 29 (14%) 3 (3%) 7 (7%) 9 (9%) Number of subjects with ≥ 3% BSAa 146 145 149 80 80 81 PASI 75 response, N (%) 16 (11%) 83 (57%) 93 (62%) 4 (5%) 41 (51%) 45 (56%) a Number of subjects with ≥ 3% BSA psoriasis skin involvement at baseline The percent of subjects achieving ACR 20 responses by visit is shown in Figure 1. Reference ID: 5487421 27 Figure 1: Percent of subjects achieving ACR 20 response through Week 24 PsA STUDY 1 The results of the components of the ACR response criteria are shown in Table 12. Table 12: Mean change from baseline in ACR components at Week 24 PsA STUDY 1 Ustekinumab Placebo (N = 206) 45mg (N = 205) 90 mg (N = 204) Number of swollen jointsa Baseline 15 12 13 Mean Change at Week 24 -3 -5 -6 Number of tender jointsb Baseline 25 22 23 Mean Change at Week 24 -4 -8 -9 Subject’s assessment of painc Baseline 6.1 6.2 6.6 Mean Change at Week 24 -0.5 -2.0 -2.6 Subject global assessmentc Baseline 6.1 6.3 6.4 Mean Change at Week 24 -0.5 -2.0 -2.5 Physician global assessmentc Baseline 5.8 5.7 6.1 Mean Change at Week 24 -1.4 -2.6 -3.1 Disability index (HAQ)d Baseline 1.2 1.2 1.2 Mean Change at Week 24 -0.1 -0.3 -0.4 CRP (mg/dL) e Baseline 1.6 1.7 1.8 Mean Change at Week 24 0.01 -0.5 -0.8 Reference ID: 5487421 28 a Number of swollen joints counted (0-66) b Number of tender joints counted (0-68) c Visual analogue scale; 0= best, 10=worst. d Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient’s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity. e CRP: (Normal Range 0.0-1.0 mg/dL) An improvement in enthesitis and dactylitis scores was observed in each ustekinumab group compared with placebo at Week 24. Physical Function Ustekinumab-treated subjects showed improvement in physical function compared to subjects treated with placebo as assessed by HAQ-DI at Week 24. In both trials, the proportion of HAQ- DI responders (≥0.3 improvement in HAQ-DI score) was greater in the ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24. 14.4 Crohn’s Disease Ustekinumab was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult subjects with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] score of 220 to 450). There were two 8-week intravenous induction trials (CD-1 and CD-2) followed by a 44-week subcutaneous randomized withdrawal maintenance trial (CD- 3) representing 52 weeks of therapy. Subjects in CD-1 had failed or were intolerant to treatment with one or more TNF blockers, while subjects in CD-2 had failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed treatment with a TNF blocker. Trials CD-1 and CD-2 In trials CD-1 and CD-2, 1409 subjects were randomized, of whom 1368 (CD-1, n=741; CD-2, n=627) were included in the final efficacy analysis. Induction of clinical response (defined as a reduction in CDAI score of greater than or equal to 100 points or CDAI score of less than 150) at Week 6 and clinical remission (defined as a CDAI score of less than 150) at Week 8 were evaluated. In both trials, subjects were randomized to receive a single intravenous administration of ustekinumab at either approximately 6 mg/kg, placebo (see Table 4), or 130 mg (a lower dose than recommended). In trial CD-1, subjects had failed or were intolerant to prior treatment with a TNF blocker: 29% subjects had an inadequate initial response (primary non-responders), 69% responded but subsequently lost response (secondary non-responders) and 36% were intolerant to a TNF blocker. Of these subjects, 48% failed or were intolerant to one TNF blocker and 52% had failed 2 or 3 prior TNF blockers. At baseline and throughout the trial, approximately 46% of the subjects were receiving corticosteroids and 31% of the subjects were receiving immunomodulators (AZA, 6- MP, MTX). The median baseline CDAI score was 319 in the ustekinumab approximately 6 mg/kg group and 313 in the placebo group. In trial CD-2, subjects had failed or were intolerant to prior treatment with corticosteroids (81% of subjects), at least one immunomodulator (6-MP, AZA, MTX; 68% of subjects), or both (49% of Reference ID: 5487421 29 subjects). Additionally, 69% never received a TNF blocker and 31% previously received but had not failed a TNF blocker. At baseline, and throughout the trial, approximately 39% of the subjects were receiving corticosteroids and 35% of the subjects were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score was 286 in the ustekinumab and 290 in the placebo group. In these induction trials, a greater proportion of subjects treated with ustekinumab (at the recommended dose of approximately 6 mg/kg dose) achieved clinical response at Week 6 and clinical remission at Week 8 compared to placebo (see Table 13 for clinical response and remission rates). Clinical response and remission were significant as early as Week 3 in ustekinumab-treated subjects and continued to improve through Week 8. Table 13: Induction of Clinical Response and Remission in CD-1* and CD-2** CD-1 n = 741 CD-2 n = 627 Placebo N = 247 Ustekinu mab † N = 249 Treatment difference and 95% CI Placebo N = 209 Ustekinumab † N = 209 Treatment difference and 95% CI Clinical Response (100 point), Week 6 53 (21%) 84 (34%)a 12% (4%, 20%) 60 (29%) 116 (56%)b 27% (18%, 36%) Clinical Remission, Week 8 18 (7%) 52 (21%)b 14% (8%, 20%) 41 (20%) 84 (40%)b 21% (12%, 29%) Clinical Response (100 point), Week 8 50 (20%) 94 (38%)b 18% (10%, 25%) 67 (32%) 121 (58%)b 26% (17%, 35%) 70 Point Response, Week 6 75 (30%) 109 (44%)a 13% (5%, 22%) 81 (39%) 135 (65%)b 26% (17%, 35%) 70 Point Response, Week 3 67 (27%) 101 (41%)a 13% (5%, 22%) 66 (32%) 106 (51%)b 19% (10%, 28%) Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI score by at least 100 points or being in clinical remission: 70 point response is defined as reduction in CDAI score by at least 70 points * Patient population consisted of subjects who failed or were intolerant to TNF blocker therapy ** Patient population consisted of subjects who failed or were intolerant to corticosteroids or immunomodulators (e.g., 6-MP, AZA, MTX) and previously received but not failed a TNF blocker or were never treated with a TNF blocker. † Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 4. a 0.001≤ p < 0.01 b p < 0.001 Trial CD-3 The maintenance trial (CD-3), evaluated 388 subjects who achieved clinical response (≥100 point reduction in CDAI score) at Week 8 with either induction dose of ustekinumab in trials CD-1 or CD-2. Subjects were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks or placebo for 44 weeks (see Table 14) Reference ID: 5487421 30 Table 14: Clinical Response and Remission in CD-3 (Week 44; 52 weeks from initiation of the induction dose) Placebo* N = 131† 90 mg Ustekinumab every 8 weeks N = 128† Treatment difference and 95% CI Clinical Remission 47 (36%) 68 (53%)a 17% (5%, 29%) Clinical Response 58 (44%) 76 (59%)b 15% (3%, 27%) Clinical Remission in subjects in remission at the start of maintenance therapy** 36/79 (46%) 52/78 (67%)a 21% (6%, 36%) Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI of at least 100 points or being in clinical remission * The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the start of maintenance therapy. ** Subjects in remission at the end of maintenance therapy who were in remission at the start of maintenance therapy. This does not account for any other time point during maintenance therapy. † Subjects who achieved clinical response to ustekinumab at the end of the induction trial. a p < 0.01 b 0.01≤ p < 0.05 At Week 44, 47% of subjects who received ustekinumab were corticosteroid-free and in clinical remission, compared to 30% of subjects in the placebo group. At Week 0 of trial CD-3, 34/56 (61%) ustekinumab-treated subjects who previously failed or were intolerant to TNF blocker therapies were in clinical remission and 23/56 (41%) of these subjects were in clinical remission at Week 44. In the placebo arm, 27/61 (44%) subjects were in clinical remission at Week 0 while 16/61 (26%) of these subjects were in remission at Week 44. At Week 0 of trial CD-3, 46/72 (64%) ustekinumab-treated subjects who had previously failed immunomodulator therapy or corticosteroids (but not TNF blockers) were in clinical remission and 45/72 (63%) of these subjects were in clinical remission at Week 44. In the placebo arm, 50/70 (71%) of these subjects were in clinical remission at Week 0 while 31/70 (44%) were in remission at Week 44. In the subset of these subjects who were also naïve to TNF blockers, 34/52 (65%) of ustekinumab-treated subjects were in clinical remission at Week 44 as compared to 25/51 (49%) in the placebo arm. Subjects who were not in clinical response 8 weeks after ustekinumab induction were not included in the primary efficacy analyses for trial CD-3; however, these subjects were eligible to receive a 90 mg subcutaneous injection of ustekinumab upon entry into trial CD-3. Of these subjects, 102/219 (47%) achieved clinical response eight weeks later and were followed for the duration of the trial. 14.5 Ulcerative Colitis Ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials [UC-1 and UC-2 (NCT02407236)] in adult subjects with moderately to severely active ulcerative colitis who had an inadequate response to or failed to tolerate a biologic (i.e., TNF blocker and/or vedolizumab), corticosteroids, and/or 6-MP or AZA therapy. The 8-week intravenous induction Reference ID: 5487421 31 trial (UC-1) was followed by the 44-week subcutaneous randomized withdrawal maintenance trial (UC-2) for a total of 52 weeks of therapy. Disease assessment was based on the Mayo score, which ranged from 0 to 12 and has four subscores that were each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on centrally-reviewed endoscopy, and physician global assessment. Moderately to severely active ulcerative colitis was defined at baseline (Week 0) as Mayo score of 6 to 12, including a Mayo endoscopy subscore ≥2. An endoscopy score of 2 was defined by marked erythema, absent vascular pattern, friability, erosions; and a score of 3 was defined by spontaneous bleeding, ulceration. At baseline, subjects had a median Mayo score of 9, with 84% of subjects having moderate disease (Mayo score 6-10) and 15% having severe disease (Mayo score 11-12). Subjects in these trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents (AZA, 6-MP, or MTX), and oral corticosteroids (prednisone). Trial UC-1 In UC-1, 961 subjects were randomized at Week 0 to a single intravenous administration of ustekinumab of approximately 6 mg/kg, 130 mg (a lower dose than recommended), or placebo. Subjects enrolled in UC-1 had to have failed therapy with corticosteroids, immunomodulators or at least one biologic. A total of 51% had failed at least one biologic and 17% had failed both a TNF blocker and an integrin receptor blocker. Of the total population, 46% had failed corticosteroids or immunomodulators but were biologic-naïve and an additional 3% had previously received but had not failed a biologic. At induction baseline and throughout the trial, approximately 52% subjects were receiving oral corticosteroids, 28% subjects were receiving immunomodulators (AZA, 6-MP, or MTX) and 69% subjects were receiving aminosalicylates. The primary endpoint was clinical remission at Week 8. Clinical remission with a definition of: Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0 (no rectal bleeding), and Mayo endoscopy subscore of 0 or 1 (Mayo endoscopy subscore of 0 defined as normal or inactive disease and Mayo subscore of 1 defined as presence of erythema, decreased vascular pattern and no friability) is provided in Table 15. The secondary endpoints were clinical response, endoscopic improvement, and histologic- endoscopic mucosal improvement. Clinical response with a definition of (≥ 2 points and ≥ 30% decrease in modified Mayo score, defined as 3-component Mayo score without the Physician’s Global Assessment, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1), endoscopic improvement with a definition of Mayo endoscopy subscore of 0 or 1, and histologic-endoscopic mucosal improvement with a definition of combined endoscopic improvement and histologic improvement of the colon tissue [neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue]) are provided in Table 15. In UC-1, a significantly greater proportion of subjects treated with ustekinumab (at the recommended dose of approximately 6 mg/kg dose) were in clinical remission and response and achieved endoscopic improvement and histologic-endoscopic mucosal improvement compared to placebo (see Table 15). Reference ID: 5487421 32 Table 15: Proportion of Subjects Meeting Efficacy Endpoints at Week 8 in UC-1 Endpoint Placebo N = 319 Ustekinumab† N = 322 Treatment difference and 97.5% CI a N % N % Clinical Remission* 22 7% 62 19% 12% (7%, 18%) b Bio-naïve⸸ 14/151 9% 36/147 24% Prior biologic failure 7/161 4% 24/166 14% Endoscopic Improvement§ 40 13% 80 25% 12% (6%, 19%) b Bio-naïve⸸ 28/151 19% 43/147 29% Prior biologic failure 11/161 7% 34/166 20% Clinical Response† 99 31% 186 58% 27% (18%, 35%) b Bio-naïve⸸ 55/151 36% 94/147 64% Prior biologic failure 42/161 26% 86/166 52% Histologic-Endoscopic Mucosal Improvement‡ 26 8% 54 17% 9% (3%, 14%) b Bio-naïve⸸ 19/151 13% 30/147 20% Prior biologic failure 6/161 4% 21/166 13% † Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 4. ⸸ An additional 7 subjects on placebo and 9 subjects on ustekinumab (6 mg/kg) had been exposed to, but had not failed, biologics. * Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). § Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). † Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥30% and ≥2 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. ‡ Histologic-endoscopic mucosal improvement was defined as combined endoscopic improvement (Mayo endoscopy subscore of 0 or 1) and histologic improvement of the colon tissue (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue). a Adjusted treatment difference (97.5% CI) b p < 0.001 The relationship of histologic-endoscopic mucosal improvement, as defined in UC-1, at Week 8 to disease progression and long-term outcomes was not evaluated during UC-1. Rectal Bleeding and Stool Frequency Subscores Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in ustekinumab-treated subjects. Trial UC-2 The maintenance trial (UC-2) evaluated 523 subjects who achieved clinical response 8 weeks following the intravenous administration of either induction dose of ustekinumab in UC-1. These subjects were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, or every 12 weeks (a lower dose than recommended), or placebo for 44 weeks. The primary endpoint was the proportion of subjects in clinical remission at Week 44. The secondary endpoints included the proportion of subjects maintaining clinical response at Week 44, Reference ID: 5487421 33 the proportion of subjects with endoscopic improvement at Week 44, the proportion of subjects with corticosteroid-free clinical remission at Week 44, and the proportion of subjects maintaining clinical remission at Week 44 among subjects who achieved clinical remission 8 weeks after induction. Results of the primary and secondary endpoints at Week 44 in subjects treated with ustekinumab at the recommended dosage (90 mg every 8 weeks) compared to the placebo are shown in Table 16. Table 16: Efficacy Endpoints of Maintenance at Week 44 in UC-2 (52 Weeks from Initiation of the Induction Dose) Endpoint Placebo* N = 175† 90 mg Ustekinumab every 8 weeks N = 176 Treatment difference and 95% CI N % N % Clinical Remission** 46 26% 79 45% 19% (9%, 28%) a Bio-naïve⸸ 30/84 36% 39/79 49% Prior biologic failure 16/88 18% 37/91 41% Maintenance of Clinical Response at Week 44† 84 48% 130 74% 26% (16%, 36%) a Bio-naïve⸸ 49/84 58% 62/79 78% Prior biologic failure 35/88 40% 64/91 70% Endoscopic Improvement§ 47 27% 83 47% 20% (11%, 30%) a Bio-naïve⸸ 29/84 35% 42/79 53% Prior biologic failure 18/88 20% 38/91 42% Corticosteroid-free Clinical Remission‡ 45 26% 76 43% 17% (8%, 27%) a Bio-naïve⸸ 30/84 36% 38/79 48% Prior biologic failure 15/88 17% 35/91 38% Maintenance of Clinical Remission at Week 44 in subjects who achieved clinical remission 8 weeks after induction 18/50 36% 27/41 66% 31% (12%, 50%) b Bio-naïve⸸ 12/27 44% 14/20 70% Prior biologic failure 6/23 26% 12/18 67% ⸸ An additional 3 subjects on placebo and 6 subjects on ustekinumab had been exposed to, but had not failed, biologics. * The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the start of maintenance therapy. ** Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). † Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥30% and ≥2 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. § Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). ‡ Corticosteroid-free clinical remission was defined as subjects in clinical remission and not receiving corticosteroids at Week 44. a p =<0.001 b p=0.004 Reference ID: 5487421 34 Other Endpoints Week 16 Responders to Ustekinumab Induction Subjects who were not in clinical response 8 weeks after induction with ustekinumab in UC-1 were not included in the primary efficacy analyses for trial UC-2; however, these subjects were eligible to receive a 90 mg subcutaneous injection of ustekinumab at Week 8. Of these subjects, 55/101 (54%) achieved clinical response eight weeks later (Week 16) and received ustekinumab 90 mg subcutaneously every 8 weeks during the UC-2 trial. At Week 44, there were 97/157 (62%) subjects who maintained clinical response and there were 51/157 (32%) who achieved clinical remission. Histologic-Endoscopic Mucosal Improvement at Week 44 The proportion of subjects achieving histologic-endoscopic mucosal improvement during maintenance treatment in UC-2 was 75/172 (44%) among subjects on ustekinumab and 40/172 (23%) in subjects on placebo at Week 44. The relationship of histologic-endoscopic mucosal improvement, as defined in UC-2, at Week 44 to progression of disease or long-term outcomes was not evaluated in UC-2. Endoscopic Normalization Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0. At Week 8 in UC-1, endoscopic normalization was achieved in 25/322 (8%) of subjects treated with ustekinumab and 12/319 (4%) of subjects in the placebo group. At Week 44 of UC-2, endoscopic normalization was achieved in 51/176 (29%) of subjects treated with ustekinumab and in 32/175 (18%) of subjects in placebo group. 15 REFERENCES 1 Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973- 2007) - Linked To County Attributes - Total U.S., 1969-2007 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2010, based on the November 2009 submission. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied YESINTEK (ustekinumab-kfce) injection is a sterile, preservative-free, clear and colorless to pale yellow solution. It is supplied as individually packaged, single-dose prefilled syringes or single- dose vials. For Subcutaneous Use Prefilled Syringes • 45 mg/0.5 mL (NDC- 83257-023-41) • 90 mg/mL (NDC- 83257-025-41) Reference ID: 5487421 35 Each prefilled syringe is equipped with a 29 gauge fixed ½ inch needle, a needle safety guard, and a needle cover. Single-dose Vial • 45 mg/0.5 mL (NDC- 83257-024-11) For Intravenous Infusion Single-dose Vial • 130 mg/26 mL (5 mg/mL) (NDC- 83257-026-11) Storage and Handling Store YESINTEK vials and prefilled syringes refrigerated between 2ºC to 8ºC (36ºF to 46ºF). Store YESINTEK vials upright. Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. If needed, individual prefilled syringes may be stored at room temperature up to 30°C (86°F) for a maximum single period of up to 30 days in the original carton to protect from light. Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided. Once a syringe has been stored at room temperature, do not return to the refrigerator. Discard the syringe if not used within 30 days at room temperature storage. Do not use YESINTEK after the expiration date on the carton or on the prefilled syringe. 17 PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Infections Inform patients that YESINTEK may lower the ability of their immune system to fight infections and to contact their healthcare provider immediately if they develop any signs or symptoms of infection [see Warnings and Precautions (5.1)]. Malignancies Inform patients of the risk of developing malignancies while receiving YESINTEK [see Warnings and Precautions (5.4)]. Hypersensitivity Reactions • Advise patients to seek immediate medical attention if they experience any signs or symptoms of serious hypersensitivity reactions and discontinue YESINTEK [see Warnings and Precautions (5.5)]. Reference ID: 5487421 36 Posterior Reversible Encephalopathy Syndrome (PRES) Inform patients to immediately contact their healthcare provider if they experience signs and symptoms of PRES (which may include headache, seizures, confusion, or visual disturbances) [see Warnings and Precautions (5.6)]. Immunizations Inform patients that YESINTEK can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.7)]. Administration Instruct patients to follow sharps disposal recommendations, as described in the Instructions for Use. Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142 U.S.A. U.S. License No. 2324 Product of India © 2024 Biocon Biologics Inc. Reference ID: 5487421 MEDICATION GUIDE YESINTEKTM (Yes-in-tek) (ustekinumab-kfce) injection, for subcutaneous or intravenous use What is the most important information I should know about YESINTEK? YESINTEK is a medicine that affects your immune system. YESINTEK can increase your risk of having serious side effects, including: Serious infections. YESINTEK may lower the ability of your immune system to fight infections and may increase your risk of infections. Some people have serious infections while taking ustekinumab products, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their infection. • Your doctor should check you for TB before starting YESINTEK. • If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with YESINTEK and during treatment with YESINTEK. • Your doctor should watch you closely for signs and symptoms of TB while you are being treated with YESINTEK. You should not start taking YESINTEK if you have any kind of infection unless your doctor says it is okay. Before starting YESINTEK, tell your doctor if you: • think you have an infection or have symptoms of an infection such as: o fever, sweat, or chills o warm, red, or painful skin or sores on your body o muscle aches o diarrhea or stomach pain o cough o burning when you urinate or urinate more often than normal o shortness of breath o feel very tired o blood in phlegm o weight loss • are being treated for an infection or have any open cuts. • get a lot of infections or have infections that keep coming back. • have TB, or have been in close contact with someone with TB. After starting YESINTEK, call your doctor right away if you have any symptoms of an infection (see above). These may be signs of infections such as chest infections, or skin infections or shingles that could have serious complications. YESINTEK can make you more likely to get infections or make an infection that you have worse. People who have a genetic problem where the body does not make any of the proteins interleukin 12 (IL-12) and interleukin 23 (IL-23) are at a higher risk for certain serious infections. These infections can spread throughout the body and cause death. People who take YESINTEK may also be more likely to get these infections. Cancers. YESINTEK may decrease the activity of your immune system and increase your risk for certain types of cancers. Tell your doctor if you have ever had any type of cancer. Some people who are receiving ustekinumab products and have risk factors for skin cancer have developed certain types of skin cancers. During your treatment with YESINTEK, tell your doctor if you develop any new skin growths. Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a rare condition that affects the brain and can cause death. The cause of PRES is not known. If PRES is found early and treated, most people recover. Tell your doctor right away if you have any new or worsening medical problems including: o headache o confusion o seizures o vision problems What is YESINTEK? YESINTEK is a prescription medicine used to treat: • adults and children 6 years and older with moderate or severe psoriasis who may benefit from taking injections or pills Reference ID: 5487421 (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills). • adults and children 6 years and older with active psoriatic arthritis. • adults 18 years and older with moderately to severely active Crohn’s disease. • adults 18 years and older with moderately to severely active ulcerative colitis. It is not known if YESINTEK is safe and effective in children less than 6 years of age. Do not take YESINTEK if you are allergic to ustekinumab products or any of the ingredients in YESINTEK. See the end of this Medication Guide for a complete list of ingredients in YESINTEK. Before you receive YESINTEK, tell your doctor about all of your medical conditions, including if you: • have any of the conditions or symptoms listed in the section “What is the most important information I should know about YESINTEK?” • ever had an allergic reaction to ustekinumab products. Ask your doctor if you are not sure. • have recently received or are scheduled to receive an immunization (vaccine). People who take YESINTEK should not receive live vaccines. Tell your doctor if anyone in your house needs a live vaccine. The viruses used in some types of live vaccines can spread to people with a weakened immune system and can cause serious problems. You should not receive the BCG vaccine during the one year before receiving YESINTEK or one year after you stop receiving YESINTEK. • have any new or changing lesions within psoriasis areas or on normal skin. • are receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may not work as well for you during treatment with YESINTEK. YESINTEK may also increase your risk of having an allergic reaction to an allergy shot. • receive or have received phototherapy for your psoriasis. • are pregnant or plan to become pregnant. It is not known if YESINTEK can harm your unborn baby. You and your doctor should decide if you will receive YESINTEK. See “What should I avoid while using YESINTEK?” • received YESINTEK while you were pregnant. It is important that you tell your baby’s healthcare provider before any vaccinations are given to your baby. • are breastfeeding or plan to breastfeed. YESINTEK can pass into your breast milk. • Talk to your doctor about the best way to feed your baby if you receive YESINTEK. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I use YESINTEK? • Use YESINTEK exactly as your doctor tells you to. • Adults with Crohn’s disease and ulcerative colitis will receive the first dose of YESINTEK through a vein in the arm (intravenous infusion) in a healthcare facility by a healthcare provider. It takes at least 1 hour to receive the full dose of medicine. You will then receive YESINTEK as an injection under the skin (subcutaneous injection) 8 weeks after the first dose of YESINTEK, as described below. • Adults with psoriasis or psoriatic arthritis, and children 6 years and older with psoriasis or psoriatic arthritis will receive YESINTEK as an injection under the skin (subcutaneous injection) as described below. • Injecting YESINTEK under your skin o YESINTEK is intended for use under the guidance and supervision of your doctor. In children 6 years and older, it is recommended that YESINTEK be administered by a healthcare provider. If your doctor decides that you or a caregiver may give your injections of YESINTEK at home, you should receive training on the right way to prepare and inject YESINTEK. Your doctor will determine the right dose of YESINTEK for you, the amount for each injection, and how often you should receive it. Do not try to inject YESINTEK yourself until you or your caregiver have been shown how to inject YESINTEK by your doctor or nurse. Reference ID: 5487421 o Inject YESINTEK under the skin (subcutaneous injection) in your upper arms, buttocks, upper legs (thighs) or stomach area (abdomen). o Do not give an injection in an area of the skin that is tender, bruised, red or hard. o Use a different injection site each time you use YESINTEK. o If you inject more YESINTEK than prescribed, call your doctor right away. o Be sure to keep all of your scheduled follow-up appointments. Read the detailed Instructions for Use at the end of this Medication Guide for instructions about how to prepare and inject a dose of YESINTEK, and how to properly throw away (dispose of) used needles and syringes. The syringe, needle and vial must never be re-used. After the stopper is punctured, YESINTEK can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused portion of YESINTEK. What should I avoid while using YESINTEK? You should not receive a live vaccine while taking YESINTEK. See “Before you receive YESINTEK, tell your doctor about all of your medical conditions, including if you:” What are the possible side effects of YESINTEK? YESINTEK may cause serious side effects, including: • See “What is the most important information I should know about YESINTEK?” • Serious allergic reactions. Serious allergic reactions can occur with YESINTEK. Stop using YESINTEK and get medical help right away if you have any of the following symptoms of a serious allergic reaction: o feeling faint o chest tightness o swelling of your face, eyelids, tongue, or throat o skin rash • Lung inflammation. Cases of lung inflammation have happened in some people who receive ustekinumab products and may be serious. These lung problems may need to be treated in a hospital. Tell your doctor right away if you develop shortness of breath or a cough that doesn’t go away during treatment with YESINTEK. Common side effects of YESINTEK include: • nasal congestion, sore throat, and runny nose • redness at the injection site • upper respiratory infections • vaginal yeast infections • fever • urinary tract infections • headache • sinus infection • tiredness • bronchitis • itching • diarrhea • nausea and vomiting • stomach pain These are not all of the possible side effects of YESINTEK. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Biocon Biologics at 1-833-986-1468. How should I store YESINTEK? • Store YESINTEK vials and prefilled syringes in a refrigerator between 36°F to 46°F (2°C to 8°C). • Store YESINTEK vials standing up straight. • Store YESINTEK in the original carton to protect it from light until time to use it. • Do not freeze YESINTEK. • Do not shake YESINTEK. If needed, individual YESINTEK prefilled syringes may also be stored at room temperature up to 86ºF (30°C) for a maximum single period of up to 30 days in the original carton to protect from light. Record the date when the prefilled syringe is first Reference ID: 5487421 removed from the refrigerator on the carton in the space provided. Once a syringe has been stored at room temperature, it should not be returned to the refrigerator. Discard the syringe if not used within 30 days at room temperature storage. Do not use YESINTEK after the expiration date on the carton or on the prefilled syringe. Keep YESINTEK and all medicines out of the reach of children. General information about the safe and effective use of YESINTEK. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use YESINTEK for a condition for which it was not prescribed. Do not give YESINTEK to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about YESINTEK that was written for health professionals. What are the ingredients in YESINTEK? Active ingredient: ustekinumab-kfce Inactive ingredients: Single-dose prefilled syringe for subcutaneous use contains histidine, L-histidine monohydrochloride monohydrate, Polysorbate 80, and sucrose. Hydrochloric acid and sodium hydroxide added to adjust the pH. Single-dose vial for subcutaneous use contains histidine, L-histidine hydrochloride monohydrate, Polysorbate 80 and sucrose. Hydrochloric acid and sodium hydroxide added to adjust the pH. Single-dose vial for intravenous infusion contains edetate disodium, histidine, L-histidine hydrochloride monohydrate, methionine, Polysorbate 80, and sucrose. Hydrochloric acid and sodium hydroxide added to adjust the pH. Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142 U.S.A. U.S. License No. 2324 Product of India © 2024 Biocon Biologics Inc. For more information go to www.yesintek.com or call 1-833-986-1468. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 11/2024 Reference ID: 5487421 INSTRUCTIONS FOR USE YESINTEKTM (Yes-in-tek) (ustekinumab-kfce) injection, for subcutaneous use Instructions for injecting YESINTEK from a vial. Read this Instructions for Use before you start using YESINTEK. Your doctor or nurse should show you how to prepare, measure your dose, and give your injection of YESINTEK the right way. If you cannot give yourself the injection: • ask your doctor or nurse to help you, or • ask someone who has been trained by a doctor or nurse to give your injections. Do not try to inject YESINTEK yourself until you have been shown how to inject YESINTEK by your doctor, nurse, or health professional. Important information: • Before you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by your doctor. o If your dose is 45 mg or less you will receive one 45 mg vial. o If your dose is 90 mg, you will receive two 45 mg vials and you will need to give yourself two injections, one right after the other. • Children 12 years of age and older weighing less than 132 pounds require a dose lower than 45 mg. • Check the expiration date on the vial and carton. If the expiration date has passed, do not use it. If the expiration date has passed, call your doctor or pharmacist, or call Biocon Biologics at 1-833-986-1468 for help. • Check the vial for any particles or discoloration. Your vial should look clear and colorless to pale yellow solution. • Do not use if it is frozen, discolored, cloudy or has large particles. Get a new vial. • Do not shake the vial at any time. Shaking your vial may damage your YESINTEK medicine. If your vial has been shaken, do not use it. Get a new vial. • Do not use a YESINTEK vial more than one time, even if there is medicine left in the vial. After the rubber stopper is punctured, YESINTEK can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused YESINTEK after you give your injection. • Safely throw away (dispose of) YESINTEK vials after use. • Do not re-use syringes or needles. See “Step 6: Dispose of needles and syringes.” • To avoid needle-stick injuries, do not recap needles. Storage information • Store YESINTEK vials in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC). • Store YESINTEK vials standing up straight. • Store YESINTEK in the original carton to protect from light until the time of use. • Do not freeze YESINTEK. • Do not shake YESINTEK. • Do not use YESINTEK after the expiration date on the carton or on the vial. Gather the supplies you will need to prepare YESINTEK and to give your injection. (See Figure A) You will need: • a syringe with the needle attached, you will need a prescription from your healthcare provider to get syringes with the needles attached from your pharmacy. • antiseptic wipes • cotton balls or gauze pads • adhesive bandage Reference ID: 5487421 • your prescribed dose of YESINTEK • FDA-cleared sharps disposal container. See “Step 6: Dispose of needles and syringes.” Figure A Step 1: Prepare the injection. • Choose a well-lit, clean, flat work surface. • Wash your hands well with soap and warm water. Step 2: Prepare your injection site • Choose an injection site around your stomach area (abdomen), buttocks, and upper legs (thighs). If a caregiver is giving you the injection, the outer area of the upper arms may also be used. (See Figure B) • Use a different injection site for each injection. Do not give an injection in an area of the skin that is tender, bruised, red or hard. • Clean the skin with an antiseptic wipe where you plan to give your injection. • Do not touch this area again before giving the injection. Let your skin dry before injecting. • Do not fan or blow on the clean area. Figure B *Areas in gray are recommended injection sites Step 3: Prepare the vial. • Remove the cap from the top of the vial. Throw away the cap but do not remove the rubber stopper. (See Figure C) Reference ID: 5487421 Figure C • Clean the rubber stopper with an antiseptic swab. (See Figure D) Figure D • Do not touch the rubber stopper after you clean it. • Put the vial on a flat surface. Step 4: Prepare the needle • Pick up the syringe with the needle attached. • Remove the cap that covers the needle. (See Figure E) • Throw the needle cap away. Do not touch the needle or allow the needle to touch anything. Figure E • Carefully pull back on the plunger to the line that matches the dose prescribed by your doctor. • Hold the vial between your thumb and index (pointer) finger. • Use your other hand to push the syringe needle through the center of the rubber stopper. (See Figure F) Reference ID: 5487421 Figure F • Push down on the plunger until all of the air has gone from the syringe into the vial. • Turn the vial and the syringe upside down. (See Figure G) • Hold the YESINTEK vial with one hand. • It is important that the needle is always in the liquid in order to prevent air bubbles forming in the syringe. • Pull back on the syringe plunger with your other hand. • Fill the syringe until the black tip of the plunger lines up with the mark that matches your prescribed dose. Figure G • Do not remove the needle from the vial. Hold the syringe with the needle pointing up to see if it has any air bubbles inside. • If there are air bubbles, gently tap the side of the syringe until the air bubbles rise to the top. (See Figure H) • Slowly press the plunger up until all of the air bubbles are out of the syringe (but none of the liquid is out). • Remove the syringe from the vial. Do not lay the syringe down or allow the needle to touch anything. Figure H Reference ID: 5487421 Step 5: Inject YESINTEK • Hold the barrel of the syringe in one hand, between the thumb and index fingers. • Do not pull back on the plunger at any time. • Use the other hand to gently pinch the cleaned area of skin. Hold firmly. • Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree angle. (See Figure I) Figure I • Push the plunger with your thumb as far as it will go to inject all of the liquid. Push it slowly and evenly, keeping the skin gently pinched. • When the syringe is empty, pull the needle out of your skin and let go of the skin. (See Figure J) Figure J • When the needle is pulled out of your skin, there may be a little bleeding at the injection site. This is normal. You can press a cotton ball or gauze pad to the injection site if needed. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if necessary. If your dose is 90 mg, you will receive two 45 mg vials and you will need to give yourself a second injection right after the first. Repeat Steps 1 to 5 using a new syringe. Choose a different site for the second injection. Step 6: Dispose of the needles and syringes. • Do not re-use a syringe or needle. • To avoid needle-stick injuries, do not recap a needle. • Put your needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of heavy-duty plastic o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out o upright and stable during use o leak-resistant, o and properly labelled to warn of hazardous waste inside the container. Reference ID: 5487421 • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your sharps disposal container. • Throw away the vial into the container where you put the syringes and needles. • If you have any questions, talk to your doctor or pharmacist. Keep YESINTEK and all medicines out of the reach of children. Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142 U.S.A. U.S. License No. 2324 Product of India © 2024 Biocon Biologics Inc. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 11/2024 Reference ID: 5487421 INSTRUCTIONS FOR USE YESINTEKTM (Yes-in-tek) (ustekinumab-kfce) injection, for subcutaneous use Instructions for injecting YESINTEK using a prefilled syringe. Read this Instructions for Use before you start using YESINTEK. Your doctor or nurse should show you how to prepare and give your injection of YESINTEK the right way. If you cannot give yourself the injection: • ask your doctor or nurse to help you, or • ask someone who has been trained by a doctor or nurse to give your injections. Do not try to inject YESINTEK yourself until you have been shown how to inject YESINTEK by your doctor, nurse or health professional. Important information: • Before you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by your doctor. o If your dose is 45 mg, you will receive one 45 mg prefilled syringe. o If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself two injections, one right after the other. • Children 12 years of age and older with psoriasis who weigh 132 pounds or more may use a prefilled syringe. • Check the expiration date on the prefilled syringe and carton. If the expiration date has passed or if the prefilled syringe has been kept at room temperature up to 86°F (30°C) for longer than a maximum single period of 30 days or if the prefilled syringe has been stored above 86°F (30°C), do not use it. If the expiration date has passed or if the prefilled syringe has been stored above 86°F (30°C), call your doctor, pharmacist, or call Biocon Biologics at 1-833-986-1468 for help. • Make sure the syringe is not damaged. • Check your prefilled syringe for any particles or discoloration. Your prefilled syringe should look clear and colorless to pale yellow. • Do not use if it is frozen, discolored, cloudy or has large particles. Get a new prefilled syringe. • Do not shake the prefilled syringe at any time. Shaking your prefilled syringe may damage your YESINTEK medicine. If your prefilled syringe has been shaken, do not use it. Get a new prefilled syringe. • To reduce the risk of accidental needle sticks, each prefilled syringe has a needle guard that is automatically activated to cover the needle after you have given your injection. Do not pull back on the plunger at any time. Do not attempt to remove the needle safety guard from the prefilled syringe. Storage information • Store YESINTEK prefilled syringes in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC). • Store YESINTEK in the original carton to protect from light until the time of use. • Do not freeze YESINTEK. • Do not shake YESINTEK. • If needed, individual prefilled syringes may be stored at room temperature up to 86°F (30°C) for a maximum single period of up to 30 days in the original carton to protect from light. Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided. Once a syringe has been stored at room temperature, it should not be returned to the refrigerator. Discard the syringe if not used within 30 days at room temperature storage. Do not use YESINTEK after the expiration date on the carton or on the prefilled syringe. Gather the supplies you will need to prepare and to give your injection (See Figure A) You will need: • your prescribed dose of YESINTEK (See Figure B) • antiseptic wipes • cotton balls or gauze pads • adhesive bandage • FDA-cleared sharps disposal container. See "Step 4: Dispose of the syringe." Reference ID: 5487421 Step 1: Prepare the injection. • Choose a well-lit, clean, flat work surface. • Wash your hands well with soap and warm water. Remove prefilled syringe tray from carton • Open the tray by peeling away the cover. Hold the prefilled syringe by the Needle safety guard (as shown in the Figure C) to remove the prefilled syringe from the tray. For safety reasons: o Do not touch or grasp the plunger o Do not grasp the gray needle cover • Hold the prefilled syringe with the covered needle pointing upward. Reference ID: 5487421 Step 2: Prepare your injection site • Choose an injection site around your stomach area (abdomen), buttocks, upper legs (thighs). If a caregiver is giving you the injection, the outer area of the upper arms may also be used. (See Figure D) • Use a different injection site for each injection. Do not give an injection in an area of the skin that is tender, bruised, red or hard. • Clean the skin with an antiseptic wipe where you plan to give your injection. • Do not touch this area again before giving the injection. Let your skin dry before injecting. • Do not fan or blow on the clean area. *Areas in blue are recommended injection sites. Step 3: Inject YESINTEK • Remove the needle cover when you are ready to inject your YESINTEK. • Do not touch the plunger while removing the needle cover. • Hold the body of the prefilled syringe with one hand and pull the needle cover straight off. (See Figure E) • Put the needle cover in the trash. • You may also see a drop of liquid at the end of the needle. This is normal. • Do not touch the needle or let it touch anything. • Do not use the prefilled syringe if it is dropped without the needle cover in place. Call your doctor, nurse or health professional for instructions. • Hold the body of the prefilled syringe in one hand between the thumb and index fingers. (See Figure F) Reference ID: 5487421 • Do not pull back on the plunger at any time. • Use the other hand to gently pinch the cleaned area of skin. Hold firmly. • Use a quick, dart-like motion to insert the needle into the pinched skin at about a 45-degree angle. (See Figure G) • Inject all of the liquid by using your thumb to push in the plunger until the plunger head is completely between the needle guard wings. (See Figure H) • When the plunger is pushed as far as it will go, keep pressure on the plunger head. Take the needle out of the skin and let go of the skin. • Slowly take your thumb off the plunger head. This will let the empty syringe move up until the entire needle is covered by the needle guard. (See Figure I) Reference ID: 5487421 • When the needle is pulled out of your skin, there may be a little bleeding at the injection site. This is normal. You can press a cotton ball or gauze pad to the injection site if needed. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if necessary. If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself a second injection right after the first. Repeat Steps 1 to 3 for the second injection using a new syringe. Choose a different site for the second injection. Step 4: Dispose of the syringe. • Put the syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose syringes in your household trash. • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: o made of heavy-duty plastic. o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out. o upright and stable during use, o leak-resistant, o and properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be local or state laws about how to throw away syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your sharps disposal container. • If you have any questions, talk to your doctor or pharmacist. Keep YESINTEK and all medicines out of the reach of children. Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142 U.S.A. U.S. License No. 2324 Product of India © 2024 Biocon Biologics Inc. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 11/2024 Reference ID: 5487421
custom-source
2025-02-12T15:47:20.879599
{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761406s000lbl.pdf', 'application_number': 761406, 'submission_type': 'ORIG ', 'submission_number': 1}
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10 mg each 30 Tab e s 30 TABLETS HIVES RELIEF Actual Size ® HIVES Cetirizine HCl tablets 10mg/antihistamine NDC 50580-116-04 Cetirizine HCl tablets 10 mg/antihistamine The trade dress of this ZYRTEC® package is subject to trademark protection. Active ingredient made in Switzerland HIVES RELIEF 30 Tablets 10 mg each Actual Size relief Hour 24 Reduces Hives Reduces Itching Due to Hives Hives Relief Hives Relief HIVES ® Original Prescription Strength adults and children 6 years and over adults 65 years and over ch ldren under 6 years of age one 10 mg tablet once daily; do not take more than one 10 mg tablet in 24 hours. A 5 mg product may be appropriate for less severe symptoms. ask a doctor ask a doctor consumers with iver or kidney disease ask a doctor Active ingredient (in each tablet) Purpose Cetirizine HCl 10 mg... ........ ....... ....... ....... ....... ........ ....... .....Antihistamine Uses reduces hives and relieves itching due to hives (urticaria). This product will not prevent hives or an allergic skin reaction from occurring. Warnings Severe Allergy Warning: Get emergency help immediately if you have hives along with any of the following symptoms: I trouble swallowing I dizziness or loss of consciousness I swelling of tongue I swel ing in or around mouth I trouble speaking I drooling I wheezing or problems breathing These symptoms may be signs of anaphylactic shock. This condition can be life threatening if not treated by a health professional immediately. Symptoms of anaphylactic shock may occur when hives first appear or up to a few hours later. Not a Substitute for Epinephrine. If your doctor has prescribed an epinephrine injector for “anaphylaxis” or severe a lergy symptoms that could occur with your hives, never use this product as a substitute for the epinephrine injector. If you have been prescribed an epinephrine injector, you should carry it with you at a l times. Drug Facts Drug Facts (continued) Drug Facts (continued) Drug Facts (continued) Do not use I to prevent hives from any known cause such as: I foods I insect stings I medicines I latex or rubber gloves because this product will not stop hives from occurring. Avoiding the cause of your hives is the only way to prevent them. Hives can sometimes be serious. If you do not know the cause of your hives, see your doctor for a medical exam. Your doctor may be able to help you find a cause. I if you have ever had an a lergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have I iver or kidney disease. Your doctor should determine if you need a different dose. I hives that are an unusual color, look bruised or blistered I hives that do not itch Ask a doctor or pharmacist before use if you are taking tranqui izers or sedatives. When using this product I drowsiness may occur I avoid alcoholic drinks I alcohol, sedatives, and tranqu lizers may increase drowsiness I be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if I an allergic reaction to this product occurs. Seek medical help right away. I symptoms do not improve after 3 days of treatment I the hives have lasted more than 6 weeks Other information I store between 20° to 25°C (68° to 77°F) I do not use if foil inner seal imprinted with “Sealed For Your Safety” is broken or missing I meets USP Dissolution Test 2 Inactive ingredients colloidal s licon dioxide, croscarmellose sodium, hyprome lose, lactose monohydrate, magnesium stearate, microcrystalline ce lulose, polyethylene glycol, titanium dioxide Questions? call 1-800-343-7805 (toll-free) or 215-273-8755 (collect). If pregnant or breast-feeding: I if breast-feeding: not recommended I if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) Directions Important: Read all product information before using. Keep this box for important information. Distributed by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 2024 zyrtec.com Pat. www.kenvuepats.com 30056389 20.58 in 0.125” Drug Facts Format Information 79% -25 2.0 0.5 6.00 5.00 6.50 9.00 8.00 8.00 LOT: XXXXXXXX EXP: YYYY/MMM Reference ID: 5486429 (b) (4) Tablets 10 mg each 30 HIVES RELIEF ® HIVES NDC 50580-116-04 Cetirizine HCl tablets 10mg/antihistamine Active ingredient (in each tablet) Purpose Cetirizine HCl 10 mg........................Antihistamine Uses reduces hives and relieves itching due to hives (urticaria). This product will not prevent hives or an allergic skin reaction from occurring. Warnings Severe Allergy Warning: Get emergency help immediately if you have hives along with any of the following symptoms: I trouble swallowing I dizziness or loss of consciousness I swelling of tongue I swelling in or around mouth I trouble speaking I drooling I wheezing or problems breathing These symptoms may be signs of anaphylactic shock. This condition can be life threatening if not treated by a health professional immediately. Symptoms of anaphylactic shock may occur when hives first appear or up to a few hours later. Not a Substitute for Epinephrine. If your doctor has prescribed an epinephrine injector for “anaphylaxis” or severe allergy symptoms that could occur with your hives, never use this product as a substitute for the epinephrine injector. If you have been prescribed an epinephrine injector, you should carry it with you at all times. Do not use I to prevent hives from any known cause such as: I foods I insect stings I medicines I latex or rubber gloves because this product will not stop hives from occurring. Avoiding the cause of your hives is the only way to prevent them. Hives can sometimes be serious. If you do not know the cause of your hives, see your doctor for a medical exam. Your doctor may be able to help you find a cause. I if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have I liver or kidney disease. Your doctor should determine if you need a different dose. I hives that are an unusual color, look bruised or blistered I hives that do not itch Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. When using this product I drowsiness may occur I avoid alcoholic drinks I alcohol, sedatives, and tranquilizers may increase drowsiness I be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if I an allergic reaction to this product occurs. Seek medical help right away. I symptoms do not improve after 3 days of treatment I the hives have lasted more than 6 weeks If pregnant or breast-feeding: I if breast-feeding: not recommended I if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) PEEL HERE Directions Adults and children 6 years and over: one 10 mg tablet once daily; do not take more than one 10 mg tablet in 24 hours. A 5 mg product may be appropriate for less severe symptoms. Adults 65 years and over: ask a doctor Children under 6 years of age: ask a doctor Consumers with liver or kidney disease: ask a doctor Other information I store between 20° to 25°C (68° to 77°F) I do not use if foil inner seal imprinted with “Sealed For Your Safety” is broken or missing I meets USP Dissolution Test 2 Inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide Questions? call 1-800-343-7805 (toll-free) or 215-273-8755 (collect). The trade dress of this ZYRTEC® package is subject to trademark protection. Active ingredient made in Switzerland. Distributed by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division, Fort Washington, PA 19034 USA ©J&JCI 2024 Pat. www.kenvuepats.com zyrtec.com 30056340 Drug Facts Format Information 80% 0 N/A N/A 4.50 3.50 4.70 N/A N/A 4.50 LOT: XXXXXXXX EXP: YYYY/MMM Reference ID: 5486429 (b) (4) ® Cetirizine HCl oral solution 1 mg/ml/ antihistamineHIVES Grape Flavor OPEN HERE ® HIVES Cetirizine HCl oral solution 1 mg/ml/ antihistamine HIVES RELIEF relief Hour 24 Reduces Hives Reduces Itching Due to Hives Grape Flavor Dosing cup included 4 fl oz (118 ml) ® HIVES Cetirizine HCl oral solution 1 mg/ml/ antihistamine yrs & older 6 Hives Relief HIVES RELIEF relief Hour 24 Reduces Hives Reduces Itching Due to Hives Dosing cup included Grape Flavor 4 fl oz (118 ml) Drug Facts (continued) Other information ■ store between 20° to 25°C (68° to 77°F) ■ do not use if carton is opened or if bottle wrap imprinted with “Sealed For Your Safety” is broken or missing Inactive ingredients anhydrous citric acid, flavors, propylene glycol, purified water, sodium benzoate, sorbitol solution, sucralose Questions? call 1-800-343-7805 (toll-free) or 215-273-8755 (collect). 5 mL or 10 mL once daily depending upon severity of symptoms; do not take more than 10 mL in 24 hours. adults and children 6 years and over 5 mL once daily; do not take more than 5 mL in 24 hours. adults 65 years and over children under 6 years of age ask a doctor consumers with liver or kidney disease ask a doctor Drug Facts Active ingredient Purpose (in each 5 mL) Cetirizine HCl 5 mg.......................................Antihistamine Uses reduces hives and relieves itching due to hives (urticaria). This product will not prevent hives or an allergic skin reaction from occurring. Warnings Severe Allergy Warning: Get emergency help immediately if you have hives along with any of the following symptoms: ■ trouble swallowing ■ dizziness or loss of consciousness ■ swelling of tongue ■ swelling in or around mouth ■ trouble speaking ■ drooling ■ wheezing or problems breathing These symptoms may be signs of anaphylactic shock. This condition can be life threatening if not treated by a health professional immediately. Symptoms of anaphylactic shock may occur when hives first appear or up to a few hours later. Not a Substitute for Epinephrine. If your doctor has prescribed an epinephrine injector for “anaphylaxis” or severe allergy symptoms that could occur with your hives, never use this product as a substitute for the epinephrine injector. If you have been prescribed an epinephrine injector, you should carry it with you at all times. Do not use ■ to prevent hives from any known cause such as: ■ foods ■ insect stings ■ medicines ■ latex or rubber gloves because this product will not stop hives from occurring. Avoiding the cause of your hives is the only way to prevent them. Hives can sometimes be serious. If you do not know the cause of your hives, see your doctor for a medical exam. Your doctor may be able to help you find a cause. ■ if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have ■ liver or kidney disease. Your doctor should determine if you need a different dose. ■ hives that are an unusual color, look bruised or blistered ■ hives that do not itch Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. Important: Read all product information before using. Keep this box for important information. When using this product ■ drowsiness may occur ■ avoid alcoholic drinks ■ alcohol, sedatives, and tranquilizers may increase drowsiness ■ be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if ■ an allergic reaction to this product occurs. Seek medical help right away. ■ symptoms do not improve after 3 days of treatment ■ the hives have lasted more than 6 weeks If pregnant or breast-feeding: ■ if breast-feeding: not recommended ■ if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) Directions ■ use only with enclosed dosing cup ■ find right dose on chart below ■ mL = milliliter The trade dress of this ZYRTEC package is subject to trademark protection. Active ingredient made in Switzerland Distributed by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 2024 zyrtec.com Pat. www.kenvuepats.com 30056395 NDC 50580-128-04 LOT XXXXXXXX EXP YYYY/MMM 9.69 in 0.125” Drug Facts Format Information 80% -10 2.5 0.5 6.00 5.00 6.30 10.00 8.00 8.00 (b) (4) ® Cetirizine HCl 1 mg/ml oral solution antihistamine HIVES relief 24 Hour HIVES RELIEF Reduces Hives Reduces Itching Due to Hives Grape Flavor yrs & older 6 Dosing cup should be washed and left to air dry after each use. Active ingredient made in Switzerland The trade dress of this ZYRTEC® package is subject to trademark protection. Distributed by: JOHNSON & JOHNSON CONSUMER INC. McNeil Consumer Healthcare Division Fort Washington, PA 19034 USA ©J&JCI 2024 zyrtec.com Pat. www.kenvuepats.com 30056339 4 fl oz (118 ml) Active ingredient (in each 5 mL) Purpose Cetirizine HCl 5 mg.............................................................Antihistamine Uses reduces hives and relieves itching due to hives (urticaria). This product will not prevent hives or an allergic skin reaction from occurring. Warnings Severe Allergy Warning: Get emergency help immediately if you have hives along with any of the following symptoms: ■ trouble swallowing ■ dizziness or loss of consciousness ■ swelling of tongue ■ swelling in or around mouth ■ trouble speaking ■ drooling ■ wheezing or problems breathing These symptoms may be signs of anaphylactic shock. This condition can be life threatening if not treated by a health professional immediately. Symptoms of anaphylactic shock may occur when hives first appear or up to a few hours later. Not a Substitute for Epinephrine. If your doctor has prescribed an epinephrine injector for “anaphylaxis” or severe allergy symptoms that could occur with your hives, never use this product as a substitute for the epinephrine injector. If you have been prescribed an epinephrine injector, you should carry it with you at all times. Do not use ■ to prevent hives from any known cause such as: ■ foods ■ insect stings ■ medicines ■ latex or rubber gloves because this product will not stop hives from occurring. Avoiding the cause of your hives is the only way to prevent them. Hives can sometimes be serious. If you do not know the cause of your hives, see your doctor for a medical exam. Your doctor may be able to help you find a cause. ■ if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have ■ liver or kidney disease. Your doctor should determine if you need a different dose. ■ hives that are an unusual color, look bruised or blistered ■ hives that do not itch Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. When using this product ■ drowsiness may occur ■ avoid alcoholic drinks ■ alcohol, sedatives, and tranquilizers may increase drowsiness ■ be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if ■ an allergic reaction to this product occurs. Seek medical help right away. ■ symptoms do not improve after 3 days of treatment ■ the hives have lasted more than 6 weeks If pregnant or breast-feeding: ■ if breast-feeding: not recommended ■ if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222). Directions ■ use only with enclosed dosing cup ■ find right dose on chart below ■ mL = milliliter Adults and children 6 years and over: 5 mL or 10 mL once daily depending upon severity of symptoms; do not take more than 10 mL in 24 hours. Adults 65 years and over: 5 mL once daily; do not take more than 5 mL in 24 hours. Children under 6 years of age: ask a doctor Consumers with liver or kidney disease: ask a doctor Other information ■ store between 20° to 25°C (68° to 77°F) ■ do not use if bottle wrap imprinted with “Sealed For Your Safety” is broken or missing. Inactive ingredients anhydrous citric acid, flavors, propylene glycol, purified water, sodium benzoate, sorbitol solution, sucralose Questions? call 1-800-343-7805 (toll-free) or 215-273-8755 (collect) NDC 50580-128 04 Drug Facts Format Information 90% -20 N/A N/A 5.00 4.00 5.25 N/A N/A 5.00 LOT: XXXXXXXX EXP: YYYY/MMM Reference ID: 5486429 (b) (4) -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ MARTHA K LENHART 11/26/2024 03:45:08 PM Signature Page 1 of 1 Reference ID: 5486429 (b
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2025-02-12T15:47:21.176486
{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/019835Orig1s050;22155Orig1s027lbl.pdf', 'application_number': 19835, 'submission_type': 'SUPPL ', 'submission_number': 50}
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IWILFIN™ safely and effectively. See full prescribing information for IWILFIN. IWILFIN™ (eflornithine) tablets, for oral use Initial U.S. Approval: 2023 ---------------------------RECENT MAJOR CHANGES--------------------------­ Dosage and Administration (2.3) 11/2024 ----------------------------INDICATIONS AND USAGE--------------------------­ IWILFIN is an ornithine decarboxylase inhibitor indicated to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma (HRNB) who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy. (1) ------------------------DOSAGE AND ADMINISTRATION---------------------­ • Prior to initiation of IWILFIN, perform baseline audiogram, complete blood count, and liver function tests. (2.1, 5.3) • Recommended dosage of IWILFIN is based on body surface area (see Table 1). (2.2) • IWILFIN is taken orally twice daily with or without food until disease progression, unacceptable toxicity, or for a maximum of two years. (2.2) • IWILFIN tablets may be swallowed whole, chewed, or crushed and mixed with soft food or liquid. (2.5) ---------------------DOSAGE FORMS AND STRENGTHS ---------------------­ Tablets: 192 mg (3) ----------------------------CONTRAINDICATIONS--------------------------------­ None (4) -------------------------WARNINGS AND PRECAUTIONS---------------------­ • Myelosuppression: Monitor blood counts before and during treatment with IWILFIN. Withhold, reduce dose, or permanently discontinue based on severity. (5.1) • Hepatotoxicity: Monitor liver function tests before and during treatment with IWILFIN. Withhold, reduce dose, or permanently discontinue based on severity. (5.2) • Hearing Loss: Monitor hearing before and during treatment with IWILFIN. Withhold, reduce dose, or permanently discontinue based on severity. (5.3) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.4, 8.1, 8.3) ----------------------------ADVERSE REACTIONS --------------------------­ • Mostcommonadversereactions(incidence≥5%)are hearing loss, otitis media, pyrexia, pneumonia, and diarrhea. (6.1) • Most common Grade 3 or 4 laboratory abnormalities (incidence ≥2%) are increased ALT, increased AST, decreased neutrophil count, and decreased hemoglobin. (6.1) ToreportSUSPECTEDADVERSE REACTIONS, contact US WorldMeds at 1-877-IWILFIN or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -----------------------USE IN SPECIFIC POPULATIONS ----------------------­ Lactation: Advise not to breastfeed. (8.2) Renal Impairment: Reduce the dose in patients with estimated Glomerular Filtration Rate (eGFR) <30 mL/min. (2.3, 8.5, 12.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Testing Before Initiating IWILFIN 2.2 Recommended Dosage of IWILFIN 2.3 Dosage Recommendations for Renal Impairment 2.4 Dosage Modifications for Adverse Reactions 2.5 Administration, Crushed Preparation, and Missed Dose Instructions 3 DOSAGE FORMS ANDSTRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression 5.2 Hepatotoxicity 5.3 Hearing Loss 5.4 Embryofetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.1 Lactation 8.2 Females and Males of Reproductive Potential 8.3 Pediatric Use 8.4 Renal Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5486506 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE IWILFIN (eflornithine) is indicated to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma (HRNB) who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Testing Before Initiating IWILFIN Prior to initiating IWILFIN, perform complete blood count, liver function tests, and baseline audiogram [see Warnings and Precautions (5.1-5.3)]. 2.2 Recommended Dosage of IWILFIN The recommended IWILFIN dosage, based on body surface area (BSA), is provided in Table 1. Administer IWILFIN orally twice daily for two years or until recurrence of disease or unacceptable toxicity. Recalculate the BSA dosage every 3 months during treatment with IWILFIN. Table 1: Recommended Dose Body Surface Area (m2) Dosage >1.5 768 mg (four tablets) orally twice a day 0.75 to 1.5 576 mg (three tablets) orally twice a day 0.5 to < 0.75 384 mg (two tablets) orally twice a day 0.25 to < 0.5 192 mg (one tablet) orally twice a day 2.3 Dosage Recommendations for Renal Impairment For the treatment of patients with severe renal impairment (eGFR <30 mL/min), reduce the recommended dose of IWILFIN by 50% as described in Table 2 [see Use in Specific Populations (8.5), Clinical Pharmacology (12.3)]. Table 2: IWILFIN Dose Recommendations for Severely Renally Impaired Patients Body Surface Area (m2) Recommended Dosage for Patients with Severe Renal Impairment (eGFR <30 mL/min) >1.5 384 mg (two tablets) orally twice a day 0.75 to 1.5 384 mg (two tablets) in the morning and 192 mg (one tablet) in the evening 0.5 to < 0.75 192 mg (one tablet) orally twice a day Reference ID: 5486506 Body Surface Area (m2) Recommended Dosage for Patients with Severe Renal Impairment (eGFR <30 mL/min) 0.25 to < 0.5 192 mg (one tablet) once a day 2.4 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 3. Table 3: Recommended IWILFIN Dose Reductions for Toxicity Management Current Dose Reduced Dose 768 mg (four tablets) orally twice a day 576 mg (three tablets) orally twice a day 576 mg (three tablets) orally twice a day 384 mg (two tablets) orally twice a day 384 mg (two tablets) orally twice a day 192 mg (one tablet) orally twice a day 192 mg (one tablet) orally twice a day 192 mg (one tablet) orally once daily If subsequent adverse reactions occur, continue dose reduction until reaching the minimum dose of one 192 mg tablet once per day. Permanently discontinue IWILFIN if the patient is unable to tolerate the minimum dose of 192 mg once daily. The recommended dosage modifications of IWILFIN for the management of adverse reactions are provided in Table 4. Table 4: Recommended IWILFIN Dosage Modifications for Adverse Reactions Adverse Reaction Severity* Dosage Modification Myelosuppression [see Warnings and Precautions (5.1)] Neutrophil count decreased <500/mm3 Withhold IWILFIN until recovery to ≥500/mm3 . • If recovered within 7 days, resume IWILFIN at the same dose. • If recovered after 7 days, resume IWILFIN at the next reduced dose level. Platelet count decreased <25,000/mm3 Withhold IWILFIN until recovery to ≥25,000/mm3 . • If recovered within 7 days, resume IWILFIN at the same dose. • If recovered between 7 and 14 days, resume IWILFIN at the next reduced dose level. • If not recovered within 14 days, permanently discontinue IWILFIN. Anemia <8g/dL Withhold IWILFIN until recovery to ≥8g/dL. • Resume IWILFIN at the same dose. If anemia recurs (<8g/dL) • Withhold IWILFIN until recovery to ≥8g/dL. Reference ID: 5486506 Adverse Reaction Severity* Dosage Modification • Resume IWILFIN at the next reduced dose level. Hepatotoxicity [see Warnings and Precautions (5.2)] Aspartate aminotransferase increased or Alanine aminotransferase increased AST or ALT ≥10 × ULN Withhold IWILFIN until recovery to <10 × ULN. • If recovered within 7 days, resume IWILFIN at the same dose. • If recovered after 7 days, resume IWILFIN at the next reduced dose level. Hearing Loss [see Warnings and Precautions (5.3)] Hearing loss Clinically concerning new or worsening hearing loss compared to IWILFIN baseline audiogram Continue dosing with IWILFIN and repeat audiogram in 3 weeks. • If improved, continue IWILFIN at the same dose. • If clinically concerning changes persist, hold IWILFIN for up to 30 days and repeat audiogram. • If stable or improved, resume IWILFIN at the next reduced dose level. Other Adverse Reactions [see Adverse Reactions (6.1)] Nausea, vomiting, or diarrhea Grade 3 If symptoms respond to supportive treatment (e.g., anti-emetic, anti-diarrheal), continue dosing with IWILFIN at the same dose. If symptoms do not respond to treatment, • Withhold IWILFIN until recovery to ≤ Grade 2. • Resume IWILFIN at the next reduced dose level. Other adverse reactions Grade 3 or 4 Withhold IWILFIN until recovery to ≤ Grade 2. • Resume IWILFIN at the next reduced dose level. Recurrent Grade 4 Permanently discontinue IWILFIN. *Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 2.5 Administration, Crushed Preparation, and Missed Dose Instructions Administration • Administer IWILFIN orally twice daily, with or without food, for two years or until recurrence of disease or unacceptable toxicity [see Clinical Pharmacology (12.3)]. • IWILFIN tablets can be swallowed whole, chewed, or crushed. Reference ID: 5486506 Crushed Preparation • For patients who have difficulty swallowing tablets, IWILFIN can be chewed, or crushed then mixed with two tablespoons of soft food or liquid. • Visually confirm the entire contents are consumed. If any crushed tablet particles remain in the container, mix with an additional small volume (e.g., no more than one ounce, 30 mL) of soft food or liquid. • Discard crushed tablet preparation after one hour. Missed Dose • A missed dose of IWILFIN should be administered as soon as possible. If the next dose is due within 7 hours, the missed dose should be skipped. • If vomiting occurs after taking IWILFIN, an additional dose should not be administered. Continue with the next scheduled dose. 3 DOSAGE FORMS AND STRENGTHS Tablets: 192 mg eflornithine, white to off-white, round, imprinted with “EFL” on one side and “192” on the other side. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression IWILFIN can cause myelosuppression. In the pooled safety population [see Adverse Reactions (6.1)], Grade 3 or 4 neutropenia occurred in 4.2% of patients. Febrile neutropenia occurred in 0.6% of patients. Bone marrow failure occurred in 1 patient. Grade 3 or 4 thrombocytopenia occurred in 1.4% of patients. Grade 3 anemia occurred in 3.3% of patients. Monitor blood counts including neutrophil count, platelet count, and hemoglobin level prior to administration of IWILFIN and periodically during treatment. Withhold, reduce the dose, or permanently discontinue IWILFIN based on severity [see Dosage and Administration (2.4)]. 5.2 Hepatotoxicity IWILFIN can cause hepatotoxicity. In the pooled safety population [see Adverse Reactions (6.1)], Grade 3 or 4 events of increased alanine aminotransferase (ALT) occurred in 11% of patients. Grade 3 or 4 events of increased aspartate aminotransferase (AST) occurred in 6% of patients. Grade 3 or 4 events of increased bilirubin occurred in 0.3% of patients. Increased ALT/AST leading to dose interruption or reduction occurred in 2.5% of patients. IWILFIN was discontinued due to increased ALT/AST in 0.6% of patients. Perform liver function tests (ALT, AST, and total bilirubin) prior to the start of IWILFIN, every month for the first six months of treatment, then once every 3 months or as clinically indicated, with more frequent testing in Reference ID: 5486506 5.3 6 patients who develop transaminase or bilirubin elevations. Withhold and reduce the dose or permanently discontinue IWILFIN based on severity [see Dosage and Administration (2.4) and Adverse Reactions (6.1)]. Hearing Loss IWILFIN can cause hearing loss. In the pooled safety population [see Adverse Reactions (6.1)], 81% of patients had an abnormal audiogram at baseline. New or worsening hearing loss occurred in 13% of patients who received IWILFIN; hearing loss worsened from baseline to Grade 3 or 4 in 12% of patients. Tinnitus occurred in 1 patient. Hearing loss leading to dose interruption or reduction occurred in 4% of patients. New or worsening hearing loss requiring new use of hearing aids occurred in 7% of patients. IWILFIN was discontinued due to hearing loss in 1.4% of patients. Among all patients with new or worsening hearing loss during IWILFIN treatment, the hearing loss resolved to baseline in 9% of patients. Among 18 patients who experienced new or worsening hearing loss and had dose modifications, 67% (N=12) improved or resolved to baseline. Perform audiogram prior to initiation of therapy and at 6 month intervals, or as clinically indicated, to monitor for potential hearing loss. Withhold and reduce the dose or permanently discontinue IWILFIN based on severity [see Dosage and Administration (2.1, 2.4)]. 5.4 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, IWILFIN can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of eflornithine to pregnant rats and rabbits during the period of organogenesis resulted in embryolethality at doses equivalent to the recommended human dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IWILFIN and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IWILFIN and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)]. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Myelosuppression [see Warnings and Precautions (5.1)] • Hepatotoxicity [see Warnings and Precautions (5.2)] • Hearing Loss [see Warnings and Precautions (5.3)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in clinical practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to IWILFIN as a single agent, taken orally at doses ranging from 192 - 768 mg twice daily, based on body surface area (BSA), until disease progression, unacceptable toxicity, or for a maximum of 2 years in patients who demonstrated at least a partial response to prior multiagent, multimodality therapy for newly diagnosed or relapsed/refractory high-risk neuroblastoma in Study 3b (n=101; NCT02395666) and Study 14 (n=259; Reference ID: 5486506 6.1 NCT02679144). Among 360 patients who received IWILFIN, 84% were exposed for 6 months or longer and 73% were exposed for greater than one year. In this pooled safety population, the most common (≥5%) adverse reactions were hearing loss (11%), otitis media (10%), pyrexia (7%), pneumonia (5%), and diarrhea (5%). The most common (≥2%) Grade 3 or 4 laboratory abnormalities were increased ALT (11%), increased AST (6%), decreased neutrophils (4.2%), and decreased hemoglobin (3.3%). Study 3b The safety of IWILFIN was evaluated in Study 3b [see Clinical Studies (14.1)]. Eligible patients were pediatric patients with high-risk neuroblastoma (HRNB) who demonstrated at least a partial response to prior multiagent, multimodality therapy including induction, consolidation, and anti-GD2 immunotherapy. Patients received IWILFIN as a single agent taken orally at doses ranging from 192 - 768 mg twice daily, based on body surface area (BSA), until disease progression, unacceptable toxicity, or for a maximum of 2 years (N=85). Among patients who received IWILFIN, 93% were exposed for 6 months or longer and 89% were exposed for greater than one year. The median age of patients who received IWILFIN was 4 years (range: 1 to 17); 59% male; 85% White, 7% Black, 1% Asian, 8% Hispanic or Latino; 87% had International Neuroblastoma Staging System Stage 4 disease; 47% had neuroblastoma with known MYCN-amplification. Serious adverse reactions occurred in 12% of patients who received IWILFIN. Serious adverse reactions in >1 patient included skin infection (3 patients). Permanent discontinuation of IWILFIN due to an adverse reaction occurred in 11% of patients. Adverse reactions which resulted in permanent discontinuation of IWILFIN in >1 patient included hearing loss. Dose reductions of IWILFIN due to an adverse reaction occurred in 8% of patients. Adverse reactions which required dose reductions in >1 patient included hearing loss. The most common (≥5%) adverse reactions, including laboratory abnormalities, were otitis media, diarrhea, cough, sinusitis, pneumonia, upper respiratory tract infection, conjunctivitis, vomiting, pyrexia, allergic rhinitis, decreased neutrophils, increased ALT, increased AST, hearing loss, skin infection, and urinary tract infection. Table 5 summarizes the adverse reactions in Study 3b. Table 5: Adverse Reactions (≥5%) in Patients with HRNB Who Received IWILFIN in Study 3b Adverse Reactiona IWILFIN (n=85) All Gradesb,c (%) Grade 3 (%) Infections Otitis media 32 2.4 Sinusitis 13 0 Pneumonia 12 1.2 Upper respiratory tract infection 11 0 Conjunctivitis 11 0 Skin infection 7 4.7 Reference ID: 5486506 Adverse Reactiona IWILFIN (n=85) All Gradesb,c (%) Grade 3 (%) Urinary tract infection 6 1.2 Gastrointestinal Disorders Diarrhead 15 3.5 Vomiting 11 1.2 Respiratory Disorders Cough 15 0 Allergic rhinitis 11 0 General Disorders Pyrexia 11 1.2 Ear and Labyrinth Disorders Hearing loss 7 7 a Severity as defined by CTCAE Version 4.03. b Grade 1 adverse events were not comprehensively collected in Study 3b. c No Grade 4 or 5 events were reported. d Includes colitis. Clinically relevant adverse reactions in <5% of patients who received IWILFIN included rash, extremity pain, and alopecia. Table 6 summarizes the laboratory abnormalities in Study 3b. Table 6: Select Laboratory Abnormalities (≥1%) in Patients with HRNB Who Received IWILFIN in Study 3b Laboratory Abnormalitya IWILFIN (n=85) All Gradesb,c (%) Grade 3 or 4 (%) Chemistry Increased ALT 9 7d Increased AST 8 6d Increased alkaline phosphatase 4.7 2.4d Decreased potassium 2.4 2.4d Decreased glucose 2.4 1.1 Decreased sodium 2.4 2.4d Reference ID: 5486506 8 Increased potassium 1.2 0 Increased glucose 1.2 0 Hematology Decreased neutrophils 9 8 Decreased hemoglobin 4.7 2.4d Decreased white blood cells 2.4 0 Decreased platelets 1.2 0 a Severity as defined by CTCAE Version 4.03. b Grade 1 adverse events were not comprehensively collected in Study 3b. c No Grade 5 events occurred. d No Grade 4 events occurred. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], IWILFIN can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of eflornithine to pregnant rats and rabbits during the period of organogenesis resulted in embryolethality at doses equivalent to the recommended human dose [see Data]. There are no available data on the use of IWILFIN in pregnant women. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study, once daily oral administration of 30, 80 or 200 mg/kg/day eflornithine to pregnant rats during the period of organogenesis (gestation day 6 to 7) resulted in reduced fetal body weights and an increase in the incidence of skeletal variations (presence of a 14th rudimentary rib, 14th full rib, 27th presacral vertebrae) at 200 mg/kg/day [approximately 0.8 to 2 times the recommended human dose of 1152 ± 384 mg/m2/day based on body surface area (BSA)]. In a dose range-finding embryo-fetal development study, pregnant rats receiving oral administration of up to 2000 mg/kg/day eflornithine during the period of organogenesis exhibited increased early resorptions and post-implantation loss beginning at 300 mg/kg/day (approximately 1 to 2 times the recommended human dose of 1152 ± 384 mg/m2/day based on BSA), with 100% post-implantation loss and no viable fetuses at ≥800 mg/kg/day (approximately ≥3 to 6 times the recommended human dose of 1152 ± 384 mg/m2/day based on BSA). In an embryo-fetal development study in rabbits, once daily oral administration of 15, 45 or 135 mg/kg/day eflornithine to pregnant animals during the period of organogenesis (gestation day 7 to 20) resulted in reduced gravid uterine weight accompanied by increased pre-implantation and post-implantation loss, increased early resorptions, and reduced fetal body weights at 135 mg/kg/day (approximately 1 to 2 times the recommended human dose of 1152 ± 384 mg/m2/day based on BSA). Eflornithine resulted in abortions in one animal at 15 Reference ID: 5486506 mg/kg/day (approximately 0.1 to 0.2 times the recommended human dose of 1152 ± 384 mg/m2/day based on BSA) and one animal at 135 mg/kg/day. In a dose range-finding embryo-fetal development study, pregnant rabbits receiving oral administration of up to 500 mg/kg/day eflornithine during the period of organogenesis exhibited 100% post-implantation loss and no viable fetuses at 500 mg/kg/day (approximately 4 to 8 times the recommended human dose of 1152 ± 384 mg/m2/day based on BSA). There was no clear evidence of eflornithine-related fetal malformations in rats or rabbits. 8.2 Lactation Risk Summary There are no data on the presence of eflornithine in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with IWILFIN and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Based on animal data and its mechanism of action, IWILFIN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating IWILFIN [see Use in Specific Populations (8.1)]. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with IWILFIN and for 1 week after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with IWILFIN and for 1 week after the last dose. 8.4 Pediatric Use The safety and effectiveness of IWILFIN have been established to reduce the risk of relapse in pediatric patients with high-risk neuroblastoma (HRNB) who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy. Use of IWILFIN for this indication is supported by evidence from adequate and well-controlled studies in pediatric patients with a median age of 4 years (range: 1 to 17) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)]. The safety and effectiveness of IWILFIN have not been established in pediatric patients for other indications [see Indications and Usage (1)]. 8.5 Renal Impairment Patients with moderate (eGFR <60 mL/min) and severe (eGFR <30 mL/min) renal impairment have a higher exposure to eflornithine than patients with normal renal function which can increase the risk for toxicity [see Clinical Pharmacology (12.3)]. Reduce the dose in patients with severe renal impairment [see Dosage and Reference ID: 5486506 Administration (2.3)]. Monitor patients with moderate renal impairment closely for increased adverse reactions including hepatotoxicity, myelosuppression, and hearing loss [see Dosage and Administration (2.4)]. 11 DESCRIPTION IWILFIN is an ornithine decarboxylase inhibitor. The chemical name of eflornithine hydrochloride is 2,5­ diamino-2-(difluoromethyl) pentanoic acid hydrochloride hydrate with a molecular formula of C6H12F2N2O2•HCl•H2O. Its molecular weight is 236.65g/mol for the salt and hydrate form and 182.17 g/mol for the anhydrous free base form. Eflornithine hydrochloride is a white to off-white powder, freely soluble in water and sparingly soluble in ethanol. The chemical structure of eflornithine hydrochloride is: IWILFIN is available as a round, white to off-white tablet for oral administration. Each tablet contains 192 mg eflornithine, equivalent to 250 mg of eflornithine hydrochloride, and the following inactive ingredients: 220 mg silicified microcrystalline cellulose, 25 mg partially pregelatinized maize starch, 2.5 mg colloidal silicon dioxide, and 2.5 mg vegetable source magnesium stearate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eflornithine is an irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), the first and rate-limiting enzyme in the biosynthesis of polyamines and a transcriptional target of MYCN. Polyamines are involved in differentiation and proliferation of mammalian cells and are important for neoplastic transformation. Inhibition of polyamine synthesis by eflornithine restored the balance of the LIN28/Let-7 metabolic pathway, which is involved in regulation of cancer stem cells and glycolytic metabolism, by decreasing expression of the oncogenic drivers MYCN and LIN28B in MYCN-amplified neuroblastoma. In vitro, eflornithine induced senescence and suppressed neurosphere formation in MYCN-amplified and MYCN non-amplified neuroblastoma cells, indicating a cytostatic effect. Treatment with eflornithine prevented or delayed tumor formation in mice injected with limiting dilutions of MYCN-amplified neuroblastoma cells. 12.2 Pharmacodynamics Eflornithine exposure-response relationships and the time course of pharmacodynamic responses are unknown. Cardiac Electrophysiology At the recommended dose, IWILFIN did not result in a large mean increase (i.e., >20 ms) of the QTc interval. Reference ID: 5486506 12.3 Pharmacokinetics Absorption Following oral administrations of IWILFIN, peak plasma concentrations of eflornithine (Cmax) were achieved (Tmax) 3.5 hours post dosing. Effect of Food The Cmax and AUC (area under the concentration-time curve) of eflornithine were not affected by food (high fat and high calories). Administration of crushed tablets in a standard pudding admixture had no effect on eflornithine exposure (Cmax and AUC6h). Distribution Eflornithine does not specifically bind to human plasma proteins. Eflornithine volume of distribution (Vz/F) is 24.3 L. Elimination Excretion Terminal plasma elimination half-life of eflornithine is 3.5 hours. Clearance (CL/F) is 5.3 L/h. Specific Populations Pharmacokinetic analyses from patients in Study 14 suggested that age (1 year to 19 years), sex, or body surface area (0.4 m2 to 2 m2), and mild hepatic impairment (bilirubin ≤ULN and AST>ULN or bilirubin >1 x ULN and any AST) had no clinically meaningful effects on eflornithine exposure. Renal Impairment Following oral administration of a single IWILFIN dose of 576 mg, exposure (AUC) of eflornithine was 2-fold higher in adults with moderate renal impairment and 4-fold higher in adults with severe renal impairment when compared to adults with normal renal function. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study, once daily oral administration of eflornithine to female rats did not result in drug-related neoplasms at doses up to 600 mg/kg/day (10.5 times the human Cmax at the recommended clinical dose of 1152 ± 384 mg/m2). Eflornithine was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Dedicated fertility studies were not conducted with eflornithine. 14 CLINICAL STUDIES The efficacy of IWILFIN is based on an externally controlled trial comparison of Study 3b (investigational arm) and Study ANBL0032 (clinical trial-derived external control arm). Study 3b Reference ID: 5486506 Study 3b (NCT02395666) was a multi-center, open label, non-randomized trial with two cohorts. Eligible patients in one cohort (Stratum 1) were pediatric patients with high-risk neuroblastoma (HRNB) who demonstrated at least a partial response to prior multiagent, multimodality therapy, including induction, consolidation, and anti-GD2 immunotherapy. A total of 105 eligible patients received IWILFIN orally twice daily, dosage based on body surface area (BSA) until disease progression, unacceptable toxicity, or for a maximum of 2 years [see Dosage and Administration (2.1)]. Tumor assessments were performed at 3, 6, 9, 12, 18 months, completion of treatment, and as clinically indicated. Following completion of IWILFIN therapy, patients were followed for a total duration of 7 years. The major efficacy outcome measure was event free survival (EFS), defined as disease progression, relapse, secondary cancer, or death due to any cause. An additional efficacy outcome measure was overall survival (OS), defined as death due to any cause. Study 3b was prospectively designed to compare outcomes to the historical EFS rate from Study ANBL0032 reported in published literature. External Comparator: ANBL0032 The external control arm was derived from 1,241 patients on the experimental arm of Study ANBL0032, a multi-center, open-label, randomized trial of dinutuximab, granulocyte-macrophage colony-stimulating factor, interleukin-2, and cis-retinoic acid compared to cis-retinoic acid alone in pediatric patients with HRNB previously treated with induction and consolidation therapy who achieved at least a partial response to prior autologous stem cell transplant. Tumor assessments were performed post-immunotherapy at 3, 6, 9, 12, 18, 24, 30, and 36 months, then per standard of care for a total of 10 years. Externally Controlled Trial The efficacy population for the comparative analysis of Study 3b and ANBL0032 included patients from both studies who were less than 21 years of age with histologic verification of HRNB and who demonstrated at least a partial response based on imaging, with no evidence of disease in the bone marrow, at the end of immunotherapy, and did not experience an EFS event prior to starting IWILFIN maintenance therapy (for Study 3b), or for at least 30 days from the end of immunotherapy (for ANBL0032). Eligible patients on Study 3b received immunotherapy on ANBL0032 or were treated off study according to the ANBL0032 protocol. Patients who met the criteria for the comparison and had complete data for specified clinical covariates were matched (1:3) using propensity scores; the matched efficacy populations for the primary analysis included 90 patients treated with IWILFIN and 270 control patients from ANBL0032. The demographic characteristics of the primary analysis population (N=360) were 59% male; median age at diagnosis 3 years (range: 0.1 to 20.1); 88% White, 6% Black, 4% Asian, 7% Hispanic. The majority of patients had Stage 4 disease (86%) and MYCN amplification was observed in 44% of tumors. End of immunotherapy responses were complete response (CR; 87%), very good partial response (VGPR; 8%), or partial response (PR; 5%). In the protocol-specified primary analysis, the EFS hazard ratio (HR) was 0.48 (95% CI: 0.27, 0.85) and OS HR was 0.32 (95% CI: 0.15, 0.70). The Kaplan-Meier plot for the primary analysis of EFS, with shaded bands for each curve representing the point-wise 95% confidence intervals, is shown in Figure 1. Given the uncertainty associated with the externally controlled study design, supplementary analyses in subpopulations or using alternative statistical methods were performed. In these analyses, the EFS HR ranged from 0.43 (95% CI: 0.23, 0.79) to 0.59 (95% CI: 0.28, 1.27), and the OS HR ranged from 0.29 (95% CI: 0.11, 0.72) to 0.45 (95% CI: 0.21, 0.98). Reference ID: 5486506 1.0 0.9 Q,) 0.8 - RI c:::: 0.7 iii oh ~111111111 II Ill • + ••-+ +II- ••++- > ·== 0.6 '- ::::, (J) Q,) 0.5 e u. 04 - C: Q,) 0.3 > w 0.2 0.1 --- IWILFIN Control 00 0 2 3 4 5 6 7 8 9 10 11 12 At risk Time From End of lmmunotherapy (Years) IWILFIN 90 83 78 77 76 70 47 27 2 0 Control 270 229 211 200 164 117 80 49 29 15 9 3 0 Figure 1: Kaplan-Meier Curve for Event Free Survival for Protocol-Specified Primary Analysis in the Externally Controlled Trial 16 HOW SUPPLIED/STORAGE AND HANDLING IWILFIN (eflornithine) is available as 192 mg round, white to off-white tablets imprinted with EFL on one side and 192 on the other side; approximately 11 mm in diameter and supplied as follows: • Bottle of 100 tablets containing desiccant, NDC 78670-150-01 Store at room temperature, 20oC to 25°C (68oF to77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myelosuppression Inform patients and caregivers of the risk of bone marrow suppression and to promptly report any signs or symptoms of thrombocytopenia, anemia, or infection [see Warnings and Precautions (5.1)]. Hepatotoxicity Inform patients and caregivers of the risk of hepatotoxicity and to promptly report any signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.2)]. Hearing Loss Inform patients and caregivers of the risk of hearing loss, and to promptly report any signs or symptoms of new or worsening hearing loss [see Warnings and Precautions (5.3)]. Reference ID: 5486506 US W fbrldMeds· Embryofetal Toxicity Inform patients and caregivers that IWILFIN can be harmful to a developing fetus and cause loss of pregnancy [see Warnings and Precautions (5.4)]. Advise females of reproductive potential to use effective contraception during treatment with IWILFIN and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IWILFIN and for 1 week after the last dose [see Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment with IWILFIN and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Distributed by: USWM, LLC 4441 Springdale Road Louisville, KY 40241 ©2023. IWILFIN™ is a trademark of USWM, LLC. FPI-0026.1 Reference ID: 5486506
custom-source
2025-02-12T15:47:22.598576
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PAXIL safely and effectively. See full prescribing information for PAXIL. PAXIL (paroxetine) tablets, for oral use PAXIL (paroxetine) oral suspension Initial U.S. Approval: 1992 WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant- treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. PAXIL is not approved for use in pediatric patients. (5.1, 8.4) -------------------------RECENT MAJOR CHANGES--------------------------- Warnings and Precautions (5.4) 11/2024 ----------------------------INDICATIONS AND USAGE--------------------------- PAXIL is a selective serotonin reuptake inhibitor (SSRI) indicated in adults for the treatment of (1): • Major Depressive Disorder (MDD) • Obsessive Compulsive Disorder (OCD) • Panic Disorder (PD) • Social Anxiety Disorder (SAD) • Generalized Anxiety Disorder (GAD) • Posttraumatic Stress Disorder (PTSD) ----------------------DOSAGE AND ADMINISTRATION---------------------- • Shake oral suspension well before administration (2.1) • Recommended starting and maximum daily dosage for MDD, OCD, PD, and PTSD: (2.2) Indication Starting Daily Dose Maximum Daily Dose MDD 20 mg 50 mg OCD 20 mg 60 mg PD 10 mg 60 mg PTSD 20 mg 50 mg • Recommended starting dosage for SAD and GAD is 20 mg daily. (2.3) • Elderly patients, patients with severe renal impairment or severe hepatic impairment: Starting dosage is 10 mg daily. Maximum dosage is 40 mg daily. (2.4) • When discontinuing PAXIL, reduce dosage gradually. (2.6, 5.7) ----------------------DOSAGE FORMS AND STRENGTHS--------------------- • Extended-release tablets: 10 mg, scored; 20 mg, scored; 30 mg; and 40 mg tablets. (3) • Oral suspension: 10 mg/5 mL (not currently marketed) (3) -------------------------------CONTRAINDICATIONS----------------------------- • Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing a MAOI. (4, 5.3, 7) • Concomitant use of pimozide or thioridazine. (4, 5.3,7) • Known hypersensitivity to paroxetine or to any of the inactive ingredients in PAXIL. (4) -----------------------WARNINGS AND PRECAUTIONS------------------------ • Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If occurs, discontinue PAXIL and serotonergic agents and initiate supportive measures. (5.2) • Embryofetal Toxicity: May cause fetal harm. Meta-analyses of epidemiological studies have shown increased risk (less than 2-fold) of cardiovascular malformations with exposure during the first trimester. (5.4, 8.1) • Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti- inflammatory drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk. (5.5) • Activation of Mania/Hypomania: Screen patients for bipolar disorder. (5.6) • Seizures: Use with caution in patients with seizure disorders. (5.8) • Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.9) • Sexual Dysfunction: PAXIL may cause symptoms of sexual dysfunction. (5.13) -------------------------------ADVERSE REACTIONS-------------------------- Most common adverse reactions (≥5% and at least twice placebo) are abnormal ejaculation, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, infection, insomnia, libido decreased, male genital disorder, nausea, nervousness, somnolence, sweating, tremor, yawn. (6) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------------DRUG INTERACTIONS----------------------------------- • Drugs Highly Bound to Plasma Protein: Monitor for adverse reactions and reduce dosage of PAXIL or other protein-bound drugs (e.g., warfarin) as warranted. (7) • Drugs Metabolized by CYP2D6: Reduce dosage of drugs metabolized by CYP2D6 as warranted. (7) • Concomitant use with tamoxifen: Consider use of an alternative antidepressant with little or no CYP2D6 inhibition. (5.11, 7) ---------------------USE IN SPECIFIC POPULATIONS--------------------- • Pregnancy: SSRI use, particularly later in pregnancy, may increase the risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, irritability) in the neonate. (8.1) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5486158 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SUICIDAL THOUGHTS AND BEHAVIORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Administration Information 2.2 Recommended Dosage for MDD, OCD, PD, and PTSD 2.3 Recommended Dosage for SAD and GAD 2.4 Screen for Bipolar Disorder Prior to Starting PAXIL 2.5 Recommended Dosage for Elderly Patients, Patients with Severe Renal Impairment, and Patients with Severe Hepatic Impairment 2.6 Switching Patients to or From a Monoamine Oxidase Inhibitor (MAOI) 2.7 Discontinuation of Treatment With PAXIL 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults 5.2 Serotonin Syndrome 5.3 Drug Interactions Leading to QT Prolongation 5.4 Embryofetal Toxicity 5.5 Increased Risk of Bleeding 5.6 Activation of Mania or Hypomania 5.7 Discontinuation Syndrome 5.8 Seizures 5.9 Angle-Closure Glaucoma 5.10 Hyponatremia 5.11 Reduction of Efficacy of Tamoxifen 5.12 Bone Fracture 5.13 Sexual Dysfunction 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric use 8.6 Renal and Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Major Depressive Disorder 14.2 Obsessive Compulsive Disorder 14.3 Panic Disorder 14.4 Social Anxiety Disorder 14.5 Generalized Anxiety Disorder 14.6 Posttraumatic Stress Disorder 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5486158 FULL PRESCRIBING INFORMATION WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)]. PAXIL is not approved for use in pediatric patients [see Use in Specific Populations (8.4)]. 1 INDICATIONS AND USAGE PAXIL is indicated in adults for the treatment of: • Major depressive disorder (MDD) • Obsessive compulsive disorder (OCD) • Panic disorder (PD) • Social anxiety disorder (SAD) • Generalized anxiety disorder (GAD) • Posttraumatic stress disorder (PTSD) 2 DOSAGE AND ADMINISTRATION 2.1 Administration Information Administer PAXIL as a single daily dose in the morning, with or without food. Shake the oral suspension well before administration. 2.2 Recommended Dosage for MDD, OCD, PD, and PTSD The recommended starting dosages and maximum dosages of PAXIL in patients with MDD, OCD, PD, and PTSD are presented in Table 1. In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability. Table 1: Recommended Daily Dosage of PAXIL in Patients with MDD, OCD, PD, and PTSD Indication Starting Dose Maximum Dose MDD 20 mg 50 mg OCD 20 mg 60 mg PD 10 mg 60 mg PTSD 20 mg 50 mg Reference ID: 5486158 2.3 Recommended Dosage for SAD and GAD SAD The starting and recommended dosage in patients with SAD is 20 mg daily. In clinical trials the effectiveness of PAXIL was demonstrated in patients dosed in a range of 20 mg to 60 mg daily. While the safety of PAXIL has been evaluated in patients with SAD at doses up to 60 mg daily, available information does not suggest any additional benefit for doses above 20 mg daily [see Clinical Studies (14.4)]. GAD The starting and recommended dosage in patients with GAD is 20 mg daily. In clinical trials the effectiveness of PAXIL in GAD was demonstrated in patients dosed in a range of 20 mg to 50 mg daily. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg daily [see Clinical Studies (14.5)]. In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability. 2.4 Screen for Bipolar Disorder Prior to Starting PAXIL Prior to initiating treatment with PAXIL or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6)]. 2.5 Recommended Dosage for Elderly Patients, Patients with Severe Renal Impairment, and Patients with Severe Hepatic Impairment The recommended initial dosage is 10 mg per day for elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment. Dosage should not exceed 40 mg/day. 2.6 Switching Patients to or From a Monoamine Oxidase Inhibitor (MAOI) At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI and initiation of PAXIL. In addition, at least 14 days must elapse after stopping PAXIL before starting an MAOI antidepressant [see Contraindications (4), Warnings and Precautions (5.2)]. 2.7 Discontinuation of Treatment With PAXIL Adverse reactions may occur upon discontinuation of PAXIL [see Warnings and Precautions (5.7)]. Gradually reduce the dosage rather than stopping PAXIL abruptly whenever possible. 3 DOSAGE FORMS AND STRENGTHS PAXIL tablets are available as: • 10 mg yellow, scored tablet engraved on the front with “PAXIL” and on the back with “10”. • 20 mg pink, scored tablet engraved on the front with “PAXIL” and on the back with “20”. • 30 mg blue tablet engraved on the front with “PAXIL” and on the back with “30”. • 40 mg green tablet engraved on the front with “PAXIL” and on the back with “40”. PAXIL oral suspension is available as: Reference ID: 5486158 • 10 mg/5 mL orange colored, orange flavored suspension in bottles containing 250 mL (not currently marketed). 4 CONTRAINDICATIONS PAXIL is contraindicated in patients: • Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.2), Drug Interactions (7)]. • Taking thioridazine because of risk of QT prolongation [see Warnings and Precautions (5. 3), Drug Interactions (7)] • Taking pimozide because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug Interactions (7)]. • With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or any of the inactive ingredients in PAXIL [see Adverse Reactions (6.1), (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 2. Table 2: Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo <18 years old 14 additional cases 18-24 years old 5 additional cases Decreases Compared to Placebo 25-64 years old 1 fewer case 65 years old 6 fewer cases PAXIL is not approved for use in pediatric patients. Reference ID: 5486158 It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing PAXIL, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome SSRIs, including PAXIL, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of PAXIL with MAOIs is contraindicated. In addition, do not initiate PAXIL in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking PAXIL discontinue PAXIL before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7)]. Monitor all patients taking PAXIL for the emergence of serotonin syndrome. Discontinue treatment with PAXIL and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of PAXIL with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Drug Interactions Leading to QT Prolongation The CYP2D6 inhibitory properties of paroxetine can elevate plasma levels of thioridazine and pimozide. Since thioridazine and pimozide given alone produce prolongation of the QTc interval and increase the risk of serious ventricular arrhythmias, the use of PAXIL is contraindicated in combination with thioridazine and pimozide [see Contraindications (4), Drug Interactions (7), Clinical Pharmacology (12.3)]. Reference ID: 5486158 5.4 Embryofetal Toxicity Based on meta-analyses of epidemiological studies, exposure to paroxetine in the first trimester of pregnancy is associated with a less than 2-fold increase in the rate of cardiovascular malformations among infants. For women who intend to become pregnant or who are in their first trimester of pregnancy, PAXIL, should be initiated only after consideration of the other available treatment options [see Use in Specific Populations (8.1)]. 5.5 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including PAXIL, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)]. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of PAXIL and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio. 5.6 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with PAXIL or another antidepressant may precipitate a mixed/manic episode. During controlled clinical trials of PAXIL, hypomania or mania occurred in approximately 1% of PAXIL-treated unipolar patients compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. Prior to initiating treatment with PAXIL, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.7 Discontinuation Syndrome Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.7)]. During clinical trials of GAD and PTSD, gradual decreases in the daily dose by 10 mg/day at weekly intervals followed by 1 week at 20 mg/day was used before treatment was discontinued. The following adverse reactions were reported at an incidence of 2% or greater for PAXIL and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness adverse reactions have been reported upon discontinuation of treatment with PAXIL in pediatric patients. The safety and effectiveness of PAXIL in pediatric patients have not been established [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.4)]. Reference ID: 5486158 5.8 Seizures PAXIL tablets and oral suspension have not been systematically evaluated in patients with seizure disorders. Patients with history of seizures were excluded from clinical studies. During clinical studies, seizures occurred in 0.1% of patients treated with PAXIL. PAXIL should be prescribed with caution in patients with a seizure disorder. Discontinue PAXIL in any patient who develops seizures. 5.9 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including PAXIL may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Cases of angle-closure glaucoma associated with use of PAXIL have been reported. Avoid use of antidepressants, including PAXIL in patients with untreated anatomically narrow angles. 5.10 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs, including PAXIL. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In patients with symptomatic hyponatremia, discontinue PAXIL and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs [see Use in Specific Populations (8.5)]. 5.11 Reduction of Efficacy of Tamoxifen Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced with concomitant use of PAXIL as a result of paroxetine’s irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen [see Drug Interactions (7)]. One study suggests that the risk may increase with longer duration of coadministration. However, other studies have failed to demonstrate such a risk. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition. 5.12 Bone Fracture Epidemiological studies on bone fracture risk during exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation, and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. 5.13 Sexual Dysfunction Use of SSRIs, including PAXIL, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm. Reference ID: 5486158 It is important for prescribers to inquire about sexual function prior to initiation of PAXIL and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment. 6 ADVERSE REACTIONS The following adverse reactions are included in more detail in other sections of the prescribing information: • Hypersensitivity reactions to paroxetine [see Contraindications (4)] • Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)] • Serotonin Syndrome [see Warnings and Precautions (5.2)] • Embryofetal Toxicity [see Warnings and Precautions (5.4)] • Increased Risk of Bleeding [see Warnings and Precautions (5.5)] • Activation of Mania/Hypomania [see Warnings and Precautions (5.6)] • Discontinuation Syndrome [see Warnings and Precautions (5.7)] • Seizures [see Warnings and Precautions (5.8)] • Angle-closure Glaucoma [see Warnings and Precautions (5.9)] • Hyponatremia [see Warnings and Precautions (5.10)] • Bone Fracture [see Warnings and Precautions (5.12)] • Sexual Dysfunction [see Warnings and Precautions (5.13)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data for PAXIL are from: • 6-week clinical trials in MDD patients who received PAXIL 20 mg to 50 mg once daily • 12-week clinical trials in OCD patients who received PAXIL 20 mg to 60 mg once daily • 10- to 12-week clinical trials in PD patients who received PAXIL 10 mg to 60 mg once daily • 12-week clinical trials in SAD patients who received PAXIL 20 mg to 50 mg once daily • 8-week clinical trials in GAD patients who received PAXIL 10 mg to 50 mg once daily • 12-week clinical trials in PTSD patients who received PAXIL 20 mg to 50 mg once daily Adverse Reactions Leading to Discontinuation Twenty percent (1,199/6,145) of patients treated with PAXIL in clinical trials in MDD and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients treated with PAXIL in clinical trials in SAD, OCD, PD, GAD, and PTSD, respectively, discontinued treatment due to an adverse reaction. The most common adverse reactions (1%) associated with discontinuation (i.e., those adverse reactions associated with dropout at a rate approximately twice or greater for PAXIL compared to placebo) are presented in Table 3: Reference ID: 5486158 Table 3: Adverse Reactions Reported as Leading to Discontinuation (≥1% of PAXIL- Treated Patients and Greater than Placebo) in MDD, OCD, PD, SAD, GAD, and PTSD Trials MDD OCD PD SAD GAD PTSD PAXIL % Placebo % PAXIL % Placebo % PAXIL % Placebo % PAXIL % Placebo % PAXIL % Placebo % PAXIL % Placebo % CNS Somnolence 2.3 0.7 — 1.9 0.3 3.4 0.3 2.0 0.2 2.8 0.6 Insomnia — — 1.7 0 1.3 0.3 3.1 0 — — Agitation 1.1 0.5 — — — Tremor 1.1 0.3 — 1.7 0 1.0 0.2 Anxiety — — — 1.1 0 — — Dizziness — — 1.5 0 1.9 0 1.0 0.2 — — Gastroin- testinal Constipation — 1.1 0 — — Nausea 3.2 1.1 1.9 0 3.2 1.2 4.0 0.3 2.0 0.2 2.2 0.6 Diarrhea 1.0 0.3 — Dry mouth 1.0 0.3 — — — Vomiting 1.0 0.3 — 1.0 0 — — Flatulence 1.0 0.3 — — Other Asthenia 1.6 0.4 1.9 0.4 2.5 0.6 1.8 0.2 1.6 0.2 Abnormal Ejaculationa 1.6 0 2.1 0 4.9 0.6 2.5 0.5 — — Sweating 1.0 0.3 — 1.1 0 1.1 0.2 — — Impotencea — 1.5 0 — — Libido Decreased 1.0 0 — — Where numbers are not provided the incidence of the adverse reactions in patients treated with PAXIL was not >1% or was not greater than or equal to 2 times the incidence of placebo. a. Incidence corrected for gender. Most Common Adverse Reactions The most commonly observed adverse reactions associated with the use of PAXIL (incidence of 5% or greater and at least twice that for placebo) were: MDD: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders. Reference ID: 5486158 OCD: Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation. PD: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence. SAD: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence. GAD: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation. PTSD: Asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence. Adverse Reactions in Patients with MDD Table 4 presents the adverse reactions that occurred at an incidence of 1% or more and greater than placebo in clinical trials of PAXIL-treated patients with MDD. Table 4: Adverse Reactions (≥1% of PAXIL-Treated Patients and Greater than Placebo) in 6-Week Clinical Trials for MDD Body System/ Adverse Reaction PAXIL (n = 421) % Placebo (n = 421) % Body as a Whole Headache Asthenia 18 15 17 6 Cardiovascular Palpitation Vasodilation 3 3 1 1 Dermatologic Sweating Rash 11 2 2 1 Gastrointestinal Nausea Dry Mouth Constipation Diarrhea Decreased Appetite 26 18 14 12 6 9 12 9 8 2 Reference ID: 5486158 Flatulence Oropharynx Disordera Dyspepsia 4 2 2 2 0 1 Musculoskeletal Myopathy Myalgia Myasthenia 2 2 1 1 1 0 Nervous System Somnolence Dizziness Insomnia Tremor Nervousness Anxiety Paresthesia Libido Decreased Drugged Feeling Confusion 23 13 13 8 5 5 4 3 2 1 9 6 6 2 3 3 2 0 1 0 Respiration Yawn 4 0 Special Senses Blurred Vision Taste Perversion 4 2 1 0 Urogenital System Ejaculatory Disturbanceb,c Other Male Genital Disordersb,d Urinary Frequency Urination Disordere Female Genital Disordersb,f 13 10 3 3 2 0 0 1 0 0 a. Includes mostly “lump in throat” and “tightness in throat.” b. Percentage corrected for gender. c. Mostly “ejaculatory delay.” d. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,” and “impotence.” e. Includes mostly “difficulty with micturition” and “urinary hesitancy.” f. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.” Adverse Reactions in Patients with OCD, PD, and SAD Reference ID: 5486158 Table 5 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with OCD, PD, and SAD. Table 5. Adverse Reactions (≥2% of PAXIL-Treated Patients and Greater than Placebo) in 10 to 12-Week Clinical Trials for OCD, PD, and SAD Body System/Preferred Term Obsessive Compulsive Disorder Panic Disorder Social Anxiety Disorder PAXIL (n = 542) % Placebo (n = 265) % PAXIL (n = 469) % Placebo (n = 324) % PAXIL (n = 425) % Placebo (n = 339) % Body as a Whole Asthenia 22 14 14 5 22 14 Abdominal Pain - - 4 3 — — Chest Pain 3 2 - - - - Back Pain Chills - 2 - 1 3 2 2 1 - — - — Trauma — — — — 3 1 Cardiovascular Vasodilation 4 1 — — — — Palpitation 2 0 — — — — Dermatologic Sweating Rash 9 3 3 2 14 — 6 — 9 — 2 — Gastrointestinal Nausea Dry Mouth Constipation Diarrhea Decreased Appetite Dyspepsia Flatulence Increased Appetite Vomiting 23 18 16 10 9 - - 4 - 10 9 6 10 3 - - 3 - 23 18 8 12 7 - - 2 - 17 11 5 7 3 - - 1 - 25 9 5 9 8 4 4 - 2 7 3 2 6 2 2 2 - 1 Musculoskeletal Myalgia — — — — 4 3 Nervous System Insomnia 24 13 18 10 21 16 Somnolence 24 7 19 11 22 5 Dizziness 12 6 14 10 11 7 Tremor 11 1 9 1 9 1 Reference ID: 5486158 Body System/Preferred Term Obsessive Compulsive Disorder Panic Disorder Social Anxiety Disorder PAXIL (n = 542) % Placebo (n = 265) % PAXIL (n = 469) % Placebo (n = 324) % PAXIL (n = 425) % Placebo (n = 339) % Nervousness 9 8 — — 8 7 Libido Decreased 7 4 9 1 12 1 Agitation — — 5 4 3 1 Anxiety — — 5 4 5 4 Abnormal Dreams 4 1 — — — — Concentration Impaired 3 2 — — 4 1 Depersonalization Myoclonus 3 3 0 0 — 3 — 2 — 2 — 1 Amnesia 2 1 - - - - Respiratory System Rhinitis Pharyngitis Yawn - — - - — - 3 — - 0 — - - 4 5 - 2 1 Special Senses Abnormal Vision Taste Perversion 4 2 2 0 — - — - 4 - 1 - Urogenital System Abnormal Ejaculationa 23 1 21 1 28 1 Dysmenorrhea — — — — 5 4 Female Genital Disordera 3 0 9 1 9 1 Impotencea 8 1 5 0 5 1 Urinary Frequency 3 1 2 0 — — Urination Impaired 3 0 — — — — Urinary Tract Infection 2 1 2 1 — — a. Percentage corrected for gender. Adverse Reactions in Patients with GAD and PTSD Reference ID: 5486158 Table 6 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with GAD and PTSD. Table 6. Adverse Reactions (≥2% of PAXIL-Treated Patients and Greater than Placebo) in 8- to 12-Week Clinical Trials for GAD and PTSDa Body System/ Preferred Term Generalized Anxiety Disorder Posttraumatic Stress Disorder PAXIL (n= 735) % Placebo (n = 529) % PAXIL (n = 676) % Placebo (n = 504) % Body as a Whole Asthenia Headache Infection Abdominal Pain Trauma 14 17 6 6 14 3 12 --- 5 4 6 4 --- 4 3 5 Cardiovascular Vasodilation 3 1 2 1 Dermatologic Sweating 6 2 5 1 Gastrointestinal Nausea Dry Mouth Constipation Diarrhea Decreased Appetite Vomiting Dyspepsia 20 11 10 9 5 3 --- 5 5 2 7 1 2 --- 19 10 5 11 6 3 5 8 5 3 5 3 2 3 Reference ID: 5486158 Body System/ Preferred Term Generalized Anxiety Disorder Posttraumatic Stress Disorder PAXIL (n= 735) % Placebo (n = 529) % PAXIL (n = 676) % Placebo (n = 504) % Nervous System Insomnia Somnolence Dizziness Tremor Nervousness Libido Decreased Abnormal Dreams 11 15 6 5 4 9 8 5 5 1 3 2 12 16 6 4 --- 5 3 11 5 5 1 --- 2 Respiratory System Respiratory Disorder Sinusitis Yawn 7 4 4 5 3 --- --- --- 2 --- --- <1 Special Senses Abnormal Vision 2 1 3 1 Urogenital System Abnormal Ejaculationa Female Genital Disordera Impotencea 25 4 4 2 1 3 13 5 9 2 1 1 a. Percentage corrected for gender. Dose Dependent Adverse Reactions MDD A comparison of adverse reaction rates in a fixed-dose study comparing PAXIL10 mg, 20 mg, 30 mg, and 40 mg once daily with placebo in the treatment of MDD revealed dose dependent adverse reactions, as shown in Table 7: Table 7. Adverse Reactions (≥5% of PAXIL-Treated Patients and ≥ Twice the Rate of Placebo) (in a Dose-Comparison Trial in the Treatment of MDD Body System/Preferred Term Placebo PAXIL n = 51 % 10 mg n = 102 % 20 mg n = 104 % 30 mg n = 101 % 40 mg n = 102 % Body as a Whole Asthenia 0.0 2.9 10.6 13.9 12.7 Dermatology Reference ID: 5486158 Body System/Preferred Term Placebo PAXIL n = 51 % 10 mg n = 102 % 20 mg n = 104 % 30 mg n = 101 % 40 mg n = 102 % Sweating 2.0 1.0 6.7 8.9 11.8 Gastrointestinal Constipation 5.9 4.9 7.7 9.9 12.7 Decreased Appetite 2.0 2.0 5.8 4.0 4.9 Diarrhea 7.8 9.8 19.2 7.9 14.7 Dry Mouth 2.0 10.8 18.3 15.8 20.6 Nausea 13.7 14.7 26.9 34.7 36.3 Nervous System Anxiety 0.0 2.0 5.8 5.9 5.9 Dizziness 3.9 6.9 6.7 8.9 12.7 Nervousness 0.0 5.9 5.8 4.0 2.9 Paresthesia 0.0 2.9 1.0 5.0 5.9 Somnolence 7.8 12.7 18.3 20.8 21.6 Tremor 0.0 0.0 7.7 7.9 14.7 Special Senses Blurred Vision 2.0 2.9 2.9 2.0 7.8 Urogenital System Abnormal Ejaculation 0.0 5.8 6.5 10.6 13.0 Impotence 0.0 1.9 4.3 6.4 1.9 Male Genital Disorders 0.0 3.8 8.7 6.4 3.7 OCD In a fixed-dose study comparing placebo and PAXIL 20 mg, 40 mg, and 60 mg in the treatment of OCD, there was no clear relationship between adverse reactions and the dose of PAXIL to which patients were assigned. PD In a fixed-dose study comparing placebo and PAXIL 10 mg, 20 mg, and 40 mg in the treatment of PD, the following adverse reactions were shown to be dose-dependent: asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. SAD In a fixed-dose study comparing placebo and PAXIL 20 mg, 40 mg and 60 mg in the treatment of SAD, for most of the adverse reactions, there was no clear relationship between adverse reactions and the dose of PAXIL to which patients were assigned. Reference ID: 5486158 GAD In a fixed-dose study comparing placebo and PAXIL 20 mg and 40 mg in the treatment of GAD, the following adverse reactions were shown to be dose-dependent: asthenia, constipation, and abnormal ejaculation. PTSD In a fixed-dose study comparing placebo and PAXIL 20 mg and 40 mg in the treatment of PTSD, the following adverse reactions were shown to be dose-dependent: impotence and abnormal ejaculation. Male and Female Sexual Dysfunction Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence. The percentage of patients reporting symptoms of sexual dysfunction in males and females with MDD, OCD, PD, SAD, GAD, and PTSD are displayed in Table 8. Table 8. Adverse Reactions Related to Sexual Dysfunction in Patients Treated with PAXIL in Clinical Trials of MDD, OCD, PD, SAD, GAD, and PTSD PAXIL Placebo n (males) 1446 % 1042 % Decreased Libido 6 to15 0 to 5 Ejaculatory Disturbance 13 to 28 0 to 2 Impotence 2 to 9 0 to 3 n (females) 1822 % 1340 % Decreased Libido 0 to 9 0 to 2 Orgasmic Disturbance 2 to 9 0 to 1 PAXIL treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae. Hallucinations Reference ID: 5486158 In pooled clinical trials of PAXIL, hallucinations were observed in 0.2% of PAXIL-treated patients compared to 0.1% of patients receiving placebo. Less Common Adverse Reactions The following adverse reactions occurred during the clinical studies of PAXIL and are not included elsewhere in the labeling. Adverse reactions are categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse reactions are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients. Body as a Whole Infrequent: Allergic reaction, chills, face edema, malaise, neck pain; rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer. Cardiovascular System Frequent: Hypertension, tachycardia; infrequent: Bradycardia, hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles. Digestive System Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, abnormal liver function tests, rectal hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries. Endocrine System Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis. Hemic and Lymphatic Systems Infrequent: Anemia, leukopenia, lymphadenopathy, purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, Reference ID: 5486158 leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia. Metabolic and Nutritional Frequent: Weight gain; infrequent: Edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased. Musculoskeletal System Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare: Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany. Nervous System Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome. Respiratory System Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration. Skin and Appendages Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis; herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash. Special Senses Reference ID: 5486158 Frequent: Tinnitus; infrequent: Abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect. Urogenital System Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis. 6.2 Postmarketing Experience The following reactions have been identified during post approval use of PAXIL. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), syndrome of inappropriate ADH secretion, prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, oculogyric crisis which has been associated with concomitant use of pimozide; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anosmia, hyposmia, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch- Schönlein purpura), and premature births in pregnant women. There has been a case report of severe hypotension when PAXIL was added to chronic metoprolol treatment. 7 DRUG INTERACTIONS Table 9 presents clinically significant drug interactions with PAXIL. Reference ID: 5486158 Table 9 : Clinically Significant Drug Interactions with PAXIL Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of SSRIs, including PAXIL, and MAOIs increases the risk of serotonin syndrome. Intervention PAXIL is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)]. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Pimozide and Thioridazine Clinical Impact Increased plasma concentrations of pimozide and thioridazine, drugs with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias. Intervention PAXIL is contraindicated in patients taking pimozide or thioridazine [see Contraindications (4)]. Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with PAXIL increases the risk of serotonin syndrome. Intervention Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of PAXIL and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)]. Examples other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort. Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants) Clinical Impact The concurrent use of an antiplatelet agent or anticoagulant with PAXIL may potentiate the risk of bleeding. Intervention Inform patients of the increased risk of bleeding associated with the concomitant use of PAXIL and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warnings and Precautions (5.5)]. Examples aspirin, clopidogrel, heparin, warfarin Drugs Highly Bound to Plasma Protein Clinical Impact PAXIL is highly bound to plasma protein. The concomitant use of PAXIL with another drug that is highly bound to plasma protein may increase free concentrations of PAXIL or other tightly-bound drugs in plasma. Intervention Monitor for adverse reactions and reduce dosage of PAXIL or other protein-bound drugs as warranted. Reference ID: 5486158 Examples Warfarin Drugs Metabolized by CYP2D6 Clinical Impact PAXIL is a CYP2D6 inhibitor [see Clinical Pharmacology (12.3)]. The concomitant use of PAXIL with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate. Intervention Decrease the dosage of a CYP2D6 substrate if needed with concomitant PAXIL use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if PAXIL is discontinued. Examples propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone. Tamoxifen Clinical Impact Concomitant use of tamoxifen with PAXIL may lead to reduced plasma concentrations of the active metabolite (endoxifen) and reduced efficacy of tamoxifen Intervention Consider use of an alternative antidepressant with little or no CYP2D6 inhibition [see Warnings and Precautions (5.11)]. Fosamprenavir/Ritonavir Clinical Impact Co-administration of fosamprenavir/ritonavir with PAXIL significantly decreased plasma levels of PAXIL. Intervention Any dose adjustment should be guided by clinical effect (tolerability and efficacy). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including PAXIL, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Antidepressants 1-866- 961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research- programs/pregnancyregistry/antidepressants/. Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.5) and Clinical Considerations]. Paxil is associated with a less than 2-fold increase in cardiovascular malformations when administered to a pregnant woman during the first trimester. While individual epidemiological studies on the association between paroxetine use and cardiac malformations have reported Reference ID: 5486158 inconsistent findings, some meta-analyses of epidemiological studies have identified an increased risk of cardiovascular malformations (see Data). There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including PAXIL during pregnancy. There also are risks associated with untreated depression in pregnancy (see Clinical Considerations). For women who intend to become pregnant or who are in their first trimester of pregnancy, paroxetine should be initiated only after consideration of the other available treatment options. No evidence of treatment related malformations was observed in animal reproduction studies, when paroxetine was administered during the period of organogenesis at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits. These doses are approximately 8 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD – 60 mg) on an mg/m2 basis. When paroxetine was administered to female rats during the last trimester of gestation and continued through lactation, there was an increase in the number of pup deaths during the first four days of lactation. This effect occurred at a dose of 1 mg/kg/day which is less than the MRHD on an mg/m2 basis (See Data). The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryofetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and the postpartum. Maternal Adverse Reactions Use of PAXIL in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.5)]. Fetal/Neonatal adverse reactions Neonates exposed to PAXIL and other SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs or possibly a drug Reference ID: 5486158 discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)]. Data Human Data Published epidemiological studies on the association between first trimester paroxetine use and cardiovascular malformations have reported inconsistent results; however, meta-analyses of population-based cohort studies published between 1996 – 2017 indicate a less than 2-fold increased risk for overall cardiovascular malformations. Specific cardiac malformations identified in two meta-analyses include an approximately 2 to 2.5-fold increased risk for right ventricular outflow tract defects. One meta-analysis also identified an increased risk (less than 2-fold) for bulbus cordis anomalies and anomalies of cardiac septal closure, and an increased risk for atrial septal defect (pooled OR 2.38, 95% CI 1.14-4.97). Important limitations of the studies included in these meta-analyses include potential confounding by indication, depression severity, and potential exposure misclassification. Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for PPHN. PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD – 60 mg) on an mg/m2 basis. These studies have revealed no evidence of developmental effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day which is less than the MRHD on an mg/m2 basis. The no effect dose for rat pup mortality was not determined. The cause of these deaths is not known. 8.2 Lactation Risk Summary Data from the published literature report the presence of paroxetine in human milk (see Data). There are reports of agitation, irritability, poor feeding and poor weight gain in infants exposed to paroxetine through breast milk (see Clinical Considerations). There are no data on the effect of paroxetine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Paxil and any potential adverse effects on the breastfed child from Paxil or from underlying maternal condition. Clinical Considerations Infants exposed to PAXIL should be monitored for agitation, irritability, poor feeding and poor weight gain. Data Published literature suggests the presence of paroxetine in human milk with relative infant doses ranging between 0.4% to 2.2%, and a milk/plasma ratio of <1. No significant amounts were detected in the plasma of infants after breastfeeding. Reference ID: 5486158 8.3 Females and Males of Reproductive Potential Infertility Male Based on findings from clinical studies, paroxetine may affect sperm quality which may impair fertility; it is not known if this effect is reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of PAXIL in pediatric patients have not been established [see Box Warning]. Effectiveness was not demonstrated in three placebo-controlled trials in 752 PAXIL- treated pediatric patients with MDD. Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.1)]. Decreased appetite and weight loss have been observed in association with the use of SSRIs. In placebo-controlled clinical trials conducted with pediatric patients, the following adverse reactions were reported in at least 2% of pediatric patients treated with PAXIL and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self- harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation. Adverse reactions upon discontinuation of treatment with PAXIL in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients and at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain. 8.5 Geriatric Use In premarketing clinical trials with PAXIL, 17% of patients treated with PAXIL (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended;, however, no overall differences in safety or effectiveness were observed between elderly and younger patients [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. SSRIs including PAXIL, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.7)]. 8.6 Renal and Hepatic Impairment Increased plasma concentrations of paroxetine occur in patients with renal and hepatic impairment. The initial dosage of PAXIL should be reduced in patients with severe renal impairment and in patients with severe hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. 10 OVERDOSAGE The following have been reported with paroxetine tablet overdosage: • Seizures, which may be delayed, and altered mental status including coma. Reference ID: 5486158 • Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol. • Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk). Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a paroxetine overdose. Consider contacting a poison center (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. 11 DESCRIPTION PAXIL contains paroxetine hydrochloride, an SSRI. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'- methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8 (329.4 as free base). The structural formula of paroxetine hydrochloride is: Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 120 to 138C and a solubility of 5.4 mg/mL in water. PAXIL Tablets PAXIL tablets are for oral administration. Each film-coated tablet contains 10 mg, 20 mg, 30 mg, or 40 mg of paroxetine equivalent to 11.1 mg, 22.2 mg, 33.3 mg or 44.4 mg of paroxetine hydrochloride, respectively. Inactive ingredients consist of dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1 or more of the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake. PAXIL Oral Suspension PAXIL oral suspension is for oral administration. Each 5 mL contains 10 mg of paroxetine equivalent to 11.1 mg of paroxetine hydrochloride. The oral suspension is not currently marketed. F ):;a ov I Reference ID: 5486158 Inactive ingredients consist of citric acid (anhydrous), FD&C yellow No. 6, flavorings, glycerin, methylparaben, microcrystalline cellulose and carboxymethylcellulose sodium, polacrilin potassium, propylene glycol, propylparaben, purified water, saccharin sodium, simethicone emulsion and sodium citrate (dihydrate). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of PAXIL in the treatment of MDD, SAD, OCD, PD, GAD, and PTSD is unknown, but is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). 12.2 Pharmacodynamics Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake (SSRI) and has only very weak effects on norepinephrine and dopamine neuronal reuptake. 12.3 Pharmacokinetics Nonlinearity in pharmacokinetics is observed with increasing doses of PAXIL. In a meta-analysis of paroxetine from 4 studies done in healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower Cmax or AUC than females. Absorption Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of Cmax, Tmax, Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21 hours (CV 32%), respectively. The steady-state Cmax and Cmin values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable. Paroxetine is equally bioavailable from the oral suspension and tablet. Effect of Food The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. Reference ID: 5486158 Distribution Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin. Elimination Metabolism The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of PAXIL. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions [see Drug Interactions (7)]. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers). Excretion Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period. Drug Interaction Studies There are clinically significant, known drug interactions between paroxetine and other drugs [see Drug Interactions (7)]. Reference ID: 5486158 Figure 1. Impact of Paroxetine on the Pharmacokinetics of Co-Administered Drugs (log scale) Figure 2. Impact of Co-Administered Drugs on the Pharmacokinetics of Paroxetine Theophylline: Reports of elevated theophylline levels associated with PAXIL treatment have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered. Drugs Metabolized by Cytochrome CYP3A4 An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, triazolam, and cyclosporine. Paroxetine’s extent of inhibition of CYP3A4 activity is not expected to be of clinical significance. Interacting d rug Pimozide 2 m g Desipramin e 100 m g Propranolol 80 mg twice daily Digoxin 0 .25 mg once daily Phenytoin 300 mg lnteraamg drug PK C max AUC C max AUC C max A U C C max AUC C max AUC 0.1 Clm<>1.k:Slno 300 mg thmo times d:uly Phonobart>ital 100 mg once daity Phenytom 300 mg once d'3 ily ~xin 0 .25 mg on,oo dally Dlozepa1n S mg th.-- times d ity Fo ld change and 90% C l ,., 1------9------- ... f---e----1 1 .0 10.0 Change relativ e to reference PK Fold change and 90"- CI c ,.,..,. AUC c ,.,..,. AUC --• -----1 c .-.- AUC C rna,c .... AUC C mmc AUC , 0 1 2 Change rel-atlve to ..-.terence Reference ID: 5486158 Specific Populations The impact of specific populations on the pharmacokinetics of paroxetine are shown in Figure 3. The recommended starting dosage and maximum dosage of PAXIL is reduced in elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment [see Dosage and Administration (2.4)]. Figure 3. Impact of Specific Population on the Pharmacokinetics of Paroxetine (log scale) 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2 (mouse) and 3 (rat) times the MRHD of 60 mg on a mg/m2 basis. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown. Mutagenesis Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats. Population description Renal Impairment : Mild Moderate Severe H e patic Impairment Age (>65 years) : Dose=20 mg once daily Dose=30 mg once daily Dose=40 mg once daily Gender: Males PK Cmax AUC C max AUC C max AUC C min AUC Cmin C min C min Cmax AUC 0 .5 ,. ,_. Fold change and 90% Cl __, 1---- • -l . ,-.------, •-< ---------, I- 1 .0 5 .0 10.0 Change relative to reference 50.0 Reference ID: 5486158 Impairment of Fertility A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2 times the MRHD of 60 mg on a mg/m2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (8 and 4 times the MRHD of 60 mg on a mg/m2 basis). 14 CLINICAL STUDIES 14.1 Major Depressive Disorder The efficacy of PAXIL as a treatment for major depressive disorder (MDD) has been established in 6 placebo-controlled studies of patients with MDD (aged 18 to 73). In these studies, PAXIL was shown to be statistically significantly more effective than placebo in treating MDD by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. PAXIL was statistically significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor. Long-term efficacy of PAXIL for treatment of MDD in outpatients was demonstrated in a randomized withdrawal study. Patients who responded to PAXIL (HDRS total score <8) during an initial 8-week open-label treatment phase were then randomized to continue PAXIL or placebo, for up to 1 year. Patients treated with PAXIL demonstrated a statistically significant lower relapse rate during the withdrawal phase (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients. 14.2 Obsessive Compulsive Disorder The effectiveness of PAXIL in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. In study 1, a dose-range finding study, patients received fixed daily doses of PAXIL 20 mg, 40 mg, or 60 mg. Study 1 demonstrated that daily doses of PAXIL 40 mg and 60 mg are effective in the treatment of OCD. Patients receiving doses of PAXIL 40 mg and 60 mg experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was statistically significantly greater than the approximate 4-point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible-dose study comparing PAXIL 20 mg to 60 mg daily with clomipramine 25 mg to 250 mg daily or placebo). In this study, patients receiving PAXIL experienced a mean reduction of approximately 7 points on the YBOCS total score, which was statistically significantly greater than the mean reduction of approximately 4 points in placebo-treated patients. The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impression (CGI) scale for Study 1. Reference ID: 5486158 Table 10: Outcome Classification (%) on CGI-Global Improvement Item for Completers in Study 1 in Patients with OCD Outcome Classification Placebo (n = 74) % PAXIL 20 mg (n = 75) % PAXIL 40 mg (n = 66) % PAXIL 60 mg (n = 66) % Worse 14 7 7 3 No Change 44 35 22 19 Minimally Improved 24 33 29 34 Much Improved 11 18 22 24 Very Much Improved 7 7 20 20 Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. The long-term efficacy of PAXIL for the treatment of OCD was established in a long-term extension to Study 1. Patients who responded to PAXIL during the 3-month double-blind phase and a 6-month extension on open-label PAXIL 20 mg to 60 mg daily were randomized to either PAXIL or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to PAXIL were statistically significantly less likely to relapse than placebo-treated patients. 14.3 Panic Disorder The effectiveness of PAXIL in the treatment of panic disorder (PD) was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1, 2, and 3). Patients had PD (DSM-IIIR), with or without agoraphobia. In these studies, PAXIL was shown to be statistically significantly more effective than placebo in treating PD by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score. Study 1 was a 10-week dose-range finding study; patients received fixed doses of PAXIL 10 mg, 20 mg, or 40 mg daily or placebo. A statistically significant difference from placebo was observed only for the PAXIL 40 mg daily group. At endpoint, 76% of patients receiving PAXIL 40 mg daily were free of panic attacks, compared to 44% of placebo-treated patients. Study 2 was a 12-week flexible-dose study comparing PAXIL 10 mg to 60 mg daily and placebo. At endpoint, 51% of PAXIL-treated patients were free of panic attacks compared to 32% of placebo-treated patients. Study 3 was a 12-week flexible-dose study comparing PAXIL 10 mg to 60 mg daily to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the PAXIL-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo- treated patients. In Studies 2 and 3, the mean PAXIL dose for completers at endpoint was approximately 40 mg daily. Long-term efficacy of PAXIL in PD was demonstrated in an extension to Study 1. Patients who responded to PAXIL during the 10-week double-blind phase and during a 3-month double-blind Reference ID: 5486158 extension phase were randomized to either PAXIL 10 mg, 20 mg, or 40 mg daily or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to PAXIL were statistically significantly less likely to relapse than placebo-treated patients. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. 14.4 Social Anxiety Disorder The effectiveness of PAXIL in the treatment of social anxiety disorder (SAD) was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with SAD (DSM-IV). In these studies, the effectiveness of PAXIL compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS). Studies 1 and 2 were flexible-dose studies comparing PAXIL 20 mg to 50 mg daily and placebo. PAXIL demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of PAXIL-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the PAXIL- and placebo-treated patients, respectively. Study 3 was a 12-week study comparing fixed doses of PAXIL 20 mg, 40 mg, or 60 mg daily with placebo. PAXIL 20 mg was statistically significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the PAXIL 40 mg and 60 mg daily dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg daily. Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender. 14.5 Generalized Anxiety Disorder The effectiveness of PAXIL in the treatment of generalized anxiety disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with GAD (DSM-IV). Study 1 was an 8-week study comparing fixed doses of PAXIL 20 mg or 40 mg daily with placebo. Doses of PAXIL 20 mg or 40 mg were both demonstrated to be statistically significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest a greater benefit for the PAXIL 40 mg daily dose compared to the 20 mg daily dose. Study 2 was a flexible-dose study comparing PAXIL 20 mg to 50 mg daily and placebo. PAXIL demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. Reference ID: 5486158 A third study, a flexible-dose study comparing PAXIL 20 mg to 50 mg daily to placebo, did not demonstrate statistically significant superiority of PAXIL over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome. Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age. In a long-term trial, 566 patients meeting DSM-IV criteria for GAD, who had responded during a single-blind, 8-week acute treatment phase with PAXIL 20 mg to 50 mg daily, were randomized to continuation of PAXIL at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of 2 points compared to baseline on the CGI-Severity of Illness scale, to a score of 3. Relapse during the double-blind phase was defined as an increase of 2 points compared to baseline on the CGI- Severity of Illness scale to a score of 4, or withdrawal due to lack of efficacy. Patients continuing to receive PAXIL experienced a statistically significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo. 14.6 Posttraumatic Stress Disorder The effectiveness of PAXIL in the treatment of Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from 0.1 year to 57 years). The percentage of patients with secondary MDD or non-PTSD anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out of 858 patients), respectively. Study outcome was assessed by (1) the Clinician-Administered PTSD Scale Part 2 (CAPS-2) score and (2) the Clinical Global Impression-Global Improvement Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal. The 2 primary outcomes for each trial were (1) change from baseline to endpoint on the CAPS-2 total score (17 items), and (2) proportion of responders on the CGI-I, where responders were defined as patients having a score of 1 (very much improved) or 2 (much improved). Study 1 was a 12-week study comparing fixed doses of PAXIL 20 mg or 40 mg daily to placebo. Doses of PAXIL 20 mg and 40 mg were demonstrated to be statistically significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg daily dose compared to the 20 mg daily dose. Study 2 was a 12-week flexible-dose study comparing PAXIL 20 mg to 50 mg daily to placebo. PAXIL was demonstrated to be significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. A third study, a flexible-dose study comparing PAXIL 20 mg to 50 mg daily to placebo, demonstrated PAXIL to be statistically significantly superior to placebo on change from baseline for CAPS-2 total score, but not on proportion of responders on the CGI-I. Reference ID: 5486158 The majority of patients in these trials were women (68% women: 377 out of 551 subjects in Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not indicate differences in treatment outcomes as a function of gender. There were an insufficient number of patients who were 65 years and older or were non-Caucasian to conduct subgroup analyses on the basis of age or race, respectively. 16 HOW SUPPLIED/STORAGE AND HANDLING PAXIL (paroxetine) tablets are oval shaped tablets supplied as: Tablet Strength Color Engraved Descriptors Package Configuration NDC Number 10 mg yellow Scored, “PAXIL” on front and “10” on back Bottles of 30 NDC 60505-4517-3 20 mg pink Scored, “PAXIL” on front and “20” on back Bottles of 30 NDC 60505-4518-3 30 mg blue “PAXIL” on front and “30” on back Bottles of 30 NDC 60505-4519-3 40 mg green “PAXIL” on front and “40” on back Bottles of 30 NDC 60505-4520-3 Store tablets between 15 and 30C (59 and 86F). PAXIL (paroxetine) oral suspension is supplied as: Strength Color/Flavor Package Configuration NDC Number 10 mg/5 mL Orange/orange Bottles containing 250 mL NDC 60505-0402-5 Store suspension at or below 25C (77F). The oral suspension is not currently marketed. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)]. Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of PAXIL with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Instruct patients to contact their health care provider or report to the emergency Reference ID: 5486158 room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions (5.2), Drug Interactions (7)]. Concomitant Medications Advise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for drug-drug interactions [see Warning and Precautions (5.3), Drug Interactions (7)]. Increased Risk of Bleeding Inform patients about the concomitant use of PAXIL with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-the counter medications that increase the risk of bleeding [see Warnings and Precautions (5.5)]. Activation of Mania/Hypomania Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.6)]. Discontinuation Syndrome Advise patients not to abruptly discontinue PAXIL and to discuss any tapering regimen with their healthcare provider. Inform patients that adverse reactions can occur when PAXIL is discontinued [See Warnings and Precautions (5.7)]. Sexual Dysfunction Advise patients that use of PAXIL may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.13)]. Administration Information for Oral Suspension Instruct patients to shake the oral suspension well before administration [see Dosage and Administration (2.1)]. Allergic Reactions Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [see Adverse Reactions (6.1, 6.2)]. EmbryoFetal Toxicity Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with PAXIL. Advise women of risks associated with first trimester use of PAXIL and that use later in pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN) [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]. Advise women that there is a pregnancy exposure registry that monitors Reference ID: 5486158 pregnancy outcomes in women exposed to PAXIL during pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]. Lactation Advise breastfeeding women using PAXIL to monitor infants for agitation, irritability, poor feeding, and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)]. Females and Males of Reproductive Potential Advise men that PAXIL may affect sperm quality, which may impair fertility; it is not known if this effect is reversible [see Use in Specific Populations (8.3)]. Manufactured by: Apotex Inc. Toronto, Ontario M9L 1T9 Manufactured for: Apotex Corp., Weston, Florida USA 33326 PAXIL® are registered trademarks of the GlaxoSmithKline group of companies. All registered trademarks in this document are the property of their respective owners Reference ID: 5486158 MEDICATION GUIDE PAXIL® (PAX-il) (paroxetine) tablets oral suspension What is the most important information I should know about PAXIL? PAXIL can cause serious side effects, including: • Increased risk of suicidal thoughts or actions. PAXIL and other antidepressant medicines may increase suicidal thoughts and actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. PAXIL is not for use in children. o Depression or other mental illnesses are the most important causes of suicidal thoughts and actions. How can I watch for and try to prevent suicidal thoughts and actions? o Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the does is changed. o Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions. o Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Call your healthcare provider or get emergency medical help right away if you have any of the following symptoms, especially if they are new, worse, or worry you: o attempts to commit suicide o acting on dangerous impulses o acting aggressive or violent o thoughts about suicide or dying o new or worse depression o new or worse anxiety or panic attacks o feeling agitated, restless, angry, or irritable o trouble sleeping o an increase in activity and talking more than what is normal for you o other unusual changes in behavior or mood What is PAXIL? PAXIL is a prescription medicine used in adults to treat: • A certain type of depression called Major Depressive Disorder (MDD) • Obsessive Compulsive Disorder (OCD) • Panic Disorder (PD) • Social Anxiety Disorder (SAD) • Generalized Anxiety Disorder (GAD) • Posttraumatic Stress Disorder (PTSD) Do not take PAXIL if you: • take a monoamine oxidase inhibitor (MAOI) • have stopped taking an MAOI in the last 14 days • are being treated with the antibiotic linezolid or the intravenous methylene blue • are taking pimozide • are taking thioridazine Reference ID: 5486158 • are allergic to paroxetine or any of the ingredients in PAXIL. See the end of this Medication Guide for a complete list of ingredients in PAXIL. Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI or one of these medicines, including the antibiotic linezolid or intravenous methylene blue. Do not start taking an MAOI for at least 14 days after you stop treatment with PAXIL. Before taking PAXIL, tell your healthcare provider about all your medical conditions, including if you: • have heart problems • have or had bleeding problems • have, or have a family history of, bipolar disorder, mania or hypomania • have or had seizures or convulsions • have glaucoma (high pressure in the eye) • have low sodium levels in your blood • have bone problems • have kidney or liver problems • are pregnant or plan to become pregnant. PAXIL may harm your unborn baby. o Taking PAXIL during your first trimester of pregnancy may cause your baby to be at an increased risk of having a heart problem (cardiac malformations) at birth. o Taking PAXIL during your third trimester of pregnancy may cause your baby to have breathing, temperature, and feeding problems, low muscle tone, and irritability after birth and may cause your baby to be at an increased risk of a serious lung problem at birth. Talk to your healthcare provider about the risk to your unborn baby if you take PAXIL during pregnancy. o Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with PAXIL. o There is a pregnancy registry for females who are exposed to PAXIL during pregnancy. The purpose of the registry is to collect information about the health of females exposed to PAXIL and their baby. If you become pregnant during treatment with PAXIL talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visit online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. • are breastfeeding or plan to breastfeed. PAXIL passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with PAXIL. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. PAXIL and some other medicines may affect each other causing possible serious side effects. PAXIL may affect the way other medicines work and other medicines may affect the way PAXIL works. Especially tell your healthcare provider if you take: • medicines used to treat migraine headaches called triptans • tricyclic antidepressants • lithium • tramadol, fentanyl, meperidine, methadone, or other opioids • tryptophan • buspirone • amphetamines • St. John’s Wort • medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin • diuretics • tamoxifen Reference ID: 5486158 • medicines used to treat mood, anxiety, psychotic, or thought disorders, including selective serotonin reuptake (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take PAXIL with your other medicines. Do not start or stop any other medicines during treatment with PAXIL without talking to your healthcare provider first. Stopping PAXIL suddenly may cause you to have serious side effects. See, “What are the possible side effects of PAXIL?” Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. How should I take PAXIL? • Take PAXIL exactly as prescribed. Your healthcare provider may need to change the dose of PAXIL until it is the right dose for you. • Take PAXIL 1 time each day in the morning. • PAXIL may be taken with or without food. • If you are taking PAXIL oral suspension, shake the suspension well before taking. • If you take too much PAXIL, call your poison control center at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are possible side effects of PAXIL? PAXIL can cause serious side effects, including: • See, “What is the most important information I should know about PAXIL?” • Serotonin syndrome. A potentially life-threatening problem called serotonin syndrome can happen when you take PAXIL with certain other medicines. See, “Who should not take PAXIL?” Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome: o agitation o sweating o seeing or hearing things that are not real (hallucinations) o flushing o confusion o high body temperature (hyperthermia) o coma o shaking (tremors), stiff muscles, or muscle twitching o fast heart beat o loss of coordination o changes in blood pressure o seizures o dizziness o nausea, vomiting, diarrhea • Eye problems (angle-closure glaucoma). PAXIL may cause a type of eye problem called angle-closure glaucoma in people with certain other eye conditions. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye. • Medicine interactions. Taking PAXIL with certain other medicines including thioridazine and pimozide may increase the risk of developing a serious heart problem called QT prolongation. • Seizures (convulsions). • Manic episodes. Manic episodes may happen in people with bipolar disorder who take PAXIL. Symptoms may include: o greatly increased energy o severe problems sleeping o racing thoughts o reckless behavior o unusually grand ideas o excessive happiness or irritability o talking more or faster than usual • Discontinuation syndrome. Suddenly stopping PAXIL may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include: o nausea o electric shock feeling (paresthesia) o tiredness o sweating o tremor o problems sleeping o changes in your mood o anxiety o hypomania o irritability and agitation o confusion o ringing in your ears (tinnitus) Reference ID: 5486158 o dizziness o headache o seizures • Low sodium levels in your blood (hyponatremia). Low sodium levels in your blood that may be serious and may cause death, can happen during treatment with PAXIL. Elderly people and people who take certain medicines may be at a greater risk for developing low sodium levels in your blood. Signs and symptoms may include: o headache o difficulty concentrating o memory changes o confusion o weakness and unsteadiness on your feet which can lead to falls In more severe or more sudden cases, signs and symptoms include: o seeing or hearing things that are not real (hallucinations) o fainting o seizures o coma o stopping breathing (respiratory arrest) • Abnormal bleeding. Taking PAXIL with aspirin, NSAIDs, or blood thinners may increase this risk. Tell your healthcare provider about any unusual bleeding or bruising. • Bone fractures. • Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including PAXIL, may cause sexual problems. Symptoms in males may include: o Delayed ejaculation or inability to have an ejaculation o Decreased sex drive o Problems getting or keeping an erection Symptoms in females may include: o Decreased sex drive o Delayed orgasm or inability to have an orgasm Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with PAXIL. There may be treatments your healthcare provider can suggest. The most common side effects of PAXIL include: • male and female sexual function problems • weakness (asthenia) • constipation • decreased appetite • diarrhea • dizziness • dry mouth • infection • problems sleeping • nausea • nervousness • sleepiness • sweating • yawning • shaking (tremor) These are not all the possible side effects of PAXIL. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store PAXIL? • Store PAXIL tablets between 59F to 86F (15C to 30C). • Store PAXIL oral suspension at or below 77ºF (25ºC). Reference ID: 5486158 Keep PAXIL and all medicines out of the reach of children. General information about the safe and effective use of PAXIL. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take PAXIL for a condition for which it was not prescribed. Do not give PAXIL to other people, even if they have the same symptoms that you have. It may harm them. You may ask your healthcare provider or pharmacist for information about PAXIL that is written for healthcare professionals. What are the ingredients in PAXIL? Active ingredient: paroxetine hydrochloride Inactive ingredients: Tablets: dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1 or more of the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake Oral suspension: citric acid (anhydrous), FD&C yellow No. 6, flavorings, glycerin, methylparaben, microcrystalline cellulose and carboxymethylcellulose sodium, polacrilin potassium, propylene glycol, propylparaben, purified water, saccharin sodium, simethicone emulsion and sodium citrate (dihydrate) Manufactured by: Apotex Inc., Toronto, Ontario, Canada M9L 1T9 Manufactured for: Apotex Corp.: Weston, Florida USA 33326 PAXIL® and PAXIL CR® are registered trademarks of the GlaxoSmithKline group of companies. All other registered trademarks are the property of their respective owners. For more information about PAXIL call 1-800-706-5575. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5486158
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2025-02-12T15:47:22.652620
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PAXIL safely and effectively. See full prescribing information for PAXIL. PAXIL (paroxetine) tablets, for oral use PAXIL (paroxetine) oral suspension Initial U.S. Approval: 1992 WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant- treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. PAXIL is not approved for use in pediatric patients. (5.1, 8.4) -------------------------RECENT MAJOR CHANGES--------------------------- Warnings and Precautions (5.4) 11/2024 ----------------------------INDICATIONS AND USAGE--------------------------- PAXIL is a selective serotonin reuptake inhibitor (SSRI) indicated in adults for the treatment of (1): • Major Depressive Disorder (MDD) • Obsessive Compulsive Disorder (OCD) • Panic Disorder (PD) • Social Anxiety Disorder (SAD) • Generalized Anxiety Disorder (GAD) • Posttraumatic Stress Disorder (PTSD) ----------------------DOSAGE AND ADMINISTRATION---------------------- • Shake oral suspension well before administration (2.1) • Recommended starting and maximum daily dosage for MDD, OCD, PD, and PTSD: (2.2) Indication Starting Daily Dose Maximum Daily Dose MDD 20 mg 50 mg OCD 20 mg 60 mg PD 10 mg 60 mg PTSD 20 mg 50 mg • Recommended starting dosage for SAD and GAD is 20 mg daily. (2.3) • Elderly patients, patients with severe renal impairment or severe hepatic impairment: Starting dosage is 10 mg daily. Maximum dosage is 40 mg daily. (2.4) • When discontinuing PAXIL, reduce dosage gradually. (2.6, 5.7) ----------------------DOSAGE FORMS AND STRENGTHS--------------------- • Extended-release tablets: 10 mg, scored; 20 mg, scored; 30 mg; and 40 mg tablets. (3) • Oral suspension: 10 mg/5 mL (not currently marketed) (3) -------------------------------CONTRAINDICATIONS----------------------------- • Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing a MAOI. (4, 5.3, 7) • Concomitant use of pimozide or thioridazine. (4, 5.3,7) • Known hypersensitivity to paroxetine or to any of the inactive ingredients in PAXIL. (4) -----------------------WARNINGS AND PRECAUTIONS------------------------ • Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If occurs, discontinue PAXIL and serotonergic agents and initiate supportive measures. (5.2) • Embryofetal Toxicity: May cause fetal harm. Meta-analyses of epidemiological studies have shown increased risk (less than 2-fold) of cardiovascular malformations with exposure during the first trimester. (5.4, 8.1) • Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti- inflammatory drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk. (5.5) • Activation of Mania/Hypomania: Screen patients for bipolar disorder. (5.6) • Seizures: Use with caution in patients with seizure disorders. (5.8) • Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.9) • Sexual Dysfunction: PAXIL may cause symptoms of sexual dysfunction. (5.13) -------------------------------ADVERSE REACTIONS-------------------------- Most common adverse reactions (≥5% and at least twice placebo) are abnormal ejaculation, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, infection, insomnia, libido decreased, male genital disorder, nausea, nervousness, somnolence, sweating, tremor, yawn. (6) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------------DRUG INTERACTIONS----------------------------------- • Drugs Highly Bound to Plasma Protein: Monitor for adverse reactions and reduce dosage of PAXIL or other protein-bound drugs (e.g., warfarin) as warranted. (7) • Drugs Metabolized by CYP2D6: Reduce dosage of drugs metabolized by CYP2D6 as warranted. (7) • Concomitant use with tamoxifen: Consider use of an alternative antidepressant with little or no CYP2D6 inhibition. (5.11, 7) ---------------------USE IN SPECIFIC POPULATIONS--------------------- • Pregnancy: SSRI use, particularly later in pregnancy, may increase the risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, irritability) in the neonate. (8.1) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5486158 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SUICIDAL THOUGHTS AND BEHAVIORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Administration Information 2.2 Recommended Dosage for MDD, OCD, PD, and PTSD 2.3 Recommended Dosage for SAD and GAD 2.4 Screen for Bipolar Disorder Prior to Starting PAXIL 2.5 Recommended Dosage for Elderly Patients, Patients with Severe Renal Impairment, and Patients with Severe Hepatic Impairment 2.6 Switching Patients to or From a Monoamine Oxidase Inhibitor (MAOI) 2.7 Discontinuation of Treatment With PAXIL 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults 5.2 Serotonin Syndrome 5.3 Drug Interactions Leading to QT Prolongation 5.4 Embryofetal Toxicity 5.5 Increased Risk of Bleeding 5.6 Activation of Mania or Hypomania 5.7 Discontinuation Syndrome 5.8 Seizures 5.9 Angle-Closure Glaucoma 5.10 Hyponatremia 5.11 Reduction of Efficacy of Tamoxifen 5.12 Bone Fracture 5.13 Sexual Dysfunction 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric use 8.6 Renal and Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Major Depressive Disorder 14.2 Obsessive Compulsive Disorder 14.3 Panic Disorder 14.4 Social Anxiety Disorder 14.5 Generalized Anxiety Disorder 14.6 Posttraumatic Stress Disorder 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5486158 FULL PRESCRIBING INFORMATION WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)]. PAXIL is not approved for use in pediatric patients [see Use in Specific Populations (8.4)]. 1 INDICATIONS AND USAGE PAXIL is indicated in adults for the treatment of: • Major depressive disorder (MDD) • Obsessive compulsive disorder (OCD) • Panic disorder (PD) • Social anxiety disorder (SAD) • Generalized anxiety disorder (GAD) • Posttraumatic stress disorder (PTSD) 2 DOSAGE AND ADMINISTRATION 2.1 Administration Information Administer PAXIL as a single daily dose in the morning, with or without food. Shake the oral suspension well before administration. 2.2 Recommended Dosage for MDD, OCD, PD, and PTSD The recommended starting dosages and maximum dosages of PAXIL in patients with MDD, OCD, PD, and PTSD are presented in Table 1. In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability. Table 1: Recommended Daily Dosage of PAXIL in Patients with MDD, OCD, PD, and PTSD Indication Starting Dose Maximum Dose MDD 20 mg 50 mg OCD 20 mg 60 mg PD 10 mg 60 mg PTSD 20 mg 50 mg Reference ID: 5486158 2.3 Recommended Dosage for SAD and GAD SAD The starting and recommended dosage in patients with SAD is 20 mg daily. In clinical trials the effectiveness of PAXIL was demonstrated in patients dosed in a range of 20 mg to 60 mg daily. While the safety of PAXIL has been evaluated in patients with SAD at doses up to 60 mg daily, available information does not suggest any additional benefit for doses above 20 mg daily [see Clinical Studies (14.4)]. GAD The starting and recommended dosage in patients with GAD is 20 mg daily. In clinical trials the effectiveness of PAXIL in GAD was demonstrated in patients dosed in a range of 20 mg to 50 mg daily. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg daily [see Clinical Studies (14.5)]. In patients with an inadequate response, increase dosage in increments of 10 mg per day at intervals of at least 1 week, depending on tolerability. 2.4 Screen for Bipolar Disorder Prior to Starting PAXIL Prior to initiating treatment with PAXIL or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6)]. 2.5 Recommended Dosage for Elderly Patients, Patients with Severe Renal Impairment, and Patients with Severe Hepatic Impairment The recommended initial dosage is 10 mg per day for elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment. Dosage should not exceed 40 mg/day. 2.6 Switching Patients to or From a Monoamine Oxidase Inhibitor (MAOI) At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI and initiation of PAXIL. In addition, at least 14 days must elapse after stopping PAXIL before starting an MAOI antidepressant [see Contraindications (4), Warnings and Precautions (5.2)]. 2.7 Discontinuation of Treatment With PAXIL Adverse reactions may occur upon discontinuation of PAXIL [see Warnings and Precautions (5.7)]. Gradually reduce the dosage rather than stopping PAXIL abruptly whenever possible. 3 DOSAGE FORMS AND STRENGTHS PAXIL tablets are available as: • 10 mg yellow, scored tablet engraved on the front with “PAXIL” and on the back with “10”. • 20 mg pink, scored tablet engraved on the front with “PAXIL” and on the back with “20”. • 30 mg blue tablet engraved on the front with “PAXIL” and on the back with “30”. • 40 mg green tablet engraved on the front with “PAXIL” and on the back with “40”. PAXIL oral suspension is available as: Reference ID: 5486158 • 10 mg/5 mL orange colored, orange flavored suspension in bottles containing 250 mL (not currently marketed). 4 CONTRAINDICATIONS PAXIL is contraindicated in patients: • Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.2), Drug Interactions (7)]. • Taking thioridazine because of risk of QT prolongation [see Warnings and Precautions (5. 3), Drug Interactions (7)] • Taking pimozide because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug Interactions (7)]. • With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or any of the inactive ingredients in PAXIL [see Adverse Reactions (6.1), (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 2. Table 2: Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo <18 years old 14 additional cases 18-24 years old 5 additional cases Decreases Compared to Placebo 25-64 years old 1 fewer case 65 years old 6 fewer cases PAXIL is not approved for use in pediatric patients. Reference ID: 5486158 It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing PAXIL, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome SSRIs, including PAXIL, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of PAXIL with MAOIs is contraindicated. In addition, do not initiate PAXIL in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking PAXIL discontinue PAXIL before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7)]. Monitor all patients taking PAXIL for the emergence of serotonin syndrome. Discontinue treatment with PAXIL and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of PAXIL with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Drug Interactions Leading to QT Prolongation The CYP2D6 inhibitory properties of paroxetine can elevate plasma levels of thioridazine and pimozide. Since thioridazine and pimozide given alone produce prolongation of the QTc interval and increase the risk of serious ventricular arrhythmias, the use of PAXIL is contraindicated in combination with thioridazine and pimozide [see Contraindications (4), Drug Interactions (7), Clinical Pharmacology (12.3)]. Reference ID: 5486158 5.4 Embryofetal Toxicity Based on meta-analyses of epidemiological studies, exposure to paroxetine in the first trimester of pregnancy is associated with a less than 2-fold increase in the rate of cardiovascular malformations among infants. For women who intend to become pregnant or who are in their first trimester of pregnancy, PAXIL, should be initiated only after consideration of the other available treatment options [see Use in Specific Populations (8.1)]. 5.5 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including PAXIL, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)]. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of PAXIL and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio. 5.6 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with PAXIL or another antidepressant may precipitate a mixed/manic episode. During controlled clinical trials of PAXIL, hypomania or mania occurred in approximately 1% of PAXIL-treated unipolar patients compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. Prior to initiating treatment with PAXIL, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.7 Discontinuation Syndrome Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.7)]. During clinical trials of GAD and PTSD, gradual decreases in the daily dose by 10 mg/day at weekly intervals followed by 1 week at 20 mg/day was used before treatment was discontinued. The following adverse reactions were reported at an incidence of 2% or greater for PAXIL and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness adverse reactions have been reported upon discontinuation of treatment with PAXIL in pediatric patients. The safety and effectiveness of PAXIL in pediatric patients have not been established [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.4)]. Reference ID: 5486158 5.8 Seizures PAXIL tablets and oral suspension have not been systematically evaluated in patients with seizure disorders. Patients with history of seizures were excluded from clinical studies. During clinical studies, seizures occurred in 0.1% of patients treated with PAXIL. PAXIL should be prescribed with caution in patients with a seizure disorder. Discontinue PAXIL in any patient who develops seizures. 5.9 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including PAXIL may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Cases of angle-closure glaucoma associated with use of PAXIL have been reported. Avoid use of antidepressants, including PAXIL in patients with untreated anatomically narrow angles. 5.10 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs, including PAXIL. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In patients with symptomatic hyponatremia, discontinue PAXIL and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs [see Use in Specific Populations (8.5)]. 5.11 Reduction of Efficacy of Tamoxifen Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced with concomitant use of PAXIL as a result of paroxetine’s irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen [see Drug Interactions (7)]. One study suggests that the risk may increase with longer duration of coadministration. However, other studies have failed to demonstrate such a risk. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition. 5.12 Bone Fracture Epidemiological studies on bone fracture risk during exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation, and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. 5.13 Sexual Dysfunction Use of SSRIs, including PAXIL, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm. Reference ID: 5486158 It is important for prescribers to inquire about sexual function prior to initiation of PAXIL and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment. 6 ADVERSE REACTIONS The following adverse reactions are included in more detail in other sections of the prescribing information: • Hypersensitivity reactions to paroxetine [see Contraindications (4)] • Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)] • Serotonin Syndrome [see Warnings and Precautions (5.2)] • Embryofetal Toxicity [see Warnings and Precautions (5.4)] • Increased Risk of Bleeding [see Warnings and Precautions (5.5)] • Activation of Mania/Hypomania [see Warnings and Precautions (5.6)] • Discontinuation Syndrome [see Warnings and Precautions (5.7)] • Seizures [see Warnings and Precautions (5.8)] • Angle-closure Glaucoma [see Warnings and Precautions (5.9)] • Hyponatremia [see Warnings and Precautions (5.10)] • Bone Fracture [see Warnings and Precautions (5.12)] • Sexual Dysfunction [see Warnings and Precautions (5.13)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data for PAXIL are from: • 6-week clinical trials in MDD patients who received PAXIL 20 mg to 50 mg once daily • 12-week clinical trials in OCD patients who received PAXIL 20 mg to 60 mg once daily • 10- to 12-week clinical trials in PD patients who received PAXIL 10 mg to 60 mg once daily • 12-week clinical trials in SAD patients who received PAXIL 20 mg to 50 mg once daily • 8-week clinical trials in GAD patients who received PAXIL 10 mg to 50 mg once daily • 12-week clinical trials in PTSD patients who received PAXIL 20 mg to 50 mg once daily Adverse Reactions Leading to Discontinuation Twenty percent (1,199/6,145) of patients treated with PAXIL in clinical trials in MDD and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients treated with PAXIL in clinical trials in SAD, OCD, PD, GAD, and PTSD, respectively, discontinued treatment due to an adverse reaction. The most common adverse reactions (1%) associated with discontinuation (i.e., those adverse reactions associated with dropout at a rate approximately twice or greater for PAXIL compared to placebo) are presented in Table 3: Reference ID: 5486158 Table 3: Adverse Reactions Reported as Leading to Discontinuation (≥1% of PAXIL- Treated Patients and Greater than Placebo) in MDD, OCD, PD, SAD, GAD, and PTSD Trials MDD OCD PD SAD GAD PTSD PAXIL % Placebo % PAXIL % Placebo % PAXIL % Placebo % PAXIL % Placebo % PAXIL % Placebo % PAXIL % Placebo % CNS Somnolence 2.3 0.7 — 1.9 0.3 3.4 0.3 2.0 0.2 2.8 0.6 Insomnia — — 1.7 0 1.3 0.3 3.1 0 — — Agitation 1.1 0.5 — — — Tremor 1.1 0.3 — 1.7 0 1.0 0.2 Anxiety — — — 1.1 0 — — Dizziness — — 1.5 0 1.9 0 1.0 0.2 — — Gastroin- testinal Constipation — 1.1 0 — — Nausea 3.2 1.1 1.9 0 3.2 1.2 4.0 0.3 2.0 0.2 2.2 0.6 Diarrhea 1.0 0.3 — Dry mouth 1.0 0.3 — — — Vomiting 1.0 0.3 — 1.0 0 — — Flatulence 1.0 0.3 — — Other Asthenia 1.6 0.4 1.9 0.4 2.5 0.6 1.8 0.2 1.6 0.2 Abnormal Ejaculationa 1.6 0 2.1 0 4.9 0.6 2.5 0.5 — — Sweating 1.0 0.3 — 1.1 0 1.1 0.2 — — Impotencea — 1.5 0 — — Libido Decreased 1.0 0 — — Where numbers are not provided the incidence of the adverse reactions in patients treated with PAXIL was not >1% or was not greater than or equal to 2 times the incidence of placebo. a. Incidence corrected for gender. Most Common Adverse Reactions The most commonly observed adverse reactions associated with the use of PAXIL (incidence of 5% or greater and at least twice that for placebo) were: MDD: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders. Reference ID: 5486158 OCD: Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation. PD: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence. SAD: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence. GAD: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation. PTSD: Asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence. Adverse Reactions in Patients with MDD Table 4 presents the adverse reactions that occurred at an incidence of 1% or more and greater than placebo in clinical trials of PAXIL-treated patients with MDD. Table 4: Adverse Reactions (≥1% of PAXIL-Treated Patients and Greater than Placebo) in 6-Week Clinical Trials for MDD Body System/ Adverse Reaction PAXIL (n = 421) % Placebo (n = 421) % Body as a Whole Headache Asthenia 18 15 17 6 Cardiovascular Palpitation Vasodilation 3 3 1 1 Dermatologic Sweating Rash 11 2 2 1 Gastrointestinal Nausea Dry Mouth Constipation Diarrhea Decreased Appetite 26 18 14 12 6 9 12 9 8 2 Reference ID: 5486158 Flatulence Oropharynx Disordera Dyspepsia 4 2 2 2 0 1 Musculoskeletal Myopathy Myalgia Myasthenia 2 2 1 1 1 0 Nervous System Somnolence Dizziness Insomnia Tremor Nervousness Anxiety Paresthesia Libido Decreased Drugged Feeling Confusion 23 13 13 8 5 5 4 3 2 1 9 6 6 2 3 3 2 0 1 0 Respiration Yawn 4 0 Special Senses Blurred Vision Taste Perversion 4 2 1 0 Urogenital System Ejaculatory Disturbanceb,c Other Male Genital Disordersb,d Urinary Frequency Urination Disordere Female Genital Disordersb,f 13 10 3 3 2 0 0 1 0 0 a. Includes mostly “lump in throat” and “tightness in throat.” b. Percentage corrected for gender. c. Mostly “ejaculatory delay.” d. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,” and “impotence.” e. Includes mostly “difficulty with micturition” and “urinary hesitancy.” f. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.” Adverse Reactions in Patients with OCD, PD, and SAD Reference ID: 5486158 Table 5 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with OCD, PD, and SAD. Table 5. Adverse Reactions (≥2% of PAXIL-Treated Patients and Greater than Placebo) in 10 to 12-Week Clinical Trials for OCD, PD, and SAD Body System/Preferred Term Obsessive Compulsive Disorder Panic Disorder Social Anxiety Disorder PAXIL (n = 542) % Placebo (n = 265) % PAXIL (n = 469) % Placebo (n = 324) % PAXIL (n = 425) % Placebo (n = 339) % Body as a Whole Asthenia 22 14 14 5 22 14 Abdominal Pain - - 4 3 — — Chest Pain 3 2 - - - - Back Pain Chills - 2 - 1 3 2 2 1 - — - — Trauma — — — — 3 1 Cardiovascular Vasodilation 4 1 — — — — Palpitation 2 0 — — — — Dermatologic Sweating Rash 9 3 3 2 14 — 6 — 9 — 2 — Gastrointestinal Nausea Dry Mouth Constipation Diarrhea Decreased Appetite Dyspepsia Flatulence Increased Appetite Vomiting 23 18 16 10 9 - - 4 - 10 9 6 10 3 - - 3 - 23 18 8 12 7 - - 2 - 17 11 5 7 3 - - 1 - 25 9 5 9 8 4 4 - 2 7 3 2 6 2 2 2 - 1 Musculoskeletal Myalgia — — — — 4 3 Nervous System Insomnia 24 13 18 10 21 16 Somnolence 24 7 19 11 22 5 Dizziness 12 6 14 10 11 7 Tremor 11 1 9 1 9 1 Reference ID: 5486158 Body System/Preferred Term Obsessive Compulsive Disorder Panic Disorder Social Anxiety Disorder PAXIL (n = 542) % Placebo (n = 265) % PAXIL (n = 469) % Placebo (n = 324) % PAXIL (n = 425) % Placebo (n = 339) % Nervousness 9 8 — — 8 7 Libido Decreased 7 4 9 1 12 1 Agitation — — 5 4 3 1 Anxiety — — 5 4 5 4 Abnormal Dreams 4 1 — — — — Concentration Impaired 3 2 — — 4 1 Depersonalization Myoclonus 3 3 0 0 — 3 — 2 — 2 — 1 Amnesia 2 1 - - - - Respiratory System Rhinitis Pharyngitis Yawn - — - - — - 3 — - 0 — - - 4 5 - 2 1 Special Senses Abnormal Vision Taste Perversion 4 2 2 0 — - — - 4 - 1 - Urogenital System Abnormal Ejaculationa 23 1 21 1 28 1 Dysmenorrhea — — — — 5 4 Female Genital Disordera 3 0 9 1 9 1 Impotencea 8 1 5 0 5 1 Urinary Frequency 3 1 2 0 — — Urination Impaired 3 0 — — — — Urinary Tract Infection 2 1 2 1 — — a. Percentage corrected for gender. Adverse Reactions in Patients with GAD and PTSD Reference ID: 5486158 Table 6 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with GAD and PTSD. Table 6. Adverse Reactions (≥2% of PAXIL-Treated Patients and Greater than Placebo) in 8- to 12-Week Clinical Trials for GAD and PTSDa Body System/ Preferred Term Generalized Anxiety Disorder Posttraumatic Stress Disorder PAXIL (n= 735) % Placebo (n = 529) % PAXIL (n = 676) % Placebo (n = 504) % Body as a Whole Asthenia Headache Infection Abdominal Pain Trauma 14 17 6 6 14 3 12 --- 5 4 6 4 --- 4 3 5 Cardiovascular Vasodilation 3 1 2 1 Dermatologic Sweating 6 2 5 1 Gastrointestinal Nausea Dry Mouth Constipation Diarrhea Decreased Appetite Vomiting Dyspepsia 20 11 10 9 5 3 --- 5 5 2 7 1 2 --- 19 10 5 11 6 3 5 8 5 3 5 3 2 3 Reference ID: 5486158 Body System/ Preferred Term Generalized Anxiety Disorder Posttraumatic Stress Disorder PAXIL (n= 735) % Placebo (n = 529) % PAXIL (n = 676) % Placebo (n = 504) % Nervous System Insomnia Somnolence Dizziness Tremor Nervousness Libido Decreased Abnormal Dreams 11 15 6 5 4 9 8 5 5 1 3 2 12 16 6 4 --- 5 3 11 5 5 1 --- 2 Respiratory System Respiratory Disorder Sinusitis Yawn 7 4 4 5 3 --- --- --- 2 --- --- <1 Special Senses Abnormal Vision 2 1 3 1 Urogenital System Abnormal Ejaculationa Female Genital Disordera Impotencea 25 4 4 2 1 3 13 5 9 2 1 1 a. Percentage corrected for gender. Dose Dependent Adverse Reactions MDD A comparison of adverse reaction rates in a fixed-dose study comparing PAXIL10 mg, 20 mg, 30 mg, and 40 mg once daily with placebo in the treatment of MDD revealed dose dependent adverse reactions, as shown in Table 7: Table 7. Adverse Reactions (≥5% of PAXIL-Treated Patients and ≥ Twice the Rate of Placebo) (in a Dose-Comparison Trial in the Treatment of MDD Body System/Preferred Term Placebo PAXIL n = 51 % 10 mg n = 102 % 20 mg n = 104 % 30 mg n = 101 % 40 mg n = 102 % Body as a Whole Asthenia 0.0 2.9 10.6 13.9 12.7 Dermatology Reference ID: 5486158 Body System/Preferred Term Placebo PAXIL n = 51 % 10 mg n = 102 % 20 mg n = 104 % 30 mg n = 101 % 40 mg n = 102 % Sweating 2.0 1.0 6.7 8.9 11.8 Gastrointestinal Constipation 5.9 4.9 7.7 9.9 12.7 Decreased Appetite 2.0 2.0 5.8 4.0 4.9 Diarrhea 7.8 9.8 19.2 7.9 14.7 Dry Mouth 2.0 10.8 18.3 15.8 20.6 Nausea 13.7 14.7 26.9 34.7 36.3 Nervous System Anxiety 0.0 2.0 5.8 5.9 5.9 Dizziness 3.9 6.9 6.7 8.9 12.7 Nervousness 0.0 5.9 5.8 4.0 2.9 Paresthesia 0.0 2.9 1.0 5.0 5.9 Somnolence 7.8 12.7 18.3 20.8 21.6 Tremor 0.0 0.0 7.7 7.9 14.7 Special Senses Blurred Vision 2.0 2.9 2.9 2.0 7.8 Urogenital System Abnormal Ejaculation 0.0 5.8 6.5 10.6 13.0 Impotence 0.0 1.9 4.3 6.4 1.9 Male Genital Disorders 0.0 3.8 8.7 6.4 3.7 OCD In a fixed-dose study comparing placebo and PAXIL 20 mg, 40 mg, and 60 mg in the treatment of OCD, there was no clear relationship between adverse reactions and the dose of PAXIL to which patients were assigned. PD In a fixed-dose study comparing placebo and PAXIL 10 mg, 20 mg, and 40 mg in the treatment of PD, the following adverse reactions were shown to be dose-dependent: asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. SAD In a fixed-dose study comparing placebo and PAXIL 20 mg, 40 mg and 60 mg in the treatment of SAD, for most of the adverse reactions, there was no clear relationship between adverse reactions and the dose of PAXIL to which patients were assigned. Reference ID: 5486158 GAD In a fixed-dose study comparing placebo and PAXIL 20 mg and 40 mg in the treatment of GAD, the following adverse reactions were shown to be dose-dependent: asthenia, constipation, and abnormal ejaculation. PTSD In a fixed-dose study comparing placebo and PAXIL 20 mg and 40 mg in the treatment of PTSD, the following adverse reactions were shown to be dose-dependent: impotence and abnormal ejaculation. Male and Female Sexual Dysfunction Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence. The percentage of patients reporting symptoms of sexual dysfunction in males and females with MDD, OCD, PD, SAD, GAD, and PTSD are displayed in Table 8. Table 8. Adverse Reactions Related to Sexual Dysfunction in Patients Treated with PAXIL in Clinical Trials of MDD, OCD, PD, SAD, GAD, and PTSD PAXIL Placebo n (males) 1446 % 1042 % Decreased Libido 6 to15 0 to 5 Ejaculatory Disturbance 13 to 28 0 to 2 Impotence 2 to 9 0 to 3 n (females) 1822 % 1340 % Decreased Libido 0 to 9 0 to 2 Orgasmic Disturbance 2 to 9 0 to 1 PAXIL treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae. Hallucinations Reference ID: 5486158 In pooled clinical trials of PAXIL, hallucinations were observed in 0.2% of PAXIL-treated patients compared to 0.1% of patients receiving placebo. Less Common Adverse Reactions The following adverse reactions occurred during the clinical studies of PAXIL and are not included elsewhere in the labeling. Adverse reactions are categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse reactions are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients. Body as a Whole Infrequent: Allergic reaction, chills, face edema, malaise, neck pain; rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer. Cardiovascular System Frequent: Hypertension, tachycardia; infrequent: Bradycardia, hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles. Digestive System Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, abnormal liver function tests, rectal hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries. Endocrine System Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis. Hemic and Lymphatic Systems Infrequent: Anemia, leukopenia, lymphadenopathy, purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, Reference ID: 5486158 leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia. Metabolic and Nutritional Frequent: Weight gain; infrequent: Edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased. Musculoskeletal System Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare: Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany. Nervous System Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome. Respiratory System Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration. Skin and Appendages Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis; herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash. Special Senses Reference ID: 5486158 Frequent: Tinnitus; infrequent: Abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect. Urogenital System Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis. 6.2 Postmarketing Experience The following reactions have been identified during post approval use of PAXIL. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), syndrome of inappropriate ADH secretion, prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, oculogyric crisis which has been associated with concomitant use of pimozide; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anosmia, hyposmia, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch- Schönlein purpura), and premature births in pregnant women. There has been a case report of severe hypotension when PAXIL was added to chronic metoprolol treatment. 7 DRUG INTERACTIONS Table 9 presents clinically significant drug interactions with PAXIL. Reference ID: 5486158 Table 9 : Clinically Significant Drug Interactions with PAXIL Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of SSRIs, including PAXIL, and MAOIs increases the risk of serotonin syndrome. Intervention PAXIL is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)]. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Pimozide and Thioridazine Clinical Impact Increased plasma concentrations of pimozide and thioridazine, drugs with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias. Intervention PAXIL is contraindicated in patients taking pimozide or thioridazine [see Contraindications (4)]. Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with PAXIL increases the risk of serotonin syndrome. Intervention Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of PAXIL and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)]. Examples other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort. Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants) Clinical Impact The concurrent use of an antiplatelet agent or anticoagulant with PAXIL may potentiate the risk of bleeding. Intervention Inform patients of the increased risk of bleeding associated with the concomitant use of PAXIL and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warnings and Precautions (5.5)]. Examples aspirin, clopidogrel, heparin, warfarin Drugs Highly Bound to Plasma Protein Clinical Impact PAXIL is highly bound to plasma protein. The concomitant use of PAXIL with another drug that is highly bound to plasma protein may increase free concentrations of PAXIL or other tightly-bound drugs in plasma. Intervention Monitor for adverse reactions and reduce dosage of PAXIL or other protein-bound drugs as warranted. Reference ID: 5486158 Examples Warfarin Drugs Metabolized by CYP2D6 Clinical Impact PAXIL is a CYP2D6 inhibitor [see Clinical Pharmacology (12.3)]. The concomitant use of PAXIL with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate. Intervention Decrease the dosage of a CYP2D6 substrate if needed with concomitant PAXIL use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if PAXIL is discontinued. Examples propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, venlafaxine, risperidone. Tamoxifen Clinical Impact Concomitant use of tamoxifen with PAXIL may lead to reduced plasma concentrations of the active metabolite (endoxifen) and reduced efficacy of tamoxifen Intervention Consider use of an alternative antidepressant with little or no CYP2D6 inhibition [see Warnings and Precautions (5.11)]. Fosamprenavir/Ritonavir Clinical Impact Co-administration of fosamprenavir/ritonavir with PAXIL significantly decreased plasma levels of PAXIL. Intervention Any dose adjustment should be guided by clinical effect (tolerability and efficacy). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including PAXIL, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Antidepressants 1-866- 961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research- programs/pregnancyregistry/antidepressants/. Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.5) and Clinical Considerations]. Paxil is associated with a less than 2-fold increase in cardiovascular malformations when administered to a pregnant woman during the first trimester. While individual epidemiological studies on the association between paroxetine use and cardiac malformations have reported Reference ID: 5486158 inconsistent findings, some meta-analyses of epidemiological studies have identified an increased risk of cardiovascular malformations (see Data). There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including PAXIL during pregnancy. There also are risks associated with untreated depression in pregnancy (see Clinical Considerations). For women who intend to become pregnant or who are in their first trimester of pregnancy, paroxetine should be initiated only after consideration of the other available treatment options. No evidence of treatment related malformations was observed in animal reproduction studies, when paroxetine was administered during the period of organogenesis at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits. These doses are approximately 8 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD – 60 mg) on an mg/m2 basis. When paroxetine was administered to female rats during the last trimester of gestation and continued through lactation, there was an increase in the number of pup deaths during the first four days of lactation. This effect occurred at a dose of 1 mg/kg/day which is less than the MRHD on an mg/m2 basis (See Data). The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryofetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and the postpartum. Maternal Adverse Reactions Use of PAXIL in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.5)]. Fetal/Neonatal adverse reactions Neonates exposed to PAXIL and other SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs or possibly a drug Reference ID: 5486158 discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)]. Data Human Data Published epidemiological studies on the association between first trimester paroxetine use and cardiovascular malformations have reported inconsistent results; however, meta-analyses of population-based cohort studies published between 1996 – 2017 indicate a less than 2-fold increased risk for overall cardiovascular malformations. Specific cardiac malformations identified in two meta-analyses include an approximately 2 to 2.5-fold increased risk for right ventricular outflow tract defects. One meta-analysis also identified an increased risk (less than 2-fold) for bulbus cordis anomalies and anomalies of cardiac septal closure, and an increased risk for atrial septal defect (pooled OR 2.38, 95% CI 1.14-4.97). Important limitations of the studies included in these meta-analyses include potential confounding by indication, depression severity, and potential exposure misclassification. Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for PPHN. PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD – 60 mg) on an mg/m2 basis. These studies have revealed no evidence of developmental effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day which is less than the MRHD on an mg/m2 basis. The no effect dose for rat pup mortality was not determined. The cause of these deaths is not known. 8.2 Lactation Risk Summary Data from the published literature report the presence of paroxetine in human milk (see Data). There are reports of agitation, irritability, poor feeding and poor weight gain in infants exposed to paroxetine through breast milk (see Clinical Considerations). There are no data on the effect of paroxetine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Paxil and any potential adverse effects on the breastfed child from Paxil or from underlying maternal condition. Clinical Considerations Infants exposed to PAXIL should be monitored for agitation, irritability, poor feeding and poor weight gain. Data Published literature suggests the presence of paroxetine in human milk with relative infant doses ranging between 0.4% to 2.2%, and a milk/plasma ratio of <1. No significant amounts were detected in the plasma of infants after breastfeeding. Reference ID: 5486158 8.3 Females and Males of Reproductive Potential Infertility Male Based on findings from clinical studies, paroxetine may affect sperm quality which may impair fertility; it is not known if this effect is reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of PAXIL in pediatric patients have not been established [see Box Warning]. Effectiveness was not demonstrated in three placebo-controlled trials in 752 PAXIL- treated pediatric patients with MDD. Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.1)]. Decreased appetite and weight loss have been observed in association with the use of SSRIs. In placebo-controlled clinical trials conducted with pediatric patients, the following adverse reactions were reported in at least 2% of pediatric patients treated with PAXIL and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self- harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation. Adverse reactions upon discontinuation of treatment with PAXIL in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients and at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain. 8.5 Geriatric Use In premarketing clinical trials with PAXIL, 17% of patients treated with PAXIL (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended;, however, no overall differences in safety or effectiveness were observed between elderly and younger patients [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. SSRIs including PAXIL, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.7)]. 8.6 Renal and Hepatic Impairment Increased plasma concentrations of paroxetine occur in patients with renal and hepatic impairment. The initial dosage of PAXIL should be reduced in patients with severe renal impairment and in patients with severe hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. 10 OVERDOSAGE The following have been reported with paroxetine tablet overdosage: • Seizures, which may be delayed, and altered mental status including coma. Reference ID: 5486158 • Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol. • Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk). Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a paroxetine overdose. Consider contacting a poison center (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. 11 DESCRIPTION PAXIL contains paroxetine hydrochloride, an SSRI. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'- methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8 (329.4 as free base). The structural formula of paroxetine hydrochloride is: Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 120 to 138C and a solubility of 5.4 mg/mL in water. PAXIL Tablets PAXIL tablets are for oral administration. Each film-coated tablet contains 10 mg, 20 mg, 30 mg, or 40 mg of paroxetine equivalent to 11.1 mg, 22.2 mg, 33.3 mg or 44.4 mg of paroxetine hydrochloride, respectively. Inactive ingredients consist of dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1 or more of the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake. PAXIL Oral Suspension PAXIL oral suspension is for oral administration. Each 5 mL contains 10 mg of paroxetine equivalent to 11.1 mg of paroxetine hydrochloride. The oral suspension is not currently marketed. F ):;a ov I Reference ID: 5486158 Inactive ingredients consist of citric acid (anhydrous), FD&C yellow No. 6, flavorings, glycerin, methylparaben, microcrystalline cellulose and carboxymethylcellulose sodium, polacrilin potassium, propylene glycol, propylparaben, purified water, saccharin sodium, simethicone emulsion and sodium citrate (dihydrate). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of PAXIL in the treatment of MDD, SAD, OCD, PD, GAD, and PTSD is unknown, but is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). 12.2 Pharmacodynamics Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake (SSRI) and has only very weak effects on norepinephrine and dopamine neuronal reuptake. 12.3 Pharmacokinetics Nonlinearity in pharmacokinetics is observed with increasing doses of PAXIL. In a meta-analysis of paroxetine from 4 studies done in healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower Cmax or AUC than females. Absorption Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of Cmax, Tmax, Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21 hours (CV 32%), respectively. The steady-state Cmax and Cmin values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable. Paroxetine is equally bioavailable from the oral suspension and tablet. Effect of Food The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. Reference ID: 5486158 Distribution Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin. Elimination Metabolism The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of PAXIL. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions [see Drug Interactions (7)]. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers). Excretion Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period. Drug Interaction Studies There are clinically significant, known drug interactions between paroxetine and other drugs [see Drug Interactions (7)]. Reference ID: 5486158 Figure 1. Impact of Paroxetine on the Pharmacokinetics of Co-Administered Drugs (log scale) Figure 2. Impact of Co-Administered Drugs on the Pharmacokinetics of Paroxetine Theophylline: Reports of elevated theophylline levels associated with PAXIL treatment have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered. Drugs Metabolized by Cytochrome CYP3A4 An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, triazolam, and cyclosporine. Paroxetine’s extent of inhibition of CYP3A4 activity is not expected to be of clinical significance. Interacting d rug Pimozide 2 m g Desipramin e 100 m g Propranolol 80 mg twice daily Digoxin 0 .25 mg once daily Phenytoin 300 mg lnteraamg drug PK C max AUC C max AUC C max A U C C max AUC C max AUC 0.1 Clm<>1.k:Slno 300 mg thmo times d:uly Phonobart>ital 100 mg once daity Phenytom 300 mg once d'3 ily ~xin 0 .25 mg on,oo dally Dlozepa1n S mg th.-- times d ity Fo ld change and 90% C l ,., 1------9------- ... f---e----1 1 .0 10.0 Change relativ e to reference PK Fold change and 90"- CI c ,.,..,. AUC c ,.,..,. AUC --• -----1 c .-.- AUC C rna,c .... AUC C mmc AUC , 0 1 2 Change rel-atlve to ..-.terence Reference ID: 5486158 Specific Populations The impact of specific populations on the pharmacokinetics of paroxetine are shown in Figure 3. The recommended starting dosage and maximum dosage of PAXIL is reduced in elderly patients, patients with severe renal impairment, and patients with severe hepatic impairment [see Dosage and Administration (2.4)]. Figure 3. Impact of Specific Population on the Pharmacokinetics of Paroxetine (log scale) 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2 (mouse) and 3 (rat) times the MRHD of 60 mg on a mg/m2 basis. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown. Mutagenesis Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats. Population description Renal Impairment : Mild Moderate Severe H e patic Impairment Age (>65 years) : Dose=20 mg once daily Dose=30 mg once daily Dose=40 mg once daily Gender: Males PK Cmax AUC C max AUC C max AUC C min AUC Cmin C min C min Cmax AUC 0 .5 ,. ,_. Fold change and 90% Cl __, 1---- • -l . ,-.------, •-< ---------, I- 1 .0 5 .0 10.0 Change relative to reference 50.0 Reference ID: 5486158 Impairment of Fertility A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2 times the MRHD of 60 mg on a mg/m2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (8 and 4 times the MRHD of 60 mg on a mg/m2 basis). 14 CLINICAL STUDIES 14.1 Major Depressive Disorder The efficacy of PAXIL as a treatment for major depressive disorder (MDD) has been established in 6 placebo-controlled studies of patients with MDD (aged 18 to 73). In these studies, PAXIL was shown to be statistically significantly more effective than placebo in treating MDD by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. PAXIL was statistically significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor. Long-term efficacy of PAXIL for treatment of MDD in outpatients was demonstrated in a randomized withdrawal study. Patients who responded to PAXIL (HDRS total score <8) during an initial 8-week open-label treatment phase were then randomized to continue PAXIL or placebo, for up to 1 year. Patients treated with PAXIL demonstrated a statistically significant lower relapse rate during the withdrawal phase (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients. 14.2 Obsessive Compulsive Disorder The effectiveness of PAXIL in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. In study 1, a dose-range finding study, patients received fixed daily doses of PAXIL 20 mg, 40 mg, or 60 mg. Study 1 demonstrated that daily doses of PAXIL 40 mg and 60 mg are effective in the treatment of OCD. Patients receiving doses of PAXIL 40 mg and 60 mg experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was statistically significantly greater than the approximate 4-point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible-dose study comparing PAXIL 20 mg to 60 mg daily with clomipramine 25 mg to 250 mg daily or placebo). In this study, patients receiving PAXIL experienced a mean reduction of approximately 7 points on the YBOCS total score, which was statistically significantly greater than the mean reduction of approximately 4 points in placebo-treated patients. The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impression (CGI) scale for Study 1. Reference ID: 5486158 Table 10: Outcome Classification (%) on CGI-Global Improvement Item for Completers in Study 1 in Patients with OCD Outcome Classification Placebo (n = 74) % PAXIL 20 mg (n = 75) % PAXIL 40 mg (n = 66) % PAXIL 60 mg (n = 66) % Worse 14 7 7 3 No Change 44 35 22 19 Minimally Improved 24 33 29 34 Much Improved 11 18 22 24 Very Much Improved 7 7 20 20 Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. The long-term efficacy of PAXIL for the treatment of OCD was established in a long-term extension to Study 1. Patients who responded to PAXIL during the 3-month double-blind phase and a 6-month extension on open-label PAXIL 20 mg to 60 mg daily were randomized to either PAXIL or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to PAXIL were statistically significantly less likely to relapse than placebo-treated patients. 14.3 Panic Disorder The effectiveness of PAXIL in the treatment of panic disorder (PD) was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1, 2, and 3). Patients had PD (DSM-IIIR), with or without agoraphobia. In these studies, PAXIL was shown to be statistically significantly more effective than placebo in treating PD by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score. Study 1 was a 10-week dose-range finding study; patients received fixed doses of PAXIL 10 mg, 20 mg, or 40 mg daily or placebo. A statistically significant difference from placebo was observed only for the PAXIL 40 mg daily group. At endpoint, 76% of patients receiving PAXIL 40 mg daily were free of panic attacks, compared to 44% of placebo-treated patients. Study 2 was a 12-week flexible-dose study comparing PAXIL 10 mg to 60 mg daily and placebo. At endpoint, 51% of PAXIL-treated patients were free of panic attacks compared to 32% of placebo-treated patients. Study 3 was a 12-week flexible-dose study comparing PAXIL 10 mg to 60 mg daily to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the PAXIL-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo- treated patients. In Studies 2 and 3, the mean PAXIL dose for completers at endpoint was approximately 40 mg daily. Long-term efficacy of PAXIL in PD was demonstrated in an extension to Study 1. Patients who responded to PAXIL during the 10-week double-blind phase and during a 3-month double-blind Reference ID: 5486158 extension phase were randomized to either PAXIL 10 mg, 20 mg, or 40 mg daily or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to PAXIL were statistically significantly less likely to relapse than placebo-treated patients. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. 14.4 Social Anxiety Disorder The effectiveness of PAXIL in the treatment of social anxiety disorder (SAD) was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with SAD (DSM-IV). In these studies, the effectiveness of PAXIL compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS). Studies 1 and 2 were flexible-dose studies comparing PAXIL 20 mg to 50 mg daily and placebo. PAXIL demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of PAXIL-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the PAXIL- and placebo-treated patients, respectively. Study 3 was a 12-week study comparing fixed doses of PAXIL 20 mg, 40 mg, or 60 mg daily with placebo. PAXIL 20 mg was statistically significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the PAXIL 40 mg and 60 mg daily dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg daily. Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender. 14.5 Generalized Anxiety Disorder The effectiveness of PAXIL in the treatment of generalized anxiety disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with GAD (DSM-IV). Study 1 was an 8-week study comparing fixed doses of PAXIL 20 mg or 40 mg daily with placebo. Doses of PAXIL 20 mg or 40 mg were both demonstrated to be statistically significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest a greater benefit for the PAXIL 40 mg daily dose compared to the 20 mg daily dose. Study 2 was a flexible-dose study comparing PAXIL 20 mg to 50 mg daily and placebo. PAXIL demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. Reference ID: 5486158 A third study, a flexible-dose study comparing PAXIL 20 mg to 50 mg daily to placebo, did not demonstrate statistically significant superiority of PAXIL over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome. Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age. In a long-term trial, 566 patients meeting DSM-IV criteria for GAD, who had responded during a single-blind, 8-week acute treatment phase with PAXIL 20 mg to 50 mg daily, were randomized to continuation of PAXIL at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of 2 points compared to baseline on the CGI-Severity of Illness scale, to a score of 3. Relapse during the double-blind phase was defined as an increase of 2 points compared to baseline on the CGI- Severity of Illness scale to a score of 4, or withdrawal due to lack of efficacy. Patients continuing to receive PAXIL experienced a statistically significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo. 14.6 Posttraumatic Stress Disorder The effectiveness of PAXIL in the treatment of Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from 0.1 year to 57 years). The percentage of patients with secondary MDD or non-PTSD anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out of 858 patients), respectively. Study outcome was assessed by (1) the Clinician-Administered PTSD Scale Part 2 (CAPS-2) score and (2) the Clinical Global Impression-Global Improvement Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal. The 2 primary outcomes for each trial were (1) change from baseline to endpoint on the CAPS-2 total score (17 items), and (2) proportion of responders on the CGI-I, where responders were defined as patients having a score of 1 (very much improved) or 2 (much improved). Study 1 was a 12-week study comparing fixed doses of PAXIL 20 mg or 40 mg daily to placebo. Doses of PAXIL 20 mg and 40 mg were demonstrated to be statistically significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg daily dose compared to the 20 mg daily dose. Study 2 was a 12-week flexible-dose study comparing PAXIL 20 mg to 50 mg daily to placebo. PAXIL was demonstrated to be significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. A third study, a flexible-dose study comparing PAXIL 20 mg to 50 mg daily to placebo, demonstrated PAXIL to be statistically significantly superior to placebo on change from baseline for CAPS-2 total score, but not on proportion of responders on the CGI-I. Reference ID: 5486158 The majority of patients in these trials were women (68% women: 377 out of 551 subjects in Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not indicate differences in treatment outcomes as a function of gender. There were an insufficient number of patients who were 65 years and older or were non-Caucasian to conduct subgroup analyses on the basis of age or race, respectively. 16 HOW SUPPLIED/STORAGE AND HANDLING PAXIL (paroxetine) tablets are oval shaped tablets supplied as: Tablet Strength Color Engraved Descriptors Package Configuration NDC Number 10 mg yellow Scored, “PAXIL” on front and “10” on back Bottles of 30 NDC 60505-4517-3 20 mg pink Scored, “PAXIL” on front and “20” on back Bottles of 30 NDC 60505-4518-3 30 mg blue “PAXIL” on front and “30” on back Bottles of 30 NDC 60505-4519-3 40 mg green “PAXIL” on front and “40” on back Bottles of 30 NDC 60505-4520-3 Store tablets between 15 and 30C (59 and 86F). PAXIL (paroxetine) oral suspension is supplied as: Strength Color/Flavor Package Configuration NDC Number 10 mg/5 mL Orange/orange Bottles containing 250 mL NDC 60505-0402-5 Store suspension at or below 25C (77F). The oral suspension is not currently marketed. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)]. Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of PAXIL with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Instruct patients to contact their health care provider or report to the emergency Reference ID: 5486158 room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions (5.2), Drug Interactions (7)]. Concomitant Medications Advise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for drug-drug interactions [see Warning and Precautions (5.3), Drug Interactions (7)]. Increased Risk of Bleeding Inform patients about the concomitant use of PAXIL with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-the counter medications that increase the risk of bleeding [see Warnings and Precautions (5.5)]. Activation of Mania/Hypomania Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.6)]. Discontinuation Syndrome Advise patients not to abruptly discontinue PAXIL and to discuss any tapering regimen with their healthcare provider. Inform patients that adverse reactions can occur when PAXIL is discontinued [See Warnings and Precautions (5.7)]. Sexual Dysfunction Advise patients that use of PAXIL may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.13)]. Administration Information for Oral Suspension Instruct patients to shake the oral suspension well before administration [see Dosage and Administration (2.1)]. Allergic Reactions Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [see Adverse Reactions (6.1, 6.2)]. EmbryoFetal Toxicity Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with PAXIL. Advise women of risks associated with first trimester use of PAXIL and that use later in pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN) [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]. Advise women that there is a pregnancy exposure registry that monitors Reference ID: 5486158 pregnancy outcomes in women exposed to PAXIL during pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]. Lactation Advise breastfeeding women using PAXIL to monitor infants for agitation, irritability, poor feeding, and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)]. Females and Males of Reproductive Potential Advise men that PAXIL may affect sperm quality, which may impair fertility; it is not known if this effect is reversible [see Use in Specific Populations (8.3)]. Manufactured by: Apotex Inc. Toronto, Ontario M9L 1T9 Manufactured for: Apotex Corp., Weston, Florida USA 33326 PAXIL® are registered trademarks of the GlaxoSmithKline group of companies. All registered trademarks in this document are the property of their respective owners Reference ID: 5486158 MEDICATION GUIDE PAXIL® (PAX-il) (paroxetine) tablets oral suspension What is the most important information I should know about PAXIL? PAXIL can cause serious side effects, including: • Increased risk of suicidal thoughts or actions. PAXIL and other antidepressant medicines may increase suicidal thoughts and actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. PAXIL is not for use in children. o Depression or other mental illnesses are the most important causes of suicidal thoughts and actions. How can I watch for and try to prevent suicidal thoughts and actions? o Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the does is changed. o Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings or if you develop suicidal thoughts or actions. o Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Call your healthcare provider or get emergency medical help right away if you have any of the following symptoms, especially if they are new, worse, or worry you: o attempts to commit suicide o acting on dangerous impulses o acting aggressive or violent o thoughts about suicide or dying o new or worse depression o new or worse anxiety or panic attacks o feeling agitated, restless, angry, or irritable o trouble sleeping o an increase in activity and talking more than what is normal for you o other unusual changes in behavior or mood What is PAXIL? PAXIL is a prescription medicine used in adults to treat: • A certain type of depression called Major Depressive Disorder (MDD) • Obsessive Compulsive Disorder (OCD) • Panic Disorder (PD) • Social Anxiety Disorder (SAD) • Generalized Anxiety Disorder (GAD) • Posttraumatic Stress Disorder (PTSD) Do not take PAXIL if you: • take a monoamine oxidase inhibitor (MAOI) • have stopped taking an MAOI in the last 14 days • are being treated with the antibiotic linezolid or the intravenous methylene blue • are taking pimozide • are taking thioridazine Reference ID: 5486158 • are allergic to paroxetine or any of the ingredients in PAXIL. See the end of this Medication Guide for a complete list of ingredients in PAXIL. Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI or one of these medicines, including the antibiotic linezolid or intravenous methylene blue. Do not start taking an MAOI for at least 14 days after you stop treatment with PAXIL. Before taking PAXIL, tell your healthcare provider about all your medical conditions, including if you: • have heart problems • have or had bleeding problems • have, or have a family history of, bipolar disorder, mania or hypomania • have or had seizures or convulsions • have glaucoma (high pressure in the eye) • have low sodium levels in your blood • have bone problems • have kidney or liver problems • are pregnant or plan to become pregnant. PAXIL may harm your unborn baby. o Taking PAXIL during your first trimester of pregnancy may cause your baby to be at an increased risk of having a heart problem (cardiac malformations) at birth. o Taking PAXIL during your third trimester of pregnancy may cause your baby to have breathing, temperature, and feeding problems, low muscle tone, and irritability after birth and may cause your baby to be at an increased risk of a serious lung problem at birth. Talk to your healthcare provider about the risk to your unborn baby if you take PAXIL during pregnancy. o Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with PAXIL. o There is a pregnancy registry for females who are exposed to PAXIL during pregnancy. The purpose of the registry is to collect information about the health of females exposed to PAXIL and their baby. If you become pregnant during treatment with PAXIL talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visit online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. • are breastfeeding or plan to breastfeed. PAXIL passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with PAXIL. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. PAXIL and some other medicines may affect each other causing possible serious side effects. PAXIL may affect the way other medicines work and other medicines may affect the way PAXIL works. Especially tell your healthcare provider if you take: • medicines used to treat migraine headaches called triptans • tricyclic antidepressants • lithium • tramadol, fentanyl, meperidine, methadone, or other opioids • tryptophan • buspirone • amphetamines • St. John’s Wort • medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin • diuretics • tamoxifen Reference ID: 5486158 • medicines used to treat mood, anxiety, psychotic, or thought disorders, including selective serotonin reuptake (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take PAXIL with your other medicines. Do not start or stop any other medicines during treatment with PAXIL without talking to your healthcare provider first. Stopping PAXIL suddenly may cause you to have serious side effects. See, “What are the possible side effects of PAXIL?” Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. How should I take PAXIL? • Take PAXIL exactly as prescribed. Your healthcare provider may need to change the dose of PAXIL until it is the right dose for you. • Take PAXIL 1 time each day in the morning. • PAXIL may be taken with or without food. • If you are taking PAXIL oral suspension, shake the suspension well before taking. • If you take too much PAXIL, call your poison control center at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are possible side effects of PAXIL? PAXIL can cause serious side effects, including: • See, “What is the most important information I should know about PAXIL?” • Serotonin syndrome. A potentially life-threatening problem called serotonin syndrome can happen when you take PAXIL with certain other medicines. See, “Who should not take PAXIL?” Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome: o agitation o sweating o seeing or hearing things that are not real (hallucinations) o flushing o confusion o high body temperature (hyperthermia) o coma o shaking (tremors), stiff muscles, or muscle twitching o fast heart beat o loss of coordination o changes in blood pressure o seizures o dizziness o nausea, vomiting, diarrhea • Eye problems (angle-closure glaucoma). PAXIL may cause a type of eye problem called angle-closure glaucoma in people with certain other eye conditions. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye. • Medicine interactions. Taking PAXIL with certain other medicines including thioridazine and pimozide may increase the risk of developing a serious heart problem called QT prolongation. • Seizures (convulsions). • Manic episodes. Manic episodes may happen in people with bipolar disorder who take PAXIL. Symptoms may include: o greatly increased energy o severe problems sleeping o racing thoughts o reckless behavior o unusually grand ideas o excessive happiness or irritability o talking more or faster than usual • Discontinuation syndrome. Suddenly stopping PAXIL may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include: o nausea o electric shock feeling (paresthesia) o tiredness o sweating o tremor o problems sleeping o changes in your mood o anxiety o hypomania o irritability and agitation o confusion o ringing in your ears (tinnitus) Reference ID: 5486158 o dizziness o headache o seizures • Low sodium levels in your blood (hyponatremia). Low sodium levels in your blood that may be serious and may cause death, can happen during treatment with PAXIL. Elderly people and people who take certain medicines may be at a greater risk for developing low sodium levels in your blood. Signs and symptoms may include: o headache o difficulty concentrating o memory changes o confusion o weakness and unsteadiness on your feet which can lead to falls In more severe or more sudden cases, signs and symptoms include: o seeing or hearing things that are not real (hallucinations) o fainting o seizures o coma o stopping breathing (respiratory arrest) • Abnormal bleeding. Taking PAXIL with aspirin, NSAIDs, or blood thinners may increase this risk. Tell your healthcare provider about any unusual bleeding or bruising. • Bone fractures. • Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including PAXIL, may cause sexual problems. Symptoms in males may include: o Delayed ejaculation or inability to have an ejaculation o Decreased sex drive o Problems getting or keeping an erection Symptoms in females may include: o Decreased sex drive o Delayed orgasm or inability to have an orgasm Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with PAXIL. There may be treatments your healthcare provider can suggest. The most common side effects of PAXIL include: • male and female sexual function problems • weakness (asthenia) • constipation • decreased appetite • diarrhea • dizziness • dry mouth • infection • problems sleeping • nausea • nervousness • sleepiness • sweating • yawning • shaking (tremor) These are not all the possible side effects of PAXIL. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store PAXIL? • Store PAXIL tablets between 59F to 86F (15C to 30C). • Store PAXIL oral suspension at or below 77ºF (25ºC). Reference ID: 5486158 Keep PAXIL and all medicines out of the reach of children. General information about the safe and effective use of PAXIL. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take PAXIL for a condition for which it was not prescribed. Do not give PAXIL to other people, even if they have the same symptoms that you have. It may harm them. You may ask your healthcare provider or pharmacist for information about PAXIL that is written for healthcare professionals. What are the ingredients in PAXIL? Active ingredient: paroxetine hydrochloride Inactive ingredients: Tablets: dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1 or more of the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake Oral suspension: citric acid (anhydrous), FD&C yellow No. 6, flavorings, glycerin, methylparaben, microcrystalline cellulose and carboxymethylcellulose sodium, polacrilin potassium, propylene glycol, propylparaben, purified water, saccharin sodium, simethicone emulsion and sodium citrate (dihydrate) Manufactured by: Apotex Inc., Toronto, Ontario, Canada M9L 1T9 Manufactured for: Apotex Corp.: Weston, Florida USA 33326 PAXIL® and PAXIL CR® are registered trademarks of the GlaxoSmithKline group of companies. All other registered trademarks are the property of their respective owners. For more information about PAXIL call 1-800-706-5575. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5486158
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-------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ BERNARD A FISCHER on behalf of TIFFANY R FARCHIONE 11/29/2024 12:06:23 PM Signature Page 1 of 1 Reference ID: 5487503 (
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RALDESYTM safely and effectively. See full prescribing information for RALDESYTM. RALDESYTM (trazodone hydrochloride) oral solution Initial U.S. Approval: 1981 • Orthostatic Hypotension and Syncope: Warn patients of risk and symptoms of hypotension (5.4). • Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk (5.5). • Priapism: Cases of painful and prolonged penile erections and priapism have been reported. Immediate medical attention should be sought if signs and symptoms of prolonged penile erections or priapism are observed (5.6). • Activation of Mania or Hypomania: Screen for bipolar disorder and monitor for mania or hypomania (5.7). • Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Advise patients to use caution when operating machinery (5.9). • Angle-Closure Glaucoma: Avoid use of antidepressants, including RALDESY, in patients with untreated anatomically narrow angles (5.10). -----------------------------INDICATIONS AND USAGE----------------------- RALDESY is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of major depressive disorder (MDD) in adults (1). ------------------------DOSAGE AND ADMINISTRATION-------------------- • Starting dosage: 150 mg orally in divided doses daily. May be increased by 50 mg per day every three to four days. Maximum dosage: 400 mg per day in divided doses (2.1). • Administer RALDESY shortly after a meal or light snack (2.1). • When discontinuing RALDESY, gradually reduce dose (2.5). ---------------------DOSAGE FORMS AND STRENGTHS------------------ • Oral solution: 10 mg/mL -------------------------------CONTRAINDICATIONS------------------------------ • Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs (4). ------------------------WARNINGS AND PRECAUTIONS-------------------- • Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue RALDESY and initiate supportive treatment (5.2). • Cardiac Arrhythmias: Increases the QT interval. Avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval (5.3). -------------------------------ADVERSE REACTIONS---------------------------------- Most common adverse reactions (incidence ≥ 5% and twice that of placebo) are: edema, blurred vision, syncope, drowsiness, fatigue, diarrhea, nasal congestion, weight loss (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-982-5438 or FDA at 1-800-FDA- 1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------------ • CNS Depressants: RALDESY may enhance effects of alcohol, barbiturates, or other CNS depressants (7). • CYP3A4 Inhibitors: Consider RALDESY dose reduction based on tolerability (2.5, 7). • CYP3A4 Inducers: Increase in RALDESY dosage may be necessary (2.5, 7). • Digoxin or Phenytoin: Monitor for increased digoxin or phenytoin serum levels (7). • Warfarin: Monitor for increased or decreased prothrombin time (7). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 WARNING: SUICIDAL THOUGHTS and BEHAVIORS See full prescribing information for complete boxed warning. • Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients. Closely monitor for clinical worsening and emergence of suicidal thoughts and behaviors (5.1). • RALDESY is not approved for use in pediatric patients (8.4). Reference ID: 5485509 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SUICIDAL THOUGHTS AND BEHAVIORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Screen for Bipolar Disorder Prior to Starting RALDESY 2.3 Switching to or from Monoamine Oxidase Inhibitor Antidepressant 2.4 Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inhibitors or Inducers 2.5 Discontinuation of Treatment with RALDESY 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients 5.2 Serotonin Syndrome 5.3 Cardiac Arrhythmias 5.4 Orthostatic Hypotension and Syncope 5.5 Increased Risk of Bleeding 5.6 Priapism 5.7 Activation of Mania or Hypomania 5.8 Discontinuation Syndrome 5.9 Potential for Cognitive and Motor Impairment 5.10 Angle-Closure Glaucoma 5.11 Hyponatremia 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5485509 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE RALDESYTM is indicated for the treatment of major depressive disorder (MDD) in adults. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The initial dosage of RALDESY for the treatment of MDD in adults is 150 mg daily, taken orally, in divided doses. The dosage should be initiated at a low-dose and increased gradually, depending on clinical response and an tolerance. Occurrence of drowsiness may require the administration of a major portion of the daily dose at bedtime or a reduction of dosage [see Dosage and Administration (2.5)]. The dose may be increased by 50 mg daily every 3 to 4 days. The maximum recommended dosage for outpatients usually should not exceed 400 mg daily in divided doses. Inpatients (i.e., more severely depressed patients) may be given up to, but not in excess, of 600 mg daily in divided doses. Administer RALDESY orally after a meal or light snack [see Clinical Pharmacology (12.3)]. 2.2 Screen for Bipolar Disorder Prior to Starting RALDESY Prior to initiating treatment with RALDESY or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.7)]. 2.3 Switching to or from Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of RALDESY. In addition, at least 14 days must elapse after stopping RALDESY before starting an MAOI antidepressant [see Contraindications (4), Warnings and Precautions (5.2)]. 2.4 Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inhibitors or Inducers Coadministration with Strong CYP3A4 Inhibitors Consider reducing RALDESY dose based on tolerability when RALDESY is coadministered with a strong CYP3A4 inhibitor [see Drug Interactions (7.1)]. Coadministration with Strong CYP3A4 Inducers Consider increasing RALDESY dose based on therapeutic response when RALDESY is coadministered with a strong CYP3A4 inducer [see Drug Interactions (7.1)]. 2.5 Discontinuation of Treatment with RALDESY Adverse reactions may occur upon discontinuation of RALDESY [see Warnings and Precautions (5.8)]. Gradually reduce the dosage rather than stopping RALDESY abruptly whenever possible. 3 DOSAGE FORMS AND STRENGTHS RALDESY (10 mg/mL) Oral Solution: Clear, colorless solution 4 CONTRAINDICATIONS RALDESY is contraindicated in patients taking, or within 14 days of stopping, monoamine oxidase inhibitors (MAOIs), including MAOIs such as linezolid or intravenous methylene blue, because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.2), Drug WARNING: SUICIDAL THOUGHTS and BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)]. RALDESY is not approved for use in pediatric patients [see Use in Specific Populations (8.4)]. Reference ID: 5485509 Interactions (7.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range (years) Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18-24 5 additional patients Decreases Compared to Placebo 25-64 1 fewer patient ≥65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing RALDESY, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome SSRIs, including RALDESY, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of RALDESY with MAOIs is contraindicated. In addition, do not initiate RALDESY in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking RALDESY, discontinue RALDESY before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7.1)]. Monitor all patients taking RALDESY for the emergence of serotonin syndrome. Discontinue treatment with RALDESY and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of RALDESY with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Cardiac Arrhythmias Clinical studies indicate that trazodone hydrochloride may be arrhythmogenic in patients with preexisting cardiac disease. Arrhythmias identified include isolated PVCs, ventricular couplets, tachycardia with syncope, and torsade de pointes. Postmarketing reports, including torsade de pointes have been reported at doses of 100 mg or less with the immediate-release trazodone hydrochloride tablets. RALDESY should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval. RALDESY is not recommended for use during the initial recovery phase of myocardial infarction. Caution should be used when administering RALDESY to patients with cardiac disease Reference ID: 5485509 and such patients should be closely monitored, since antidepressant drugs (including RALDESY ) may cause cardiac arrhythmias [see Adverse Reactions (6.2)]. Trazodone hydrochloride prolongs the QT/QTc interval. The use of RALDESY should be avoided in patients with known QT prolongation or in combination with other drugs that are inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, voriconazole), or known to prolong QT interval including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and certain antibiotics (e.g., gatifloxacin). Concomitant administration of drugs may increase the risk of cardiac arrhythmia [see Drug Interactions (7.1)]. 5.4 Orthostatic Hypotension and Syncope Hypotension, including orthostatic hypotension and syncope has been reported in patients receiving trazodone hydrochloride. Concomitant use with an antihypertensive may require a reduction in the dose of the antihypertensive drug. 5.5 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including RALDESY, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the risk of bleeding associated with the concomitant use of RALDESY and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing RALDESY . 5.6 Priapism Cases of priapism (painful erections greater than 6 hours in duration) have been reported in males receiving trazodone hydrochloride tablets. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Males who have an erection lasting greater than 4 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention [see Adverse Reactions (6.2), Overdosage (10)]. RALDESY should be used with caution in males who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease). 5.7 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with RALDESY or another antidepressant may precipitate a mixed/manic episode. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with antidepressants. Prior to initiating treatment with RALDESY, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration (2.3)]. 5.8 Discontinuation Syndrome Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations),tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [See Dosage and Administration (2.6)]. 5.9 Potential for Cognitive and Motor Impairment RALDESYTM may cause somnolence or sedation and may impair the mental and/or physical ability required for the performance of potentially hazardous tasks. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. 5.10 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including RALDESY may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including RALDESY, in patients with untreated anatomically narrow angles. 5.11 Hyponatremia Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including RALDESY. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the Reference ID: 5485509 result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In patients with symptomatic hyponatremia, discontinue RALDESY and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs and SNRIs [see Use in Specific Populations (8.5)]. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Suicidal Thoughts and Behaviors inPediatric and Young Adult Patients [see Boxed Warning and Warnings and Precautions (5.1)] • Serotonin Syndrome [see Warnings and Precautions (5.2)] • Cardiac Arrythmias (see Warnings and Precautions (5.3)] • Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.4)] • Increased Risk of Bleeding [see Warnings and Precautions (5.5)] • Priapism [see Warnings and Precautions (5.6)] • Activation of Mania or Hypomania [see Warnings and Precautions (5.7)] • Discontinuation Syndrome [see Warnings and Precautions (5.8)] • Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.9)] • Angle-Closure Glaucoma [see Warnings and Precautions (5.10)] • Hyponatremia [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of RALDESY for the treatment of MDD in adults is based on studies of trazodone hydrochloride tablets. Below is a display of adverse reactions of trazodone hydrochloride tablets from those studies. Table 2: Common Adverse Reactions Occurring in ≥ 2% of Trazodone hydrochloride Tablets-treated Patients and Greater than the Rate of Placebo-Treated Patients as Observed in Controlled Clinical Studies Inpatients Outpatients Trazodone hydrochloride N=142 Placebo N=95 Trazodone hydrochloride N=157 Placebo N=158 Allergic Skin Condition/Edema 3% 1% 7% 1% Autonomic Blurred Vision 6% 4% 15% 4% Constipation 7% 4% 8% 6% Dry Mouth 15% 8% 34% 20% Cardiovascular Hypertension 20% 1% 1% * Hypotension 7% 1% 4% 0 Syncope 3% 2% 5% 1% CNS Confusion 5% 0 6% 8% Decreased Concentration 3% 2% 1% 0 Disorientation 2% 0 * 0 Dizziness/Light-Headedness 20% 5% 28% 15% Drowsiness 24% 6% 41% 20% Fatigue 11% 4% 6% 3% Headache 10% 5% 20% 16% Nervousness 15% 11% 6% 8% Gastrointestinal Abdominal/Gastric Disorder 4% 4% 6% 4% Diarrhea 0 1% 5% 1% Nausea/Vomiting 10% 1% 13% 10% Musculoskeletal Aches/Pains 6% 3% 5% 3% Neurological Incoordination 5% 0 2% * Tremors 3% 1% 5% 4% Other Eyes Red/Tired/Itching 3% 0 0 0 Head Full-Heavy 3% 0 0 0 Malaise 3% 0 0 0 Nasal/Sinus Congestion 3% 0 6% 3% Reference ID: 5485509 Weight Gain 1% 0 5% 2% Weight Loss * 3% 6% 3% Other adverse reactions occurring at an incidence of <2% with the use of trazodone hydrochloride in the controlled clinical studies: akathisia, allergic reaction, anemia, chest pain, delayed urine flow, early menses, flatulence, hallucinations/delusions, hematuria, hypersalivation, hypomania, impaired memory, impaired speech, impotence, increased appetite, increased libido, increased urinary frequency, missed periods, muscle twitches, numbness, paresthesia, retrograde ejaculation, shortness of breath, and tachycardia/palpitations. Occasional sinus bradycardia has occurred in long-term studies. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of trazodone hydrochloride tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure: Blood and lymphatic system disorders: hemolytic anemia, leukocytosis Cardiac disorders: cardiospasm, congestive heart failure, conduction block, orthostatic hypotension and syncope, palpitations, bradycardia, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, ventricular ectopic activity, including ventricular tachycardia and QT prolongation. Prolonged QT interval, torsade de pointes, and ventricular tachycardia have been reported at doses of 100 mg per day or less [see Warnings and Precautions (5.3)]. Endocrine disorders: inappropriate ADH syndrome Eye disorders: diplopia Gastrointestinal disorders: increased salivation, nausea/vomiting General disorders and administration site conditions: chills, edema, unexplained death, weakness Hepatobiliary disorders: cholestasis, jaundice, hyperbilirubinemia, liver enzyme alterations Investigations: increased amylase Metabolism and nutrition disorders: methemoglobinemia Nervous system disorders: aphasia, ataxia, cerebrovascular accident, extrapyramidal symptoms, grand mal seizures, paresthesia, tardive dyskinesia, vertigo Psychiatric disorders: abnormal dreams, agitation, anxiety, hallucinations, insomnia, paranoid reaction, psychosis, stupor Renal and urinary disorders: urinary incontinence, urinary retention Reproductive system and breast disorders: breast enlargement or engorgement, clitorism, lactation, priapism [see Warnings and Precautions (5.6)] Respiratory, thoracic and mediastinal disorders: apnea Skin and subcutaneous tissue disorders: alopecia, hirsutism, leukonychia, pruritus, psoriasis, rash, urticaria Vascular disorders: vasodilation 7 DRUG INTERACTIONS Table 3 displays clinically significant drug interactions with RALDESY. Table 3: Clinically Significant Drug Interactions with RALDESY Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: The concomitant use of MAOIs and serotonergic drugs including RALDESY increases the risk of serotonin syndrome. Intervention: RALDESY is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications (4), Dosage and Administration (2.3, 2.4), and Warnings and Precautions (5.2)]. Other Serotonergic Drugs Clinical Impact: The concomitant use of serotonergic drugs, including RALDESY and other serotonergic drugs increases the risk of serotonin syndrome. Intervention: Monitor patients for signs and symptoms of serotonin syndrome, particularly during RALDESY initiation. If serotonin syndrome occurs, consider discontinuation of RALDESY and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)]. Antiplatelet Agents and Anticoagulants Clinical Impact: Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with RALDESY may potentiate the risk of bleeding. Intervention: Inform patients of the increased risk of bleeding with the concomitant use of RALDESY and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing RALDESY [see Warnings and Precautions (5.5)]. Strong CYP3A4 Inhibitors Clinical Impact: The concomitant use of RALDESY and strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of RALDESY alone. Reference ID: 5485509 Intervention: If RALDESY is used with a potent CYP3A4 inhibitor, the risk of adverse reactions, including cardiac arrhythmias, may be increased and a lower dose of RALDESY should be considered [see Dosage and Administration (2.5), Warnings and Precautions (5.3)]. Strong CYP3A4 Inducers Clinical Impact: The concomitant use of RALDESY and strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of RALDESY alone. Intervention: Patients should be closely monitored to see if there is a need for an increased dose of RALDESY when taking CYP3A4 inducers [see Dosage and Administration (2.5)]. Digoxin and Phenytoin Clinical Impact: Digoxin and phenytoin are narrow therapeutic index drugs. Concomitant use of RALDESY can increase digoxin or phenytoin concentrations. Intervention: Measure serum digoxin or phenytoin concentrations before initiating concomitant use of RALDESY. Continue monitoring and reduce digoxin or phenytoin dose as necessary. Central Nervous System (CNS) Depressants Clinical Impact: RALDESY may enhance the response CNS depressants. Intervention: Patients should be counseled that RALDESY may enhance the response to alcohol, barbiturates, and other CNS depressants. QT Interval Prolongation Clinical Impact: Concomitant use of drugs that prolong the QT interval may add to the QT effects of RALDESY and increase the risk of cardiac arrhythmia. Intervention: Avoid the use of RALDESY in combination with other drugs known to prolong QTc [see Warnings and Precautions (5.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers should encourage patients to enroll by calling the National Pregnancy Registry for Antidepressants at 1-866-961- 2388 or visiting online at https://womensmentalhealth.org/ research/pregnancyregistry/antidepressants/. Risk Summary Published prospective cohort studies, case series, and case reports over several decades with trazodone hydrochloride tablets use in pregnant women have not identified any drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes (see Data). There are risks associated with untreated depression in pregnancy (see Clinical Considerations).Trazodone hydrochloride has been shown to cause increased fetal resorption and other adverse effects on the fetus in the rat when given at dose levels approximately 7.3 to 11 times the maximum recommended human dose (MRHD) of 400 mg/day in adults on a mg/m2 basis. There was also an increase in congenital anomalies in the rabbit at approximately 7.3 to 22 times the MRHD on a mg/m2 basis (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryofetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study of 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with trazodone use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. All available studies have methodological limitations, including small sample size and inconsistent comparator groups. Animal Data No teratogenic effects were observed when trazodone was given to pregnant rats and rabbits during the period of organogenesis at oral doses up to 450 mg/kg/day. This dose is 11 and 22 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 400 mg/day in adults on a mg/m2 basis. Increased fetal resorption and other adverse effects on the fetus in rats at 7.3 to 11 times the MRHD and increase in congenital anomalies in rabbits at 7.3 to 22 times the MRHD on a mg/m2 basis were observed. No further details on these studies are available. Reference ID: 5485509 8.2 Lactation Risk Summary Data from published literature report the transfer of trazodone into human milk. There are no data on the effect of trazodone on milk production. Limited data from postmarketing reports have not identified an association of adverse effects on the breastfed child. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RALDESY and any potential adverse effects on the breastfed child from RALDESY or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of RALDESY in the pediatric patients have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.1)]. 8.5 Geriatric Use Reported clinical literature and experience with trazodone has not identified differences in responses between geriatric and younger patients. However, as experience with trazodone hydrochloride in geriatric patients is limited, RALDESY should be used with caution in these patients. Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.11)]. 8.6 Renal Impairment Trazodone has not been studied in patients with renal impairment. RALDESY should be used with caution in this population. 8.7 Hepatic Impairment Trazodone has not been studied in patients with hepatic impairment. RALDESY should be used with caution in this population. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Trazodone hydrochloride is not a controlled substance. 9.2 Abuse Although trazodone hydrochloride has not been systematically studied in preclinical or clinical studies for its potential for abuse, no indication of drug-seeking behavior was seen in the clinical studies with trazodone hydrochloride. 10 OVERDOSAGE Death from overdose has occurred in patients ingesting trazodone and other CNS depressant drugs concurrently (alcohol; alcohol and chloral hydrate and diazepam; amobarbital; chlordiazepoxide; or meprobamate). The most severe reactions reported to have occurred with overdose of trazodone alone have been priapism, respiratory arrest, seizures, and ECG changes, including QT prolongation. The reactions reported most frequently have been drowsiness and vomiting. Overdosage may cause an increase in incidence or severity of any of the reported adverse reactions. There is no specific antidote for trazodone hydrochloride overdose. Consider contacting the Poison Help line 1-888-222-1222 or a medical toxicologist for additional overdose management recommendations. 11 DESCRIPTION RALDESY contains trazodone hydrochloride, a selective serotonin reuptake inhibitor and 5HT2 receptor antagonist. Trazodone hydrochloride is a triazolopyridine derivative designated as 2-[3-[4-(3-chlorophenyl)-1- piperazinyl]propyl]-1,2,4-triazolo [4,3-a]pyridin- 3(2H)-one hydrochloride. It is a white odorless crystalline powder which is freely soluble in water. The structural formula is represented Reference ID: 5485509 as follows: Molecular Formula: C19H22CIN5O • HCl Molecular Weight: 408.33 RALDESY Oral Solution: Each mL contains 10 mg of Trazodone Hydrochloride, USP equivalent to 9.1 mg of trazodone base. The following inactive ingredients: disodium edetate, glycerin, ortho phosphoric acid, propyl gallate, propylene glycol, purified water, sodium benzoate, sorbitol, and sucralose. The pH of the oral solution is 3.8 to 4.8. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of trazodone’s antidepressant action is unclear, but is thought to be related to its enhancement of serotonergic activity in the CNS. Trazodone is both a selective serotonin reuptake inhibitor (SSRI) and a 5HT2 receptor antagonist and the net result of this action on serotonergic transmission and its role in trazodone’s antidepressant effect is unknown. 12.2 Pharmacodynamics Preclinical studies have shown that trazodone selectively inhibits neuronal reuptake of serotonin (Ki = 367 nM) and acts as an antagonist at 5-HT-2A (Ki = 35.6 nM) serotonin receptors. Trazodone is also an antagonist at several other monoaminergic receptors including 5-HT2B (Ki = 78.4 nM), 5-HT2C (Ki = 224 nM), α1A (Ki = 153 nM), α2C (Ki = 155 nM) receptors and it is a partial agonist at 5- HT1A (Ki = 118 nM) receptor. Trazodone antagonizes alpha 1-adrenergic receptors, a property which may be associated with postural hypotension. 12.3 Pharmacokinetics No clinically significant difference in pharmacokinetics of trazodone was observed between RALDESY and immediate-release trazodone hydrochloride tablet administered under fed conditions. Absorption Peak plasma levels occur approximately one hour after administration under fed conditions. Effect of Food Ingestion of a high-fat meal with RALDESY lowers mean Cmax of trazodone by 31% and increases mean AUC by 8%. Median Tmax was similar between fed and fasted conditions. Distribution Trazodone is 89% to 95% protein bound in vitro at concentrations attained with therapeutic doses in humans. Metabolism In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m- chlorophenylpiperazine (mCPP) by CYP3A4. Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. Trazodone is extensively metabolized; less than 1% of an oral dose is excreted unchanged in the urine. Elimination The average terminal elimination half-life of RALDESY under fed state is 18 hours. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No drug- or dose-related occurrence of carcinogenesis was evident in rats receiving trazodone in daily oral doses up to 7.3 times the maximum recommended human dose (MRHD) of 400 mg/day in adults on a mg/m2 basis. Mutagenesis No genotoxicity studies were conducted with trazodone. Impairment of Fertility Trazodone has no effect on fertility in rats at doses up to 7.3 times the MRHD in adults on a mg/m2 basis. 14 CLINICAL STUDIES The efficacy of RALDESY for the treatment of MDD in adults is based on studies of trazodone hydrochloride tablets. Reference ID: 5485509 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied RALDESYTM contains 10 mg/mL of trazodone hydrochloride. It is a clear, colorless solution and is supplied as: 150 mL amber glass bottle • NDC 30698-455-03 with child-resistant cap along with a 10 mL calibrated oral dosing syringe and bottle adapter. 150 mL white, opaque, high-density polyethylene (HDPE) bottle • NDC 30698-455-02 with child-resistant cap along with a 10 mL calibrated oral dosing syringe and bottle adapter. 300 mL amber glass bottle • NDC 30698-455-04 with child-resistant cap along with a 10 mL calibrated oral dosing syringe and bottle adapter. 300 mL white, opaque, HDPE bottle • NDC 30698-455-01 with child-resistant cap along with a 10 mL calibrated oral dosing syringe and bottle adapter. The bottle, bottle adapter and the dosing syringe are placed in a carton. Storage and Handling Store at 20°C to 25°C (68°F to 77°F). Excursions permitted between 15ºC to 30ºC (59°F to 86ºF) [see USP Controlled Room Temperature]. Protect from light. Discard any unused RALDESY remaining in the bottle 20 days after first opening the bottle. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider [see Box Warning and Warnings and Precautions (5.1)]. Dosage and Administration Advise patients that RALDESY should be taken shortly after a meal or light snack. Advise patients regarding the importance of following dosage titration instructions [see Dosage and Administration (2)]. Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of RALDESY with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Patients should contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Increased Risk of Bleeding Inform patients about the concomitant use of RALDESY with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use of drugs that interfere with serotonin reuptake and these medications has been associated with an increased risk of bleeding. Advise them to inform their health care providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions (5.5)]. Activation of Mania or Hypomania Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.7)]. Discontinuation Syndrome Advise patients not to abruptly discontinue RALDESY and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when RALDESY is discontinued [see Warnings and Precautions (5.8)]. Concomitant Medications Advise patients to inform their health care providers if they are taking, or plan to take any prescription or over-the-counter medications since there is a potential for interactions [see Drug Interactions (7.1)]. Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy with RALDESY. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to RALDESY during pregnancy [see Use in Special Populations (8.1)]. Manufactured for and distributed by: Validus Pharmaceuticals LLC Parsippany, NJ 07054 Reference ID: 5485509 MEDICATION GUIDE RALDESYTM (ral DEH see) (trazodone hydrochloride) oral solution What is the most important information I should know about RALDESY? RALDESY can cause serious side effects, including: • Increased risk of suicidal thoughts or actions. RALDESY and other antidepressant medicines increase the risk of suicidal thoughts and actions in people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. RALDESY is not for use in children. o Depression and other mental illnesses are the most important causes of suicidal thoughts and actions. How can I watch for and try to prevent suicidal thoughts and actions? o Pay close attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed. o Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings, or if you develop suicidal thoughts or actions. o Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Call a healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you: • attempts to commit suicide • acting on dangerous impulses • acting aggressive or violent • thoughts about suicide or dying • new or worse depression • a new or worse anxiety or panic attacks • feeling agitated, restless, angry, or irritable • trouble sleeping • an increase in activity or talking more than what is normal for you • other unusual changes in behavior and mood See “What are the possible side effects of RALDESY?” for more information about side effects. What is RALDESY? RALDESY is a prescription medicine used in adults to treat major depressive disorder (MDD). It is not known if RALDESY is safe and effective for use in children. Who should not take RALDESY? Do not take RALDESY if you: • are taking, or have stopped taking within the last 14 days, a medicine called Monoamine Oxidase Inhibitor (MAOI), including the antibiotic linezolid and intravenous methylene blue Ask your healthcare provider or pharmacist is you are not sure if you take an MAOI, including the antibiotic linezolid or intravenous blue. Do not start taking an MAOI for at least 14 days after you stop treatment with RALDESY. Before taking RALDESY tell your healthcare provider about all of your medical conditions, including if you: • have or have a family history of heart problems, including fast or slow heartbeat, or changes in the electrical activity of your heart (QT prolongation) • have ever had a heart attack • have or have had bleeding problems • are male and have conditions that may cause a prolonged or painful erection (priapism) such as sickle cell anemia, multiple myeloma, leukemia, or a deformed penis • have or have a family history of bipolar disorder, mania, or hypomania • have high pressure in the eye (glaucoma) • have low sodium levels in your blood • are pregnant or plan to become pregnant. It is not known if RALDESY will harm your unborn baby. Talk to your healthcare provider about the risks to you or your unborn baby if you take RALDESY during pregnancy. o Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with RALDESY. o There is a pregnancy registry for females who are exposed to RALDESY during pregnancy. The purpose of this registry is to collect information about the health of females exposed to RALDESY and their baby. If you become pregnant during treatment with RALDESY, talk to your healthcare provider about registering with the National Reference ID: 5485509 Pregnancy Registry for Antidepressants. You can register by calling 1-866-961-2388 or visiting online at https://womensmentalhealth.org/ research/pregnancyregistry/antidepressants/. • are breastfeeding or plan to breastfeed. RALDESY passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with RALDESY. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. RALDESY and some other medicines may affect each other causing serious side effects. RALDESY may affect the way other medicines work and other medicines may affect the way RALDESY works. Especially tell your healthcare provider if you take: • MAOIs • medicines used to treat migraine headache called triptans • medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclic antidepressants, lithium, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), buspirone, or antipsychotics • tramadol, fentanyl, or other opioids • over-the-counter supplements such as tryptophan or St. John’s Wort • medicines used to treat high blood pressure • medicines used to treat irregular heartbeats • medicines that affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), warfarin or other blood thinners • digoxin • medicines used to treat seizures or convulsions • diuretics Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take RALDESY with your other medicines. Do not start or stop any other medicines during treatment with RALDESY without talking to your healthcare provider first. Stopping RALDESY suddenly may cause you to have serious side effects. See, “What are the possible side effects of RALDESY?” Know the medicines you take. Keep a list of them to show it to your healthcare provider and pharmacist when you get a new medicine. How should I take RALDESY? See the detailed Instructions for Use that comes with RALDESY for information on how to take RADELSY oral solution. • Take RALDESY exactly as your healthcare provider tells you. Your healthcare provider may need to change your dose of RALDESY until it is the right dose for you. • If you feel sleepy after taking RALDESY, talk to your healthcare provider. Your healthcare provider may change your dose or the time of day you take your RALDESY. • Take RALDESY after a meal or light snack. • Do not stop taking RALDESY without talking to your healthcare provider. • If you take too much RALDESY, call your healthcare provider, your Poison Help Line at 1-800-222-1222, or go to the nearest hospital emergency room right away. What should I avoid while taking RALDESY? • Do not drive, operate heavy machinery, or do other dangerous activities until you know how RALDESY affects you. RALDESY can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. • Do not drink alcohol or take other medicines that make you sleepy or dizzy during treatment with RALDESY until you talk with your healthcare provider. RALDESY may make your sleepiness or dizziness worse if you drink alcohol or take other medicines that cause sleepiness or dizziness. What are the possible side effects of RALDESY? RALDESY can cause serious side effects, including: • See “What is the most important information I should know about RALDESY?” Serotonin syndrome. A potentially life-threating problem called serotonin syndrome can happen when you take RALDESY with certain other medicines. See “Who should not take RALDESY?” Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome: o agitation o flushing o seeing or hearing things that are not real (hallucinations) o high body temperature (hyperthermia) Reference ID: 5485509 o confusion o shaking (tremors), stiff muscles, or muscle twitching o coma o loss of coordination o fast heartbeat o seizures o changes in blood pressure o nausea, vomiting, diarrhea o sweating o dizziness • Changes in the electrical activity of your heart (QT prolongation). Call your healthcare provider right away if you have any of the following symptoms: abnormal heartbeats, dizziness, feel lightheaded or faint. • Low blood pressure and fainting. Low blood pressure can happen when you change positions from sitting to standing or laying down. You may feel dizzy, lightheaded, or faint. • Increased risk of bleeding. Taking RALDESY with aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), warfarin, or blood thinners may add to this risk. Tell your healthcare provider right away about any unusual bleeding or bruising. • Painful erection lasting for more than 6 hours (priapism). If you have an erection that lasts more than 4 hours, get medical help right away. • Manic episodes. Manic episodes may happen in people with bipolar disorder who take RALDESY. Symptoms may include: o greatly increased energy o severe problems sleeping o racing thoughts o reckless behavior o unusually grand ideas o excessive happiness or irritability o talking more or faster than usual • Discontinuation syndrome. Suddenly stopping RALDESY may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include: o nausea o electric shock feeling (paresthesia) o tiredness o sweating o tremor o problems sleeping o changes in your mood o anxiety o hypomania o irritability and agitation o confusion o ringing in the ears (tinnitus) o dizziness o headache o seizures • Eye problems (angle-closure glaucoma). RALDESY can cause a type of eye problem called angle-closure glaucoma in people with certain eye conditions. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your healthcare provider if you have changes in your vision, eye pain, or swelling or redness in or around the eye. • Low sodium in your blood (hyponatremia). Low sodium levels in your blood that may be serious and may cause death, can happen during treatment with RALDESY. Elderly people and people who take certain medicines may be at greater risk for this. Signs and symptoms may include: o headache o confusion o difficulty concentrating o weakness and unsteadiness on your feet, which can lead to falls o memory changes In more severe or sudden cases, signs and symptoms include: o seeing or hearing things that are not real (hallucinations) o coma o fainting o stopping breathing (respiratory arrest) o seizures The most common side effects of RALDESY include: • swelling • blurred vision • fainting • sleepiness • tiredness • diarrhea • stuffy nose • weight loss These are not all of the possible side effects of RALDESY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store RALDESY? • Store RALDESY at room temperature between 68°F to 77°F (20°C to 25°C). • RALDESY comes in a bottle with a child-resistant cap. • Keep RALDESY out of the light. Reference ID: 5485509 • Throw away (discard) RALDESY 20 days after first opening the bottle. • Safely throw away medicine that is out of date or no longer needed. Keep RALDESY and all medicines out of the reach of children General information about the safe and effective use of RALDESY. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RALDESY for a condition for which it was not prescribed. Do not give RALDESY to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about RALDESY that is written for health professionals. What are the ingredients in RALDESY? Active ingredient: trazodone hydrochloride, USP Inactive ingredients: disodium edetate, glycerin, ortho phosphoric acid, propyl gallate, propylene glycol, purified water, sodium benzoate, sorbitol, and sucralose. Manufactured for and distributed by: Validus Pharmaceuticals LLC Parsippany, NJ 07054 For more information, go to www.RALDESY.com or call Validus Pharmaceuticals LLC at 1-866-982-5438. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 11/2024 Reference ID: 5485509 INSTRUCTIONS FOR USE RALDESYTM (ral DEH see) (trazodone hydrochloride) oral solution This Instructions for Use contains information on how to take RALDESY. Read this Instructions for Use before you start taking RALDESY for the first time and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Supplies needed to take RALDESY Each carton of RALDESY contains: • 1 bottle of RALDESY oral solution • 1 plastic adapter • One 10 mL oral dosing syringe Important Information You Need to Know Before Taking RALDESY • For oral use only (taken by mouth). • Use the plastic adapter and oral dosing syringe that comes in the carton. If you did not receive the plastic adapter and oral dosing syringe, contact your pharmacist. • Ask your pharmacist how to measure your prescribed doses. • Take RALDESY exactly as prescribed by your healthcare provider. Do not stop taking RALDESY without first talking to your healthcare provider. • Take RALDESY after a meal or light snack. • Check the expiration date on the bottle. If you have not opened the RALDESY bottle, do not use RALDESY if the expiration date on the bottle has passed. Contact your healthcare provider or pharmacist. • Do not use RALDESY 20 days after first opening the bottle. Reference ID: 5485509 Preparing the RALDESY bottle Step 1. Remove the child-resistant cap by pushing it firmly down and turning it counterclockwise (to the left), as shown on the top of the child- resistant cap. Note: Save the child-resistant cap so you can close the bottle after each use. Step 2. Hold the open bottle upright on a table and push the ribbed end of the plastic adapter firmly into the neck of the bottle as far as you can. Step 3. Put the child-resistant cap back on the bottle to make sure the plastic adapter has been fully inserted into the neck of the bottle. Note: You may not be able to push the plastic adapter all the way down, but it will be forced into the bottle when you put the child-resistant cap back on. Now the bottle is ready to use with the oral dosing syringe. Do not remove the adapter. The plastic adapter must always stay in the bottle. The child-resistant cap should seal the bottle in between use. Write the date of first opening the RALDESY bottle. Preparing the dose of RALDESY oral solution Step 4. Push down and turn the child- resistant cap to the left to open the bottle. Note: Always replace the cap after use. Step 5. Check that the plunger is all the way down inside the barrel of the oral dosing syringe. Step 6. Keep the bottle upright and push the tip of the oral dosing syringe firmly into the plastic adapter. Reference ID: 5485509 Step 7. Hold the syringe in place and carefully turn the bottle upside down. Step 8. Slowly pull down the plunger to fill the oral dosing syringe slightly past your prescribed dose line to help remove any air bubbles. Step 9. Tap oral dosing syringe to move air bubbles to the top. Doing this helps set the correct dose. Step 10. Push the plunger back slowly just far enough to completely push out any large or small air bubbles that may be trapped in the oral dosing syringe. Step 11. Slowly pull the plunger down until the top edge of the plunger is level with the marker on the syringe barrel for the prescribed dose. Note: If the prescribed dose is more than 10 mL, you will need to refill the oral dosing syringe to make up the full dose. Reference ID: 5485509 Step 12. Carefully turn the bottle upright. Take out the oral dosing syringe by gently twisting it out of the plastic adapter. The plastic adapter should stay in the bottle. Taking the dose of RALDESY oral solution Note: Sit up straight while taking RALDESY. Step 13. Place the oral dosing syringe gently into your mouth. Push the plunger slowly until the plunger moves all of the medicine out of the oral dosing syringe. Step 14. Swallow all of the medicine. Step 15. Close the bottle by screwing the child-resistant cap back on the bottle after use. Make sure the child-resistant cap is tightly closed. Step 16. Cleaning: After use, rinse the oral dosing syringe with warm water and allow it to dry thoroughly. Step 17. Throw away (discard): Safely throw away medicine that is expired or no longer needed. Do not throw away any medicine down the sink or in your household trash. Ask your pharmacist how to throw away medicines you no longer use. Storing RALDESY • Store RALDESY at room temperature between 68°F to 77°F (20°C to 25°C). • RALDESY comes in a bottle with a child-resistant cap. • Keep RALDESY out of the light. • Throw away (discard) RALDESY 20 days after first opening the bottle. • Safely throw away medicine that is out of date or no longer needed. Keep RALDESY and all medicines out of the reach of children. Manufactured for and distributed by: Validus Pharmaceuticals LLC Parsippany, NJ 07054 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Approved: 11/2024 Reference ID: 5485509
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_________________________________________________________________________________________________________________________ _______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION mediated pneumonitis, immune-mediated colitis, immune-mediated These highlights do not include all the information needed to use hepatitis, immune-mediated endocrinopathies, immune-mediated BAVENCIO safely and effectively. See full prescribing information for nephritis with renal dysfunction, immune-mediated dermatologic adverse BAVENCIO. reactions, and may result in solid organ transplant rejection. • Monitor for early identification and management. Evaluate liver enzymes, BAVENCIO® (avelumab) injection, for intravenous use creatinine, and thyroid function at baseline and periodically during Initial U.S. Approval: 2017 treatment. • Withhold or permanently discontinue based on severity and type of ----------------------------RECENT MAJOR CHANGES-------------------------­ reaction. Warnings and Precautions (5.1) 03/2024 • Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue BAVENCIO based on severity of reaction. (5.2) ----------------------------INDICATIONS AND USAGE--------------------------­ • Complications of allogeneic HSCT: Fatal and other serious complications BAVENCIO is a programmed death ligand-1 (PD-L1) blocking antibody can occur in patients who receive allogeneic HSCT before or after being indicated for: treated with a PD-1/PD-L1 blocking antibody. (5.3) Merkel Cell Carcinoma (MCC) • Major adverse cardiovascular events: Optimize management of • Adults and pediatric patients 12 years and older with metastatic MCC. (1.1, cardiovascular risk factors. Discontinue BAVENCIO in combination with 14.1) axitinib for Grade 3-4 events. (5.4) Urothelial Carcinoma (UC) • Embryo-fetal toxicity: BAVENCIO can cause fetal harm. Advise females of • Maintenance treatment of patients with locally advanced or metastatic UC reproductive potential of the potential risk to a fetus and use of effective that has not progressed with first-line platinum-containing chemotherapy. contraception. (5.5, 8.1, 8.3) (1.2, 14.2) • Patients with locally advanced or metastatic UC who: -------------------------------ADVERSE REACTIONS-----------------------------­ • Have disease progression during or following platinum-containing Most common adverse reactions (> 20%) in patients were: chemotherapy. (1.2, 14.2) • MCC: • Have disease progression within 12 months of neoadjuvant or adjuvant • Fatigue, musculoskeletal pain, infusion-related reaction, rash, nausea, treatment with platinum-containing chemotherapy. (1.2, 14.2) constipation, cough, and diarrhea. (6.1) Renal Cell Carcinoma (RCC) • UC: • First-line treatment, in combination with axitinib, of patients with advanced • Maintenance treatment: fatigue, musculoskeletal pain, urinary tract RCC. (1.3, 14.3) infection, and rash. (6.1) • Previously-treated: fatigue, infusion-related reaction, musculoskeletal -----------------------DOSAGE AND ADMINISTRATION----------------------­ pain, nausea, decreased appetite, and urinary tract infection. (6.1) • Premedicate for the first 4 infusions and subsequently as needed. (2.1) • RCC (with axitinib): diarrhea, fatigue, hypertension, musculoskeletal pain, • Merkel Cell Carcinoma: 800 mg every 2 weeks. (2.2) nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased • Urothelial Carcinoma; 800 mg every 2 weeks. (2.3) appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal • Renal Cell Carcinoma: 800 mg every 2 weeks in combination with axitinib pain, and headache. (6.1) 5 mg orally twice daily. (2.4) Administer BAVENCIO as an intravenous infusion over 60 minutes. To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or ---------------------DOSAGE FORMS AND STRENGTHS---------------------- www.fda.gov/medwatch. Injection: 200 mg/10 mL (20 mg/mL) solution in single-dose vial. (3) ------------------------USE IN SPECIFIC POPULATIONS----------------------­ -------------------------------CONTRAINDICATIONS------------------------------ Lactation: Advise not to breastfeed. (8.2) None. (4) See 17 for PATIENT COUNSELING INFORMATION and Medication ------------------------WARNINGS AND PRECAUTIONS----------------------­ Guide. • Immune-Mediated Adverse Reactions (5.1) Revised: 11/2024 • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune- FULL PRESCRIBING INFORMATION: CONTENTS* 8 USE IN SPECIFIC POPULATIONS 1 INDICATIONS AND USAGE 8.1 Pregnancy 1.1 Metastatic Merkel Cell Carcinoma 8.2 Lactation 1.2 Locally Advanced or Metastatic Urothelial Carcinoma 8.3 Females and Males of Reproductive Potential 1.3 Advanced Renal Cell Carcinoma 8.4 Pediatric Use 2 DOSAGE AND ADMINISTRATION 8.5 Geriatric Use 2.1 Premedication 11 DESCRIPTION 2.2 Recommended Dosage for MCC 12 CLINICAL PHARMACOLOGY 2.3 Recommended Dosage for UC 12.1 Mechanism of Action 2.4 Recommended Dosage for RCC 12.2 Pharmacodynamics 2.5 Dose Modifications 12.3 Pharmacokinetics 2.6 Preparation and Administration 12.6 Immunogenicity 3 DOSAGE FORMS AND STRENGTHS 13 NONCLINICAL TOXICOLOGY 4 CONTRAINDICATIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5 WARNINGS AND PRECAUTIONS 13.2 Animal Toxicology and/or Pharmacology 5.1 Severe and Fatal Immune-Mediated Adverse Reactions 14 CLINICAL STUDIES 5.2 Infusion-Related Reactions 14.1 Metastatic Merkel Cell Carcinoma 5.3 Complications of Allogeneic HSCT 14.2 Locally Advanced or Metastatic Urothelial Carcinoma 5.4 Major Adverse Cardiovascular Events (MACE) 14.3 Advanced Renal Cell Carcinoma 5.5 Embryo-Fetal Toxicity 16 HOW SUPPLIED/STORAGE AND HANDLING 6 ADVERSE REACTIONS 17 PATIENT COUNSELING INFORMATION 6.1 Clinical Trials Experience 6.2 Postmarketing Experience *Sections or subsections omitted from the full prescribing information are not listed Page 1 of 39 Reference ID: 5486483 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Metastatic Merkel Cell Carcinoma BAVENCIO (avelumab) is indicated for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC) [see Clinical Studies (14.1)]. 1.2 Locally Advanced or Metastatic Urothelial Carcinoma First-Line Maintenance Treatment of Urothelial Carcinoma BAVENCIO is indicated for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy [see Clinical Studies (14.2)]. Previously-treated Urothelial Carcinoma BAVENCIO is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who: • Have disease progression during or following platinum-containing chemotherapy • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Clinical Studies (14.2)]. 1.3 Advanced Renal Cell Carcinoma BAVENCIO in combination with axitinib is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC) [see Clinical Studies (14.3)]. 2 DOSAGE AND ADMINISTRATION 2.1 Premedication Premedicate patients with an antihistamine and with acetaminophen prior to the first 4 infusions of BAVENCIO. Premedication should be administered for subsequent BAVENCIO doses based upon clinical judgment and presence/severity of prior infusion reactions [see Dosage and Administration (2.5) and Warnings and Precautions (5.2)]. 2.2 Recommended Dosage for MCC The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for UC The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Page 2 of 39 Reference ID: 5486483 2.4 Recommended Dosage for RCC The recommended dosage of BAVENCIO is 800 mg administered as an intravenous infusion over 60 minutes every 2 weeks in combination with axitinib 5 mg orally taken twice daily (12 hours apart) with or without food until disease progression or unacceptable toxicity. When axitinib is used in combination with BAVENCIO, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of two weeks or longer. Review the Full Prescribing Information for axitinib prior to initiation. 2.5 Dose Modifications No dose reduction for BAVENCIO is recommended. In general, withhold BAVENCIO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue BAVENCIO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. Dosage modifications for BAVENCIO for adverse reactions that require management different from these general guidelines are summarized in Table 1. Table 1: Recommended Monotherapy Dosage Modifications for Adverse Reactions Adverse Reaction Severity* Dosage Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] Pneumonitis Grade 2 Withholda Grade 3 or 4 Permanently discontinue Colitis Grade 2 or 3 Withholda Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy, see Table 2 AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN Withholda AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Page 3 of 39 Reference ID: 5486483 Adverse Reaction Severity* Dosage Modification Hepatitis with tumor involvement of the liverb Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN Withholda AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Endocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withholda Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withholda Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grade 2, 3 or 4 Permanently discontinue Neurological Toxicities Grade 2 Withholda Grade 3 or 4 Permanently discontinue Other Adverse Reactions Infusion-related reactions [see Warnings and Precautions (5.2)] Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal, SJS = Stevens- Johnson syndrome, TEN = toxic epidermal necrosis, DRESS = drug rash with eosinophilia and systemic symptoms * Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating corticosteroids. b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue BAVENCIO based on recommendations for hepatitis where there is no tumor involvement of the liver. Table 2 presents dosage modifications that are different from those described above in Table 1 for BAVENCIO used as monotherapy or in the Full Prescribing Information for the drug administered in combination. Page 4 of 39 Reference ID: 5486483 Table 2: Recommended Specific Dosage Modifications for Adverse Reactions for Combination Therapy [see Warnings and Precautions (5.1)] Treatment Adverse Reaction Severity* Dosage Modification BAVENCIO in combination with axitinib Liver enzyme elevations ALT or AST at least 3 times ULN but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN Withhold both BAVENCIO and axitinib until adverse reactions recover to Grades 0-1a Consider rechallenge with BAVENCIO or axitinib or sequential rechallenge with both BAVENCIO and ** axitinib after recovery ALT or AST at least 10 times ULN or more than 3 times ULN with concurrent total bilirubin at least 2 times ULN Permanently discontinue both BAVENCIO and axitiniba * Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 ** Dose reduction according to the axitinib Full Prescribing Information should be considered if rechallenging with axitinib. a Consider corticosteroid therapy 2.6 Preparation and Administration Preparation • Visually inspect vial for particulate matter and discoloration. BAVENCIO is a clear, colorless to slightly yellow solution. Discard vial if the solution is cloudy, discolored, or contains particulate matter. • Withdraw the required volume of BAVENCIO from the vial(s) and inject it into a 250 mL infusion bag containing either 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection. • Gently invert the bag to mix the diluted solution and avoid foaming or excessive shearing. • Inspect the solution to ensure it is clear, colorless, and free of visible particles. • Discard any partially used or empty vials. Storage of diluted BAVENCIO solution Protect from light. Store diluted BAVENCIO solution: • At room temperature up to 77°F (25°C) for no more than 4 hours from the time of dilution. Or • Under refrigeration at 36°F to 46°F (2°C to 8°C) for no more than 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Page 5 of 39 Reference ID: 5486483 Do not freeze or shake diluted solution. Administration • Administer the diluted solution over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron). • Do not co-administer other drugs through the same intravenous line. 3 DOSAGE FORMS AND STRENGTHS Injection: 200 mg/10 mL (20 mg/mL), clear, colorless to slightly yellow solution in a single-dose vial. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Severe and Fatal Immune-Mediated Adverse Reactions BAVENCIO is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue BAVENCIO depending on severity [see Dosage and Administration (2.5)]. In general, if BAVENCIO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Page 6 of 39 Reference ID: 5486483 Toxicity management guidelines for adverse reactions that do not necessarily require systemic corticosteroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis BAVENCIO can cause immune-mediated pneumonitis. Immune-mediated pneumonitis occurred in 1.1% (21/1854) of patients receiving BAVENCIO, including fatal (0.1%), Grade 4 (0.1%), Grade 3 (0.3%) and Grade 2 (0.6%) adverse reactions. Pneumonitis led to permanent discontinuation of BAVENCIO in 0.3% and withholding of BAVENCIO in 0.3% of patients. Systemic corticosteroids were required in all (21/21) patients with pneumonitis. Pneumonitis resolved in 57% (12/21) of the patients. Of the 5 patients in whom BAVENCIO was withheld for pneumonitis, 5 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of pneumonitis. With other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-Mediated Colitis BAVENCIO can cause immune-mediated colitis. The primary component of the immune- mediated colitis consisted of diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.5% (27/1854) of patients receiving BAVENCIO, including Grade 3 (0.4%) and Grade 2 (0.8%) adverse reactions. Colitis led to permanent discontinuation of BAVENCIO in 0.5% and withholding of BAVENCIO in 0.4% of patients. Systemic corticosteroids were required in all (27/27) patients with colitis. Colitis resolved in 70% (19/27) of the patients. Of the 8 patients in whom BAVENCIO was withheld for colitis, 5 reinitiated treatment with BAVENCIO after symptom improvement; of these, 40% had recurrence of colitis. Hepatotoxicity and Immune-Mediated Hepatitis BAVENCIO as a single agent BAVENCIO can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 1.1% (20/1854) of patients receiving BAVENCIO, including fatal (0.1%), Grade 3 (0.8%), and Grade 2 (0.2%) adverse reactions. Hepatitis led to permanent discontinuation of BAVENCIO in 0.6% and withholding of BAVENCIO in 0.2% of patients. Systemic corticosteroids were required in all (20/20) patients with hepatitis. Hepatitis resolved in 60% (12/20) of the patients. Of the 4 patients in whom BAVENCIO was withheld for hepatitis, 4 reinitiated treatment with BAVENCIO after symptom improvement; of these, 25% had recurrence of hepatitis. Page 7 of 39 Reference ID: 5486483 BAVENCIO with Axitinib BAVENCIO in combination with axitinib can cause hepatotoxicity with higher-than-expected frequencies of Grade 3 and 4 ALT and AST elevation compared to BAVENCIO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. For elevated liver enzymes, interrupt BAVENCIO and axitinib and consider administering corticosteroids as needed [see Dosage and Administration (2.5)]. In patients treated with BAVENCIO in combination with axitinib in the advanced RCC trials, increased ALT and increased AST were reported in 9% (Grade 3) and 7% (Grade 4) of patients. In patients with ALT ≥ 3 times ULN (Grades 2-4, n=82), ALT resolved to Grades 0-1 in 92%. Among the 73 patients who were rechallenged with either BAVENCIO (n=3) or axitinib (n=25) administered as a single agent or with both (n=45), recurrence of ALT ≥3 times ULN was observed in no patient receiving BAVENCIO, 6 patients receiving axitinib, and 15 patients receiving both BAVENCIO and axitinib. Twenty-two (88%) patients with a recurrence of ALT ≥3 ULN subsequently recovered to Grade 0-1 from the event. Immune-mediated hepatitis was reported in 7% of patients, including 4.9% with Grade 3 or 4 immune-mediated hepatitis. Hepatotoxicity led to permanent discontinuation in 6.5% and immune-mediated hepatitis led to permanent discontinuation of either BAVENCIO or axitinib in 5.3% of patients. Thirty-four patients were treated with corticosteroids and one patient was treated with a non-steroidal immunosuppressant. Resolution of hepatitis occurred in 31 of the 35 patients at the time of data cut-off. Immune-Mediated Endocrinopathies Adrenal Insufficiency BAVENCIO can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement, as clinically indicated. Withhold BAVENCIO depending on severity [see Dosage and Administration (2.5)]. Immune-mediated adrenal insufficiency occurred in 0.6% (11/1854) of patients receiving BAVENCIO, including Grade 3 (0.1%), and Grade 2 (0.4%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of BAVENCIO in 0.1% and withholding of BAVENCIO in 0.1% of patients. Systemic corticosteroids were required in all (11/11) patients with adrenal insufficiency. Adrenal insufficiency resolved in 18% (2/11) of patients. Of the 2 patients in whom BAVENCIO was withheld for adrenal insufficiency, none reinitiated treatment with BAVENCIO. Hypophysitis BAVENCIO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement, as clinically indicated. Withhold or permanently discontinue BAVENCIO depending on severity [see Dosage and Administration (2.5)]. Page 8 of 39 Reference ID: 5486483 Immune-mediated pituitary disorders occurred in 0.1% (1/1854) of patients receiving BAVENCIO which was a Grade 2 (0.1%) adverse reactions. Hypopituitarism did not lead to withholding of BAVENCIO in this patient. Systemic corticosteroids were not required in this patient. Thyroid Disorders BAVENCIO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism, as clinically indicated. Withhold or permanently discontinue BAVENCIO depending on severity [see Dosage and Administration (2.5)]. Thyroiditis occurred in 0.2% (4/1854) of patients receiving BAVENCIO, including Grade 2 (0.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation or withholding of BAVENCIO in any patients. No patients with thyroiditis required systemic corticosteroids. Thyroiditis did not resolve in any patients (0/4). Hyperthyroidism occurred in 0.4% (8/1854) of patients receiving BAVENCIO, including Grade 2 (0.3%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of BAVENCIO in any patients and led to withholding of BAVENCIO in 0.1% of patients. Systemic corticosteroids were required in 25% (2/8) of patients with hyperthyroidism. Hyperthyroidism resolved in 88% (7/8) of the patients. Of the 2 patients in whom BAVENCIO was withheld for hyperthyroidism, 2 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of hyperthyroidism. Hypothyroidism occurred in 5% (97/1854) of patients receiving BAVENCIO, including Grade 3 (0.2%) and Grade 2 (3.6%) adverse reactions. Hypothyroidism led to permanent discontinuation of BAVENCIO in 0.1% and withholding of BAVENCIO in 0.4% of patients. Systemic corticosteroids were required in 6% (6/97) of patients with hypothyroidism. Hypothyroidism resolved in 6% (6/97) of the patients. Of the 8 patients in whom BAVENCIO was withheld for hypothyroidism, none reinitiated BAVENCIO. Type I Diabetes Mellitus, which can present with Diabetic Ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold BAVENCIO depending on severity [see Dosage and Administration (2.5)]. Immune-mediated Type I diabetes mellitus occurred in 0.2% (3/1854) of patients receiving BAVENCIO, including Grade 3 (0.2%) adverse reactions. Type I diabetes mellitus led to permanent discontinuation of BAVENCIO in 0.1% of patients. Type I diabetes mellitus did not lead to withholding of BAVENCIO in any patient. Systemic corticosteroids were not required in any patient with Type I diabetes mellitus. Type I diabetes mellitus resolved in no patient and all patients required ongoing insulin treatment. Page 9 of 39 Reference ID: 5486483 Immune-Mediated Nephritis with Renal Dysfunction BAVENCIO can cause immune-mediated nephritis. Immune-mediated nephritis with renal dysfunction occurred in 0.1% (2/1854) of patients receiving BAVENCIO, including Grade 3 (0.1%) and Grade 2 (0.1%) adverse reactions. Nephritis with renal dysfunction led to permanent discontinuation of BAVENCIO in 0.1% of patients. Nephritis did not lead to withholding of BAVENCIO in any patient. Systemic corticosteroids were required in 100% of patients with nephritis with renal dysfunction. Nephritis with renal dysfunction resolved in 50% of the patients. Immune-Mediated Dermatologic Adverse Reactions BAVENCIO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue BAVENCIO depending on severity [see Dosage and Administration (2.5)]. Immune-mediated dermatologic adverse reactions occurred in 6% (108/1854) of patients receiving BAVENCIO, including Grade 3 (0.1%) and Grade 2 (1.9%) adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of BAVENCIO in 0.3% of patients and withholding of BAVENCIO in 0.4% of patients. Systemic corticosteroids were required in 25% (27/108) of patients with dermatologic adverse reactions. One patient required the addition of tacrolimus to high-dose corticosteroids. Dermatologic adverse reactions resolved in 46% (50/108) of the patients. Of the 8 patients in whom BAVENCIO was withheld for dermatologic adverse reactions, 4 reinitiated treatment with BAVENCIO after symptom improvement; of these, none had recurrence of dermatologic adverse reaction. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% (unless otherwise noted) in patients who received BAVENCIO or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis. Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis. Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy. Page 10 of 39 Reference ID: 5486483 Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada like syndrome, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss. Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatica. Endocrine: Hypoparathyroidism. Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection. 5.2 Infusion-Related Reactions BAVENCIO can cause severe or life-threatening infusion-related reactions [see Adverse Reactions (6.1)]. Premedicate with antihistamine and acetaminophen prior to the first 4 infusions. Monitor patients for signs and symptoms of infusion-related reactions including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions. Stop the infusion and permanently discontinue BAVENCIO for severe (Grade 3) or life- threatening (Grade 4) infusion-related reactions [see Dosage and Administration (2.5) and Adverse Reactions (6.1)]. Infusion-related reactions occurred in 26% of patients treated with BAVENCIO including 3 (0.2%) Grade 4 and 10 (0.5%) Grade 3 infusion-related reactions. Ninety-three percent of patients received premedication with antihistamine and acetaminophen. Eleven (85%) of the 13 patients with Grade ≥ 3 reactions were treated with intravenous corticosteroids. Fifteen percent of patients had infusion-related reactions that occurred after the BAVENCIO infusion was completed. 5.3 Complications of Allogeneic HSCT Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT. Page 11 of 39 Reference ID: 5486483 5.4 Major Adverse Cardiovascular Events (MACE) BAVENCIO in combination with axitinib can cause severe and fatal cardiovascular events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue BAVENCIO and axitinib for Grade 3-4 cardiovascular events. MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with axitinib compared to 3.4% treated with sunitinib in a randomized trial, JAVELIN Renal 101. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%). Median time to onset of MACE was 4.2 months (range: 2 days to 24.5 months). 5.5 Embryo-Fetal Toxicity Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking BAVENCIO, inform the patient of the potential risk to a fetus. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least one month after the last dose of BAVENCIO [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)] • Infusion-related reactions [see Warnings and Precautions (5.2)] • Complications of allogeneic HSCT [see Warnings and Precautions (5.3)] • Major adverse cardiovascular events [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to BAVENCIO 10 mg/kg intravenously every 2 weeks as a single agent in 1854 patients enrolled in the JAVELIN Merkel 200 and JAVELIN Solid Tumor trials and to BAVENCIO 10 mg/kg intravenously every 2 weeks in combination with axitinib 5 mg orally twice daily in 489 patients enrolled in the JAVELIN Renal 100 and JAVELIN Renal 101 trials. In the BAVENCIO monotherapy population, 25% of patients were exposed for ≥ 6 months and 9% were exposed for ≥ 12 months. The population characteristics of BAVENCIO in combination with axitinib are shown below. When BAVENCIO was used in combination with axitinib, 70% of patients were exposed for ≥ 6 months and 31% were exposed for ≥ 12 months. The following criteria were used to classify an adverse reaction as immune-mediated: onset within 90 days after last dose of BAVENCIO, no spontaneous resolution within 7 days of onset, treatment with corticosteroids or Page 12 of 39 Reference ID: 5486483 other immunosuppressant or hormone replacement therapy, biopsy consistent with immune- mediated reaction, and no other clear etiology. Metastatic Merkel Cell Carcinoma The safety of BAVENCIO was evaluated in 204 patients enrolled in the JAVELIN Merkel 200 trial with metastatic MCC. Patients received BAVENCIO 10 mg/kg intravenously every 2 weeks or 800 mg intravenously every 2 weeks until disease progression or unacceptable toxicity. The median duration of exposure to BAVENCIO was 4.1 months (range: 2 weeks to 48 months). [see Clinical Studies (14.1)]. Serious adverse reactions occurred in 52% of patients receiving BAVENCIO. The most frequent serious adverse reactions (≥ 2% of patients) were general physical health deterioration, anemia, abdominal pain, acute kidney injury, sepsis, hyponatremia, and infusion-related reaction. Permanent discontinuation of BAVENCIO due to an adverse reaction occurred in 27% of patients. The most frequent adverse reactions (> 1% of patients) that resulted in permanent discontinuation were infusion-related reaction, anemia, increased ALT, and increased AST. Dosage interruptions of BAVENCIO due to an adverse reaction, excluding temporary interruptions due to infusion-related reactions, occurred in 29% of patients. The most frequent adverse reactions (> 1% of patients) that required dosage interruption were nasopharyngitis, anemia, diarrhea, lung infection, and ALT increased. The most common adverse reactions (≥ 20%) that occurred in patients receiving BAVENCIO were fatigue, musculoskeletal pain, infusion-related reaction, rash, nausea, constipation, cough, and diarrhea. Table 3 and Table 4 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in patients receiving BAVENCIO. Page 13 of 39 Reference ID: 5486483 I Table 3: Adverse Reactions in ≥ 10% of Patients with Metastatic MCC Receiving BAVENCIO in the JAVELIN Merkel 200 Trial Adverse Reactions BAVENCIO (N=204) All Grades % Grade 3-4 % General Disorders Fatiguea 47 2.9 Infusion-related reactionb 26 0.5 Edemac 17 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal paind 29 1.5 Arthralgia 13 0.5 Skin and Subcutaneous Tissue Disorders Rashe 25 0 Pruritusf 16 0.5 Gastrointestinal Disorders Nausea 23 0 Constipation 22 0.5 Diarrheag 21 1 Abdominal painh 16 3.4 Vomiting 12 1 Respiratory, Thoracic and Mediastinal Disorders Cough 22 0 Dyspneai 15 1 Metabolism and Nutrition Disorders Decreased appetite 18 3.4 Decreased weight 16 0.5 Vascular Disorders Hypertension 11 6 a Includes fatigue and asthenia. b Includes infusion-related reaction, chills, pyrexia, back pain, hypotension, drug hypersensitivity, dyspnea, flushing and hypersensitivity. c Includes peripheral edema, peripheral swelling, and genital edema. d Includes musculoskeletal pain, back pain, pain in extremity, myalgia, musculoskeletal pain, and neck pain. e Includes rash, erythema, rash maculo-papular, rash pruritic, dermatitis bullous, rash erythematous, and rash macular. f Includes pruritus and pruritus generalized. g Includes diarrhea and colitis. hIncludes abdominal pain, abdominal pain upper, and abdominal pain lower. i Includes dyspnea and dyspnea exertional. Other clinically significant adverse reactions in < 10% of patients receiving BAVENCIO in the JAVELIN Merkel 200 trial were dizziness, headache, transaminase increased, creatine phosphokinase increased, and tubulointerstitial nephritis. Page 14 of 39 Reference ID: 5486483 Table 4: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with Metastatic MCC Receiving BAVENCIO in the JAVELIN Merkel 200 Trial Laboratory Tests Any Grade %a Grade 3-4 %a Hematology Lymphocyte count decreased 51 16 Hemoglobin decreased 40 6 Platelet count decreased 23 1.5 Chemistry Aspartate aminotransferase (AST) increased 31 3 Alanine aminotransferase (ALT) increased 22 3.5 Lipase increased 21 5 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (range: 185 to 199 patients). Locally Advanced or Metastatic Urothelial Carcinoma First-Line Maintenance Treatment of Urothelial Carcinoma The safety of BAVENCIO was evaluated in the JAVELIN Bladder 100 trial where patients received BAVENCIO 10 mg/kg every 2 weeks plus best supportive care (BSC) (N=344) or BSC alone (N=345). Patients with autoimmune diseases or conditions requiring systemic immunosuppression were excluded. In the BAVENCIO plus BSC arm, 47% were exposed to BAVENCIO for > 6 months and 28% were exposed for > 1 year [see Clinical Studies (14.2)]. The median age of patients treated with BAVENCIO plus BSC was 69 years (range: 37 to 90), 63% of patients were 65 years or older, 76% were male, 67% were White, and the ECOG performance score was 0 (61%) or 1 (39%). A fatal adverse reaction (sepsis) occurred in one (0.3%) patient receiving BAVENCIO plus BSC. Serious adverse reactions occurred in 28% of patients receiving BAVENCIO plus BSC. Serious adverse reactions in ≥ 1% of patients included urinary tract infection (including kidney infection, pyelonephritis, and urosepsis) (6.1%), pain (including abdominal, back, bone, flank, extremity, and pelvic pain) (3.2%), acute kidney injury (1.7%), hematuria (1.5%), sepsis (1.2%), and infusion-related reaction (1.2%). Permanent discontinuation due to an adverse reaction of BAVENCIO plus BSC occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of BAVENCIO in > 1% of patients were myocardial infarction (including acute myocardial infarction and troponin T increased) (1.5%) and infusion-related reaction (1.2%). Dose interruptions due to an adverse reaction, excluding temporary interruptions of BAVENCIO infusions due to infusion-related reactions, occurred in 41% of patients receiving BAVENCIO Page 15 of 39 Reference ID: 5486483 plus BSC. Adverse reactions leading to interruption of BAVENCIO in > 2% of patients were urinary tract infection (including pyelonephritis) (4.7%) and blood creatinine increased (including acute kidney injury, renal impairment, and renal failure) (3.8%). The most common adverse reactions (≥ 20%) in patients receiving BAVENCIO plus BSC were fatigue, musculoskeletal pain, urinary tract infection, and rash. Thirty-one (9%) patients treated with BAVENCIO plus BSC received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5)]. Table 5 summarizes adverse reactions that occurred in ≥ 10% of patients treated with BAVENCIO plus BSC. Page 16 of 39 Reference ID: 5486483 Table 5: Adverse Reactions (≥ 10%) of Patients Receiving BAVENCIO plus BSC (JAVELIN Bladder 100 Trial) Adverse Reactions BAVENCIO plus BSC (N=344) BSC (N=345) All Grades % Grade 3-4 % All Grades % Grade 3-4 % General Disorders and Administration Site Conditions Fatiguea 35 1.7 13 1.7 Pyrexia 15 0.3 3.5 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal painb 24 1.2 15 2.6 Arthralgia 16 0.6 6 0 Skin and Subcutaneous Tissue Disorders Rashc 20 1.2 2.3 0 Pruritus 17 0.3 1.7 0 Infections and Infestations Urinary tract infectiond 20 6 11 3.8 Gastrointestinal Disorders Diarrhea 17 0.6 4.9 0.3 Constipation 16 0.6 9.0 0 Nausea 16 0.3 6 0.6 Vomiting 13 1.2 3.5 0.6 Respiratory, Thoracic and Mediastinal Disorders Coughe 14 0.3 4.6 0 Metabolism and Nutrition Disorders Decreased appetite 14 0.3 7 0.6 Endocrine disorders Hypothyroidism 12 0.3 0.6 0 Injury, Poisoning and Procedural Complications Infusion-related reaction 10 0.9 0 0 a Fatigue is a composite term that includes fatigue, asthenia and malaise. b Musculoskeletal pain is a composite term that includes musculoskeletal pain, back pain, myalgia, and neck pain. c Rash is a composite term that includes rash, rash maculo-papular, erythema, dermatitis acneiform, eczema, erythema multiforme, rash erythematous, rash macular, rash papular, rash pruritic, drug eruption and lichen planus. d Urinary tract infection is a composite term that includes urinary tract infection, urosepsis, cystitis, kidney infection, pyuria, pyelonephritis, bacteriuria, pyelonephritis acute, urinary tract infection bacterial, and Escherichia urinary tract infection. e Cough is a composite term that includes cough and productive cough. Patients received pre-medication with an anti-histamine and acetaminophen prior to each infusion. Infusion-related reactions occurred in 10% (Grade 3: 0.9%) of patients treated with BAVENCIO plus BSC. Page 17 of 39 Reference ID: 5486483 Table 6: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 10% of Patients Receiving BAVENCIO plus BSC (JAVELIN Bladder 100 Trial) Laboratory Abnormality BAVENCIO plus BSC * BSC * Any Grade % Grade 3-4 % Any Grade % Grade 3-4 % Chemistry Blood triglycerides increased 34 2.1 28 1.2 Alkaline phosphatase increased 30 2.9 20 2.3 Blood sodium decreased 28 6 20 2.6 Lipase increased 25 8 16 6 Aspartate aminotransferase (AST) increased 24 1.7 12 0.9 Blood potassium increased 24 3.8 16 0.9 Alanine aminotransferase (ALT) increased 24 2.6 12 0.6 Blood cholesterol increased 22 1.2 16 0.3 Serum amylase increased 21 5 12 1.8 CPK increased 19 2.4 12 0 Phosphate decreased 19 3.2 15 1.2 Hematology Hemoglobin decreased 28 4.4 18 3.2 White blood cell decreased 20 0.6 10 0 Platelet count decreased 18 0.6 12 0.3 *Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: BAVENCIO plus BSC group (range: 339 to 344 patients) and BSC group (range: 329 to 341 patients). Previously-treated Urothelial Carcinoma The safety of BAVENCIO was evaluated in 242 patients with locally advanced or metastatic UC receiving BAVENCIO at 10 mg/kg every 2 weeks in the UC cohorts of the JAVELIN Solid Tumor trial. Patients received pre-medication with an anti-histamine and acetaminophen prior to each infusion. The median duration of exposure to BAVENCIO was 12 weeks (range: 2 weeks to 92 weeks) [see Clinical Studies (14.2)]. Fourteen patients (6%) who were treated with BAVENCIO experienced either pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal adverse events, which led to death. Grade 1-4 serious adverse reactions were reported in 41% of patients. The most frequent serious adverse reactions reported in ≥ 2% of patients were urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestine obstruction, and pyrexia. Page 18 of 39 Reference ID: 5486483 Permanent discontinuation due to an adverse reaction for BAVENCIO occurred in 12% of patients. The adverse reaction that resulted in permanent discontinuation in > 1% of patients was fatigue. Dose interruptions due to an adverse reaction, excluding temporary interruptions due to infusion-related reactions, occurred in 29% of patients receiving BAVENCIO. Adverse reactions leading to interruption of BAVENCIO in > 1% of patients were diarrhea, fatigue, dyspnea, urinary tract infection, and rash. The most common Grade 3 and 4 adverse reactions (≥ 3%) were anemia, fatigue, hyponatremia, hypertension, urinary tract infection, and musculoskeletal pain. The most common adverse reactions (≥ 20%) were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection. Eleven (4.5%) patients received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5)]. Advanced Renal Cell Carcinoma The safety of BAVENCIO was evaluated in JAVELIN Renal 101. Patients with autoimmune disease other than type I diabetes mellitus, vitiligo, psoriasis, or thyroid disorders not requiring immunosuppressive treatment were excluded. Patients received BAVENCIO 10 mg/kg every 2 weeks administered in combination with axitinib 5 mg twice daily (N=434) or sunitinib 50 mg once daily for 4 weeks followed by 2 weeks off (N=439). In the BAVENCIO plus axitinib arm, 70% were exposed to BAVENCIO for ≥ 6 months and 29% were exposed for ≥ 1 year in JAVELIN Renal 101 [see Clinical Studies (14.3)]. The median age of patients treated with BAVENCIO in combination with axitinib was 62 years (range: 29 to 83), 38% of patients were 65 years or older, 71% were male, 75% were White, and the ECOG performance score was 0 (64%) or 1 (36%). Fatal adverse reactions occurred in 1.8% of patients receiving BAVENCIO in combination with axitinib. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%). Serious adverse reactions occurred in 35% of patients receiving BAVENCIO in combination with axitinib. Serious adverse reactions in ≥ 1% of patients included diarrhea (2.5%), dyspnea (1.8%), hepatotoxicity (1.8%), venous thromboembolic disease (1.6%), acute kidney injury (1.4%), and pneumonia (1.2%). Permanent discontinuation due to an adverse reaction of either BAVENCIO or axitinib occurred in 22% of patients: 19% BAVENCIO only, 13% axitinib only, and 8% both drugs. The most common adverse reactions (> 1%) resulting in permanent discontinuation of BAVENCIO or the combination were hepatotoxicity (6%) and infusion-related reaction (1.8%). Page 19 of 39 Reference ID: 5486483 Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of BAVENCIO infusions due to infusion-related reactions, occurred in 76% of patients receiving BAVENCIO in combination with axitinib. This includes interruption of BAVENCIO in 50% of patients. Axitinib was interrupted in 66% and dose reduced in 19% of patients. The most common adverse reaction (> 10%) resulting in interruption of BAVENCIO was diarrhea (10%) and the most common adverse reactions resulting in either interruption or dose reduction of axitinib were diarrhea (19%), hypertension (18%), palmar-plantar erythrodysesthesia (18%), and hepatotoxicity (10%). The most common adverse reactions (≥ 20%) in patients receiving BAVENCIO in combination with axitinib were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache. Forty-eight (11%) patients treated with BAVENCIO in combination with axitinib received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5)]. Table 7 summarizes adverse reactions that occurred in ≥ 20% of BAVENCIO in combination with axitinib-treated patients. Page 20 of 39 Reference ID: 5486483 Table 7: Adverse Reactions (≥ 20%) of Patients Receiving BAVENCIO in Combination with Axitinib (JAVELIN Renal 101 Trial) Adverse Reactions BAVENCIO plus Axitinib (N=434) Sunitinib (N=439) All Grades % Grade 3-4 % All Grades % Grade 3-4 % Gastrointestinal Disorders Diarrheaa 62 8 48 2.7 Nausea 34 1.4 39 1.6 Mucositisb 34 2.8 35 2.1 Hepatotoxicityc 24 9 18 3.6 Abdominal paind 22 1.4 19 2.1 General Disorders and Administration Site Conditions Fatiguee 53 6 54 6 Vascular Disorders Hypertensionf 50 26 36 17 Musculoskeletal and Connective Tissue Disorders Musculoskeletal paing 40 3.2 33 2.7 Skin and Subcutaneous Tissue Disorders Palmar-plantar erythrodysesthesia 33 6 34 4 Rashh 25 0.9 16 0.5 Respiratory, Thoracic and Mediastinal Disorders Dysphonia 31 0.5 3.2 0 Dyspneai 23 3 16 1.8 Cough 23 0.2 19 0 Metabolism and Nutrition Disorders Decreased appetite 26 2.1 29 0.9 Endocrine Disorders Hypothyroidism 25 0.2 14 0.2 Nervous System Disorders Headache 21 0.2 16 0.2 a Diarrhea is a composite term that includes diarrhea, autoimmune colitis, and colitis. b Mucositis is a composite term that includes mucosal inflammation and stomatitis. c Hepatotoxicity is a composite term that includes ALT increased, AST increased, autoimmune hepatitis, bilirubin conjugated, bilirubin conjugated increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver disorder, liver injury, and transaminases increased. d Abdominal pain is a composite term that includes abdominal pain, flank pain, abdominal pain upper, and abdominal pain lower. e Fatigue is a composite term that includes fatigue and asthenia. f Hypertension is a composite term that includes hypertension and hypertensive crisis. g Musculoskeletal pain is a composite term that includes musculoskeletal pain, musculoskeletal chest pain, myalgia, back pain, bone pain, musculoskeletal discomfort, neck pain, spinal pain, and pain in extremity. h Rash is a composite term that includes rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash erythematous, rash papular, and rash pustular. Page 21 of 39 Reference ID: 5486483 i Dyspnea is a composite term that includes dyspnea, dyspnea exertional and dyspnea at rest. Other clinically important adverse reactions that occurred in less than 20% of patients in JAVELIN Renal 101 included arthralgia, weight decreased, and chills. Patients received pre-medication with an anti-histamine and acetaminophen prior to each infusion. Infusion-related reactions occurred in 12% (Grade 3: 1.6%; no Grade 4) of patients treated with BAVENCIO in combination with axitinib. Table 8 summarizes selected laboratory abnormalities that occurred in ≥ 20% of BAVENCIO in combination with axitinib-treated patients. Table 8: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving BAVENCIO in Combination with Axitinib (JAVELIN Renal 101 Trial) Laboratory Abnormality BAVENCIO plus Axitinib* Sunitinib* Any Grade % Grade 3-4 % Any Grade % Grade 3-4 % Chemistry Blood triglycerides increased 71 13 48 5 Blood creatinine increased 62 2.3 68 1.4 Blood cholesterol increased 57 1.9 22 0.7 Alanine aminotransferase increased (ALT) 50 9 46 3.2 Aspartate aminotransferase increased (AST) 47 7 57 3.2 Blood sodium decreased 38 9 37 10 Lipase increased 37 14 25 7 Blood potassium increased 35 3 28 3.9 Blood bilirubin increased 21 1.4 23 1.4 Hematology Platelet count decreased 27 0.7 80 15 Hemoglobin decreased 21 2.1 65 8 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: BAVENCIO in combination with axitinib group (range: 413 to 428 patients) and sunitinib group (range: 405 to 433 patients). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of BAVENCIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary disorders: sclerosing cholangitis Page 22 of 39 Reference ID: 5486483 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of BAVENCIO in pregnant women [see Clinical Pharmacology (12.1)]. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death [see Data]. Human IgG1 immunoglobulins (IgG1) are known to cross the placenta. Therefore, BAVENCIO has the potential to be transmitted from the mother to the developing fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Animal reproduction studies have not been conducted with BAVENCIO to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering BAVENCIO during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to BAVENCIO may increase the risk of developing immune-mediated disorders or altering the normal immune response. 8.2 Lactation Risk Summary There is no information regarding the presence of avelumab in human milk, the effects on the breastfed infant, or the effects on milk production. Since many drugs including antibodies are excreted in human milk, advise a lactating woman not to breastfeed during treatment and for at least one month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants. 8.3 Females and Males of Reproductive Potential Contraception Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. Page 23 of 39 Reference ID: 5486483 8.4 Pediatric Use The safety and effectiveness of BAVENCIO have been established in pediatric patients aged 12 years and older for metastatic MCC. Use of BAVENCIO in this age group is supported by evidence from adequate and well-controlled studies of BAVENCIO in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the steady state exposure of avelumab, that drug exposure is generally similar between adults and pediatric patients age 12 years and older for monoclonal antibodies, and that the course of MCC is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients. The recommended dose in pediatric patients 12 years of age or greater is the same as that in adults [see Dosage and Administration (2.2), Clinical Pharmacology (12.3), and Clinical Studies (14)]. Safety and effectiveness of BAVENCIO have not been established in pediatric patients less than 12 years of age. 8.5 Geriatric Use Metastatic Merkel Cell Carcinoma Of the 204 patients with MCC who received BAVENCIO in the JAVELIN Merkel 200 trial, 78% were 65 years or older and 43% were 75 years or older. No overall differences in safety or efficacy were observed between elderly patients and younger patients. Locally Advanced or Metastatic Urothelial Carcinoma Of the 344 patients randomized to BAVENCIO 10 mg/kg plus BSC in the JAVELIN Bladder 100 trial, 63% were 65 years or older and 24% were 75 years or older. No overall differences in safety or efficacy were reported between elderly patients and younger patients. Advanced Renal Cell Carcinoma Of the 434 patients randomized to BAVENCIO 10 mg/kg administered in combination with axitinib 5 mg twice daily in the JAVELIN Renal 101 trial, 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety or efficacy were reported between elderly patients and younger patients. 11 DESCRIPTION Avelumab is a programmed death ligand1 (PD-L1) blocking antibody. Avelumab is a human IgG1 lambda monoclonal antibody produced in Chinese hamster ovary cells and has a molecular weight of approximately 147 kDa. BAVENCIO (avelumab) Injection for intravenous use is a sterile, preservative-free, non­ pyrogenic, clear, colorless to slightly yellow solution. Each single-dose vial contains 200 mg avelumab in 10 mL (20 mg/mL). Each mL contains 20 mg avelumab, D-mannitol (51 mg), glacial acetic acid (0.6 mg), polysorbate 20 (0.5 mg), sodium hydroxide (0.3 mg), and Water for Injection. The pH range of the solution is 5.0 – 5.6. Page 24 of 39 Reference ID: 5486483 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1. This interaction releases the inhibitory effects of PD-L1 on the immune response resulting in the restoration of immune responses, including anti-tumor immune responses. Avelumab has also been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth. 12.2 Pharmacodynamics Avelumab exposure-response relationships and the time course of pharmacodynamic response are not fully characterized. 12.3 Pharmacokinetics The pharmacokinetics (PK) of avelumab as a single agent was characterized in patients who received BAVENCIO at doses ranging from 1 to 20 mg/kg every 2 weeks (0.1 to 2 times of the approved recommended dosage). The exposure of avelumab increased dose-proportionally from 10 to 20 mg/kg every 2 weeks. Steady-state concentrations of avelumab were reached after approximately 4 to 6 weeks (2 to 3 cycles) and the systemic accumulation was 1.25-fold. Distribution The mean volume of distribution at steady state after patients received a dose of 10 mg/kg was 4.7 L (coefficient of variation (% CV) of 44%). Elimination The primary elimination mechanism of avelumab is proteolytic degradation. The total systemic clearance (% CV) was 0.59 L/day (25%) and the terminal half-life (% CV) was 6.1 days (92%) in patients who received a dose of 10 mg/kg every 2 weeks. Avelumab clearance decreased over time in patients with MCC, with a mean maximal reduction (CV%) from baseline value of approximately 32% (36%), which is not considered clinically important. A change of avelumab clearance over time was not observed in patients with UC or with RCC. Specific Populations No clinically meaningful differences in pharmacokinetics were observed in the clearance of avelumab based on age; body weight; sex; race; PD-L1 status; tumor burden; mild to severe renal impairment (calculated creatinine clearance of 89 to 15 mL/min, as estimated by the Cockcroft-Gault formula), and mild or moderate hepatic impairment (bilirubin less than or equal to 3 times ULN). The effect of severe hepatic impairment (bilirubin greater than 3 times ULN) on the pharmacokinetics of avelumab is unknown. Page 25 of 39 Reference ID: 5486483 Drug Interactions BAVENCIO with axitinib: Avelumab PK was assessed following administration of BAVENCIO in combination with axitinib. There are no clinically meaningful differences in exposure of avelumab when administered in combination with axitinib. 12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of BAVENCIO or of other avelumab products. ADA responses following administration of BAVENCIO 10 mg/kg every 2 weeks were evaluated during the respective treatment periods in each trial. The ADA and neutralizing antibody (nAb) incidences are listed in Table 9. Table 9: BAVENCIO ADA Incidence Trial Name* Treatment Period (months) ADA nAb JAVELIN Merkel 200 Part A 48 8.9% (7/79) 71% (5/7) JAVELIN Merkel 200 Part B 35 8.2% (9/110) 89% (8/9) JAVELIN Bladder 100 37 19% (62/326) 97% (60/62) JAVELIN Solid Tumor, UC Cohort 59 18% (41/226) Not tested JAVELIN Renal 101 29 16% (65/411) 78% (51/65) * Details of each treatment regimen are described in Section 14 [see Clinical Studies (14)]. ADA: anti-avelumab antibodies; UC: urothelial carcinoma In patients with advanced UC or advanced RCC, avelumab clearance was approximately 15% higher in patients who tested positive for ADA as compared to clearance in patients who tested negative for ADA; which is not considered clinically meaningful. The effect of ADA on the efficacy or safety could not be determined due to the low occurrence of ADAs. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted to assess the potential of avelumab for genotoxicity or carcinogenicity. Fertility studies have not been conducted with avelumab; however, an assessment of male and female reproductive organs was included in 3-month repeat-dose toxicity study in Cynomolgus monkeys. Weekly administration of avelumab did not result in any notable effects in the male and female reproductive organs. 13.2 Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased Page 26 of 39 Reference ID: 5486483 bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus. 14 CLINICAL STUDIES 14.1 Metastatic Merkel Cell Carcinoma The efficacy and safety of BAVENCIO was demonstrated in the JAVELIN Merkel 200 trial (NCT02155647), an open-label, single--arm, multi-center study conducted in patients with histologically confirmed metastatic MCC. This trial consisted of two parts; Part A enrolled patients with metastatic MCC whose disease had progressed on or after chemotherapy administered for distant metastatic disease, and Part B enrolled patients with metastatic MCC who were treatment-naïve. The trial excluded patients with autoimmune disease; medical conditions requiring systemic immunosuppression; prior organ or allogeneic stem cell transplantation; prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies; CNS metastases; infection with HIV, hepatitis B, or hepatitis C; or ECOG performance score ≥ 2. Patients received BAVENCIO 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Patients with radiological disease progression not associated with significant clinical deterioration, defined as no new or worsening symptoms, no change in performance status for greater than 2 weeks, and no need for salvage therapy, could continue treatment. Tumor response assessments were performed every 6 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by a blinded independent central review committee (IRC) and IRC-assessed duration of response. Previously-treated Merkel Cell Carcinoma A total of 88 patients were enrolled in Part A. Baseline patient characteristics were a median age of 73 years (range: 33 to 88), 74% of patients were male, 92% were White, and the ECOG performance score was 0 (56%) or 1 (44%). Seventy-five percent of patients were 65 years or older, 35% were 75 or older, and 3% were 85 or older. Sixty-five percent of patients were reported to have had one prior anti-cancer therapy for metastatic MCC and 35% had two or more prior therapies. Fifty-three percent of patients had visceral metastases. Sixty-six percent were PD­ L1-positive (≥ 1% of tumor cells), 18% were PD-L1 negative, and 16% had non-evaluable results by an investigational immunohistochemistry assay. Archival tumor samples were evaluated for Merkel cell polyomavirus (MCV) using an investigational assay; of the 77 patients with evaluable results, 52% had evidence of MCV. Efficacy results are summarized in Table 10. Responses were observed in patients regardless of tumor PD-L1 expression or presence of MCV. Page 27 of 39 Reference ID: 5486483 Table 10: Efficacy Results from the JAVELIN Merkel 200 Trial in Previously-Treated Patients with Metastatic MCC (Part A) Efficacy Endpoints BAVENCIO (N=88) Overall Response Rate (ORR) Overall response rate, n (%) (95% CI) Complete responses, n (%) Partial responses, n (%) 29 (33%) (23, 44) 10 (11%) 19 (22%) Duration of Response (DOR) Median DOR in months (range) Patients with DOR ≥ 6 months, n (%) Patients with DOR ≥ 12 months, n (%) N=29 40.5 (2.8, 41.5+) 26 (90%) 19 (66%) CI: Confidence interval. Treatment-naïve Merkel Cell Carcinoma A total of 116 patients were enrolled in Part B. Baseline patient characteristics were median age of 74 years (range: 41 to 93); 70% of patients were male; 65% were White, 31% were unknown or not collected, 2.6% were Asian, and 1.7% were Black; ECOG performance score was 0 (62%) or 1 (38%). Eighteen percent of patients were PD-L1-positive (≥ 1% of tumor cells), 75% were PD-L1-negative, and 7% had non-evaluable results by an investigational immunohistochemistry assay. Sixty percent of patients had Merkel cell polyomavirus (MCV). Efficacy results are presented in Table 11. Responses were observed in patients regardless of tumor PD-L1 expression or presence of MCV. Table 11: Efficacy Results of the JAVELIN Merkel 200 Trial in Patients with Treatment- Naïve Metastatic MCC (Part B) Efficacy Endpoints BAVENCIO (N=116) Overall Response Rate (ORR) Overall response rate, n (%) (95% CI) Complete responses, n (%) Partial responses, n (%) 46 (40%) (31, 49) 19 (16%) 27 (23%) Duration of Response (DOR) Median DOR in months, (range) Patients with DOR ≥ 6 months, n (%) Patients with DOR ≥ 12 months, n (%) N=46 18.2 (1.2+, 28.3+) 35 (76%) 24 (52%) CI: Confidence interval. Page 28 of 39 Reference ID: 5486483 14.2 Locally Advanced or Metastatic Urothelial Carcinoma First-Line Maintenance Treatment of Urothelial Carcinoma The efficacy and safety of BAVENCIO was demonstrated in the JAVELIN Bladder 100 trial (NCT02603432), a randomized, multi-center, open-label study conducted in 700 patients with unresectable, locally advanced or metastatic urothelial carcinoma that did not progress with first- line platinum-containing chemotherapy. Patients with autoimmune disease or a medical condition that required immunosuppression were excluded. Randomization was stratified by best response to chemotherapy (CR/PR vs. stable disease [SD]) and site of metastasis (visceral vs. non-visceral) at the time of initiating first-line chemotherapy. Patients were randomized (1:1) to receive either BAVENCIO 10 mg/kg intravenous infusion every 2 weeks plus best supportive care (BSC) or BSC alone. Treatment was initiated within 4-10 weeks after the last dose of chemotherapy. Treatment with BAVENCIO continued until RECIST v1.1-defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration of BAVENCIO was permitted beyond RECIST-defined disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, 8 weeks after randomization, then every 8 weeks up to 12 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression based on BICR assessment per RECIST v1.1. Baseline characteristics were well-balanced between arms. Overall, the median age was 69 years (range: 32 to 90), with 66% of patients ≥ 65 years of age and 24% of patients ≥ 75 years of age. Most patients were male (77%). The majority of patients were White (67%) and 22% were Asian. Baseline ECOG PS was 0 (61%) or 1 (39%). Fifty-six percent (56%) of patients received prior gemcitabine plus cisplatin, 38% of patients received prior gemcitabine plus carboplatin, and 6% of patients received prior gemcitabine plus cisplatin and gemcitabine plus carboplatin. Best response to first-line chemotherapy was CR or PR (72%) or SD (28%). Sites of metastasis prior to chemotherapy were visceral (55%) or non- visceral (45%). Fifty-one (51%) of patients had PD-L1-positive-tumors, 39% of patients had PD-L1-negative tumors, and 10% of patients had unknown PD-L1 tumor status. Six percent (6%) of patients received another PD-1/PD-L1 checkpoint inhibitor after discontinuation of treatment in the BAVENCIO plus BSC arm and 44% of patients in the BSC arm. The major efficacy outcome measure was overall survival (OS) in all randomized patients and patients with PD-L1-positive tumors. The results from a pre-specified interim analysis demonstrated a statistically significant improvement in OS for patients randomized to BAVENCIO plus BSC as compared with BSC alone. An updated OS analysis was conducted when 452 deaths were observed. Consistent results were observed across the pre-specified subgroups of CR/PR versus SD to first-line chemotherapy. Page 29 of 39 Reference ID: 5486483 1.0 0.9 0.8 0.7 "' ~ 0.6 0 g 0.5 :.g ~ 0.4 0.. 0.3 0.2 0.1 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 Overall Smvival Time (Months) No. at risk Avelumab+BSC: 350 318 274 237 216 183 164 140 99 74 53 31 13 4 0 BSC: 350 304 243 190 158 131 121 103 82 62 46 27 10 7 0 c - Avelumab+BSC - BSC Table 12: Efficacy Results from the JAVELIN Bladder 100 Trial Efficacy Endpoints BAVENCIO BSC plus BSC (N=350) (N=350) Primary OS Events (%) 145 (41.4) 179 (51.1) Median in months 21.4 14.3 (95% CI) (18.9, 26.1) (12.9, 17.9) Hazard ratio (95% CI) 0.69 (0.56, 0.86) p-value* 0.001 Updated OS Events (%) 215 (61.4) 237 (67.7) Median in months 23.8 15.0 (95% CI) (19.9, 28.8) (13.5, 18.2) Hazard ratio (95% CI) 0.76 (0.63, 0.92) BSC: Best supportive care; CI: Confidence interval; OS: overall survival. * p-value based on 2-sided stratified log-rank. Figure 1: K-M Estimates for Updated OS from the JAVELIN Bladder 100 Trial In the pre-specified endpoint of OS among patients with PD-L1-positive tumors (n=358, 51%), the hazard ratio was 0.69 (95% CI: 0.52, 0.90) in the updated OS analysis for patients Page 30 of 39 Reference ID: 5486483 randomized to BAVENCIO plus BSC versus BSC alone. In an exploratory analysis of patients with PD-L1-negative tumors (n=270, 39%), the updated OS hazard ratio was 0.82 (95% CI: 0.62, 1.09). Previously-treated Urothelial Carcinoma The efficacy and safety of BAVENCIO was demonstrated in the UC cohorts of the JAVELIN Solid Tumor trial, an open-label, single-arm, multi-center study that included 242 patients with locally advanced or metastatic urothelial carcinoma (UC) with disease progression on or after platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients with active or history of central nervous system metastasis; other malignancies within the last 5 years; organ transplant; conditions requiring therapeutic immune suppression; or active infection with HIV, hepatitis B, or hepatitis C were excluded. Patients with autoimmune disease, other than type I diabetes, vitiligo, psoriasis, or thyroid disease that did not require immunosuppressive treatment, were excluded. Patients were included regardless of their PD-L1 status. Patients received BAVENCIO at a dose of 10 mg/kg intravenously every 2 weeks until radiographic or clinical progression or unacceptable toxicity. Tumor response assessments were performed every 6 weeks. Efficacy outcome measures included confirmed overall response rate (ORR), as assessed by an Independent Endpoint Review Committee (IERC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and duration of response (DOR). Efficacy was evaluated in patients who were followed for a minimum of both 13 weeks and 6 months at the time of data cut-off. Baseline demographic and disease characteristics for the 226 patients with a minimum of 13 weeks of follow-up were median age 68 years (range: 30 to 89), 72% male, 80% White, and 34% and 66% of patients had an ECOG performance status 0 and 1, respectively. Forty-four percent of patients had non-bladder urothelial carcinoma including 23% of patients with upper tract disease, and 83% of patients had visceral metastases (baseline target and/or non-target lesions present outside of the lymph nodes). Nine (4%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Forty-seven percent of patients only received prior cisplatin-based regimens, 32% received only prior carboplatin-based regimens, and 20% received both cisplatin and carboplatin-based regimens. At baseline, 17% of patients had a hemoglobin < 10 g/dL and 34% of patients had liver metastases. Efficacy results are presented in Table 13. The median time to response was 2.0 months (range: 1.3 to 11.0) among patients followed for either > 13 weeks or > 6 months. Using a clinical trial assay to assess PD-L1 staining, with 16% of patients not evaluable, there were no clear differences in response rates based on PD-L1 tumor expression. Among the total 30 responding patients followed for > 13 weeks, 22 patients (73%) had an ongoing response of 6 months or longer and 4 patients (13%) had ongoing responses of 12 months or longer. Among the total 26 responding patients followed for > 6 months, 22 patients (85%) had ongoing responses of 6 months or longer and 4 patients (15%) had ongoing responses of 12 months or longer. Page 31 of 39 Reference ID: 5486483 Table 13: Efficacy Results of the UC Cohorts in the JAVELIN Solid Tumor Trial Efficacy Endpoints ≥ 13 Weeks Follow-Up (N=226) ≥ 6 Months Follow-Up (N=161) Confirmed Overall Response Rate (ORR) Overall Response Rate n (%) (95% CI) Complete Response (CR) n (%) Partial Response (PR) n (%) 30 (13.3%) (9.1, 18.4) 9 (4.0%) 21 (9.3%) 26 (16.1%) (10.8, 22.8) 9 (5.6%) 17 (10.6%) Duration of Response (DOR) Median, months (range) NE (1.4+ to 17.4+) NE (1.4+ to 17.4+) CI: Confidence interval; NE: Not estimable; + denotes a censored value. 14.3 Advanced Renal Cell Carcinoma The efficacy and safety of BAVENCIO in combination with axitinib was demonstrated in the JAVELIN Renal 101 trial (NCT02684006), a randomized, multicenter, open-label, study of BAVENCIO in combination with axitinib in 886 patients with untreated advanced RCC regardless of tumor PD-L1 expression [intent-to-treat (ITT) population]. Patients with autoimmune disease or conditions requiring systemic immunosuppression were excluded. Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (0 vs. 1) and region (United States vs. Canada/Western Europe vs. the rest of the world). Patients were randomized (1:1) to one of the following treatment arms: • BAVENCIO 10 mg/kg intravenous infusion every 2 weeks in combination with axitinib 5 mg twice daily orally (N=442). Patients who tolerated axitinib 5 mg twice daily without Grade 2 or greater axitinib-related adverse events for 2 consecutive weeks could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity. • Sunitinib 50 mg once daily orally for 4 weeks followed by 2 weeks off (N=444) until radiographic or clinical progression or unacceptable toxicity. Treatment with BAVENCIO and axitinib continued until RECIST v1.1-defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration BAVENCIO and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at 6 weeks, then every 6 weeks thereafter up to 18 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression by BICR. Baseline characteristics were a median age of 61 years (range: 27 to 88); 38% of patients were 65 years or older; 75% were male; 75% were White, 15% Asian, 2% Black, 1% American Indian or Alaskan Native, 7% unknown; 4% were Hispanic or Latino; ECOG PS was 0 (63%) or 1 (37%); and 63% of patients were PD-L1 positive, 28% were PD-L1 negative, and 8% had Page 32 of 39 Reference ID: 5486483 unknown PD-L1 status. Patient distribution by International Metastatic Renal Cell Carcinoma Database (IMDC) risk groups was 21% favorable, 62% intermediate, and 16% poor. The major efficacy outcome measures were progression-free survival (PFS), as assessed by an BICR using RECIST v1.1 and overall survival (OS) in patients with PD-L1-positive tumors using a clinical trial assay (PD-L1 expression level ≥ 1%). PFS was statistically significant in patients with PD-L1-positive tumors [HR 0.61 (95% CI: 0.48, 0.79)] and in the ITT population. The final analysis for OS was not statistically significant for either the PD-L1-positive or ITT population. Efficacy results for the ITT population are presented in Table 14 and Figure 2. Table 14: Efficacy Results from JAVELIN Renal 101 Trial - ITT Efficacy Endpoints BAVENCIO plus Sunitinib Axitinib (N=444) (N=442) Progression-Free Survival (PFS)a Events (%) 180 (41) 216 (49) Median in months (95% CI) 13.8 (11.1, NE) 8.4 (6.9, 11.1) Hazard ratio (95% CI) 0.69 (0.56, 0.84) p-valueb 0.0002 Overall Survival (OS) Events (%) 283 (64) 295 (66) Median in months (95% CI) 44.8 (39.7, 51.1) 38.9 (31.4, 45.2) Hazard ratio (95% CI) 0.88 (0.75, 1.04) p-valueb NS Confirmed Objective Response Rate (ORR)a Objective Response Rate n (%) 227 (51.4) 114 (25.7) (95% CI) (46.6, 56.1) (21.7, 30.0) Complete Response (CR) n (%) 15 (3.4) 8 (1.8) Partial Response (PR) n (%) 212 (48) 106 (24) BICR: Blinded Independent Central Review; CI: Confidence interval; NE: Not estimable; NS: not statistically significant. a Based on BICR assessment. b p-value based on 2-sided stratified log-rank. Page 33 of 39 Reference ID: 5486483 1.0 0.9 0.8 0.7 Vi "' 0.6 p.. ._ 0 -~ 0.5 "' .D "' .D 0.4 .t 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 Progression-Free Smvival Time (Months) No. at risk Avelmnab + Axitinib: 442 364 321 250 193 127 94 57 42 24 8 0 Sunitinib: 444 329 271 192 144 90 64 29 20 8 2 0 A velumab + Axitinib: ---+-- Sunitinib: Figure 2: K-M Estimates for PFS based on BICR Assessment – ITT 16 HOW SUPPLIED/STORAGE AND HANDLING BAVENCIO (avelumab) Injection is a sterile, preservative-free, and clear, colorless to slightly yellow solution for intravenous infusion supplied as a single-dose vial of 200 mg/10 mL (20 mg/mL), individually packed into a carton (NDC 44087-3535-1). Store refrigerated at 36°F to 46°F (2°C to 8°C) in original package to protect from light. Do not freeze or shake the vial. The vial stopper is not made with natural rubber latex. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Immune-Mediated Adverse Reactions Inform patients of the risk of immune-mediated adverse reactions requiring corticosteroids or hormone replacement therapy, including, but not limited to: • Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)]. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.1)]. Page 34 of 39 Reference ID: 5486483 • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.1)]. • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus [see Warnings and Precautions (5.1)]. • Nephritis with Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions (5.1)]. • Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of skin rash, itchy skin, rash with tiny spots and bumps, reddening of skin, blisters or peeling [see Warnings and Precautions (5.1)]. Infusion-Related Reactions Advise patients to contact their healthcare provider immediately for signs or symptoms of potential infusion-related reactions [see Warnings and Precautions (5.2)]. Complications of Allogeneic HSCT Advise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications [see Warnings and Precautions (5.3)]. Major Adverse Cardiovascular Events Advise patients receiving BAVENCIO in combination with axitinib to contact their healthcare provider immediately for signs or symptoms of cardiovascular events including but not limited to new or worsening chest discomfort, dyspnea, or peripheral edema [see Warnings and Precautions (5.4)]. Embryo-Fetal Toxicity Advise females of reproductive potential that BAVENCIO can cause fetal harm. Instruct females of reproductive potential to use effective contraception during and for at least one month after the last dose of BAVENCIO [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1, 8.3)]. Lactation Advise nursing mothers not to breastfeed while taking BAVENCIO and for at least one month after the final dose [see Use in Specific Populations (8.2)]. Manufactured by: Marketed by: EMD Serono, Inc. EMD Serono, Inc., MA, USA Boston, MA 02210 U.S.A. US License No: 1773 BAVENCIO is a trademark of Merck KGaA, Darmstadt, Germany Product of Switzerland Page 35 of 39 Reference ID: 5486483 MEDICATION GUIDE BAVENCIO® (buh-VEN-see-oh) (avelumab) injection What is the most important information I should know about BAVENCIO? BAVENCIO is a medicine that may treat certain cancers by working with your immune system. BAVENCIO can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life- threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended. Call or see your healthcare provider right away if you get any new or worsening signs or symptoms, including: Lung problems. • cough • shortness of breath • chest pain Intestinal problems. • diarrhea (loose stools) or more frequent bowel movements than usual • stools that are black, tarry, sticky, or have blood or mucus • severe stomach-area (abdomen) pain or tenderness Liver problems. • yellowing of your skin or the whites of your eyes • dark urine (tea colored) • severe nausea or vomiting • bleeding or bruising more easily than normal • pain on the right side of your stomach-area (abdomen) Hormone gland problems. • headache that will not go away or unusual • urinating more often than usual headaches • hair loss • eye sensitivity to light • feeling cold • eye problems • constipation • rapid heartbeat • your voice gets deeper • increased sweating • dizziness or fainting • extreme tiredness • changes in mood or behavior, such as • weight gain or weight loss decreased sex drive, irritability, or forgetfulness • feeling more hungry or thirsty than usual Kidney problems. • decrease in your amount of urine • swelling of your ankles • blood in your urine • loss of appetite Skin problems. • rash • painful sores or ulcers in mouth or nose, throat, or genital area • itching • fever or flu-like symptoms • skin blistering or peeling • swollen lymph nodes Problems can also happen in other organs and tissues. These are not all of the signs or symptoms of immune system problems that can happen with BAVENCIO. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include: • chest pain, irregular heartbeat, shortness of breath or swelling of ankles • confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs Page 36 of 39 Reference ID: 5486483 • double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight • persistent or severe muscle pain or weakness, muscle cramps • low red blood cells, bruising Infusion-related reactions can sometimes be severe or life-threatening. Signs and symptoms of infusion-related reactions may include: • chills or shaking • dizziness • hives • feel like passing out • flushing • fever • shortness of breath or wheezing • back pain • stomach area (abdomen) pain Complications, including graft-versus-host-disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with BAVENCIO. Your healthcare provider will monitor you for these complications. Heart problems. When BAVENCIO is used with the medicine axitinib, severe heart problems can happen and can lead to death. Signs and symptoms of heart problems may include: • swelling of your stomach area (abdomen), • weight gain legs, hands, feet, or ankles • pain or discomfort in your arms, back, • shortness of breath neck, or jaw • nausea or vomiting • breaking out in a cold sweat • new or worsening chest discomfort, including • feeling lightheaded or dizzy pain or pressure Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with BAVENCIO. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with BAVENCIO if you have severe side effects. What is BAVENCIO? BAVENCIO is a prescription medicine used to treat: • a type of skin cancer called Merkel cell carcinoma (MCC) in adults and children 12 years of age and older. BAVENCIO may be used when your skin cancer has spread. • a type of cancer in the bladder or urinary tract called urothelial carcinoma (UC) when it has spread or cannot be removed by surgery (advanced UC). BAVENCIO may be used: o as maintenance treatment when your cancer has responded or stabilized after you have received platinum-containing chemotherapy as your first treatment. o when you have received platinum-containing chemotherapy, and it did not work or is no longer working. • a type of kidney cancer called renal cell carcinoma (RCC). BAVENCIO may be used with the medicine axitinib as your first treatment when your kidney cancer has spread or cannot be removed by surgery (advanced RCC). It is not known if BAVENCIO is safe and effective in children under the age of 12. Before you receive BAVENCIO, tell your healthcare provider about all of your medical conditions, including if you: • have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus • have received an organ transplant • have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic) • have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome • have heart problems or high blood pressure • have diabetes Page 37 of 39 Reference ID: 5486483 • have a high cholesterol level in your blood • are pregnant or plan to become pregnant. BAVENCIO can harm your unborn baby. Females who are able to become pregnant: o You should use an effective method of birth control during your treatment and for at least 1 month after the last dose of BAVENCIO. Talk to your healthcare provider about birth control methods that you can use during this time. • are breastfeeding or plan to breastfeed. It is not known if BAVENCIO passes into your breast milk. Do not breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO. Tell your healthcare provider about all the medicines you take, including prescription and over­ the-counter medicines, vitamins, and herbal supplements. How will I receive BAVENCIO? • Your healthcare provider will give you BAVENCIO into your vein through an intravenous (IV) line over 60 minutes. • BAVENCIO is usually given every 2 weeks. • Your healthcare provider will give you medicines before the first 4 infusions and then as needed to help reduce infusion reactions. • Your healthcare provider will decide how many treatments you need. • Your healthcare provider will do blood tests to check you for certain side effects. • If you miss an appointment, call your healthcare provider as soon as possible to reschedule your appointment. What are the possible side effects of BAVENCIO? BAVENCIO can cause serious side effects, including: • See “What is the most important information I should know about BAVENCIO?” The most common side effects of BAVENCIO in people with MCC include: • feeling tired • nausea • muscle and bone pain • constipation • infusion-related reactions including chills, fever, and • cough back pain • diarrhea • rash The most common side effects of BAVENCIO as maintenance treatment in people with UC whose cancer responded or stabilized after platinum-containing chemotherapy as first treatment include: • feeling tired • urinary tract infection • muscle and bone pain • rash The most common side effects of BAVENCIO in people with UC after platinum-containing chemotherapy that did not work, or is no longer working, include: • feeling tired • muscle and bone pain • infusion-related reactions including chills, • nausea fever, back pain, redness, and shortness of • decreased appetite breath • urinary tract infection The most common side effects of BAVENCIO when given with axitinib in people with RCC include: • diarrhea • hoarseness • feeling tired • decreased appetite • high blood pressure • low levels of thyroid hormone • muscle and bone pain • rash • nausea • liver problems • mouth sores • cough • shortness of breath Page 38 of 39 Reference ID: 5486483 • blisters or rash on the palms of • stomach area (abdomen) pain your hands and soles of your feet • headache These are not all the possible side effects of BAVENCIO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800­ FDA-1088. General information about the safe and effective use of BAVENCIO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about BAVENCIO that is written for health professionals. What are the ingredients in BAVENCIO? Active ingredient: avelumab Inactive ingredients: D-mannitol, glacial acetic acid, polysorbate 20, sodium hydroxide, and Water for Injection Manufactured by: EMD Serono, Inc., Boston, MA 02210, USA, U.S. License No. 1773. Marketed by: EMD Serono, Inc., MA, USA. BAVENCIO is a trademark of Merck KGaA, Darmstadt, Germany. For more information, call toll-free 1-844-826-8371 or go to www.bavencio.com. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Page 39 of 39 Reference ID: 5486483
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_________________ ______________ ______________ ______________ _______________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AUSTEDO XR or AUSTEDO safely and effectively. See full prescribing information for AUSTEDO XR and AUSTEDO. AUSTEDO® XR (deutetrabenazine) extended-release tablets, for oral use AUSTEDO® (deutetrabenazine) tablets, for oral use Initial U.S. Approval: 2017 WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE See full prescribing information for complete boxed warning. • Increases the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease (5.1) • Balance risks of depression and suicidality with the clinical need for treatment of chorea when considering the use of AUSTEDO XR or AUSTEDO (5.1) • Monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior (5.1) • Inform patients, caregivers, and families of the risk of depression and suicidality and instruct to report behaviors of concern promptly to the treating physician (5.1) • Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation (5.1) • AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression (4, 5.1) __________________ INDICATIONS AND USAGE AUSTEDO XR and AUSTEDO are vesicular monoamine transporter 2 (VMAT2) inhibitors indicated in adults for the treatment of: • Chorea associated with Huntington’s disease (1) • Tardive dyskinesia (1) _______________ DOSAGE AND ADMINISTRATION AUSTEDO XR AUSTEDO Recommended Starting Dosage 12 mg once daily (12 mg per day) 6 mg twice daily (12 mg per day) • Titrate at weekly intervals by 6 mg per day based on reduction of chorea or tardive dyskinesia, and tolerability, up to a maximum recommended daily dosage of 48 mg (2.1) • Administer AUSTEDO XR with or without food in once-daily doses (2.1) • Administer AUSTEDO with food and administer total daily dosages of 12 mg or above in two divided doses (2.1) • Swallow tablets whole; do not chew, crush, or break (2.1) • If switching patients from tetrabenazine, discontinue tetrabenazine and initiate AUSTEDO XR or AUSTEDO the following day. See full prescribing information for recommended conversion table (2.2) • Maximum recommended dosage of AUSTEDO XR or AUSTEDO in poor CYP2D6 metabolizers is 36 mg per day (2.4, 8.7) DOSAGE FORMS AND STRENGTHS • Extended-release tablets: 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, and 48 mg (3) • Tablets: 6 mg, 9 mg, and 12 mg (3) ___________________ CONTRAINDICATIONS____________________ • Suicidal, or untreated/inadequately treated depression in patients with Huntington’s disease (4, 5.1) • Hepatic impairment (4, 8.6, 12.3) • Taking reserpine, MAOIs, tetrabenazine, or valbenazine (4, 7.2, 7.3, 7.6) _______________ WARNINGS AND PRECAUTIONS _______________ • QT Prolongation: Avoid use in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval (5.3) • Neuroleptic Malignant Syndrome (NMS): Discontinue if this occurs (5.4) • Akathisia, agitation, restlessness, and parkinsonism: Reduce dose or discontinue if this occurs (5.5, 5.6) • Sedation/somnolence: May impair the patient’s ability to drive or operate complex machinery (5.7) ____________________ADVERSE REACTIONS____________________ • Most common adverse reactions (>8% of AUSTEDO-treated patients with Huntington’s disease and greater than placebo): somnolence, diarrhea, dry mouth, and fatigue (6.1) • Most common adverse reactions (that occurred in 4% of AUSTEDO- treated patients with tardive dyskinesia and greater than placebo): nasopharyngitis and insomnia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ____________________DRUG INTERACTIONS____________________ • Concomitant use of strong CYP2D6 inhibitors: Maximum recommended dose of AUSTEDO XR or AUSTEDO is 36 mg per day (2.3, 7.1) • Alcohol or other sedating drugs: May have additive sedation and somnolence (7.5) USE IN SPECIFIC POPULATIONS _______________ Pregnancy: Based on animal data, may cause fetal harm (8.1) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 7/2024 1 Reference ID: 5486197 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON'S DISEASE 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2 Switching Patients from Tetrabenazine to AUSTEDO XR or AUSTEDO 2.3 Dosage Adjustment with Strong CYP2D6 Inhibitors 2.4 Dosage Adjustment in Poor CYP2D6 Metabolizers 2.5 Discontinuation and Interruption of Treatment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Depression and Suicidality in Patients with Huntington's Disease 5.2 Clinical Worsening and Adverse Events in Patients with Huntington's Disease 5.3 QTc Prolongation 5.4 Neuroleptic Malignant Syndrome (NMS) 5.5 Akathisia, Agitation, and Restlessness 5.6 Parkinsonism 5.7 Sedation and Somnolence 5.8 Hyperprolactinemia 5.9 Binding to Melanin-Containing Tissues 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Strong CYP2D6 Inhibitors 7.2 Reserpine 7.3 Monoamine Oxidase Inhibitors (MAOIs) 7.4 Neuroleptic Drugs 7.5 Alcohol or Other Sedating Drugs 7.6 Concomitant Tetrabenazine or Valbenazine 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Poor CYP2D6 Metabolizers 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Chorea Associated with Huntington's Disease 14.2 Tardive Dyskinesia 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 2 Reference ID: 5486197 FULL PRESCRIBING INFORMATION WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease. Anyone considering the use of AUSTEDO XR or AUSTEDO must balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Patients, their caregivers, and families should be informed of the risk of depression and suicidality and should be instructed to report behaviors of concern promptly to the treating physician. Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntington’s disease. AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression [see Contraindications (4) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE AUSTEDO® XR and AUSTEDO® are indicated in adults for the treatment of: • chorea associated with Huntington’s disease [see Clinical Studies (14.1)] • tardive dyskinesia [see Clinical Studies (14.2)] 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The dose of AUSTEDO XR and AUSTEDO is determined individually for each patient based on reduction of chorea or tardive dyskinesia and tolerability. Table 1 displays the recommended dosage and important administration instructions of AUSTEDO XR and AUSTEDO when first prescribed to patients who are not being switched from tetrabenazine (a related VMAT2 inhibitor). 3 Reference ID: 5486197 Table 1: Recommended Dosage and Important Administration Instructions for AUSTEDO XR and AUSTEDO AUSTEDO XR extended-release tablet AUSTEDO tablet Recommended Starting Dosage 12 mg once daily (12 mg per day) 6 mg twice daily (12 mg per day) Recommended Dose Titration The dosage of AUSTEDO XR or AUSTEDO may be increased at weekly intervals in increments of 6 mg per day based on reduction of chorea or tardive dyskinesia, and tolerability, up to a maximum recommended daily dosage of 48 mg [see Clinical Trials (14.1, 14.2)]. Important Administration Instructions • Administer AUSTEDO XR with or without food [see Clinical Pharmacology (12.3)]. • Swallow AUSTEDO XR whole. Do not chew, crush, or break tablets. • Administer AUSTEDO XR once daily. • Administer AUSTEDO with food [see Clinical Pharmacology (12.3)]. • Swallow AUSTEDO whole. Do not chew, crush, or break tablets. • Administer AUSTEDO total daily dosages of 12 mg or above in two divided doses. Switching Between AUSTEDO and AUSTEDO XR When switching between AUSTEDO tablets (twice daily) and AUSTEDO XR extended-release tablets (once daily), switch to the same total daily dosage. 2.2 Switching Patients from Tetrabenazine to AUSTEDO XR or AUSTEDO Discontinue tetrabenazine and initiate AUSTEDO XR or AUSTEDO the following day. The recommended initial dosing regimen of AUSTEDO XR or AUSTEDO in patients switching from tetrabenazine to AUSTEDO XR or AUSTEDO is shown in Table 2. Table 2: Recommended Initial Dosing Regimen when Switching from Tetrabenazine to AUSTEDO XR or AUSTEDO Current tetrabenazine daily dosage Initial regimen of AUSTEDO XR extended-release tablet Initial regimen of AUSTEDO tablet 12.5 mg 6 mg once daily 6 mg once daily 25 mg 12 mg once daily 6 mg twice daily 37.5 mg 18 mg once daily 9 mg twice daily 50 mg 24 mg once daily 12 mg twice daily 62.5 mg 30 mg once daily 15 mg twice daily 75 mg 36 mg once daily 18 mg twice daily 87.5 mg 42 mg once daily 21 mg twice daily 100 mg 48 mg once daily 24 mg twice daily 4 Reference ID: 5486197 After patients are switched to AUSTEDO XR or AUSTEDO, the dose may be adjusted at weekly intervals [see Dosage and Administration (2.1)]. 2.3 Dosage Adjustment with Strong CYP2D6 Inhibitors In patients receiving strong CYP2D6 inhibitors, the total daily dosage of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 2.4 Dosage Adjustment in Poor CYP2D6 Metabolizers In patients who are poor CYP2D6 metabolizers, the total daily dosage of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Use in Specific Populations (8.7)]. 2.5 Discontinuation and Interruption of Treatment Treatment with AUSTEDO XR or AUSTEDO can be discontinued without tapering. Following treatment interruption of greater than one week, AUSTEDO XR or AUSTEDO therapy should be re-titrated when resumed. For treatment interruption of less than one week, treatment can be resumed at the previous maintenance dose without titration. 3 DOSAGE FORMS AND STRENGTHS AUSTEDO XR extended-release tablets are available in the following strengths: • The 6 mg extended-release tablets are round, grey-coated tablets, with “Q6” printed in black ink on one side. • The 12 mg extended-release tablets are round, blue-coated tablets, with “Q12” printed in black ink on one side. • The 18 mg extended-release tablets are round, light grey-coated tablets, with “Q18” printed in black ink on one side. • The 24 mg extended-release tablets are round, purple-coated tablets, with “Q24” printed in black ink on one side. • The 30 mg extended-release tablets are round, light orange-coated tablets, with “Q30” printed in black ink on one side. • The 36 mg extended-release tablets are round, light purple-coated tablets, with “Q36” printed in black ink on one side. • The 42 mg extended-release tablets are round, orange-coated tablets, with “Q42” printed in black ink on one side. • The 48 mg extended-release tablets are round, pink-coated tablets, with “Q48” printed in black ink on one side. 5 Reference ID: 5486197 AUSTEDO tablets are available in the following strengths: • The 6 mg tablets are round, purple-coated tablets, with “SD” over “6” printed in black ink on one side. • The 9 mg tablets are round, blue-coated tablets, with “SD” over “9” printed in black ink on one side. • The 12 mg tablets are round, beige-coated tablets, with “SD” over “12” printed in black ink on one side. 4 CONTRAINDICATIONS AUSTEDO XR and AUSTEDO are contraindicated in patients: • With Huntington’s disease who are suicidal, or have untreated or inadequately treated depression [see Warnings and Precautions (5.1)]. • With hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. • Taking reserpine. At least 20 days should elapse after stopping reserpine before starting AUSTEDO XR or AUSTEDO [see Drug Interactions (7.2)]. • Taking monoamine oxidase inhibitors (MAOIs). AUSTEDO XR and AUSTEDO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI [see Drug Interactions (7.3)]. • Taking tetrabenazine or valbenazine [see Drug Interactions (7.6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Depression and Suicidality in Patients with Huntington’s Disease Patients with Huntington’s disease are at increased risk for depression, and suicidal ideation or behaviors (suicidality). AUSTEDO XR and AUSTEDO may increase the risk for suicidality in patients with Huntington’s disease. In a 12-week, double-blind, placebo-controlled trial, suicidal ideation was reported by 2% of patients treated with AUSTEDO, compared to no patients on placebo; no suicide attempts and no completed suicides were reported. Depression was reported by 4% of patients treated with AUSTEDO. When considering the use of AUSTEDO XR or AUSTEDO, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with AUSTEDO XR or AUSTEDO should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with AUSTEDO XR or AUSTEDO. Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with AUSTEDO XR and AUSTEDO, and should be 6 Reference ID: 5486197 instructed to report behaviors of concern promptly to the treating physician. Patients with Huntington’s disease who express suicidal ideation should be evaluated immediately. 5.2 Clinical Worsening and Adverse Events in Patients with Huntington’s Disease Huntington’s disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. VMAT2 inhibitors, including AUSTEDO XR and AUSTEDO, may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects, including sedation/somnolence, depression and suicidality, parkinsonism, akathisia, restlessness, and cognitive decline. It may be difficult to distinguish between adverse reactions and progression of the underlying disease; decreasing the dose or stopping the drug may help the clinician to distinguish between the two possibilities. In some patients, the underlying chorea itself may improve over time, decreasing the need for AUSTEDO XR or AUSTEDO. 5.3 QTc Prolongation AUSTEDO XR and AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO XR or AUSTEDO is administered within the recommended dosage range [see Clinical Pharmacology (12.2)]. AUSTEDO XR and AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval. 5.4 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with drugs that reduce dopaminergic transmission. While NMS has not been observed in patients receiving AUSTEDO XR or AUSTEDO, it has been observed in patients receiving tetrabenazine (a closely related VMAT2 inhibitor). Clinicians should be alerted to the signs and symptoms associated with NMS. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include (1) immediate discontinuation of AUSTEDO XR and AUSTEDO; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of 7 Reference ID: 5486197 any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. Recurrence of NMS has been reported with resumption of drug therapy. If treatment with AUSTEDO XR or AUSTEDO is needed after recovery from NMS, patients should be monitored for signs of recurrence. 5.5 Akathisia, Agitation, and Restlessness AUSTEDO XR and AUSTEDO may increase the risk of akathisia, agitation, and restlessness in patients with Huntington’s disease and tardive dyskinesia. In a 12-week, double-blind, placebo-controlled trial in patients with Huntington’s disease, akathisia, agitation, or restlessness was reported by 4% of patients treated with AUSTEDO, compared to 2% of patients on placebo; in patients with tardive dyskinesia, 2% of patients treated with AUSTEDO and 1% of patients on placebo experienced these events. Patients receiving AUSTEDO XR or AUSTEDO should be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia during treatment with AUSTEDO XR or AUSTEDO, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy. 5.6 Parkinsonism AUSTEDO XR and AUSTEDO may cause parkinsonism in patients with Huntington’s disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. Because rigidity can develop as part of the underlying disease process in Huntington’s disease, it may be difficult to distinguish between potential drug-induced parkinsonism and progression of underlying Huntington’s disease. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington’s disease. Postmarketing cases of parkinsonism in patients treated with AUSTEDO for tardive dyskinesia have been reported. Signs and symptoms in reported cases have included bradykinesia, gait disturbances, which led to falls in some cases, and the emergence or worsening of tremor. In most cases, the development of parkinsonism occurred within the first two weeks after starting or increasing the dose of AUSTEDO. In cases in which follow-up clinical information was available, parkinsonism was reported to resolve following discontinuation of AUSTEDO therapy. If a patient develops parkinsonism during treatment with AUSTEDO XR or AUSTEDO, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy. 5.7 Sedation and Somnolence Sedation is a common dose-limiting adverse reaction of AUSTEDO XR and AUSTEDO. In a 12-week, double-blind, placebo-controlled trial examining patients with Huntington’s disease, 11% of AUSTEDO-treated patients reported somnolence compared with 4% of patients on placebo and 9% of AUSTEDO-treated patients reported fatigue compared with 4% of placebo- treated patients. 8 Reference ID: 5486197 Patients should not perform activities requiring mental alertness to maintain the safety of themselves or others, such as operating a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of AUSTEDO XR or AUSTEDO and know how the drug affects them. 5.8 Hyperprolactinemia Serum prolactin levels were not evaluated in the AUSTEDO XR and AUSTEDO development program. Tetrabenazine, a closely related VMAT2 inhibitor, elevates serum prolactin concentrations in humans. Following administration of 25 mg of tetrabenazine to healthy volunteers, peak plasma prolactin levels increased 4- to 5-fold. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if AUSTEDO XR or AUSTEDO is being considered for a patient with previously detected breast cancer. Although amenorrhea, galactorrhea, gynecomastia, and impotence can be caused by elevated serum prolactin concentrations, the clinical significance of elevated serum prolactin concentrations for most patients is unknown. Chronic increase in serum prolactin levels (although not evaluated in the AUSTEDO XR, AUSTEDO, or tetrabenazine development programs) has been associated with low levels of estrogen and increased risk of osteoporosis. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of AUSTEDO XR and AUSTEDO. 5.9 Binding to Melanin-Containing Tissues Since deutetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that AUSTEDO XR and AUSTEDO may cause toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic examination of the eye has been conducted in the chronic toxicity studies in a pigmented species such as dogs. Ophthalmologic monitoring in humans was inadequate to exclude the possibility of injury occurring after long-term exposure. The clinical relevance of deutetrabenazine’s binding to melanin-containing tissues is unknown. Although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects [see Clinical Pharmacology (12.2)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Depression and Suicidality in Patients with Huntington’s disease [see Warnings and Precautions (5.1)] • QTc Prolongation [see Warnings and Precautions (5.3)] • Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4)] 9 Reference ID: 5486197 • Akathisia, Agitation, and Restlessness [see Warnings and Precautions (5.5)] • Parkinsonism [see Warnings and Precautions (5.6)] • Sedation and Somnolence [see Warnings and Precautions (5.7)] • Hyperprolactinemia [see Warnings and Precautions (5.8)] • Binding to Melanin-Containing Tissues [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The studies described below were conducted with AUSTEDO tablets; adverse reactions with AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets. Patients with Huntington’s Disease Study 1 [see Clinical Studies (14.1)] was a randomized, 12-week, placebo-controlled study in patients with chorea associated with Huntington’s disease. A total of 45 patients received AUSTEDO, and 45 patients received placebo. Patients ranged in age between 23 and 74 years (mean 54 years); 56% were male, and 92% were Caucasian. The most common adverse reactions occurring in greater than 8% of AUSTEDO-treated patients were somnolence, diarrhea, dry mouth, and fatigue. Adverse reactions occurring in 4% or more of patients treated with AUSTEDO, and with a greater incidence than in patients on placebo, are summarized in Table 3. Table 3: Adverse Reactions in Patients with Huntington’s Disease (Study 1) Experienced by at Least 4% of Patients on AUSTEDO and with a Greater Incidence than on Placebo Adverse Reaction AUSTEDO (N = 45) % Placebo (N = 45) % Somnolence 11 4 Diarrhea 9 0 Dry mouth 9 7 Fatigue 9 4 Urinary tract infection 7 2 Insomnia 7 4 Anxiety 4 2 Constipation 4 2 Contusion 4 2 10 Reference ID: 5486197 One or more adverse reactions resulted in a reduction of the dose of study medication in 7% of patients in Study 1. The most common adverse reaction resulting in dose reduction in patients receiving AUSTEDO was dizziness (4%). Agitation led to discontinuation in 2% of patients treated with AUSTEDO in Study 1. Patients with Tardive Dyskinesia The data described below reflect 410 tardive dyskinesia patients participating in clinical trials. AUSTEDO was studied primarily in two 12-week, placebo-controlled trials (fixed dose, dose escalation) [see Clinical Studies (14.2)]. The population was 18 to 80 years of age, and had tardive dyskinesia and had concurrent diagnoses of mood disorder (33%) or schizophrenia/schizoaffective disorder (63%). In these studies, AUSTEDO was administered in doses ranging from 12-48 mg per day. All patients continued on previous stable regimens of antipsychotics; 71% and 14% respective atypical and typical antipsychotic medications at study entry. The most common adverse reactions occurring in greater than 3% of AUSTEDO-treated patients and greater than placebo were nasopharyngitis and insomnia. The adverse reactions occurring in >2% or more patients treated with AUSTEDO (12-48 mg per day) and greater than in placebo patients in two double-blind, placebo-controlled studies in patients with tardive dyskinesia (Study 1 and Study 2) are summarized in Table 4. Table 4: Adverse Reactions in 2 Placebo-Controlled Tardive Dyskinesia Studies (Study 1 and Study 2) of 12-week Treatment on AUSTEDO Reported in at Least 2% of Patients and Greater than Placebo Preferred Term AUSTEDO (N=279) (%) Placebo (N=131) (%) Nasopharyngitis 4 2 Insomnia 4 1 Depression/ Dysthymic disorder 2 1 Akathisia/Agitation/Restlessness 2 1 One or more adverse reactions resulted in a reduction of the dose of study medication in 4% of AUSTEDO-treated patients and in 2% of placebo-treated patients. 7 DRUG INTERACTIONS 7.1 Strong CYP2D6 Inhibitors A reduction in AUSTEDO XR or AUSTEDO dose may be necessary when adding a strong CYP2D6 inhibitor in patients maintained on a stable dose of AUSTEDO XR or AUSTEDO. Concomitant use of strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine, bupropion) has been shown to increase the systemic exposure to the active dihydro-metabolites of deutetrabenazine by approximately 3-fold. The daily dose of AUSTEDO XR or AUSTEDO 11 Reference ID: 5486197 should not exceed 36 mg per day in patients taking strong CYP2D6 inhibitors [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. 7.2 Reserpine Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers should wait for chorea or dyskinesia to reemerge before administering AUSTEDO XR or AUSTEDO to help reduce the risk of overdosage and major depletion of serotonin and norepinephrine in the central nervous system. At least 20 days should elapse after stopping reserpine before starting AUSTEDO XR or AUSTEDO. AUSTEDO XR and AUSTEDO should not be used concomitantly with reserpine [see Contraindications (4)]. 7.3 Monoamine Oxidase Inhibitors (MAOIs) AUSTEDO XR and AUSTEDO are contraindicated in patients taking MAOIs. AUSTEDO XR and AUSTEDO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI [see Contraindications (4)]. 7.4 Neuroleptic Drugs The risk of parkinsonism, NMS, and akathisia may be increased by concomitant use of AUSTEDO XR or AUSTEDO with dopamine antagonists or antipsychotics. 7.5 Alcohol or Other Sedating Drugs Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence [see Warnings and Precautions (5.7)]. 7.6 Concomitant Tetrabenazine or Valbenazine AUSTEDO XR and AUSTEDO are contraindicated in patients currently taking tetrabenazine or valbenazine. AUSTEDO XR or AUSTEDO may be initiated the day following discontinuation of tetrabenazine [see Dosage and Administration (2.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of AUSTEDO XR or AUSTEDO in pregnant women. Administration of deutetrabenazine to rats during organogenesis produced no clear adverse effect on embryofetal development. However, administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in stillbirths and postnatal offspring mortality [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. 12 Reference ID: 5486197 Data Animal Data Oral administration of deutetrabenazine (5, 10, or 30 mg/kg/day) or tetrabenazine (30 mg/kg/day) to pregnant rats during organogenesis had no clear effect on embryofetal development. The highest dose tested was 6 times the maximum recommended human dose of 48 mg/day, on a body surface area (mg/m2) basis. The effects of deutetrabenazine when administered during organogenesis to rabbits or during pregnancy and lactation to rats have not been assessed. Tetrabenazine had no effects on embryofetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day. When tetrabenazine was administered to female rats (doses of 5, 15, and 30 mg/kg/day) from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day, and delayed pup maturation was observed at all doses. 8.2 Lactation Risk Summary There are no data on the presence of deutetrabenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AUSTEDO XR or AUSTEDO and any potential adverse effects on the breastfed infant from AUSTEDO XR or AUSTEDO or from the underlying maternal condition. 8.4 Pediatric Use Chorea associated with Huntington’s Disease and Tardive Dyskinesia The safety and effectiveness of AUSTEDO XR and AUSTEDO have not been established in pediatric patients for the treatment of chorea associated with Huntington’s disease or for the treatment of tardive dyskinesia. Tourette Syndrome The safety and effectiveness of AUSTEDO XR and AUSTEDO have not been established in pediatric patients for the treatment of Tourette syndrome. Efficacy was not demonstrated in two randomized, double-blind, placebo-controlled studies in pediatric patients aged 6 to 16 years with Tourette syndrome. One study evaluated fixed doses of deutetrabenazine over 8 weeks (NCT03571256); the other evaluated flexible doses of deutetrabenazine over 12 weeks (NCT03452943). The studies included a total of 274 pediatric patients who received at least one dose of deutetrabenazine or placebo. The primary efficacy endpoint in both studies was the change from baseline to end-of-treatment on the Yale Global Tic Severity Scale Total Tic Score (YGTSS-TTS). The estimated treatment effect of deutetrabenazine on the YGTSS-TTS was not statistically significantly different from placebo in either study. The placebo subtracted least squares means difference in YGTSS-TTS from 13 Reference ID: 5486197 baseline to end-of-treatment was -0.7 (95% CI: -4.1, 2.8) in the flexible dose study and -0.8 (95% CI: -3.9, 2.3) for the primary analysis in the fixed dose study. The following adverse reactions were reported in frequencies of at least 5% of pediatric patients treated with AUSTEDO and with a greater incidence than in pediatric patients receiving placebo (AUSTEDO vs placebo): headache (includes: migraine, migraine with aura, and headache; 13% vs 9%), somnolence (includes: sedation, hypersomnia, and somnolence; 11% vs 2%), fatigue (8% vs 3%), increased appetite (5% vs <1%), and increased weight (5% vs <1%). Juvenile Animal Toxicity Data Deutetrabenazine orally administered to juvenile rats from postnatal days 21 through 70 (at 2.5, 5, or 10 mg/kg/day) resulted in an increased incidence of tremor, hyperactivity, and adverse increases in motor activity at ≥5 mg/kg/day, and reduced body weight and food consumption at 10 mg/kg/day. There was no reproductive or early embryonic toxicity up to the highest dose. All drug-related findings were reversible after a drug-free period. The no observed adverse effect level (NOAEL) in juvenile rats was 2.5 mg/kg/day. These drug-related findings were similar to those observed in adult rats; however, the juvenile rats were more sensitive. 8.5 Geriatric Use Clinical studies of AUSTEDO XR and AUSTEDO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of hepatic, renal, and cardiac dysfunction, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of deutetrabenazine and its primary metabolites has not been studied; however, in a clinical study conducted with tetrabenazine, a closely related VMAT2 inhibitor, there was a large increase in exposure to tetrabenazine and its active metabolites in patients with hepatic impairment. The clinical significance of this increased exposure has not been assessed, but because of concerns for a greater risk for serious adverse reactions, the use of AUSTEDO XR or AUSTEDO in patients with hepatic impairment is contraindicated [see Contraindications (4), Clinical Pharmacology (12.3)]. 8.7 Poor CYP2D6 Metabolizers Although the pharmacokinetics of deutetrabenazine and its metabolites have not been systematically evaluated in patients who do not express the drug metabolizing enzyme, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similarly to taking a strong CYP2D6 inhibitor (approximately 3-fold). In patients who are CYP2D6 poor metabolizers, the daily dose of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. 14 Reference ID: 5486197 10 OVERDOSAGE Overdoses ranging from 100 mg to 1 g have been reported in the literature with tetrabenazine, a closely related VMAT2 inhibitor. The following adverse reactions occurred with overdosing: acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. Treatment should consist of those general measures employed in the management of overdosage with any central nervous system-active drug. General supportive and symptomatic measures are recommended. Cardiac rhythm and vital signs should be monitored. In managing overdosage, the possibility of multiple drug involvement should always be considered. The physician should consider contacting a poison control center on the treatment of any overdose. Telephone numbers for certified poison control centers are listed on the American Association of Poison Control Centers website www.aapcc.org. 11 DESCRIPTION AUSTEDO XR extended-release tablets and AUSTEDO tablets are formulated with deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor for oral administration. The molecular weight of deutetrabenazine is 323.46; the pKa is 6.31. Deutetrabenazine is a hexahydro-dimethoxybenzoquinolizine derivative and has the following chemical name: (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)­ 2H-benzo[a]quinolizin-2-one. The molecular formula for deutetrabenazine is C19H21D6NO3. Deutetrabenazine is a racemic mixture containing the following structures: D3CO D3CO N N D3CO D3CO H H O O RR - Deutetrabenazine SS - Deutetrabenazine Deutetrabenazine is a white to slightly yellow crystalline powder that is sparingly soluble in water and soluble in ethanol. AUSTEDO XR AUSTEDO XR extended-release tablets contain 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg deutetrabenazine, and the following inactive ingredients: ammonium hydroxide, black iron oxide, butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, cellulose acetate, hydroxypropyl cellulose, hypromellose, isopropyl alcohol, magnesium stearate, polyethylene glycol, polyethylene glycol 3350, polyethylene oxide, polyvinyl alcohol, propylene glycol, shellac, sodium chloride, talc, titanium dioxide, and FD&C red #40 lake. The 6 mg, 12 mg, 18 mg, 30 mg, 36 mg, and 42 mg extended-release tablets also contain FD&C yellow #6 lake. The 6 mg, 12 mg, 24 mg, and 36 mg extended-release tablets also contain FD&C blue #2 lake. The 18 mg extended-release tablets also contain carmine. 15 Reference ID: 5486197 AUSTEDO XR Delivery System Components and Performance AUSTEDO XR uses osmotic pressure to deliver deutetrabenazine at a controlled rate. The delivery system, which resembles a round tablet in appearance, consists of a bilayer core tablet that contains deutetrabenazine along with other excipients. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool. AUSTEDO AUSTEDO tablets contain 6 mg, 9 mg, or 12 mg deutetrabenazine, and the following inactive ingredients: ammonium hydroxide, black iron oxide, butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyethylene oxide, polysorbate 80, polyvinyl alcohol, povidone, propylene glycol, shellac, talc, titanium dioxide, and FD&C blue #2 lake. The 6 mg tablets also contain FD&C red #40 lake. The 12 mg tablets also contain FD&C yellow #6 lake. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanism by which deutetrabenazine exerts its effects in the treatment of tardive dyskinesia and chorea in patients with Huntington’s disease is unknown but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. The major circulating metabolites (α­ dihydrotetrabenazine [HTBZ] and β-HTBZ) of deutetrabenazine, are reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. 12.2 Pharmacodynamics Cardiac Electrophysiology At the maximum recommended dose, AUSTEDO XR and AUSTEDO do not prolong the QT interval to any clinically relevant extent. An exposure-response analysis on QTc prolongation from a study in extensive or intermediate (EM) and poor CYP2D6 metabolizers (PM) showed that a clinically-relevant effect can be excluded at exposures following single doses of 24 and 48 mg of AUSTEDO. Melanin Binding Deutetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After a single oral dose of radiolabeled deutetrabenazine, radioactivity was still detected in eye and fur at 35 days following dosing [see Warnings and Precautions (5.9)]. 12.3 Pharmacokinetics After oral dosing, plasma concentrations of deutetrabenazine are low compared to that of the active deuterated metabolites because of the extensive hepatic metabolism of deutetrabenazine. AUSTEDO XR 16 Reference ID: 5486197 Systemic exposure (i.e., peak plasma concentrations [Cmax] and the area under the plasma concentration-time curve [AUC]) for deutetrabenazine and the active, deuterated dihydro metabolites (HTBZ), α-HTBZ and β-HTBZ, increased proportionally to dose following single doses of AUSTEDO XR over the recommended clinical dosage range (6 mg to 48 mg). AUSTEDO Systemic exposure (Cmax and AUC) for the active metabolites increased proportionally to dose following single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily). Absorption Following oral administration of deutetrabenazine, the extent of absorption is at least 80%. AUSTEDO XR Peak plasma concentrations (Cmax) of deutetrabenazine, deuterated α-HTBZ, and β-HTBZ are reached within approximately 3 hours, followed by sustained plateaus for several hours allowing for a 24-hour dosing interval. AUSTEDO Peak plasma concentrations (Cmax) of deutetrabenazine, deuterated α-HTBZ and β-HTBZ are reached within 3 to 4 hours after dosing. Effect of Food AUSTEDO XR The effects of food on the bioavailability of AUSTEDO XR were studied in subjects administered a single dose with and without food. Food had no effect on Cmax or AUC of deutetrabenazine, α-HTBZ or β-HTBZ [see Dosage and Administration (2.1)]. AUSTEDO The effects of food on the bioavailability of AUSTEDO were studied in subjects administered a single dose with and without food. Food had no effect on AUC of α-HTBZ or β-HTBZ, although Cmax was increased by approximately 50% in the presence of food [see Dosage and Administration (2.1)]. Distribution The median volume of distribution (Vc/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 500 L and 730 L, respectively. Results of PET-scan studies in humans show that following intravenous injection of 11C-labeled tetrabenazine or α-HTBZ, radioactivity is rapidly distributed to the brain, with the highest binding in the striatum and lowest binding in the cortex. The in vitro protein binding of tetrabenazine, α-HTBZ, and β-HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%. Elimination 17 Reference ID: 5486197 AUSTEDO XR and AUSTEDO are primarily renally eliminated in the form of metabolites. The half-life of the active deuterated α-HTBZ, β-HTBZ, and total (α+β)-HTBZ metabolites is approximately 12 hours, 7.5 hours, and 9 to 11 hours, respectively. The clearance values (CL/F) of the α-HTBZ, and β-HTBZ metabolites of AUSTEDO are approximately 65 L/hour and 200 L/hour, respectively, for a 70 kg HD or TD patient with functional CYP2D6 metabolism in the fed state. The elimination half-life and clearance of AUSTEDO XR are similar to that of AUSTEDO. Metabolism In vitro experiments in human liver microsomes demonstrate that deutetrabenazine is extensively biotransformed, mainly by carbonyl reductase, to its major active metabolites, α-HTBZ and β­ HTBZ, which are subsequently metabolized primarily by CYP2D6, with minor contributions of CYP1A2 and CYP3A4/5, to form several minor metabolites. Excretion In a mass balance study in 6 healthy subjects, 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose. Urinary excretion of the α-HTBZ and β-HTBZ metabolites from deutetrabenazine each accounted for less than 10% of the administered dose. Sulfate and glucuronide conjugates of the α-HTBZ and β-HTBZ metabolites of deutetrabenazine, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine. Specific Populations Male and Female Patients There is no apparent effect of gender on the pharmacokinetics of α-HTBZ and β-HTBZ of deutetrabenazine. Patients with Renal Impairment No clinical studies have been conducted to assess the effect of renal impairment on the PK of deutetrabenazine and its primary metabolites. Patients with Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of deutetrabenazine and its primary metabolites has not been studied. However, in a clinical study conducted to assess the effect of hepatic impairment on the pharmacokinetics of tetrabenazine, a closely related VMAT2 inhibitor, the exposure to α-HTBZ and β-HTBZ was up to 40% greater in patients with hepatic impairment, and the mean tetrabenazine Cmax in patients with hepatic impairment was up to 190­ fold higher than in healthy subjects [see Contraindications (4), Use in Specific Populations (8.6)]. Poor CYP2D6 Metabolizers Although the pharmacokinetics of deutetrabenazine and its metabolites have not been systematically evaluated in patients who do not express the drug metabolizing enzyme CYP2D6, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similarly to taking 18 Reference ID: 5486197 strong CYP2D6 inhibitors (approximately 3-fold) [see Dosage and Administration (2.4), Drug Interactions (7.1)]. Drug Interaction Studies Deutetrabenazine, α-HTBZ, and β-HTBZ have not been evaluated in in vitro studies for induction or inhibition of CYP enzymes or interaction with P-glycoprotein. The results of in vitro studies of tetrabenazine do not suggest that tetrabenazine or its α-HTBZ or β-HTBZ metabolites are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its α-HTBZ or β-HTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19. Neither tetrabenazine nor its α-HTBZ or β-HTBZ metabolites are likely to be a substrate or inhibitor of P-glycoprotein at clinically relevant concentrations in vivo. The deutetrabenazine metabolites, 2-methylpropanoic acid of β-HTBZ (M1) and monohydroxy tetrabenazine (M4), have been evaluated in a panel of in vitro drug-drug interaction studies; the results indicate that M1/M4 are not expected to cause clinically relevant drug interactions. CYP2D6 Inhibitors In vitro studies indicate that the α-HTBZ and β-HTBZ metabolites of deutetrabenazine are substrates for CYP2D6. The effect of CYP2D6 inhibition on the pharmacokinetics of deutetrabenazine and its metabolites was studied in 24 healthy subjects following a single 22.5 mg dose of deutetrabenazine given after 8 days of administration of the strong CYP2D6 inhibitor paroxetine 20 mg daily. In the presence of paroxetine, systemic exposure (AUCinf) of α­ HTBZ was 1.9-fold higher and β-HTBZ was 6.5-fold higher, resulting in approximately 3-fold increase in AUCinf for total (α+β)-HTBZ. Paroxetine decreased the clearance of α-HTBZ and β­ HTBZ metabolites of AUSTEDO with corresponding increases in mean half-life of approximately 1.5-fold and 2.7-fold, respectively. In the presence of paroxetine, Cmax of α-HTBZ and β-HTBZ were 1.2-fold and 2.2-fold higher, respectively. The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline on the exposure of deutetrabenazine and its metabolites has not been evaluated. Digoxin AUSTEDO XR and AUSTEDO were not evaluated for interaction with digoxin. Digoxin is a substrate for P-glycoprotein. A study in healthy subjects showed that tetrabenazine (25 mg twice daily for 3 days) did not affect the bioavailability of digoxin, suggesting that at this dose, tetrabenazine does not affect P-glycoprotein in the intestinal tract. In vitro studies also do not suggest that tetrabenazine or its metabolites are P-glycoprotein inhibitors. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were performed with deutetrabenazine. 19 Reference ID: 5486197 No increase in tumors was observed in p53+/– transgenic mice treated orally with tetrabenazine at doses of 0, 5, 15, and 30 mg/kg/day for 26 weeks. Mutagenesis Deutetrabenazine and its deuterated α-HTBZ and β-HTBZ metabolites were negative in in vitro (bacterial reverse mutation and chromosome aberration in human peripheral blood lymphocytes) assays in the presence or absence of metabolic activation and in the in vivo micronucleus assay in mice. Impairment of Fertility The effects of deutetrabenazine on fertility have not been evaluated. Oral administration of deutetrabenazine (doses of 5, 10, or 30 mg/kg/day) to female rats for 3 months resulted in estrous cycle disruption at all doses; the lowest dose tested was similar to the maximum recommended human dose (48 mg/day) on a body surface area (mg/m2) basis. Oral administration of tetrabenazine (doses of 5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation, resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day. No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine at doses of 5, 15 or 30 mg/kg/day prior to and throughout mating with untreated females. 14 CLINICAL STUDIES The studies described below establishing effectiveness for Huntington’s disease and tardive dyskinesia were conducted with AUSTEDO tablets. The efficacy of AUSTEDO XR is based on a relative bioavailability study comparing AUSTEDO XR tablets administered once daily and AUSTEDO tablets administered twice daily [see Clinical Pharmacology (12.3)]. 14.1 Chorea Associated with Huntington’s Disease The efficacy of AUSTEDO as a treatment for chorea associated with Huntington's disease was established primarily in Study 1, a randomized, double-blind, placebo-controlled, multi-center trial conducted in 90 ambulatory patients with manifest chorea associated with Huntington’s disease. The diagnosis of Huntington’s disease was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including an 8-week dose titration period and a 4-week maintenance period, followed by a 1-week washout. Patients were not blinded to discontinuation. AUSTEDO was started at 6 mg per day and titrated upward, at weekly intervals, in 6 mg increments until satisfactory treatment of chorea was achieved, intolerable side effects occurred, or until a maximal dose of 48 mg per day was reached. The primary efficacy endpoint was the Total Maximal Chorea Score, an item of the Unified Huntington's Disease Rating Scale (UHDRS). On this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for 7 different parts of the body. The total score ranges from 0 to 28. Of the 90 patients enrolled, 87 patients completed the study. The mean age was 54 (range 23 to 74). Patients were 56% male and 92% Caucasian. The mean dose after titration was 40 mg per day. Table 5 and Figure 1 summarize the effects of AUSTEDO on chorea based on the Total 20 Reference ID: 5486197 15 1-- e:? AUSTEDO ··O · · Placebo Washout 0 14 (J l en f-.,, ,..-1 «s 13 e:? 0 ' ' .c: 12 ' 0 - 1- l "iij 11 ---._ ·-· ------·-!· I . -·· -·· -· -,., E , , ,., ',, + · _,,,,,, ,., . . ,, ,,,, , '5< i 10 ce 9 -- ~ *l ~ 8 w en 7 - C: Dose Titration «s 6 :I *p<0.0001 5 0 2 4 6 9 12 13 Maintenance Study Week Endpoint AUSTEDO, n• 45 45 44 44 45 45 44 45 Placebo, n 45 45 45 44 42 43 43 45 Maximal Chorea Score. Total Maximal Chorea Scores for patients receiving AUSTEDO improved by approximately 4.4 units from baseline to the maintenance period (average of Week 9 and Week 12), compared to approximately 1.9 units in the placebo group. The treatment effect of -2.5 units was statistically significant (p<0.0001). The Maintenance Endpoint is the mean of the Total Maximal Chorea Scores for the Week 9 and Week 12 visits. At the Week 13 follow-up visit (1 week after discontinuation of the study medication), the Total Maximal Chorea Scores of patients who had received AUSTEDO returned to baseline (Figure 1). Table 5: Change from Baseline to Maintenance Therapy in Total Maximal Chorea (TMC)a Score in Patients with Huntington’s Disease Treated with AUSTEDO in Study 1 Motor Endpoint AUSTEDO N = 45 Placebo N = 45 p value Change in Total Chorea Scorea from Baseline to Maintenance Therapyb -4.4 -1.9 <0.0001 aTMC is a subscale of the Unified Huntington's Disease Rating Scale (UHDRS) bPrimary efficacy endpoint Figure 1: Total Maximal Chorea Score Over Time in Study 1 21 Reference ID: 5486197 40 improvement worsening ( > en +-' C 30 Q) ·,.:::::; - AUSTEDO ctS a. - 0 20 D Placebo +-' C Q) (.) lo... Q) 10 a_ 0 a co (0 .,,,. CV a CV .,,,. (0 co co ,_ I I I I E E E E I E E E E E /\ E a co (0 .,,,. ~ a CV .,,,. (0 CV ,_ I I I /\ /\ /\ /\ ,_ I /\ /\ /\ /\ I /\ /\ Total Chorea Score: Change from Baseline to Maintenance Figure 2: Distribution of the Change in Total Maximal Chorea Scores in Study 1 Figure 2 shows the distribution of values for the change in Total Maximal Chorea Score in Study 1. Negative values indicate a reduction in chorea and positive numbers indicate an increase in chorea. A patient-rated global impression of change assessed how patients rated their overall Huntington’s disease symptoms. Fifty-one percent of patients treated with AUSTEDO rated their symptoms as “Much Improved” or “Very Much Improved” at the end of treatment, compared to 20% of placebo-treated patients. In a physician-rated clinical global impression of change, physicians rated 42% percent of patients treated with AUSTEDO as “Much Improved” or “Very Much Improved” at the end of treatment compared to 13% of placebo-treated patients. 14.2 Tardive Dyskinesia The efficacy of AUSTEDO in the treatment for tardive dyskinesia was established in two 12-week, randomized, double-blind, placebo-controlled, multi-center trials conducted in 335 adult ambulatory patients with tardive dyskinesia caused by use of dopamine receptor antagonists. Patients had a history of using a dopamine receptor antagonist (antipsychotics, metoclopramide) for at least 3 months (or 1 month in patients 60 years of age and older). Concurrent diagnoses included schizophrenia/schizoaffective disorder (62%) and mood disorder (33%). With respect to concurrent antipsychotic use, 64% of patients were receiving atypical 22 Reference ID: 5486197 antipsychotics, 12% were receiving typical or combination antipsychotics, and 24% were not receiving antipsychotics. The Abnormal Involuntary Movement Scale (AIMS) was the primary efficacy measure for the assessment of tardive dyskinesia severity. The AIMS is a 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this study. Each of the 7 items was scored on a 0 to 4 scale, rated as: 0=not present; 1=minimal, may be extreme normal (abnormal movements occur infrequently and/or are difficult to detect); 2=mild (abnormal movements occur infrequently and are easy to detect); 3=moderate (abnormal movements occur frequently and are easy to detect) or 4 =severe (abnormal movements occur almost continuously and/or of extreme intensity). The AIMS total score (sum of items 1 to 7) could thus range from 0 to 28, with a decrease in score indicating improvement. In Study 1, a 12-week, placebo-controlled, fixed-dose trial, adults with tardive dyskinesia were randomized 1:1:1:1 to 12 mg AUSTEDO, 24 mg AUSTEDO, 36 mg AUSTEDO, or placebo. Treatment duration included a 4-week dose escalation period and an 8-week maintenance period followed by a 1-week washout. The dose of AUSTEDO was started at 12 mg per day and increased at weekly intervals in 6 mg/day increments to a dose target of 12 mg, 24 mg or 36 mg per day. The population (n= 222) was 21 to 81 years old (mean 57 years), 48% male, and 79% Caucasian. In Study 1, the AIMS total score for patients receiving AUSTEDO demonstrated statistically significant improvement, from baseline to Week 12, of 3.3 and 3.2 units for the 36 mg and 24 mg arms, respectively, compared with 1.4 units in placebo (Study 1 in Table 6). The improvements on the AIMS total score over the course of the study are displayed in Figure 3. Data did not suggest substantial differences in efficacy across various demographic groups. The treatment response rate distribution, based on magnitude of AIMS total score from baseline to week 12 is displayed in Figure 4. The mean changes in the AIMS total score by visit are shown in Figure 3. In Study 2, a 12-week, placebo-controlled, flexible-dose trial, adults with tardive dyskinesia (n=113) received daily doses of placebo or AUSTEDO, starting at 12 mg per day with increases allowed in 6-mg increments at 1-week intervals until satisfactory control of dyskinesia was achieved, until intolerable side effects occurred, or until a maximal dose of 48 mg per day was reached. Treatment duration included a 6-week dose titration period and a 6-week maintenance period followed by a 1-week washout. The population was 25 to 75 years old (mean 55 years), 48% male, and 70% Caucasian. Patients were titrated to an optimal dose over 6 weeks. The average dose of AUSTEDO after treatment was 38.3 mg per day. There was no evidence suggesting substantial differences in efficacy across various demographic groups. In Study 2, AIMS total score for patients receiving AUSTEDO demonstrated statistically significant improvement by 3.0 units from baseline to endpoint (Week 12), compared with 1.6 units in the placebo group with a treatment effect of -1.4 units. Table 6 summarizes the effects of AUSTEDO on tardive dyskinesia based on the AIMS. 23 Reference ID: 5486197 IO PLACEBO □ AUSTEDO l2 MG/DAY e AUSTEDO 24 MG/DAY ♦ AUSTEDO 36 MG/DAY I 0 -l Gi' ~ = -2 " " ~ -3 -4 Study week: 0 2 4 8 12 Number of patients AUSTEDO 36 MG/DAY 55 55 52 53 52 AUSTEDO 24 MG/DAY 49 49 47 46 45 AUSTEDO 12 MG/DAY 60 60 58 56 53 PLACEBO 58 58 57 57 56 Table 6: Improvement in AIMS Total Score in Patients Treated with AUSTEDO in Study 1 and Study 2 Study Treatment Group Primary Efficacy Measure: AIMS Total Score Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Treatment Effect (95% CI) Study 1 AUSTEDO 36 mg* (n= 55) 10.1 (3.21) -3.3 (0.42) -1.9 (-3.09, -0.79) AUSTEDO 24 mg (n= 49) 9.4 (2.93) -3.2 (0.45) -1.8 (-3.00, -0.63) AUSTEDO 12 mg (n= 60) 9.6 (2.40) -2.1 (0.42) -0.7 (-1.84, 0.42) Placebo (n= 58) 9.5 (2.71) -1.4 (0.41) Study 2 AUSTEDO (12-48 mg/day)* (n= 56) 9.7 (4.14) -3.0 (0.45) -1.4 (-2.6, -0.2) Placebo (n= 57) 9.6 (3.78) -1.6 (0.46) *Dose that was statistically significantly different from placebo after adjusting for multiplicity. LS Mean = Least-squares mean; SD = Standard deviation; SE = Standard error; CI = 2-sided 95% confidence interval Figure 3: Least Square Means of Change in AIMS Total Score from Baseline for AUSTEDO Compared to Placebo (Study 1) SE = Standard error 24 Reference ID: 5486197 ID Placebo D AUSTEDO 12 mg D AUSTEDO 24 mg ■ AUSTEDO 36 mg I so 43 43 40 ~ 35 :;?_ ~ 2l = 30 " 29 ·-= "' 11. 25 "-< 0 23 = " 0 20 21 .... 20 " 11. 15 l2 10 3 0 ~-....... -'--t-- Missing No change or worsened l to 3 4 to 6 7 to 9 10 to l3 Magnitude oflmprovement from Baseline in AIMS Total Score Figure 4: Percent of Patients with Specified Magnitude of AIMS Total Score Improvement at the End of Week 12 (Study 1) 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied AUSTEDO XR extended-release tablets are supplied in the following configurations: Strength Description Package Configuration NDC Code 6 mg Round, grey-coated tablets, with “Q6” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-470-56 12 mg Round, blue-coated tablets, with “Q12” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-471-56 18 mg Round, light grey-coated tablets, with “Q18” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-479-56 24 mg Round, purple-coated tablets, with “Q24” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-472-56 30 mg Round, light orange-coated tablets, with “Q30” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-473-56 36 mg Round, light purple-coated tablets, with “Q36” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-474-56 25 Reference ID: 5486197 42 mg Round, orange-coated tablets, with “Q42” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-475-56 48 mg Round, pink-coated tablets, with “Q48” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-476-56 AUSTEDO XR Patient Titration Kits are supplied in the following configuration: Strength Description Package Configuration NDC Code 4-Week Patient Titration Kit 12 mg Round, blue-coated tablets, with “Q12” printed in black ink on one side Titration Kit / 28 count Each Titration Kit contains 1 child-resistant blister pack, containing one foil card with extended-release tablets in the following configuration: Seven 12 mg tablets taken during Week 1; seven 18 mg tablets taken during Week 2; seven 24 mg tablets taken during Week 3; and seven 30 mg tablets taken during Week 4. 68546-477-29 18 mg Round, light grey-coated tablets, with “Q18” printed in black ink on one side 24 mg Round, purple-coated tablets, with “Q24” printed in black ink on one side 30 mg Round, light orange- coated tablets, with “Q30” printed in black ink on one side AUSTEDO tablets are supplied in the following configurations: Strength Description Package Configuration NDC Code 6 mg Round, purple-coated tablets, with “SD” over “6” printed in black ink on one side Bottle with child-resistant cap / 60 count 68546-170-60 9 mg Round, blue-coated tablets, with “SD” over “9” printed in black ink on one side Bottle with child-resistant cap / 60 count 68546-171-60 12 mg Round, beige-coated tablets, with “SD” over “12” printed in black ink on one side Bottle with child-resistant cap / 60 count 68546-172-60 26 Reference ID: 5486197 16.2 Storage Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Dispense in original containers or in tight containers as defined in USP. 17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). Administration Instructions Instruct patients to swallow AUSTEDO XR or AUSTEDO whole and not to chew, crush, or break AUSTEDO XR or AUSTEDO [see Dosage and Administration (2.1)]. AUSTEDO XR Advise patients to take AUSTEDO XR with or without food in once-daily doses. Inform patients not to be concerned if they occasionally notice something that looks like a tablet shell in their stool [see Description (11)]. AUSTEDO Advise patients to take AUSTEDO with food. Advise patients to take daily dosages of 12 mg or higher in two divided doses (twice daily). Risk of Depression and Suicide in Patients with Huntington’s Disease Advise patients, their caregivers, and families that AUSTEDO XR and AUSTEDO may increase the risk of depression, worsening depression, and suicidality, and to immediately report any symptoms to a healthcare provider [see Contraindications (4), Warnings and Precautions (5.1)]. Prolongation of the QTc Interval Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations [see Warnings and Precautions (5.3)]. Advise patients to inform physicians that they are taking AUSTEDO XR or AUSTEDO before any new drug is taken. Parkinsonism Inform patients that AUSTEDO XR and AUSTEDO may cause Parkinson-like symptoms, which could be severe. Advise patients to consult their healthcare provider if they experience slight shaking, body stiffness, trouble moving, trouble keeping their balance, or falls [see Warnings and Precautions (5.6)]. Risk of Sedation and Somnolence Advise patients that AUSTEDO XR and AUSTEDO may cause sedation and somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Until they learn how they respond to a stable dose of AUSTEDO XR or AUSTEDO, patients should be careful doing activities that require them to be alert, such as driving a car or operating machinery [see Warnings and Precautions (5.7)]. Interaction with Alcohol or Other Sedating Drugs 27 Reference ID: 5486197 Advise patients that alcohol or other drugs that cause sleepiness will worsen somnolence [see Drug Interactions (7.5)]. Concomitant Medications Advise patients to notify their physician of all medications they are taking and to consult with their healthcare provider before starting any new medications because of a potential for interactions [see Contraindications (4) and Drug Interactions (7.1, 7.4)]. Dispense with Medication Guide available at: www.tevausa.com/medguides Manufactured for: Teva Neuroscience, Inc. Parsippany, NJ 07054 ©2024 Teva Neuroscience, Inc. AUS-012 AUSTEDO XR U.S. Patent Nos: 8,524,733; 9,550,780; 10,959,996; 11,179,386; 11,357,772; 11,311,488; 11,564,917; 11,446,291; 11,648,244 AUSTEDO U.S. Patent Nos: 8,524,733; 9,233,959; 9,296,739; 9,550,780; 9,814,708; 10,959,996; 11,179,386; 11,357,772; 11,564,917; 11,446,291; 11,648,244; 11,666,566 28 Reference ID: 5486197 Dispense with Medication Guide available at: www.tevausa.com/medguides MEDICATION GUIDE AUSTEDO® XR (aw-STED-oh XR) (deutetrabenazine) extended-release tablets, for oral use AUSTEDO® (aw-STED-oh) (deutetrabenazine) tablets, for oral use What is the most important information I should know about AUSTEDO XR and AUSTEDO? • AUSTEDO XR and AUSTEDO can cause serious side effects in people with Huntington’s disease, including: o depression o suicidal thoughts o suicidal actions • Do not start taking AUSTEDO XR or AUSTEDO if you have Huntington’s disease and are depressed (have untreated depression or depression that is not well controlled by medicine) or have suicidal thoughts. • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is especially important when AUSTEDO XR or AUSTEDO is started and when the dose is changed. Call your healthcare provider right away if you become depressed or have any of the following symptoms, especially if they are new, worse, or worry you: • feel sad or have crying spells • lose interest in seeing your friends or doing things you used to enjoy • sleep a lot more or a lot less than usual • feel unimportant • feel guilty • feel hopeless or helpless • feel more irritable, angry, or aggressive than usual • feel more or less hungry than usual or notice a big change in your body weight • have trouble paying attention • feel tired or sleepy all the time • have thoughts about hurting yourself or ending your life What are AUSTEDO XR and AUSTEDO? AUSTEDO XR and AUSTEDO are prescription medicines that are used to treat: • the involuntary movements (chorea) of Huntington’s disease. AUSTEDO XR and AUSTEDO do not cure the cause of the involuntary movements, and it does not treat other symptoms of Huntington’s disease, such as problems with thinking or emotions. • movements in the face, tongue, or other body parts that cannot be controlled (tardive dyskinesia). It is not known if AUSTEDO XR and AUSTEDO are safe and effective in children. Who should not take AUSTEDO XR or AUSTEDO? Do not take AUSTEDO XR or AUSTEDO if you: • have Huntington’s disease and are depressed or have thoughts of suicide. See “What is the most important information I should know about AUSTEDO XR and AUSTEDO?” • have liver problems. • are taking reserpine. Do not take medicines that contain reserpine with AUSTEDO XR or AUSTEDO. If your healthcare provider plans to switch you from taking reserpine to AUSTEDO XR or AUSTEDO, you must wait at least 20 days after your last dose of reserpine before you start taking AUSTEDO XR or AUSTEDO. • are taking a monoamine oxidase inhibitor (MAOI) medicine. Do not take an MAOI within 14 days after you stop taking AUSTEDO XR or AUSTEDO. Do not start AUSTEDO XR or AUSTEDO if you stopped taking an MAOI in the last 14 days. Ask your healthcare provider or pharmacist if you are not sure. Reference ID: 5486197 • are taking tetrabenazine. If your healthcare provider plans to switch you from tetrabenazine to AUSTEDO XR or AUSTEDO, take your first dose of AUSTEDO XR or AUSTEDO on the day after your last dose of tetrabenazine. • are taking valbenazine. Before taking AUSTEDO XR or AUSTEDO, tell your healthcare provider about all of your medical conditions, including if you: • have emotional or mental problems (for example, depression, nervousness, anxiety, anger, agitation, psychosis, previous suicidal thoughts or suicide attempts). • have liver disease. • have an irregular heart rhythm or heartbeat (QT prolongation, cardiac arrhythmia) or a heart problem called congenital long QT syndrome. • have low levels of potassium or magnesium in your blood (hypokalemia or hypomagnesemia). • have breast cancer or a history of breast cancer. • are pregnant or plan to become pregnant. It is not known if AUSTEDO XR or AUSTEDO can harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if AUSTEDO XR or AUSTEDO passes into breast milk. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking AUSTEDO XR or AUSTEDO with certain other medicines may cause side effects. Do not start any new medicines while taking AUSTEDO XR or AUSTEDO without talking to your healthcare provider first. How should I take AUSTEDO XR or AUSTEDO? • Take AUSTEDO XR or AUSTEDO exactly as your healthcare provider tells you to take it. • If you take AUSTEDO XR, take your dose by mouth one time each day, with or without food. • If you take AUSTEDO, take your dose by mouth and with food. If your dose of AUSTEDO is 12 mg or more each day, take AUSTEDO tablets 2 times a day in equal doses. • Swallow AUSTEDO XR or AUSTEDO tablets whole with water. Do not chew, crush, or break AUSTEDO XR or AUSTEDO tablets before swallowing. If you cannot swallow AUSTEDO XR or AUSTEDO tablets whole, tell your healthcare provider. You may need a different medicine. • The AUSTEDO XR tablet shell does not dissolve completely in the body after all the medicine has been released. Sometimes the tablet shell may be seen in your stool. This is normal. • Your healthcare provider may increase your dose of AUSTEDO XR or AUSTEDO each week for several weeks, until you and your healthcare provider find the right dose for you. • Tell your healthcare provider if you stop taking AUSTEDO XR or AUSTEDO for more than 1 week. Do not take another dose until you talk to your healthcare provider. What should I avoid while taking AUSTEDO XR or AUSTEDO? Sleepiness (sedation) is a common side effect of AUSTEDO XR and AUSTEDO. While taking AUSTEDO XR or AUSTEDO, do not drive a car or operate dangerous machinery until you know how AUSTEDO XR or AUSTEDO affects you. Drinking alcohol and taking other drugs that may also cause sleepiness while you are taking AUSTEDO XR or AUSTEDO may increase any sleepiness caused by AUSTEDO XR and AUSTEDO. What are the possible side effects of AUSTEDO XR and AUSTEDO? AUSTEDO XR and AUSTEDO can cause serious side effects, including: • Depression and suicidal thoughts or actions in people with Huntington’s disease. See “What is the most important information I should know about AUSTEDO XR and AUSTEDO?” • Irregular heartbeat (QT prolongation). AUSTEDO XR and AUSTEDO increases your chance of having certain changes in the electrical activity in your heart. These changes can lead to a dangerous abnormal heartbeat. Taking AUSTEDO XR or AUSTEDO with certain medicines may increase this chance. • Neuroleptic Malignant Syndrome (NMS). Call your healthcare provider right away and go to the nearest emergency room if you develop these signs and symptoms that do not have another obvious cause: o high fever o stiff muscles o problems thinking o very fast or uneven heartbeat o increased sweating • Restlessness. You may get a condition where you feel a strong urge to move. This is called akathisia. Reference ID: 5486197 • Parkinsonism. Symptoms of parkinsonism include: slight shaking, body stiffness, trouble moving, trouble keeping your balance, or falls. The most common side effects of AUSTEDO in people with Huntington’s disease include: • sleepiness (sedation) • tiredness • diarrhea • dry mouth The most common side effects of AUSTEDO in people with tardive dyskinesia include: • inflammation of the nose and throat (nasopharyngitis) • problems sleeping (insomnia) The most common side effects of AUSTEDO XR are expected to be similar to AUSTEDO in people with Huntington’s disease or tardive dyskinesia. These are not all the possible side effects of AUSTEDO XR or AUSTEDO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store AUSTEDO XR and AUSTEDO? • Store AUSTEDO XR and AUSTEDO tablets at room temperature between 68°F to 77°F (20°C to 25°C). • Keep the bottle tightly closed to protect AUSTEDO XR and AUSTEDO from light and moisture. • Do not throw away the desiccant canister in the bottle until the last dose of AUSTEDO XR or AUSTEDO is taken. Keep AUSTEDO XR and AUSTEDO and all medicines out of the reach of children. General information about the safe and effective use of AUSTEDO XR and AUSTEDO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AUSTEDO XR or AUSTEDO for a condition for which it was not prescribed. Do not give AUSTEDO XR or AUSTEDO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about AUSTEDO XR and AUSTEDO that is written for health professionals. What are the ingredients in AUSTEDO XR and AUSTEDO? AUSTEDO XR: Active ingredient: deutetrabenazine Inactive ingredients: ammonium hydroxide, black iron oxide, butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, cellulose acetate, hydroxypropyl cellulose, hypromellose, isopropyl alcohol, magnesium stearate, polyethylene glycol, polyethylene glycol 3350, polyethylene oxide, polyvinyl alcohol, propylene glycol, shellac, sodium chloride, talc, titanium dioxide, and FD&C red #40 lake. The 6 mg, 12 mg, 18 mg, 30 mg, 36 mg, and 42 mg extended- release tablets also contain FD&C yellow #6 lake. The 6 mg, 12 mg, 24 mg, and 36 mg extended-release tablets also contain FD&C blue #2 lake. The 18 mg extended-release tablets also contain carmine. AUSTEDO: Active ingredient: deutetrabenazine Inactive ingredients: ammonium hydroxide, black iron oxide, n-butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyethylene oxide, polysorbate 80, polyvinyl alcohol, povidone, propylene glycol, shellac, talc, titanium dioxide, and FD&C blue #2 lake. The 6 mg tablets also contain FD&C red #40 lake. The 12 mg tablets also contain FD&C yellow #6 lake. Manufactured for: Teva Neuroscience, Inc. Parsippany, NJ 07054 ©2024 Teva Neuroscience, Inc. AUSMG-010 For more information, go to www.AUSTEDO.com or call 1-888-483-8279. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: July 2024 Reference ID: 5486197
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2025-02-12T15:47:24.509458
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_________________ ______________ ______________ ______________ _______________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AUSTEDO XR or AUSTEDO safely and effectively. See full prescribing information for AUSTEDO XR and AUSTEDO. AUSTEDO® XR (deutetrabenazine) extended-release tablets, for oral use AUSTEDO® (deutetrabenazine) tablets, for oral use Initial U.S. Approval: 2017 WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE See full prescribing information for complete boxed warning. • Increases the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease (5.1) • Balance risks of depression and suicidality with the clinical need for treatment of chorea when considering the use of AUSTEDO XR or AUSTEDO (5.1) • Monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior (5.1) • Inform patients, caregivers, and families of the risk of depression and suicidality and instruct to report behaviors of concern promptly to the treating physician (5.1) • Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation (5.1) • AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression (4, 5.1) __________________ INDICATIONS AND USAGE AUSTEDO XR and AUSTEDO are vesicular monoamine transporter 2 (VMAT2) inhibitors indicated in adults for the treatment of: • Chorea associated with Huntington’s disease (1) • Tardive dyskinesia (1) _______________ DOSAGE AND ADMINISTRATION AUSTEDO XR AUSTEDO Recommended Starting Dosage 12 mg once daily (12 mg per day) 6 mg twice daily (12 mg per day) • Titrate at weekly intervals by 6 mg per day based on reduction of chorea or tardive dyskinesia, and tolerability, up to a maximum recommended daily dosage of 48 mg (2.1) • Administer AUSTEDO XR with or without food in once-daily doses (2.1) • Administer AUSTEDO with food and administer total daily dosages of 12 mg or above in two divided doses (2.1) • Swallow tablets whole; do not chew, crush, or break (2.1) • If switching patients from tetrabenazine, discontinue tetrabenazine and initiate AUSTEDO XR or AUSTEDO the following day. See full prescribing information for recommended conversion table (2.2) • Maximum recommended dosage of AUSTEDO XR or AUSTEDO in poor CYP2D6 metabolizers is 36 mg per day (2.4, 8.7) DOSAGE FORMS AND STRENGTHS • Extended-release tablets: 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, and 48 mg (3) • Tablets: 6 mg, 9 mg, and 12 mg (3) ___________________ CONTRAINDICATIONS____________________ • Suicidal, or untreated/inadequately treated depression in patients with Huntington’s disease (4, 5.1) • Hepatic impairment (4, 8.6, 12.3) • Taking reserpine, MAOIs, tetrabenazine, or valbenazine (4, 7.2, 7.3, 7.6) _______________ WARNINGS AND PRECAUTIONS _______________ • QT Prolongation: Avoid use in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval (5.3) • Neuroleptic Malignant Syndrome (NMS): Discontinue if this occurs (5.4) • Akathisia, agitation, restlessness, and parkinsonism: Reduce dose or discontinue if this occurs (5.5, 5.6) • Sedation/somnolence: May impair the patient’s ability to drive or operate complex machinery (5.7) ____________________ADVERSE REACTIONS____________________ • Most common adverse reactions (>8% of AUSTEDO-treated patients with Huntington’s disease and greater than placebo): somnolence, diarrhea, dry mouth, and fatigue (6.1) • Most common adverse reactions (that occurred in 4% of AUSTEDO- treated patients with tardive dyskinesia and greater than placebo): nasopharyngitis and insomnia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ____________________DRUG INTERACTIONS____________________ • Concomitant use of strong CYP2D6 inhibitors: Maximum recommended dose of AUSTEDO XR or AUSTEDO is 36 mg per day (2.3, 7.1) • Alcohol or other sedating drugs: May have additive sedation and somnolence (7.5) USE IN SPECIFIC POPULATIONS _______________ Pregnancy: Based on animal data, may cause fetal harm (8.1) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 7/2024 1 Reference ID: 5486197 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON'S DISEASE 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information 2.2 Switching Patients from Tetrabenazine to AUSTEDO XR or AUSTEDO 2.3 Dosage Adjustment with Strong CYP2D6 Inhibitors 2.4 Dosage Adjustment in Poor CYP2D6 Metabolizers 2.5 Discontinuation and Interruption of Treatment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Depression and Suicidality in Patients with Huntington's Disease 5.2 Clinical Worsening and Adverse Events in Patients with Huntington's Disease 5.3 QTc Prolongation 5.4 Neuroleptic Malignant Syndrome (NMS) 5.5 Akathisia, Agitation, and Restlessness 5.6 Parkinsonism 5.7 Sedation and Somnolence 5.8 Hyperprolactinemia 5.9 Binding to Melanin-Containing Tissues 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Strong CYP2D6 Inhibitors 7.2 Reserpine 7.3 Monoamine Oxidase Inhibitors (MAOIs) 7.4 Neuroleptic Drugs 7.5 Alcohol or Other Sedating Drugs 7.6 Concomitant Tetrabenazine or Valbenazine 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Poor CYP2D6 Metabolizers 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Chorea Associated with Huntington's Disease 14.2 Tardive Dyskinesia 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 2 Reference ID: 5486197 FULL PRESCRIBING INFORMATION WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease. Anyone considering the use of AUSTEDO XR or AUSTEDO must balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Patients, their caregivers, and families should be informed of the risk of depression and suicidality and should be instructed to report behaviors of concern promptly to the treating physician. Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntington’s disease. AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression [see Contraindications (4) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE AUSTEDO® XR and AUSTEDO® are indicated in adults for the treatment of: • chorea associated with Huntington’s disease [see Clinical Studies (14.1)] • tardive dyskinesia [see Clinical Studies (14.2)] 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The dose of AUSTEDO XR and AUSTEDO is determined individually for each patient based on reduction of chorea or tardive dyskinesia and tolerability. Table 1 displays the recommended dosage and important administration instructions of AUSTEDO XR and AUSTEDO when first prescribed to patients who are not being switched from tetrabenazine (a related VMAT2 inhibitor). 3 Reference ID: 5486197 Table 1: Recommended Dosage and Important Administration Instructions for AUSTEDO XR and AUSTEDO AUSTEDO XR extended-release tablet AUSTEDO tablet Recommended Starting Dosage 12 mg once daily (12 mg per day) 6 mg twice daily (12 mg per day) Recommended Dose Titration The dosage of AUSTEDO XR or AUSTEDO may be increased at weekly intervals in increments of 6 mg per day based on reduction of chorea or tardive dyskinesia, and tolerability, up to a maximum recommended daily dosage of 48 mg [see Clinical Trials (14.1, 14.2)]. Important Administration Instructions • Administer AUSTEDO XR with or without food [see Clinical Pharmacology (12.3)]. • Swallow AUSTEDO XR whole. Do not chew, crush, or break tablets. • Administer AUSTEDO XR once daily. • Administer AUSTEDO with food [see Clinical Pharmacology (12.3)]. • Swallow AUSTEDO whole. Do not chew, crush, or break tablets. • Administer AUSTEDO total daily dosages of 12 mg or above in two divided doses. Switching Between AUSTEDO and AUSTEDO XR When switching between AUSTEDO tablets (twice daily) and AUSTEDO XR extended-release tablets (once daily), switch to the same total daily dosage. 2.2 Switching Patients from Tetrabenazine to AUSTEDO XR or AUSTEDO Discontinue tetrabenazine and initiate AUSTEDO XR or AUSTEDO the following day. The recommended initial dosing regimen of AUSTEDO XR or AUSTEDO in patients switching from tetrabenazine to AUSTEDO XR or AUSTEDO is shown in Table 2. Table 2: Recommended Initial Dosing Regimen when Switching from Tetrabenazine to AUSTEDO XR or AUSTEDO Current tetrabenazine daily dosage Initial regimen of AUSTEDO XR extended-release tablet Initial regimen of AUSTEDO tablet 12.5 mg 6 mg once daily 6 mg once daily 25 mg 12 mg once daily 6 mg twice daily 37.5 mg 18 mg once daily 9 mg twice daily 50 mg 24 mg once daily 12 mg twice daily 62.5 mg 30 mg once daily 15 mg twice daily 75 mg 36 mg once daily 18 mg twice daily 87.5 mg 42 mg once daily 21 mg twice daily 100 mg 48 mg once daily 24 mg twice daily 4 Reference ID: 5486197 After patients are switched to AUSTEDO XR or AUSTEDO, the dose may be adjusted at weekly intervals [see Dosage and Administration (2.1)]. 2.3 Dosage Adjustment with Strong CYP2D6 Inhibitors In patients receiving strong CYP2D6 inhibitors, the total daily dosage of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 2.4 Dosage Adjustment in Poor CYP2D6 Metabolizers In patients who are poor CYP2D6 metabolizers, the total daily dosage of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Use in Specific Populations (8.7)]. 2.5 Discontinuation and Interruption of Treatment Treatment with AUSTEDO XR or AUSTEDO can be discontinued without tapering. Following treatment interruption of greater than one week, AUSTEDO XR or AUSTEDO therapy should be re-titrated when resumed. For treatment interruption of less than one week, treatment can be resumed at the previous maintenance dose without titration. 3 DOSAGE FORMS AND STRENGTHS AUSTEDO XR extended-release tablets are available in the following strengths: • The 6 mg extended-release tablets are round, grey-coated tablets, with “Q6” printed in black ink on one side. • The 12 mg extended-release tablets are round, blue-coated tablets, with “Q12” printed in black ink on one side. • The 18 mg extended-release tablets are round, light grey-coated tablets, with “Q18” printed in black ink on one side. • The 24 mg extended-release tablets are round, purple-coated tablets, with “Q24” printed in black ink on one side. • The 30 mg extended-release tablets are round, light orange-coated tablets, with “Q30” printed in black ink on one side. • The 36 mg extended-release tablets are round, light purple-coated tablets, with “Q36” printed in black ink on one side. • The 42 mg extended-release tablets are round, orange-coated tablets, with “Q42” printed in black ink on one side. • The 48 mg extended-release tablets are round, pink-coated tablets, with “Q48” printed in black ink on one side. 5 Reference ID: 5486197 AUSTEDO tablets are available in the following strengths: • The 6 mg tablets are round, purple-coated tablets, with “SD” over “6” printed in black ink on one side. • The 9 mg tablets are round, blue-coated tablets, with “SD” over “9” printed in black ink on one side. • The 12 mg tablets are round, beige-coated tablets, with “SD” over “12” printed in black ink on one side. 4 CONTRAINDICATIONS AUSTEDO XR and AUSTEDO are contraindicated in patients: • With Huntington’s disease who are suicidal, or have untreated or inadequately treated depression [see Warnings and Precautions (5.1)]. • With hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. • Taking reserpine. At least 20 days should elapse after stopping reserpine before starting AUSTEDO XR or AUSTEDO [see Drug Interactions (7.2)]. • Taking monoamine oxidase inhibitors (MAOIs). AUSTEDO XR and AUSTEDO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI [see Drug Interactions (7.3)]. • Taking tetrabenazine or valbenazine [see Drug Interactions (7.6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Depression and Suicidality in Patients with Huntington’s Disease Patients with Huntington’s disease are at increased risk for depression, and suicidal ideation or behaviors (suicidality). AUSTEDO XR and AUSTEDO may increase the risk for suicidality in patients with Huntington’s disease. In a 12-week, double-blind, placebo-controlled trial, suicidal ideation was reported by 2% of patients treated with AUSTEDO, compared to no patients on placebo; no suicide attempts and no completed suicides were reported. Depression was reported by 4% of patients treated with AUSTEDO. When considering the use of AUSTEDO XR or AUSTEDO, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with AUSTEDO XR or AUSTEDO should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with AUSTEDO XR or AUSTEDO. Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with AUSTEDO XR and AUSTEDO, and should be 6 Reference ID: 5486197 instructed to report behaviors of concern promptly to the treating physician. Patients with Huntington’s disease who express suicidal ideation should be evaluated immediately. 5.2 Clinical Worsening and Adverse Events in Patients with Huntington’s Disease Huntington’s disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. VMAT2 inhibitors, including AUSTEDO XR and AUSTEDO, may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects, including sedation/somnolence, depression and suicidality, parkinsonism, akathisia, restlessness, and cognitive decline. It may be difficult to distinguish between adverse reactions and progression of the underlying disease; decreasing the dose or stopping the drug may help the clinician to distinguish between the two possibilities. In some patients, the underlying chorea itself may improve over time, decreasing the need for AUSTEDO XR or AUSTEDO. 5.3 QTc Prolongation AUSTEDO XR and AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO XR or AUSTEDO is administered within the recommended dosage range [see Clinical Pharmacology (12.2)]. AUSTEDO XR and AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval. 5.4 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with drugs that reduce dopaminergic transmission. While NMS has not been observed in patients receiving AUSTEDO XR or AUSTEDO, it has been observed in patients receiving tetrabenazine (a closely related VMAT2 inhibitor). Clinicians should be alerted to the signs and symptoms associated with NMS. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include (1) immediate discontinuation of AUSTEDO XR and AUSTEDO; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of 7 Reference ID: 5486197 any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. Recurrence of NMS has been reported with resumption of drug therapy. If treatment with AUSTEDO XR or AUSTEDO is needed after recovery from NMS, patients should be monitored for signs of recurrence. 5.5 Akathisia, Agitation, and Restlessness AUSTEDO XR and AUSTEDO may increase the risk of akathisia, agitation, and restlessness in patients with Huntington’s disease and tardive dyskinesia. In a 12-week, double-blind, placebo-controlled trial in patients with Huntington’s disease, akathisia, agitation, or restlessness was reported by 4% of patients treated with AUSTEDO, compared to 2% of patients on placebo; in patients with tardive dyskinesia, 2% of patients treated with AUSTEDO and 1% of patients on placebo experienced these events. Patients receiving AUSTEDO XR or AUSTEDO should be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia during treatment with AUSTEDO XR or AUSTEDO, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy. 5.6 Parkinsonism AUSTEDO XR and AUSTEDO may cause parkinsonism in patients with Huntington’s disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. Because rigidity can develop as part of the underlying disease process in Huntington’s disease, it may be difficult to distinguish between potential drug-induced parkinsonism and progression of underlying Huntington’s disease. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington’s disease. Postmarketing cases of parkinsonism in patients treated with AUSTEDO for tardive dyskinesia have been reported. Signs and symptoms in reported cases have included bradykinesia, gait disturbances, which led to falls in some cases, and the emergence or worsening of tremor. In most cases, the development of parkinsonism occurred within the first two weeks after starting or increasing the dose of AUSTEDO. In cases in which follow-up clinical information was available, parkinsonism was reported to resolve following discontinuation of AUSTEDO therapy. If a patient develops parkinsonism during treatment with AUSTEDO XR or AUSTEDO, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy. 5.7 Sedation and Somnolence Sedation is a common dose-limiting adverse reaction of AUSTEDO XR and AUSTEDO. In a 12-week, double-blind, placebo-controlled trial examining patients with Huntington’s disease, 11% of AUSTEDO-treated patients reported somnolence compared with 4% of patients on placebo and 9% of AUSTEDO-treated patients reported fatigue compared with 4% of placebo- treated patients. 8 Reference ID: 5486197 Patients should not perform activities requiring mental alertness to maintain the safety of themselves or others, such as operating a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of AUSTEDO XR or AUSTEDO and know how the drug affects them. 5.8 Hyperprolactinemia Serum prolactin levels were not evaluated in the AUSTEDO XR and AUSTEDO development program. Tetrabenazine, a closely related VMAT2 inhibitor, elevates serum prolactin concentrations in humans. Following administration of 25 mg of tetrabenazine to healthy volunteers, peak plasma prolactin levels increased 4- to 5-fold. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if AUSTEDO XR or AUSTEDO is being considered for a patient with previously detected breast cancer. Although amenorrhea, galactorrhea, gynecomastia, and impotence can be caused by elevated serum prolactin concentrations, the clinical significance of elevated serum prolactin concentrations for most patients is unknown. Chronic increase in serum prolactin levels (although not evaluated in the AUSTEDO XR, AUSTEDO, or tetrabenazine development programs) has been associated with low levels of estrogen and increased risk of osteoporosis. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of AUSTEDO XR and AUSTEDO. 5.9 Binding to Melanin-Containing Tissues Since deutetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that AUSTEDO XR and AUSTEDO may cause toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic examination of the eye has been conducted in the chronic toxicity studies in a pigmented species such as dogs. Ophthalmologic monitoring in humans was inadequate to exclude the possibility of injury occurring after long-term exposure. The clinical relevance of deutetrabenazine’s binding to melanin-containing tissues is unknown. Although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects [see Clinical Pharmacology (12.2)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Depression and Suicidality in Patients with Huntington’s disease [see Warnings and Precautions (5.1)] • QTc Prolongation [see Warnings and Precautions (5.3)] • Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4)] 9 Reference ID: 5486197 • Akathisia, Agitation, and Restlessness [see Warnings and Precautions (5.5)] • Parkinsonism [see Warnings and Precautions (5.6)] • Sedation and Somnolence [see Warnings and Precautions (5.7)] • Hyperprolactinemia [see Warnings and Precautions (5.8)] • Binding to Melanin-Containing Tissues [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The studies described below were conducted with AUSTEDO tablets; adverse reactions with AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets. Patients with Huntington’s Disease Study 1 [see Clinical Studies (14.1)] was a randomized, 12-week, placebo-controlled study in patients with chorea associated with Huntington’s disease. A total of 45 patients received AUSTEDO, and 45 patients received placebo. Patients ranged in age between 23 and 74 years (mean 54 years); 56% were male, and 92% were Caucasian. The most common adverse reactions occurring in greater than 8% of AUSTEDO-treated patients were somnolence, diarrhea, dry mouth, and fatigue. Adverse reactions occurring in 4% or more of patients treated with AUSTEDO, and with a greater incidence than in patients on placebo, are summarized in Table 3. Table 3: Adverse Reactions in Patients with Huntington’s Disease (Study 1) Experienced by at Least 4% of Patients on AUSTEDO and with a Greater Incidence than on Placebo Adverse Reaction AUSTEDO (N = 45) % Placebo (N = 45) % Somnolence 11 4 Diarrhea 9 0 Dry mouth 9 7 Fatigue 9 4 Urinary tract infection 7 2 Insomnia 7 4 Anxiety 4 2 Constipation 4 2 Contusion 4 2 10 Reference ID: 5486197 One or more adverse reactions resulted in a reduction of the dose of study medication in 7% of patients in Study 1. The most common adverse reaction resulting in dose reduction in patients receiving AUSTEDO was dizziness (4%). Agitation led to discontinuation in 2% of patients treated with AUSTEDO in Study 1. Patients with Tardive Dyskinesia The data described below reflect 410 tardive dyskinesia patients participating in clinical trials. AUSTEDO was studied primarily in two 12-week, placebo-controlled trials (fixed dose, dose escalation) [see Clinical Studies (14.2)]. The population was 18 to 80 years of age, and had tardive dyskinesia and had concurrent diagnoses of mood disorder (33%) or schizophrenia/schizoaffective disorder (63%). In these studies, AUSTEDO was administered in doses ranging from 12-48 mg per day. All patients continued on previous stable regimens of antipsychotics; 71% and 14% respective atypical and typical antipsychotic medications at study entry. The most common adverse reactions occurring in greater than 3% of AUSTEDO-treated patients and greater than placebo were nasopharyngitis and insomnia. The adverse reactions occurring in >2% or more patients treated with AUSTEDO (12-48 mg per day) and greater than in placebo patients in two double-blind, placebo-controlled studies in patients with tardive dyskinesia (Study 1 and Study 2) are summarized in Table 4. Table 4: Adverse Reactions in 2 Placebo-Controlled Tardive Dyskinesia Studies (Study 1 and Study 2) of 12-week Treatment on AUSTEDO Reported in at Least 2% of Patients and Greater than Placebo Preferred Term AUSTEDO (N=279) (%) Placebo (N=131) (%) Nasopharyngitis 4 2 Insomnia 4 1 Depression/ Dysthymic disorder 2 1 Akathisia/Agitation/Restlessness 2 1 One or more adverse reactions resulted in a reduction of the dose of study medication in 4% of AUSTEDO-treated patients and in 2% of placebo-treated patients. 7 DRUG INTERACTIONS 7.1 Strong CYP2D6 Inhibitors A reduction in AUSTEDO XR or AUSTEDO dose may be necessary when adding a strong CYP2D6 inhibitor in patients maintained on a stable dose of AUSTEDO XR or AUSTEDO. Concomitant use of strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine, bupropion) has been shown to increase the systemic exposure to the active dihydro-metabolites of deutetrabenazine by approximately 3-fold. The daily dose of AUSTEDO XR or AUSTEDO 11 Reference ID: 5486197 should not exceed 36 mg per day in patients taking strong CYP2D6 inhibitors [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. 7.2 Reserpine Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers should wait for chorea or dyskinesia to reemerge before administering AUSTEDO XR or AUSTEDO to help reduce the risk of overdosage and major depletion of serotonin and norepinephrine in the central nervous system. At least 20 days should elapse after stopping reserpine before starting AUSTEDO XR or AUSTEDO. AUSTEDO XR and AUSTEDO should not be used concomitantly with reserpine [see Contraindications (4)]. 7.3 Monoamine Oxidase Inhibitors (MAOIs) AUSTEDO XR and AUSTEDO are contraindicated in patients taking MAOIs. AUSTEDO XR and AUSTEDO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI [see Contraindications (4)]. 7.4 Neuroleptic Drugs The risk of parkinsonism, NMS, and akathisia may be increased by concomitant use of AUSTEDO XR or AUSTEDO with dopamine antagonists or antipsychotics. 7.5 Alcohol or Other Sedating Drugs Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence [see Warnings and Precautions (5.7)]. 7.6 Concomitant Tetrabenazine or Valbenazine AUSTEDO XR and AUSTEDO are contraindicated in patients currently taking tetrabenazine or valbenazine. AUSTEDO XR or AUSTEDO may be initiated the day following discontinuation of tetrabenazine [see Dosage and Administration (2.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of AUSTEDO XR or AUSTEDO in pregnant women. Administration of deutetrabenazine to rats during organogenesis produced no clear adverse effect on embryofetal development. However, administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in stillbirths and postnatal offspring mortality [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. 12 Reference ID: 5486197 Data Animal Data Oral administration of deutetrabenazine (5, 10, or 30 mg/kg/day) or tetrabenazine (30 mg/kg/day) to pregnant rats during organogenesis had no clear effect on embryofetal development. The highest dose tested was 6 times the maximum recommended human dose of 48 mg/day, on a body surface area (mg/m2) basis. The effects of deutetrabenazine when administered during organogenesis to rabbits or during pregnancy and lactation to rats have not been assessed. Tetrabenazine had no effects on embryofetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day. When tetrabenazine was administered to female rats (doses of 5, 15, and 30 mg/kg/day) from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day, and delayed pup maturation was observed at all doses. 8.2 Lactation Risk Summary There are no data on the presence of deutetrabenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AUSTEDO XR or AUSTEDO and any potential adverse effects on the breastfed infant from AUSTEDO XR or AUSTEDO or from the underlying maternal condition. 8.4 Pediatric Use Chorea associated with Huntington’s Disease and Tardive Dyskinesia The safety and effectiveness of AUSTEDO XR and AUSTEDO have not been established in pediatric patients for the treatment of chorea associated with Huntington’s disease or for the treatment of tardive dyskinesia. Tourette Syndrome The safety and effectiveness of AUSTEDO XR and AUSTEDO have not been established in pediatric patients for the treatment of Tourette syndrome. Efficacy was not demonstrated in two randomized, double-blind, placebo-controlled studies in pediatric patients aged 6 to 16 years with Tourette syndrome. One study evaluated fixed doses of deutetrabenazine over 8 weeks (NCT03571256); the other evaluated flexible doses of deutetrabenazine over 12 weeks (NCT03452943). The studies included a total of 274 pediatric patients who received at least one dose of deutetrabenazine or placebo. The primary efficacy endpoint in both studies was the change from baseline to end-of-treatment on the Yale Global Tic Severity Scale Total Tic Score (YGTSS-TTS). The estimated treatment effect of deutetrabenazine on the YGTSS-TTS was not statistically significantly different from placebo in either study. The placebo subtracted least squares means difference in YGTSS-TTS from 13 Reference ID: 5486197 baseline to end-of-treatment was -0.7 (95% CI: -4.1, 2.8) in the flexible dose study and -0.8 (95% CI: -3.9, 2.3) for the primary analysis in the fixed dose study. The following adverse reactions were reported in frequencies of at least 5% of pediatric patients treated with AUSTEDO and with a greater incidence than in pediatric patients receiving placebo (AUSTEDO vs placebo): headache (includes: migraine, migraine with aura, and headache; 13% vs 9%), somnolence (includes: sedation, hypersomnia, and somnolence; 11% vs 2%), fatigue (8% vs 3%), increased appetite (5% vs <1%), and increased weight (5% vs <1%). Juvenile Animal Toxicity Data Deutetrabenazine orally administered to juvenile rats from postnatal days 21 through 70 (at 2.5, 5, or 10 mg/kg/day) resulted in an increased incidence of tremor, hyperactivity, and adverse increases in motor activity at ≥5 mg/kg/day, and reduced body weight and food consumption at 10 mg/kg/day. There was no reproductive or early embryonic toxicity up to the highest dose. All drug-related findings were reversible after a drug-free period. The no observed adverse effect level (NOAEL) in juvenile rats was 2.5 mg/kg/day. These drug-related findings were similar to those observed in adult rats; however, the juvenile rats were more sensitive. 8.5 Geriatric Use Clinical studies of AUSTEDO XR and AUSTEDO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of hepatic, renal, and cardiac dysfunction, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of deutetrabenazine and its primary metabolites has not been studied; however, in a clinical study conducted with tetrabenazine, a closely related VMAT2 inhibitor, there was a large increase in exposure to tetrabenazine and its active metabolites in patients with hepatic impairment. The clinical significance of this increased exposure has not been assessed, but because of concerns for a greater risk for serious adverse reactions, the use of AUSTEDO XR or AUSTEDO in patients with hepatic impairment is contraindicated [see Contraindications (4), Clinical Pharmacology (12.3)]. 8.7 Poor CYP2D6 Metabolizers Although the pharmacokinetics of deutetrabenazine and its metabolites have not been systematically evaluated in patients who do not express the drug metabolizing enzyme, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similarly to taking a strong CYP2D6 inhibitor (approximately 3-fold). In patients who are CYP2D6 poor metabolizers, the daily dose of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. 14 Reference ID: 5486197 10 OVERDOSAGE Overdoses ranging from 100 mg to 1 g have been reported in the literature with tetrabenazine, a closely related VMAT2 inhibitor. The following adverse reactions occurred with overdosing: acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. Treatment should consist of those general measures employed in the management of overdosage with any central nervous system-active drug. General supportive and symptomatic measures are recommended. Cardiac rhythm and vital signs should be monitored. In managing overdosage, the possibility of multiple drug involvement should always be considered. The physician should consider contacting a poison control center on the treatment of any overdose. Telephone numbers for certified poison control centers are listed on the American Association of Poison Control Centers website www.aapcc.org. 11 DESCRIPTION AUSTEDO XR extended-release tablets and AUSTEDO tablets are formulated with deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor for oral administration. The molecular weight of deutetrabenazine is 323.46; the pKa is 6.31. Deutetrabenazine is a hexahydro-dimethoxybenzoquinolizine derivative and has the following chemical name: (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)­ 2H-benzo[a]quinolizin-2-one. The molecular formula for deutetrabenazine is C19H21D6NO3. Deutetrabenazine is a racemic mixture containing the following structures: D3CO D3CO N N D3CO D3CO H H O O RR - Deutetrabenazine SS - Deutetrabenazine Deutetrabenazine is a white to slightly yellow crystalline powder that is sparingly soluble in water and soluble in ethanol. AUSTEDO XR AUSTEDO XR extended-release tablets contain 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg deutetrabenazine, and the following inactive ingredients: ammonium hydroxide, black iron oxide, butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, cellulose acetate, hydroxypropyl cellulose, hypromellose, isopropyl alcohol, magnesium stearate, polyethylene glycol, polyethylene glycol 3350, polyethylene oxide, polyvinyl alcohol, propylene glycol, shellac, sodium chloride, talc, titanium dioxide, and FD&C red #40 lake. The 6 mg, 12 mg, 18 mg, 30 mg, 36 mg, and 42 mg extended-release tablets also contain FD&C yellow #6 lake. The 6 mg, 12 mg, 24 mg, and 36 mg extended-release tablets also contain FD&C blue #2 lake. The 18 mg extended-release tablets also contain carmine. 15 Reference ID: 5486197 AUSTEDO XR Delivery System Components and Performance AUSTEDO XR uses osmotic pressure to deliver deutetrabenazine at a controlled rate. The delivery system, which resembles a round tablet in appearance, consists of a bilayer core tablet that contains deutetrabenazine along with other excipients. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool. AUSTEDO AUSTEDO tablets contain 6 mg, 9 mg, or 12 mg deutetrabenazine, and the following inactive ingredients: ammonium hydroxide, black iron oxide, butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyethylene oxide, polysorbate 80, polyvinyl alcohol, povidone, propylene glycol, shellac, talc, titanium dioxide, and FD&C blue #2 lake. The 6 mg tablets also contain FD&C red #40 lake. The 12 mg tablets also contain FD&C yellow #6 lake. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanism by which deutetrabenazine exerts its effects in the treatment of tardive dyskinesia and chorea in patients with Huntington’s disease is unknown but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. The major circulating metabolites (α­ dihydrotetrabenazine [HTBZ] and β-HTBZ) of deutetrabenazine, are reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. 12.2 Pharmacodynamics Cardiac Electrophysiology At the maximum recommended dose, AUSTEDO XR and AUSTEDO do not prolong the QT interval to any clinically relevant extent. An exposure-response analysis on QTc prolongation from a study in extensive or intermediate (EM) and poor CYP2D6 metabolizers (PM) showed that a clinically-relevant effect can be excluded at exposures following single doses of 24 and 48 mg of AUSTEDO. Melanin Binding Deutetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After a single oral dose of radiolabeled deutetrabenazine, radioactivity was still detected in eye and fur at 35 days following dosing [see Warnings and Precautions (5.9)]. 12.3 Pharmacokinetics After oral dosing, plasma concentrations of deutetrabenazine are low compared to that of the active deuterated metabolites because of the extensive hepatic metabolism of deutetrabenazine. AUSTEDO XR 16 Reference ID: 5486197 Systemic exposure (i.e., peak plasma concentrations [Cmax] and the area under the plasma concentration-time curve [AUC]) for deutetrabenazine and the active, deuterated dihydro metabolites (HTBZ), α-HTBZ and β-HTBZ, increased proportionally to dose following single doses of AUSTEDO XR over the recommended clinical dosage range (6 mg to 48 mg). AUSTEDO Systemic exposure (Cmax and AUC) for the active metabolites increased proportionally to dose following single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily). Absorption Following oral administration of deutetrabenazine, the extent of absorption is at least 80%. AUSTEDO XR Peak plasma concentrations (Cmax) of deutetrabenazine, deuterated α-HTBZ, and β-HTBZ are reached within approximately 3 hours, followed by sustained plateaus for several hours allowing for a 24-hour dosing interval. AUSTEDO Peak plasma concentrations (Cmax) of deutetrabenazine, deuterated α-HTBZ and β-HTBZ are reached within 3 to 4 hours after dosing. Effect of Food AUSTEDO XR The effects of food on the bioavailability of AUSTEDO XR were studied in subjects administered a single dose with and without food. Food had no effect on Cmax or AUC of deutetrabenazine, α-HTBZ or β-HTBZ [see Dosage and Administration (2.1)]. AUSTEDO The effects of food on the bioavailability of AUSTEDO were studied in subjects administered a single dose with and without food. Food had no effect on AUC of α-HTBZ or β-HTBZ, although Cmax was increased by approximately 50% in the presence of food [see Dosage and Administration (2.1)]. Distribution The median volume of distribution (Vc/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 500 L and 730 L, respectively. Results of PET-scan studies in humans show that following intravenous injection of 11C-labeled tetrabenazine or α-HTBZ, radioactivity is rapidly distributed to the brain, with the highest binding in the striatum and lowest binding in the cortex. The in vitro protein binding of tetrabenazine, α-HTBZ, and β-HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%. Elimination 17 Reference ID: 5486197 AUSTEDO XR and AUSTEDO are primarily renally eliminated in the form of metabolites. The half-life of the active deuterated α-HTBZ, β-HTBZ, and total (α+β)-HTBZ metabolites is approximately 12 hours, 7.5 hours, and 9 to 11 hours, respectively. The clearance values (CL/F) of the α-HTBZ, and β-HTBZ metabolites of AUSTEDO are approximately 65 L/hour and 200 L/hour, respectively, for a 70 kg HD or TD patient with functional CYP2D6 metabolism in the fed state. The elimination half-life and clearance of AUSTEDO XR are similar to that of AUSTEDO. Metabolism In vitro experiments in human liver microsomes demonstrate that deutetrabenazine is extensively biotransformed, mainly by carbonyl reductase, to its major active metabolites, α-HTBZ and β­ HTBZ, which are subsequently metabolized primarily by CYP2D6, with minor contributions of CYP1A2 and CYP3A4/5, to form several minor metabolites. Excretion In a mass balance study in 6 healthy subjects, 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose. Urinary excretion of the α-HTBZ and β-HTBZ metabolites from deutetrabenazine each accounted for less than 10% of the administered dose. Sulfate and glucuronide conjugates of the α-HTBZ and β-HTBZ metabolites of deutetrabenazine, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine. Specific Populations Male and Female Patients There is no apparent effect of gender on the pharmacokinetics of α-HTBZ and β-HTBZ of deutetrabenazine. Patients with Renal Impairment No clinical studies have been conducted to assess the effect of renal impairment on the PK of deutetrabenazine and its primary metabolites. Patients with Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of deutetrabenazine and its primary metabolites has not been studied. However, in a clinical study conducted to assess the effect of hepatic impairment on the pharmacokinetics of tetrabenazine, a closely related VMAT2 inhibitor, the exposure to α-HTBZ and β-HTBZ was up to 40% greater in patients with hepatic impairment, and the mean tetrabenazine Cmax in patients with hepatic impairment was up to 190­ fold higher than in healthy subjects [see Contraindications (4), Use in Specific Populations (8.6)]. Poor CYP2D6 Metabolizers Although the pharmacokinetics of deutetrabenazine and its metabolites have not been systematically evaluated in patients who do not express the drug metabolizing enzyme CYP2D6, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similarly to taking 18 Reference ID: 5486197 strong CYP2D6 inhibitors (approximately 3-fold) [see Dosage and Administration (2.4), Drug Interactions (7.1)]. Drug Interaction Studies Deutetrabenazine, α-HTBZ, and β-HTBZ have not been evaluated in in vitro studies for induction or inhibition of CYP enzymes or interaction with P-glycoprotein. The results of in vitro studies of tetrabenazine do not suggest that tetrabenazine or its α-HTBZ or β-HTBZ metabolites are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its α-HTBZ or β-HTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19. Neither tetrabenazine nor its α-HTBZ or β-HTBZ metabolites are likely to be a substrate or inhibitor of P-glycoprotein at clinically relevant concentrations in vivo. The deutetrabenazine metabolites, 2-methylpropanoic acid of β-HTBZ (M1) and monohydroxy tetrabenazine (M4), have been evaluated in a panel of in vitro drug-drug interaction studies; the results indicate that M1/M4 are not expected to cause clinically relevant drug interactions. CYP2D6 Inhibitors In vitro studies indicate that the α-HTBZ and β-HTBZ metabolites of deutetrabenazine are substrates for CYP2D6. The effect of CYP2D6 inhibition on the pharmacokinetics of deutetrabenazine and its metabolites was studied in 24 healthy subjects following a single 22.5 mg dose of deutetrabenazine given after 8 days of administration of the strong CYP2D6 inhibitor paroxetine 20 mg daily. In the presence of paroxetine, systemic exposure (AUCinf) of α­ HTBZ was 1.9-fold higher and β-HTBZ was 6.5-fold higher, resulting in approximately 3-fold increase in AUCinf for total (α+β)-HTBZ. Paroxetine decreased the clearance of α-HTBZ and β­ HTBZ metabolites of AUSTEDO with corresponding increases in mean half-life of approximately 1.5-fold and 2.7-fold, respectively. In the presence of paroxetine, Cmax of α-HTBZ and β-HTBZ were 1.2-fold and 2.2-fold higher, respectively. The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline on the exposure of deutetrabenazine and its metabolites has not been evaluated. Digoxin AUSTEDO XR and AUSTEDO were not evaluated for interaction with digoxin. Digoxin is a substrate for P-glycoprotein. A study in healthy subjects showed that tetrabenazine (25 mg twice daily for 3 days) did not affect the bioavailability of digoxin, suggesting that at this dose, tetrabenazine does not affect P-glycoprotein in the intestinal tract. In vitro studies also do not suggest that tetrabenazine or its metabolites are P-glycoprotein inhibitors. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were performed with deutetrabenazine. 19 Reference ID: 5486197 No increase in tumors was observed in p53+/– transgenic mice treated orally with tetrabenazine at doses of 0, 5, 15, and 30 mg/kg/day for 26 weeks. Mutagenesis Deutetrabenazine and its deuterated α-HTBZ and β-HTBZ metabolites were negative in in vitro (bacterial reverse mutation and chromosome aberration in human peripheral blood lymphocytes) assays in the presence or absence of metabolic activation and in the in vivo micronucleus assay in mice. Impairment of Fertility The effects of deutetrabenazine on fertility have not been evaluated. Oral administration of deutetrabenazine (doses of 5, 10, or 30 mg/kg/day) to female rats for 3 months resulted in estrous cycle disruption at all doses; the lowest dose tested was similar to the maximum recommended human dose (48 mg/day) on a body surface area (mg/m2) basis. Oral administration of tetrabenazine (doses of 5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation, resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day. No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine at doses of 5, 15 or 30 mg/kg/day prior to and throughout mating with untreated females. 14 CLINICAL STUDIES The studies described below establishing effectiveness for Huntington’s disease and tardive dyskinesia were conducted with AUSTEDO tablets. The efficacy of AUSTEDO XR is based on a relative bioavailability study comparing AUSTEDO XR tablets administered once daily and AUSTEDO tablets administered twice daily [see Clinical Pharmacology (12.3)]. 14.1 Chorea Associated with Huntington’s Disease The efficacy of AUSTEDO as a treatment for chorea associated with Huntington's disease was established primarily in Study 1, a randomized, double-blind, placebo-controlled, multi-center trial conducted in 90 ambulatory patients with manifest chorea associated with Huntington’s disease. The diagnosis of Huntington’s disease was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including an 8-week dose titration period and a 4-week maintenance period, followed by a 1-week washout. Patients were not blinded to discontinuation. AUSTEDO was started at 6 mg per day and titrated upward, at weekly intervals, in 6 mg increments until satisfactory treatment of chorea was achieved, intolerable side effects occurred, or until a maximal dose of 48 mg per day was reached. The primary efficacy endpoint was the Total Maximal Chorea Score, an item of the Unified Huntington's Disease Rating Scale (UHDRS). On this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for 7 different parts of the body. The total score ranges from 0 to 28. Of the 90 patients enrolled, 87 patients completed the study. The mean age was 54 (range 23 to 74). Patients were 56% male and 92% Caucasian. The mean dose after titration was 40 mg per day. Table 5 and Figure 1 summarize the effects of AUSTEDO on chorea based on the Total 20 Reference ID: 5486197 15 1-- e:? AUSTEDO ··O · · Placebo Washout 0 14 (J l en f-.,, ,..-1 «s 13 e:? 0 ' ' .c: 12 ' 0 - 1- l "iij 11 ---._ ·-· ------·-!· I . -·· -·· -· -,., E , , ,., ',, + · _,,,,,, ,., . . ,, ,,,, , '5< i 10 ce 9 -- ~ *l ~ 8 w en 7 - C: Dose Titration «s 6 :I *p<0.0001 5 0 2 4 6 9 12 13 Maintenance Study Week Endpoint AUSTEDO, n• 45 45 44 44 45 45 44 45 Placebo, n 45 45 45 44 42 43 43 45 Maximal Chorea Score. Total Maximal Chorea Scores for patients receiving AUSTEDO improved by approximately 4.4 units from baseline to the maintenance period (average of Week 9 and Week 12), compared to approximately 1.9 units in the placebo group. The treatment effect of -2.5 units was statistically significant (p<0.0001). The Maintenance Endpoint is the mean of the Total Maximal Chorea Scores for the Week 9 and Week 12 visits. At the Week 13 follow-up visit (1 week after discontinuation of the study medication), the Total Maximal Chorea Scores of patients who had received AUSTEDO returned to baseline (Figure 1). Table 5: Change from Baseline to Maintenance Therapy in Total Maximal Chorea (TMC)a Score in Patients with Huntington’s Disease Treated with AUSTEDO in Study 1 Motor Endpoint AUSTEDO N = 45 Placebo N = 45 p value Change in Total Chorea Scorea from Baseline to Maintenance Therapyb -4.4 -1.9 <0.0001 aTMC is a subscale of the Unified Huntington's Disease Rating Scale (UHDRS) bPrimary efficacy endpoint Figure 1: Total Maximal Chorea Score Over Time in Study 1 21 Reference ID: 5486197 40 improvement worsening ( > en +-' C 30 Q) ·,.:::::; - AUSTEDO ctS a. - 0 20 D Placebo +-' C Q) (.) lo... Q) 10 a_ 0 a co (0 .,,,. CV a CV .,,,. (0 co co ,_ I I I I E E E E I E E E E E /\ E a co (0 .,,,. ~ a CV .,,,. (0 CV ,_ I I I /\ /\ /\ /\ ,_ I /\ /\ /\ /\ I /\ /\ Total Chorea Score: Change from Baseline to Maintenance Figure 2: Distribution of the Change in Total Maximal Chorea Scores in Study 1 Figure 2 shows the distribution of values for the change in Total Maximal Chorea Score in Study 1. Negative values indicate a reduction in chorea and positive numbers indicate an increase in chorea. A patient-rated global impression of change assessed how patients rated their overall Huntington’s disease symptoms. Fifty-one percent of patients treated with AUSTEDO rated their symptoms as “Much Improved” or “Very Much Improved” at the end of treatment, compared to 20% of placebo-treated patients. In a physician-rated clinical global impression of change, physicians rated 42% percent of patients treated with AUSTEDO as “Much Improved” or “Very Much Improved” at the end of treatment compared to 13% of placebo-treated patients. 14.2 Tardive Dyskinesia The efficacy of AUSTEDO in the treatment for tardive dyskinesia was established in two 12-week, randomized, double-blind, placebo-controlled, multi-center trials conducted in 335 adult ambulatory patients with tardive dyskinesia caused by use of dopamine receptor antagonists. Patients had a history of using a dopamine receptor antagonist (antipsychotics, metoclopramide) for at least 3 months (or 1 month in patients 60 years of age and older). Concurrent diagnoses included schizophrenia/schizoaffective disorder (62%) and mood disorder (33%). With respect to concurrent antipsychotic use, 64% of patients were receiving atypical 22 Reference ID: 5486197 antipsychotics, 12% were receiving typical or combination antipsychotics, and 24% were not receiving antipsychotics. The Abnormal Involuntary Movement Scale (AIMS) was the primary efficacy measure for the assessment of tardive dyskinesia severity. The AIMS is a 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this study. Each of the 7 items was scored on a 0 to 4 scale, rated as: 0=not present; 1=minimal, may be extreme normal (abnormal movements occur infrequently and/or are difficult to detect); 2=mild (abnormal movements occur infrequently and are easy to detect); 3=moderate (abnormal movements occur frequently and are easy to detect) or 4 =severe (abnormal movements occur almost continuously and/or of extreme intensity). The AIMS total score (sum of items 1 to 7) could thus range from 0 to 28, with a decrease in score indicating improvement. In Study 1, a 12-week, placebo-controlled, fixed-dose trial, adults with tardive dyskinesia were randomized 1:1:1:1 to 12 mg AUSTEDO, 24 mg AUSTEDO, 36 mg AUSTEDO, or placebo. Treatment duration included a 4-week dose escalation period and an 8-week maintenance period followed by a 1-week washout. The dose of AUSTEDO was started at 12 mg per day and increased at weekly intervals in 6 mg/day increments to a dose target of 12 mg, 24 mg or 36 mg per day. The population (n= 222) was 21 to 81 years old (mean 57 years), 48% male, and 79% Caucasian. In Study 1, the AIMS total score for patients receiving AUSTEDO demonstrated statistically significant improvement, from baseline to Week 12, of 3.3 and 3.2 units for the 36 mg and 24 mg arms, respectively, compared with 1.4 units in placebo (Study 1 in Table 6). The improvements on the AIMS total score over the course of the study are displayed in Figure 3. Data did not suggest substantial differences in efficacy across various demographic groups. The treatment response rate distribution, based on magnitude of AIMS total score from baseline to week 12 is displayed in Figure 4. The mean changes in the AIMS total score by visit are shown in Figure 3. In Study 2, a 12-week, placebo-controlled, flexible-dose trial, adults with tardive dyskinesia (n=113) received daily doses of placebo or AUSTEDO, starting at 12 mg per day with increases allowed in 6-mg increments at 1-week intervals until satisfactory control of dyskinesia was achieved, until intolerable side effects occurred, or until a maximal dose of 48 mg per day was reached. Treatment duration included a 6-week dose titration period and a 6-week maintenance period followed by a 1-week washout. The population was 25 to 75 years old (mean 55 years), 48% male, and 70% Caucasian. Patients were titrated to an optimal dose over 6 weeks. The average dose of AUSTEDO after treatment was 38.3 mg per day. There was no evidence suggesting substantial differences in efficacy across various demographic groups. In Study 2, AIMS total score for patients receiving AUSTEDO demonstrated statistically significant improvement by 3.0 units from baseline to endpoint (Week 12), compared with 1.6 units in the placebo group with a treatment effect of -1.4 units. Table 6 summarizes the effects of AUSTEDO on tardive dyskinesia based on the AIMS. 23 Reference ID: 5486197 IO PLACEBO □ AUSTEDO l2 MG/DAY e AUSTEDO 24 MG/DAY ♦ AUSTEDO 36 MG/DAY I 0 -l Gi' ~ = -2 " " ~ -3 -4 Study week: 0 2 4 8 12 Number of patients AUSTEDO 36 MG/DAY 55 55 52 53 52 AUSTEDO 24 MG/DAY 49 49 47 46 45 AUSTEDO 12 MG/DAY 60 60 58 56 53 PLACEBO 58 58 57 57 56 Table 6: Improvement in AIMS Total Score in Patients Treated with AUSTEDO in Study 1 and Study 2 Study Treatment Group Primary Efficacy Measure: AIMS Total Score Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Treatment Effect (95% CI) Study 1 AUSTEDO 36 mg* (n= 55) 10.1 (3.21) -3.3 (0.42) -1.9 (-3.09, -0.79) AUSTEDO 24 mg (n= 49) 9.4 (2.93) -3.2 (0.45) -1.8 (-3.00, -0.63) AUSTEDO 12 mg (n= 60) 9.6 (2.40) -2.1 (0.42) -0.7 (-1.84, 0.42) Placebo (n= 58) 9.5 (2.71) -1.4 (0.41) Study 2 AUSTEDO (12-48 mg/day)* (n= 56) 9.7 (4.14) -3.0 (0.45) -1.4 (-2.6, -0.2) Placebo (n= 57) 9.6 (3.78) -1.6 (0.46) *Dose that was statistically significantly different from placebo after adjusting for multiplicity. LS Mean = Least-squares mean; SD = Standard deviation; SE = Standard error; CI = 2-sided 95% confidence interval Figure 3: Least Square Means of Change in AIMS Total Score from Baseline for AUSTEDO Compared to Placebo (Study 1) SE = Standard error 24 Reference ID: 5486197 ID Placebo D AUSTEDO 12 mg D AUSTEDO 24 mg ■ AUSTEDO 36 mg I so 43 43 40 ~ 35 :;?_ ~ 2l = 30 " 29 ·-= "' 11. 25 "-< 0 23 = " 0 20 21 .... 20 " 11. 15 l2 10 3 0 ~-....... -'--t-- Missing No change or worsened l to 3 4 to 6 7 to 9 10 to l3 Magnitude oflmprovement from Baseline in AIMS Total Score Figure 4: Percent of Patients with Specified Magnitude of AIMS Total Score Improvement at the End of Week 12 (Study 1) 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied AUSTEDO XR extended-release tablets are supplied in the following configurations: Strength Description Package Configuration NDC Code 6 mg Round, grey-coated tablets, with “Q6” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-470-56 12 mg Round, blue-coated tablets, with “Q12” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-471-56 18 mg Round, light grey-coated tablets, with “Q18” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-479-56 24 mg Round, purple-coated tablets, with “Q24” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-472-56 30 mg Round, light orange-coated tablets, with “Q30” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-473-56 36 mg Round, light purple-coated tablets, with “Q36” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-474-56 25 Reference ID: 5486197 42 mg Round, orange-coated tablets, with “Q42” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-475-56 48 mg Round, pink-coated tablets, with “Q48” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-476-56 AUSTEDO XR Patient Titration Kits are supplied in the following configuration: Strength Description Package Configuration NDC Code 4-Week Patient Titration Kit 12 mg Round, blue-coated tablets, with “Q12” printed in black ink on one side Titration Kit / 28 count Each Titration Kit contains 1 child-resistant blister pack, containing one foil card with extended-release tablets in the following configuration: Seven 12 mg tablets taken during Week 1; seven 18 mg tablets taken during Week 2; seven 24 mg tablets taken during Week 3; and seven 30 mg tablets taken during Week 4. 68546-477-29 18 mg Round, light grey-coated tablets, with “Q18” printed in black ink on one side 24 mg Round, purple-coated tablets, with “Q24” printed in black ink on one side 30 mg Round, light orange- coated tablets, with “Q30” printed in black ink on one side AUSTEDO tablets are supplied in the following configurations: Strength Description Package Configuration NDC Code 6 mg Round, purple-coated tablets, with “SD” over “6” printed in black ink on one side Bottle with child-resistant cap / 60 count 68546-170-60 9 mg Round, blue-coated tablets, with “SD” over “9” printed in black ink on one side Bottle with child-resistant cap / 60 count 68546-171-60 12 mg Round, beige-coated tablets, with “SD” over “12” printed in black ink on one side Bottle with child-resistant cap / 60 count 68546-172-60 26 Reference ID: 5486197 16.2 Storage Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Dispense in original containers or in tight containers as defined in USP. 17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). Administration Instructions Instruct patients to swallow AUSTEDO XR or AUSTEDO whole and not to chew, crush, or break AUSTEDO XR or AUSTEDO [see Dosage and Administration (2.1)]. AUSTEDO XR Advise patients to take AUSTEDO XR with or without food in once-daily doses. Inform patients not to be concerned if they occasionally notice something that looks like a tablet shell in their stool [see Description (11)]. AUSTEDO Advise patients to take AUSTEDO with food. Advise patients to take daily dosages of 12 mg or higher in two divided doses (twice daily). Risk of Depression and Suicide in Patients with Huntington’s Disease Advise patients, their caregivers, and families that AUSTEDO XR and AUSTEDO may increase the risk of depression, worsening depression, and suicidality, and to immediately report any symptoms to a healthcare provider [see Contraindications (4), Warnings and Precautions (5.1)]. Prolongation of the QTc Interval Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations [see Warnings and Precautions (5.3)]. Advise patients to inform physicians that they are taking AUSTEDO XR or AUSTEDO before any new drug is taken. Parkinsonism Inform patients that AUSTEDO XR and AUSTEDO may cause Parkinson-like symptoms, which could be severe. Advise patients to consult their healthcare provider if they experience slight shaking, body stiffness, trouble moving, trouble keeping their balance, or falls [see Warnings and Precautions (5.6)]. Risk of Sedation and Somnolence Advise patients that AUSTEDO XR and AUSTEDO may cause sedation and somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Until they learn how they respond to a stable dose of AUSTEDO XR or AUSTEDO, patients should be careful doing activities that require them to be alert, such as driving a car or operating machinery [see Warnings and Precautions (5.7)]. Interaction with Alcohol or Other Sedating Drugs 27 Reference ID: 5486197 Advise patients that alcohol or other drugs that cause sleepiness will worsen somnolence [see Drug Interactions (7.5)]. Concomitant Medications Advise patients to notify their physician of all medications they are taking and to consult with their healthcare provider before starting any new medications because of a potential for interactions [see Contraindications (4) and Drug Interactions (7.1, 7.4)]. Dispense with Medication Guide available at: www.tevausa.com/medguides Manufactured for: Teva Neuroscience, Inc. Parsippany, NJ 07054 ©2024 Teva Neuroscience, Inc. AUS-012 AUSTEDO XR U.S. Patent Nos: 8,524,733; 9,550,780; 10,959,996; 11,179,386; 11,357,772; 11,311,488; 11,564,917; 11,446,291; 11,648,244 AUSTEDO U.S. Patent Nos: 8,524,733; 9,233,959; 9,296,739; 9,550,780; 9,814,708; 10,959,996; 11,179,386; 11,357,772; 11,564,917; 11,446,291; 11,648,244; 11,666,566 28 Reference ID: 5486197 Dispense with Medication Guide available at: www.tevausa.com/medguides MEDICATION GUIDE AUSTEDO® XR (aw-STED-oh XR) (deutetrabenazine) extended-release tablets, for oral use AUSTEDO® (aw-STED-oh) (deutetrabenazine) tablets, for oral use What is the most important information I should know about AUSTEDO XR and AUSTEDO? • AUSTEDO XR and AUSTEDO can cause serious side effects in people with Huntington’s disease, including: o depression o suicidal thoughts o suicidal actions • Do not start taking AUSTEDO XR or AUSTEDO if you have Huntington’s disease and are depressed (have untreated depression or depression that is not well controlled by medicine) or have suicidal thoughts. • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is especially important when AUSTEDO XR or AUSTEDO is started and when the dose is changed. Call your healthcare provider right away if you become depressed or have any of the following symptoms, especially if they are new, worse, or worry you: • feel sad or have crying spells • lose interest in seeing your friends or doing things you used to enjoy • sleep a lot more or a lot less than usual • feel unimportant • feel guilty • feel hopeless or helpless • feel more irritable, angry, or aggressive than usual • feel more or less hungry than usual or notice a big change in your body weight • have trouble paying attention • feel tired or sleepy all the time • have thoughts about hurting yourself or ending your life What are AUSTEDO XR and AUSTEDO? AUSTEDO XR and AUSTEDO are prescription medicines that are used to treat: • the involuntary movements (chorea) of Huntington’s disease. AUSTEDO XR and AUSTEDO do not cure the cause of the involuntary movements, and it does not treat other symptoms of Huntington’s disease, such as problems with thinking or emotions. • movements in the face, tongue, or other body parts that cannot be controlled (tardive dyskinesia). It is not known if AUSTEDO XR and AUSTEDO are safe and effective in children. Who should not take AUSTEDO XR or AUSTEDO? Do not take AUSTEDO XR or AUSTEDO if you: • have Huntington’s disease and are depressed or have thoughts of suicide. See “What is the most important information I should know about AUSTEDO XR and AUSTEDO?” • have liver problems. • are taking reserpine. Do not take medicines that contain reserpine with AUSTEDO XR or AUSTEDO. If your healthcare provider plans to switch you from taking reserpine to AUSTEDO XR or AUSTEDO, you must wait at least 20 days after your last dose of reserpine before you start taking AUSTEDO XR or AUSTEDO. • are taking a monoamine oxidase inhibitor (MAOI) medicine. Do not take an MAOI within 14 days after you stop taking AUSTEDO XR or AUSTEDO. Do not start AUSTEDO XR or AUSTEDO if you stopped taking an MAOI in the last 14 days. Ask your healthcare provider or pharmacist if you are not sure. Reference ID: 5486197 • are taking tetrabenazine. If your healthcare provider plans to switch you from tetrabenazine to AUSTEDO XR or AUSTEDO, take your first dose of AUSTEDO XR or AUSTEDO on the day after your last dose of tetrabenazine. • are taking valbenazine. Before taking AUSTEDO XR or AUSTEDO, tell your healthcare provider about all of your medical conditions, including if you: • have emotional or mental problems (for example, depression, nervousness, anxiety, anger, agitation, psychosis, previous suicidal thoughts or suicide attempts). • have liver disease. • have an irregular heart rhythm or heartbeat (QT prolongation, cardiac arrhythmia) or a heart problem called congenital long QT syndrome. • have low levels of potassium or magnesium in your blood (hypokalemia or hypomagnesemia). • have breast cancer or a history of breast cancer. • are pregnant or plan to become pregnant. It is not known if AUSTEDO XR or AUSTEDO can harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if AUSTEDO XR or AUSTEDO passes into breast milk. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking AUSTEDO XR or AUSTEDO with certain other medicines may cause side effects. Do not start any new medicines while taking AUSTEDO XR or AUSTEDO without talking to your healthcare provider first. How should I take AUSTEDO XR or AUSTEDO? • Take AUSTEDO XR or AUSTEDO exactly as your healthcare provider tells you to take it. • If you take AUSTEDO XR, take your dose by mouth one time each day, with or without food. • If you take AUSTEDO, take your dose by mouth and with food. If your dose of AUSTEDO is 12 mg or more each day, take AUSTEDO tablets 2 times a day in equal doses. • Swallow AUSTEDO XR or AUSTEDO tablets whole with water. Do not chew, crush, or break AUSTEDO XR or AUSTEDO tablets before swallowing. If you cannot swallow AUSTEDO XR or AUSTEDO tablets whole, tell your healthcare provider. You may need a different medicine. • The AUSTEDO XR tablet shell does not dissolve completely in the body after all the medicine has been released. Sometimes the tablet shell may be seen in your stool. This is normal. • Your healthcare provider may increase your dose of AUSTEDO XR or AUSTEDO each week for several weeks, until you and your healthcare provider find the right dose for you. • Tell your healthcare provider if you stop taking AUSTEDO XR or AUSTEDO for more than 1 week. Do not take another dose until you talk to your healthcare provider. What should I avoid while taking AUSTEDO XR or AUSTEDO? Sleepiness (sedation) is a common side effect of AUSTEDO XR and AUSTEDO. While taking AUSTEDO XR or AUSTEDO, do not drive a car or operate dangerous machinery until you know how AUSTEDO XR or AUSTEDO affects you. Drinking alcohol and taking other drugs that may also cause sleepiness while you are taking AUSTEDO XR or AUSTEDO may increase any sleepiness caused by AUSTEDO XR and AUSTEDO. What are the possible side effects of AUSTEDO XR and AUSTEDO? AUSTEDO XR and AUSTEDO can cause serious side effects, including: • Depression and suicidal thoughts or actions in people with Huntington’s disease. See “What is the most important information I should know about AUSTEDO XR and AUSTEDO?” • Irregular heartbeat (QT prolongation). AUSTEDO XR and AUSTEDO increases your chance of having certain changes in the electrical activity in your heart. These changes can lead to a dangerous abnormal heartbeat. Taking AUSTEDO XR or AUSTEDO with certain medicines may increase this chance. • Neuroleptic Malignant Syndrome (NMS). Call your healthcare provider right away and go to the nearest emergency room if you develop these signs and symptoms that do not have another obvious cause: o high fever o stiff muscles o problems thinking o very fast or uneven heartbeat o increased sweating • Restlessness. You may get a condition where you feel a strong urge to move. This is called akathisia. Reference ID: 5486197 • Parkinsonism. Symptoms of parkinsonism include: slight shaking, body stiffness, trouble moving, trouble keeping your balance, or falls. The most common side effects of AUSTEDO in people with Huntington’s disease include: • sleepiness (sedation) • tiredness • diarrhea • dry mouth The most common side effects of AUSTEDO in people with tardive dyskinesia include: • inflammation of the nose and throat (nasopharyngitis) • problems sleeping (insomnia) The most common side effects of AUSTEDO XR are expected to be similar to AUSTEDO in people with Huntington’s disease or tardive dyskinesia. These are not all the possible side effects of AUSTEDO XR or AUSTEDO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store AUSTEDO XR and AUSTEDO? • Store AUSTEDO XR and AUSTEDO tablets at room temperature between 68°F to 77°F (20°C to 25°C). • Keep the bottle tightly closed to protect AUSTEDO XR and AUSTEDO from light and moisture. • Do not throw away the desiccant canister in the bottle until the last dose of AUSTEDO XR or AUSTEDO is taken. Keep AUSTEDO XR and AUSTEDO and all medicines out of the reach of children. General information about the safe and effective use of AUSTEDO XR and AUSTEDO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AUSTEDO XR or AUSTEDO for a condition for which it was not prescribed. Do not give AUSTEDO XR or AUSTEDO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about AUSTEDO XR and AUSTEDO that is written for health professionals. What are the ingredients in AUSTEDO XR and AUSTEDO? AUSTEDO XR: Active ingredient: deutetrabenazine Inactive ingredients: ammonium hydroxide, black iron oxide, butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, cellulose acetate, hydroxypropyl cellulose, hypromellose, isopropyl alcohol, magnesium stearate, polyethylene glycol, polyethylene glycol 3350, polyethylene oxide, polyvinyl alcohol, propylene glycol, shellac, sodium chloride, talc, titanium dioxide, and FD&C red #40 lake. The 6 mg, 12 mg, 18 mg, 30 mg, 36 mg, and 42 mg extended- release tablets also contain FD&C yellow #6 lake. The 6 mg, 12 mg, 24 mg, and 36 mg extended-release tablets also contain FD&C blue #2 lake. The 18 mg extended-release tablets also contain carmine. AUSTEDO: Active ingredient: deutetrabenazine Inactive ingredients: ammonium hydroxide, black iron oxide, n-butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyethylene oxide, polysorbate 80, polyvinyl alcohol, povidone, propylene glycol, shellac, talc, titanium dioxide, and FD&C blue #2 lake. The 6 mg tablets also contain FD&C red #40 lake. The 12 mg tablets also contain FD&C yellow #6 lake. Manufactured for: Teva Neuroscience, Inc. Parsippany, NJ 07054 ©2024 Teva Neuroscience, Inc. AUSMG-010 For more information, go to www.AUSTEDO.com or call 1-888-483-8279. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: July 2024 Reference ID: 5486197
custom-source
2025-02-12T15:47:25.099471
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DAYTRANA® safely and effectively. See full prescribing information for DAYTRANA. DAYTRANA® (methylphenidate transdermal system), CII Initial U.S. Approval: 2006 WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning DAYTRANA has high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including DAYTRANA, can result in overdose and death (5.1, 9.2, 10): • Before prescribing DAYTRANA, assess each patient’s risk for abuse, misuse, and addiction. • Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. • Throughout treatment, reassess each patient’s risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction. RECENT MAJOR CHANGES Dosage and Administration (2.2) 11/2024 INDICATIONS AND USAGE DAYTRANA is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age. (1) Ab DOSAGE AND ADMINISTRATION • The recommended starting dose for patients new to or converting from another formulation of methylphenidate is 10 mg. (2.2) • DAYTRANA should be applied to the hip area (using alternating sites) 2 hours before an effect is needed and should be removed 9 hours after application. DAYTRANA may be removed earlier than 9 hours if a shorter duration of effect is desired or late day side effects appear. (2.2, 2.3) • Dosage should be titrated to effect. Dose titration, final dosage, and wear time should be individualized according to the needs and response of the patient. (2.2) DOSAGE FORMS AND STRENGTHS Transdermal system: 10mg/9 hours (1.1 mg/hr), 15mg/9 hours (1.6 mg/hr), 20mg/9 hours (2.2 mg/hr), 30mg/9 hours (3.3 mg/hr) (3) CONTRAINDICATIONS • Known hypersensitivity to methylphenidate (4.1) • Patients currently using or within 2 weeks of using an MAO inhibitor (4.2) WARNINGS AND PRECAUTIONS • Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. (5.2) • Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. (5.3) • Psychiatric Adverse Reactions: Prior to initiating DAYTRANA, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing DAYTRANA. (5.4) • Seizures: Stimulants may lower the convulsive threshold. Discontinue in the presence of seizures. (5.5) • Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention. (5.6) • Peripheral Vasculopathy, including Raynaud’s phenomenon: Careful observation for digital changes is necessary during DAYTRANA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. (5.7) • Long-Term Suppression of Growth in Pediatric Patients: Closely monitor (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. (5.8) • Chemical Leukoderma: DAYTRANA use may result in a persistent loss of skin pigmentation at and around the application site. Loss of pigmentation, in some cases, has been reported at other sites distant from the application site. Monitor for signs of skin depigmentation. Discontinue DAYTRANA if it occurs. (5.9) • Contact Sensitization: Use of DAYTRANA may lead to contact sensitization. Treatment should be discontinued if contact sensitization is suspected. Erythema is commonly seen with use of DAYTRANA and is not by itself an indication of sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the transdermal system site. (5.10) • External Heat: Patients should be advised to avoid exposing the DAYTRANA application site to direct external heat sources. When heat is applied to DAYTRANA after application, both the rate and extent of absorption are significantly increased. (5.11) • Hematologic monitoring: Periodic CBC, differential, and platelet counts are advised during prolonged therapy. (5.12) • Acute Angle Closure Glaucoma: DAYTRANA-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. (5.13) • Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe DAYTRANA to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open angle glaucoma. (5.14) • Motor and Verbal Tics and Worsening of Tourette’s Syndrome: Before initiating DAYTRANA, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate. (5.15) ADVERSE REACTIONS • Pediatric patients (ages 6 to 12 years): The most commonly (≥5% and twice the rate of placebo) reported adverse reactions in pediatric patients ages 6 to 12 years included appetite decreased, insomnia, nausea, vomiting, weight decreased, tic, affect lability, and anorexia. (6.1) • Pediatric patients (ages 13 to 17 years): The most commonly (≥5% and twice the rate of placebo) reported adverse reactions in pediatric patients ages 13 to 17 years included appetite decreased, nausea, insomnia, weight decreased, dizziness, abdominal pain, and anorexia. The majority of subjects in these trials had erythema at the application site. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Noven Therapeutics, LLC at 1-877-567-7857 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. (7.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5487488 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: ABUSE, MISUSE, AND ADDICTION 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Pretreatment Screening 2.2 Recommended Dosage 2.3 Application 2.4 Removal of DAYTRANA 2.5 Dose/Wear Time Reduction and Discontinuation 3 DOSAGE FORM AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Hypersensitivity to Methylphenidate 4.2 Monoamine Oxidase Inhibitors 5 WARNINGS AND PRECAUTIONS 5.1 Abuse, Misuse, and Addiction 5.2 Risks to Patients with Serious Cardiac Disease 5.3 Increased Blood Pressure and Heart Rate 5.4 Psychiatric Adverse Reactions 5.5 Seizures 5.6 Priapism 5.7 Peripheral Vasculopathy, including Raynaud’s phenomenon 5.8 Long-Term Suppression of Growth in Pediatric Patients 5.9 Chemical Leukoderma 5.10 Contact Sensitization 5.11 Patients Using External Heat 5.12 Hematologic Monitoring 5.13 Acute Angle Closure Glaucoma 5.14 Increased Intraocular Pressure and Glaucoma 5.15 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Monoamine Oxidase Inhibitors (MAOI) 7.2 Antihypertensive Drugs 7.3 Coumarin Anticoagulants, Antidepressants, and Selective Serotonin Reuptake Inhibitors 7.4 Halogenated Anesthetics 7.5 Risperidone 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis/Mutagenesis and Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5487488 FULL PRESCRIBING INFORMATION WARNING: ABUSE, MISUSE, AND ADDICTION DAYTRANA has a high potential for abuse and misuse, which can lead to the development of substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including DAYTRANA, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing DAYTRANA, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout DAYTRANA treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2)]. 1 INDICATIONS AND USAGE DAYTRANA (methylphenidate transdermal system) is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age. 2 DOSAGE AND ADMINISTRATION 2.1 Pretreatment Screening Prior to treating patients with DAYTRANA, assess: • for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)]. • the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating DAYTRANA [see Warnings and Precautions (5.15)]. 2.2 Recommended Dosage It is recommended that DAYTRANA be applied to the hip area 2 hours before an effect is needed and should be removed 9 hours after application. Dosage should be titrated to effect. The recommended dose titration schedule is shown in the table below. Dose titration, final dosage, and wear time should be individualized according to the needs and response of the patient. Table 1 DAYTRANA - Recommended Titration Schedule (Patients New to Methylphenidate) Upward Titration, if Response is Not Maximized Week 1 Week 2 Week 3 Week 4 Transdermal System Size 12.5 cm2 18.75 cm2 25 cm2 37.5 cm2 Nominal Delivered Dose* (mg/9 hours) 10 mg 15 mg 20 mg 30 mg Delivery Rate* (1.1 mg/hr)* (1.6 mg/hr)* (2.2 mg/hr)* (3.3 mg/hr)* *Nominal in vivo delivery rate in children and adolescents when applied to the hip, based on a 9-hour wear period. Patients converting from another formulation of methylphenidate should follow the above titration schedule due to differences in bioavailability of DAYTRANA compared to other products. 2.3 Application The parent or caregiver should be encouraged to use the administration chart included with each carton of DAYTRANA to monitor application and removal time, and method of disposal. It is recommended that parents or caregivers apply and remove the transdermal system for children; responsible adolescents may apply or Reference ID: 5487488 remove the transdermal system themselves if appropriate. If a transdermal system was removed without the parent or caregiver's knowledge, or if a transdermal system is missing from the tray, the parent or caregiver should be encouraged to ask the child when and how the transdermal system was removed. The Medication Guide includes a timetable to calculate when to remove DAYTRANA, based on the 9-hour application time. The adhesive side of DAYTRANA should be placed on a clean, dry area of the hip. The area selected should not be oily, damaged, or irritated. Apply DAYTRANA to the hip area avoiding the waistline, since clothing may cause the transdermal system to rub off. When applying the transdermal system the next morning, place on the opposite hip at a new site if possible. If patients or caregivers experience difficulty separating the transdermal system from the release liner or observe transfer of adhesive to the liner, tearing and/or other damage to the transdermal system during removal from the liner, the transdermal system should be discarded and a new transdermal system should be applied. Patients or caregivers should inspect the release liner to ensure that no adhesive containing medication has transferred to the liner. If adhesive transfer has occurred, the transdermal system should be discarded. Refer to the Instructions for Use for recommendations for discarding used DAYTRANA. DAYTRANA should be applied immediately after opening the individual pouch and removing the protective liner. Do not use if the individual pouch seal is broken or if the transdermal system appears to be damaged. Do not cut transdermal systems. Only intact transdermal systems should be applied. The transdermal system should then be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure that there is good contact of the transdermal system with the skin, especially around the edges. Exposure to water during bathing, swimming, or showering can affect transdermal system adherence. DAYTRANA should not be applied or re-applied with dressings, tape, or other common adhesives. In the event that a transdermal system does not fully adhere to the skin upon application, or becomes partially or fully detached during wear time, the transdermal system should be discarded and a new transdermal system may be applied at a different site. The total recommended wear time for that day should remain 9 hours regardless of the number of transdermal systems used. All patients should be advised to avoid exposing the DAYTRANA application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing the transdermal system [see Warnings and Precautions (5.10)]. When heat is applied to DAYTRANA after transdermal system application, both the rate and the extent of absorption are significantly increased. The temperature-dependent increase in methylphenidate absorption can be greater than 2-fold [see Clinical Pharmacology (12.3)]. This increased absorption can be clinically significant and result in overdose of methylphenidate [see Overdosage (10)]. DAYTRANA should not be stored in refrigerators or freezers. 2.4 Removal of DAYTRANA DAYTRANA should be peeled off slowly. If necessary, transdermal system removal may be facilitated by gently applying an oil-based product (i.e., petroleum jelly, olive oil, or mineral oil) to the transdermal system edges, gently working the oil underneath the transdermal system edges. If any adhesive remains on the skin following transdermal system removal, an oil-based product may be applied to transdermal system sites in an effort to gently loosen and remove any residual adhesive that remains following transdermal system removal. In the unlikely event that a transdermal system remains tightly adhered despite these measures, the patient or caregiver should contact the physician or pharmacist. Nonmedical adhesive removers and acetone-based products (i.e., nail polish remover) should not be used to remove DAYTRANA or adhesive. 2.5 Dose/Wear Time Reduction and Discontinuation DAYTRANA may be removed earlier than 9 hours if a shorter duration of effect is desired or late day side effects appear. Plasma concentrations of d-methylphenidate generally begin declining when the transdermal system is removed, although absorption may continue for several hours. Individualization of wear time may Reference ID: 5487488 help manage some of the side effects caused by methylphenidate. If aggravation of symptoms or other adverse events occur, the dosage or wear time should be reduced, or, if necessary, the drug should be discontinued. Residual methylphenidate remains in used transdermal systems when worn as recommended. 3 DOSAGE FORM AND STRENGTHS Four dosage strengths are available: Transdermal Methylphenidate Nominal Dose Delivered Dosage Rate* System Size Content per Transdermal System (mg) Over 9 Hours* (mg/hr) (cm2) (mg) 10 1.1 12.5 27.5 15 1.6 18.75 41.3 20 2.2 25 55 30 3.3 37.5 82.5 *Nominal in vivo delivery rate in children and adolescents when applied to the hip, based on a 9-hour wear period. 4 CONTRAINDICATIONS 4.1 Hypersensitivity to Methylphenidate DAYTRANA is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product (polyester/ethylene vinyl acetate laminate film backing, acrylic adhesive, silicone adhesive, and fluoropolymer-coated polyester) [see Description (11)]. 4.2 Monoamine Oxidase Inhibitors DAYTRANA is contraindicated during treatment with monoamine oxidase inhibitors, and within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result). 5 WARNINGS AND PRECAUTIONS 5.1 Abuse, Misuse, and Addiction DAYTRANA has a high potential for abuse and misuse. The use of DAYTRANA exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. DAYTRANA can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including DAYTRANA, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing DAYTRANA, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their caregivers or families about these risks. Advise patients to store DAYTRANA in a safe place, preferably locked, and instruct patients to not give DAYTRANA to anyone else. Throughout DAYTRANA treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. DAYTRANA has special disposal instructions. Instruct patients to find a take back location to dispose of unused or expired DAYTRANA. If a take back program is unavailable, instruct them to: Reference ID: 5487488 1. Remove DAYTRANA from its pouch, separate it from its liner, fold it in half with the adhesive sides touching each other, and immediately flush the used transdermal system down the toilet, and 2. Place the pouch and liner in a container, close the container, and throw out the container in the trash (advise patients not to flush the pouch and liner down the toilet). 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid DAYTRANA use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants may cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases. Monitor all DAYTRANA-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Pre-Existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre­ existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disease CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating DAYTRANA treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosages, may cause psychotic or manic symptoms, (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing DAYTRANA. 5.5 Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued. 5.6 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on the methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). DAYTRANA-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. Reference ID: 5487488 5.7 Peripheral Vasculopathy, including Raynaud’s phenomenon Stimulant medications, including DAYTRANA, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports and at therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during DAYTRANA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for DAYTRANA-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.8 Long-Term Suppression of Growth in Pediatric Patients CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate for 7 days per week throughout the year had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in DAYTRANA-treated pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.9 Chemical Leukoderma DAYTRANA use may result in a persistent loss of skin pigmentation at and around the application site. Loss of pigmentation, in some cases, has been reported at other sites distant from the application site. Chemical leukoderma can mimic the appearance of vitiligo, particularly when the loss of skin pigmentation involves areas distant from the application site. Individuals with a history of vitiligo and/or a family history of vitiligo may be more at risk. Skin depigmentation may persist even after DAYTRANA use is discontinued. Monitor for signs of skin depigmentation, and advise patients to immediately inform their healthcare provider if changes in skin pigmentation occur. Discontinue use of the DAYTRANA in patients with chemical leukoderma. 5.10 Contact Sensitization In an open-label study of 305 subjects conducted to characterize dermal reactions in children with ADHD treated with DAYTRANA using a 9-hour wear time, one subject (0.3%) was confirmed by patch testing to be sensitized to methylphenidate (allergic contact dermatitis). This subject experienced erythema and edema at DAYTRANA application sites with concurrent urticarial lesions on the abdomen and legs resulting in treatment discontinuation. This subject was not transitioned to oral methylphenidate. Use of DAYTRANA may lead to contact sensitization. DAYTRANA should be discontinued if contact sensitization is suspected. Erythema is commonly seen with use of DAYTRANA and is not by itself an indication of sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the transdermal system site. Confirmation of a diagnosis of contact sensitization (allergic contact dermatitis) may require further diagnostic testing. Patients sensitized from use of DAYTRANA, as evidenced by development of an allergic contact dermatitis, may develop systemic sensitization or other systemic reactions if methylphenidate-containing products are taken via other routes, e.g., orally. Manifestations of systemic sensitization may include a flare-up of previous dermatitis or of prior positive patch-test sites, or generalized skin eruptions in previously unaffected skin. Other Reference ID: 5487488 systemic reactions may include headache, fever, malaise, arthralgia, diarrhea, or vomiting. No cases of systemic sensitization have been observed in clinical trials of DAYTRANA. Patients who develop contact sensitization to DAYTRANA and require oral treatment with methylphenidate should be initiated on oral medication under close medical supervision. It is possible that some patients sensitized to methylphenidate by exposure to DAYTRANA may not be able to take methylphenidate in any form. 5.11 Patients Using External Heat Patients should be advised to avoid exposing the DAYTRANA application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds, etc., while wearing the transdermal system. When heat is applied to DAYTRANA after application, both the rate and extent of absorption are significantly increased. The temperature-dependent increase in methylphenidate absorption can be greater than 2-fold [see Clinical Pharmacology (12.3)]. This increased absorption can be clinically significant and can result in overdose of methylphenidate [see Overdosage (10)]. 5.12 Hematologic Monitoring Periodic CBC, differential, and platelet counts are advised during prolonged therapy. 5.13 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, DAYTRANA-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.14 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2)]. Prescribe DAYTRANA to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor DAYTRANA-treated patients with a history of abnormally increased IOP or open angle glaucoma. 5.15 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6.2)]. Before initiating DAYTRANA, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor DAYTRANA-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate. 6 ADVERSE REACTIONS Detailed information on serious and adverse reactions of particular importance is provided in the Boxed Warning and Warnings and Precautions (5) sections: • Abuse, Misuse, and Addiction [see Boxed Warning] • Hypersensitivity to Methylphenidate [see Contraindications (4.1)] • Monoamine Oxidase Inhibitors [see Contraindications (4.2) and Drug Interactions (7.1)] • Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)] Reference ID: 5487488 • Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)] • Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)] • Seizures [see Warnings and Precautions (5.5)] • Priapism [see Warnings and Precautions (5.6)] • Peripheral Vasculopathy [see Warnings and Precautions (5.7)] • Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.8)] • Chemical Leukoderma [see Warnings and Precautions (5.9)] • Contact Sensitization [see Warnings and Precautions (5.10)] • External Heat [see Warnings and Precautions (5.11)] • Hematologic Monitoring [see Warnings and Precautions (5.12)] • Acute Angle Closure Glaucoma [see Warnings and Precautions (5.13)] • Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.14)] • Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.15)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most commonly reported (frequency ≥ 5% and twice the rate of placebo) adverse reactions in a controlled trial in children aged 6-12 included appetite decreased, insomnia, nausea, vomiting, weight decreased, tic, affect lability, and anorexia. The most commonly reported (frequency ≥ 5% and twice the rate of placebo) adverse reactions in a controlled trial in adolescents aged 13-17 were appetite decreased, nausea, insomnia, weight decreased, dizziness, abdominal pain, and anorexia [see Adverse Reactions (6.1)]. The most common (≥ 2% of subjects) adverse reaction associated with discontinuations in double-blind clinical trials in children or adolescents was application site reactions [see Adverse Reactions (6.1)]. The overall DAYTRANA development program included exposure to DAYTRANA in a total of 2,152 participants in clinical trials, including 1,529 children aged 6-12, 223 adolescents aged 13-17, and 400 adults. The 1,752 child and adolescent subjects aged 6-17 years were evaluated in 10 controlled clinical studies, 7 open-label clinical studies, and 5 clinical pharmacology studies. In a combined studies pool of children using DAYTRANA with a wear time of 9 hours, 212 subjects were exposed for ≥ 6 months and 115 were exposed for ≥ 1 year; 85 adolescents were exposed for ≥ 6 months. Most patients studied were exposed to DAYTRANA transdermal system sizes of 12.5 cm2, 18.75 cm2, 25 cm2 or 37.5 cm2, with a wear time of 9 hours. In the data presented below, the adverse reactions reported during exposure were obtained primarily by general inquiry at each visit, and were recorded by the clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of events into a smaller number of standardized event categories. Adverse Reactions in Clinical Studies with Discontinuation of Treatment In a 7-week double-blind, parallel-group, placebo-controlled study in children with ADHD conducted in the outpatient setting, 7.1% (7/98) of patients treated with DAYTRANA discontinued due to adverse events compared with 1.2% (1/85) receiving placebo. The most commonly reported (≥ 1% and twice the rate of placebo) adverse reactions leading to discontinuation in the DAYTRANA group were application site reaction (2%), tics (1%), headache (1%), and irritability (1%). In a 7-week double-blind, parallel-group, placebo-controlled study in adolescents with ADHD conducted in the outpatient setting, 5.5% (8/145) of patients treated with DAYTRANA discontinued due to adverse reactions compared with 2.8% (2/72) receiving placebo. The most commonly reported adverse reactions leading to Reference ID: 5487488 discontinuation in the DAYTRANA group were application site reaction (2%) and decreased appetite/anorexia (1.4%). Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Trials Skin Irritation and Application Site Reactions DAYTRANA is a dermal irritant. In addition to the most commonly reported adverse reactions presented in Table 2, the majority of subjects in those studies had minimal to definite skin erythema at the DAYTRANA application site. This erythema generally caused no or minimal discomfort and did not usually interfere with therapy or result in discontinuation from treatment. Erythema is not by itself a manifestation of contact sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the transdermal system site [see Warnings and Precautions (5.10)]. Most Commonly Reported Adverse Reactions Table 2 lists treatment-emergent adverse reactions reported in ≥ 1% DAYTRANA-treated children or adolescents with ADHD in two 7 week double-blind, parallel-group, placebo-controlled studies conducted in the outpatient setting. Overall, in these studies, 75.5% of children and 78.6% of adolescents experienced at least 1 adverse event. Table 2 Number (%) of Subjects with Commonly Reported Adverse Reactions (≥ 1% in the DAYTRANA Group) in 7-Week Placebo-controlled Studies in Either Children or Adolescents - Safety Population System Organ Class Preferred term Adolescents Children Placebo DAYTRANA N = 72 N = 145 Placebo DAYTRANA N = 85 N = 98 Cardiac Disorders Tachycardia Gastrointestinal disorders 0 (0) 1 (0.7) 0 (0) 1 (1.0) Abdominal pain 0 (0) 7 (4.8) 5 (5.9) 7 (7.1) Nausea 2 (2.8) 14 (9.7) 2 (2.4) 12 (12.2) Vomiting 1 (1.4) 5 (3.4) 4 (4.7) 10 (10.2) Investigations Weight decreased 1 (1.4) 8 (5.5) 0 (0) 9 (9.2) Metabolism and nutrition disorders Anorexia Decreased appetite 1 (1.4) 7 (4.8) 1 (1.4) 37 (25.5) 1 (1.2) 5 (5.1) 4 (4.7) 25 (25.5) Nervous system disorders Dizziness Headache 1 (1.4) 8 (5.5) 9 (12.5) 18 (12.4) 1 (1.2) 0 (0) 10 (11.8) 15 (15.3) Psychiatric disorders Affect lability 1 (1.4) 0 (0) 0 (0) 6 (6.1)* Insomnia 2 (2.8) 9 (6.2) 4 (4.7) 13 (13.3) Irritability 5 (6.9) 16 (11) 4 (4.7) 7 (7.1) Tic 0 (0) 0 (0) 0 (0) 7 (7.1) * Six subjects had affect lability, all judged as mild and described as increased emotionally sensitive, emotionality, emotional instability, emotional lability, and intermittent emotional Adverse Reactions in Studies with the Long-Term Use of DAYTRANA Reference ID: 5487488 In a long-term open-label study of up to 12 months duration in 326 children wearing DAYTRANA 9 hours daily, the most common (≥ 10%) adverse reactions were decreased appetite, headache, and weight decreased. A total of 30 subjects (9.2%) were withdrawn from the study due to adverse events and 22 additional subjects (6.7%) discontinued treatment as the result of an application site reaction. Other than application site reactions, affect lability (5 subjects, 1.5%) was the only additional adverse reaction leading to discontinuation reported with a frequency of greater than 1%. In a long-term open-label study of up to 6 months duration in 162 adolescents wearing DAYTRANA 9 hours daily, the most common (≥ 10%) adverse reactions were decreased appetite and headache. A total of 9 subjects (5.5%) were withdrawn from the study due to adverse events and 3 additional subjects (1.9%) discontinued treatment as the result of an application site reaction. Other adverse reactions leading to discontinuation that occurred with a frequency of greater than 1% included affect lability and irritability (2 subjects each, 1.2%). 6.2 Postmarketing Experience In addition, the following adverse reactions have been identified during the post-approval use of DAYTRANA. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to DAYTRANA exposure. Cardiac Disorders: palpitations. Eye Disorders: visual disturbances, blurred vision, increased intraocular pressure, mydriasis, and accommodation disorder. General Disorders and Administration Site Disorders: fatigue, application site reactions such as bleeding, bruising, burn, burning, dermatitis, discharge, discoloration, discomfort, dryness, eczema, edema, erosion, erythema, excoriation, exfoliation, fissure, hyperpigmentation, hypopigmentation, induration, infection, inflammation, irritation, pain, papules, paresthesia, pruritus, rash, scab, swelling, ulcer, urticaria, vesicles, and warmth. Immune System Disorders: hypersensitivity reactions including generalized erythematous and urticarial rashes, allergic contact dermatitis, angioedema, and anaphylaxis. Investigations: blood pressure increased. Nervous System Disorders: convulsion, dyskinesia, lethargy, somnolence, serotonin syndrome in combination with serotonergic drugs, and extrapyramidal disorder, motor and verbal tics. Psychiatric Disorders: depression, hallucination, nervousness, and libido changes. Skin and Subcutaneous Tissue Disorders: alopecia. Adverse Reactions with Oral Methylphenidate Products Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur. Other reactions include: Cardiac Disorders: angina, arrhythmia, and pulse increased or decreased. Immune System Disorders: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura. Metabolism and Nutrition Disorders: anorexia and weight loss during prolonged therapy. Nervous System Disorders: drowsiness, rare reports of Tourette's syndrome and toxic psychosis. Reference ID: 5487488 Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause. Vascular Disorders: blood pressure increased or decreased and cerebral arteritis and/or occlusion. Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate: Blood and Lymphatic System Disorders: leukopenia and/or anemia. Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury. Psychiatric Disorders: transient depressed mood. Skin and Subcutaneous Tissue Disorders: scalp hair loss. Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis. 7 DRUG INTERACTIONS 7.1 Monoamine Oxidase Inhibitors (MAOI) Concomitant use of MAOIs and CNS stimulants, including DAYTRANA, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4.2)]. Concomitant use of DAYTRANA with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. 7.2 Antihypertensive Drugs DAYTRANA may decrease the effectiveness of drugs used to treat hypertension. Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed [see Warnings and Precautions (5.2)]. 7.3 Coumarin Anticoagulants, Antidepressants, and Selective Serotonin Reuptake Inhibitors Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and some tricyclic drugs (e.g., imipramine, clomipramine, desipramine) and selective serotonin reuptake inhibitors. Downward dose adjustments of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing methylphenidate. 7.4 Halogenated Anesthetics Concomitant use of halogenated anesthetics and methylphenidate may increase the risk of sudden blood pressure and heart rate increase during surgery. Avoid use of DAYTRANA in patients being treated with anesthetics on the day of surgery. 7.5 Risperidone Combined use of methylphenidate with risperidone when there is a change in dosage, whether an increase or decrease, of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS. Reference ID: 5487488 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including DAYTRANA, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhd-medications/. Risk Summary Published studies and post-marketing reports on methylphenidate use during pregnancy are insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the fetus associated with the use of CNS stimulants during pregnancy (see Clinical Considerations). No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis. However, spina bifida was observed in rabbits when given oral doses of 200 mg/kg/day. When methylphenidate was administered orally to rats throughout pregnancy and lactation, offspring growth and survival were decreased at maternally toxic doses (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinical recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions CNS stimulants, such as DAYTRANA, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers. Data Animal Data Animal reproduction toxicity studies with transdermal methylphenidate have not been performed. In embryo- fetal development studies conducted in rats and rabbits, methylphenidate was administered orally to pregnant animals during the period of organogenesis, at doses up to 100 and 200 mg/kg/day, respectively. No evidence of morphological development effects was found in either of the species; however, increased incidences of fetal skeletal variations were observed in rats at 60 mg/kg or greater and an increase in fetal visceral variations was seen in rabbits at the highest dose. In a previous study, methylphenidate was shown to have malformations (increased incidence of fetal spina bifida) in rabbits when given oral doses of 200 mg/kg/day. When methylphenidate was administered orally to rats throughout pregnancy and lactation at doses of up to 60 mg/kg/day, offspring growth and survival were decreased at maternally toxic doses. In a study in which oral methylphenidate was given to rats throughout pregnancy and lactation at doses up to 60 mg/kg/day, offspring weights and survival were decreased at 40 mg/kg/day and above; these doses caused some maternal toxicity. 8.2 Lactation Risk Summary Reference ID: 5487488 Limited published literature, based on breast milk sampling from five mothers, reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DAYTRANA and any potential adverse effects on the breastfed infant from DAYTRANA or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 Pediatric Use The safety and effectiveness of DAYTRANA in pediatric patients less than 6 years have not been established. Long-term effects of methylphenidate in children have not been well established. The safety and effectiveness of DAYTRANA for the treatment of ADHD have been established in pediatric patients 6 to 17 years. Long Term Suppression of Growth Growth should be monitored during treatment with stimulants, including DAYTRANA. Children who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.8)]. Juvenile Animal Toxicity Data Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. Studies with transdermal methylphenidate have not been performed in juvenile animals. In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose. The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day. The clinical significance of the long-term behavioral effects observed in rats is unknown. 8.5 Geriatric Use DAYTRANA has not been studied in patients greater than 65 years of age. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance DAYTRANA contains methylphenidate, a Schedule II controlled substance. 9.2 Abuse DAYTRANA has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)]. DAYTRANA can be diverted for non- medical use into illicit channels or distribution. Reference ID: 5487488 Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including DAYTRANA, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. 9.3 Dependence Physical Dependence DAYTRANA may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including DAYTRANA include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance DAYTRANA may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). 10 OVERDOSAGE Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: • Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop. • CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. • Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop. Overdose Management Consider the possibility of multiple drug ingestion. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Remove all transdermal systems immediately and cleanse the area(s) to remove any remaining adhesive. The continuing absorption of methylphenidate from the skin, even after removal of the transdermal system, should be considered when treating patients with overdose. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations. Reference ID: 5487488 (1) Outstde backing (2) Adhe.iv,e oonta:ining methylphenrdate (3) Protective lmer (remo,·ed prior to applic-2itron) ( N ot to Scal9) 11 DESCRIPTION DAYTRANA is an adhesive-based matrix transdermal system containing methylphenidate that is applied to intact skin. The chemical name for methylphenidate is α-phenyl-2-piperidineacetic acid methyl ester. It is a white to off-white powder and is soluble in alcohol, ethyl acetate, and ether. Methylphenidate is practically insoluble in water and petrol ether. Its molecular weight is 233.31. Its empirical formula is C14H19NO2. The structural formula of methylphenidate is: Transdermal System Components DAYTRANA contains methylphenidate in a multipolymeric adhesive. The methylphenidate is dispersed in acrylic adhesive that is dispersed in a silicone adhesive. The composition per unit area of all dosage strengths is identical, and the total dose delivered is dependent on the transdermal system size and wear time. DAYTRANA consists of three layers, as seen in the figure below (cross-section of the transdermal system). Proceeding from the outer surface toward the surface adhering to the skin, the layers are (1) a polyester/ethylene vinyl acetate laminate film backing, (2) a proprietary adhesive formulation incorporating Noven Pharmaceuticals, Inc.'s DOT Matrix™ transdermal technology consisting of an acrylic adhesive, a silicone adhesive, and methylphenidate, and (3) a fluoropolymer-coated polyester protective liner, which is attached to the adhesive surface and must be removed before the transdermal system can be used. The active component of the transdermal system is methylphenidate. The remaining components are pharmacologically inactive. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate is a CNS stimulant. Its mode of therapeutic action in ADHD is not known. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d-and l-enantiomers. The d-enantiomer is more pharmacologically active than the l-enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. Reference ID: 5487488 12.3 Pharmacokinetics The pharmacokinetics of DAYTRANA when applied to the hip for 9 hours have been studied in ADHD patients 6 to 17 years old. Absorption The amount of methylphenidate absorbed systemically is a function of both wear time and transdermal system size. In patients with ADHD, peak plasma levels of methylphenidate are reached at about 10 hours after single application and 8 hours after repeat transdermal system applications (12.5cm2 to 37.5cm2) when worn up to 9 hours. On single dosing of children or adolescents with DAYTRANA, there was a delay of, on average, 2 hours before d-methylphenidate was detectable in the circulation. On repeat dosing, low concentrations (1.2-3.0 ng/mL in children and 0.5-1.7ng/mL in adolescents, on average across the dose range) were observed earlier in the profile, due to carry-over effect. Following the application of DAYTRANA once daily with a 9-hour wear time, the mean pharmacokinetic parameters of d-methylphenidate in children and adolescents with ADHD after 4 weeks of therapy are summarized in Table 3. Table 3 Mean Plasma d-Methylphenidate Pharmacokinetic Parameters After Repeated 9-Hour Applications of DAYTRANA or Oral ER-MPH for up to 28 days to Pediatric ADHD Patients (Aged 6 - 17 years) Children Parameter DAYTRANA1 12.5cm2 (N=12) DAYTRANA2 37.5cm2 (N=10) Oral ER-MPH3 18mg Oral ER-MPH3 54mg Cssmax (ng/mL) 15.7 ± 9.39 42.9 ± 22.4 8.37 ± 4.14 26.1 ± 11.2 Cssmin (ng/mL) 1.04 ± 1.17 1.96 ± 1.73 0.708 ± 1.08 1.19 ± 1.54 AUCss (ng·hr/mL) 163 ± 101 447 ± 230 97.7 ± 67.0 317 ± 160 tlag (h)4 0 (0 - 2.0) 0 (0 - 1.0) 0 0 Adolescents Cssmax (ng/mL) 8.32 ± 4.60 16.5 ± 6.94 5.23 ± 1.72 18.0 ± 6.97 Cssmin (ng/mL) 0.544 ± 0.383 1.02 ± 0.629 0.360 ± 0.478 1.50 ± 0.937 AUCss (ng·hr/mL) 85.7 ± 50.0 167 ± 66.0 59.7 ± 19.1 216 ± 80.8 tlag (h)4 0 (0 - 2.0) 0 (0 - 2.0) 0 0 1 Dose maintained fixed for 28 days; 2 Dose escalated at 7 day intervals from 12.5 cm2 through 18.75 cm2 and 25 cm2 to 37.5 cm2; 3 Dose escalated at 7 day intervals from 18 mg through 27 mg and 36 mg to 54 mg; 4 Median (minimum - maximum); tlag = Last Sampling Time Prior to Time of First Quantifiable Plasma Concentration Following administration of DAYTRANA 12.5cm2 to pediatric and adolescent ADHD patients daily for 7 days, there were 13% and 14% increases, respectively, in steady state area under the plasma concentration-time curve (AUCss) relative to that anticipated on the basis of single dose pharmacokinetics (AUC0-∞); after 28 days administration, these increments increased to 64% and 76%, respectively. Cmax increased by nearly 69% and 100% within 4 weeks of daily administration of the starting dose in children and adolescents, respectively. Reference ID: 5487488 FIGURE 1: Mean Concentration-time Profiles for d-Methylphenidate in all Patients (N:34) Following Administration of Single Applications (9-Hour Wear Time) of d,/-Methylphenidate Using Daytrana 10 mg ( □ ), 20 mg ( ◊) and 30 mg ( ~) per 9-Hour Transdermal System 30 25 '.J' t .S 20 u C 0 u .. ~ 15 ·2 .. .c <l. ~ 10 .; :Ii -6 5 0 0 5 10 15 20 25 30 Time After Daytrana Application (hr) The observed exposures with DAYTRANA could not be explained by drug accumulation predicted from observed single dose pharmacokinetics and there was no evidence that clearance or rate of elimination changed between single and repeat dosing. Neither were they explainable by differences in dosing patterns between treatments, age, race, or gender. This suggests that transdermal absorption of methylphenidate may increase with repeat dosing with DAYTRANA; on average, steady-state is likely to have been achieved by approximately 14 days of dosing. In the single- and multiple dose study described above, exposure to l-methylphenidate was 46% of the exposure to d-methylphenidate in children and 40% in adolescents. l-methylphenidate is less pharmacologically active than d-methylphenidate [see Pharmacodynamics (12.2)]. In a phase 2 PK/PD study in children aged 6-12 years, 2/3 of patients had 2-hour d-MPH concentrations < 5 ng/mL on chronic dosing, and at 3 hours 40% of patients had d-MPH concentrations < 5 ng/mL [see Clinical Studies (14)]. When DAYTRANA is applied to inflamed skin both the rate and extent of absorption are increased as compared with intact skin. When applied to inflamed skin, lag time is no greater than 1 hour, Tmax is 4 hours, and both Cmax and AUC are approximately 3-fold higher. When heat is applied to DAYTRANA after application, both the rate and the extent of absorption are significantly increased. Median Tlag occurs 1 hour earlier, Tmax occurs 0.5 hours earlier, and median Cmax and AUC are 2-fold and 2.5-fold higher, respectively. Application sites other than the hip can have different absorption characteristics and have not been adequately studied in safety or efficacy studies. Dose Proportionality Following a single 9-hour application of DAYTRANA doses of 10 mg / 9 hours to 30 mg / 9 hours transdermal systems to 34 children with ADHD, Cmax and AUC0-t of d-methylphenidate were proportional to the transdermal system dose. Mean plasma concentration-time plots are shown in Figure 1. Cmax of l­ methylphenidate was also proportional to the transdermal system dose. AUC0-t of l-methylphenidate was only slightly greater than proportional to transdermal system dose. Distribution Reference ID: 5487488 Upon removal of DAYTRANA, methylphenidate plasma concentrations in children with ADHD decline in a biexponential manner. This may be due to continued distribution of MPH from the skin after transdermal system removal. Metabolism and Excretion Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Transdermal administration of methylphenidate exhibits much less first pass effect than oral administration. Consequently, a much lower dose of DAYTRANA on a mg/kg basis compared to oral dosages may still produce higher exposures of d-MPH with transdermal administration compared to oral administration. In addition, very little, if any, l-methylphenidate is systemically available after oral administration due to first pass metabolism, whereas after transdermal administration of racemic methylphenidate exposure to l­ methylphenidate is nearly as high as to d-methylphenidate. The mean elimination t1/2 from plasma of d-methylphenidate after removal of DAYTRANA in children aged 6 to 12 years and adolescents aged 13-17 years was approximately 4 to 5 hours. The t1/2 of l-methylphenidate was shorter than for d-methylphenidate and ranged from 1.4 to 2.9 hours, on average. The Cmax and AUC of d-methylphenidate were approximately 50% lower in adolescents, compared to children, following either a 1-day or 7-day administration of DAYTRANA (10mg/9hr). Multiple-dose administration of DAYTRANA did not result in significant accumulation of methylphenidate; following 7 days of DAYTRANA administration (10mg/9hr) in children and adolescents, the accumulation index of methylphenidate was 1.1, based on the mean steady state area under the plasma concentration-time curve (AUCss) relative to that anticipated on the basis of single dose pharmacokinetics (AUC0-∞). Food Effects The pharmacokinetics or the pharmacodynamic food effect performance after application of DAYTRANA has not been studied, but because of the transdermal route of administration, no food effect is expected. Special Populations Gender The pharmacokinetics of methylphenidate after single and repeated doses of DAYTRANA were similar between boys and girls with ADHD, after allowance for differences in body weight. Race The influence of race on the pharmacokinetics of methylphenidate after administration of DAYTRANA has not been defined. Age The pharmacokinetics of methylphenidate after administration of DAYTRANA have not been studied in children less than 6 years of age. Renal Impairment There is no experience with the use of DAYTRANA in patients with renal insufficiency. Hepatic Impairment There is no experience with the use of DAYTRANA in patients with hepatic insufficiency. Reference ID: 5487488 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis/Mutagenesis and Impairment of Fertility Carcinogenesis Carcinogenicity studies of transdermal methylphenidate have not been performed. In a lifetime carcinogenicity study of oral methylphenidate carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg/day. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown. Orally administered methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day. In a 24-week oral carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. In this study, male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese hamster ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18­ week continuous breeding study. The study was conducted at doses up to 160 mg/kg/day. 14 CLINICAL STUDIES DAYTRANA was demonstrated to be effective in the treatment of ADHD in two (2) randomized double-blind, placebo-controlled studies in children aged 6 to 12 years and one (1) randomized, double-blind, placebo- controlled study in adolescents aged 13 to 17 years who met Diagnostic and Statistical Manual (DSM-IV-TR®) criteria for ADHD. DAYTRANA wear time was 9 hours in all three (3) studies. In Study 1, conducted in a classroom setting, symptoms of ADHD were evaluated by school teachers and observers using the Deportment Subscale from the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale which assesses behavior symptoms in the classroom setting. DAYTRANA was applied for 9 hours before removal. There was a 5-week open-label DAYTRANA dose optimization phase using dosages of 10, 15, 20, and 30 mg / 9 hours, followed by a 2-week randomized, double-blind, placebo-controlled crossover treatment phase using the optimal transdermal system dose for each patient or placebo. The mean differences between DAYTRANA and placebo in change from baseline in SKAMP Deportment Scores were statistically significant in favor of DAYTRANA beginning at 2 hours and remained statistically significant at all subsequent measured time points through 12 hours after application of the DAYTRANA. In Study 2, conducted in the outpatient setting, DAYTRANA or placebo was blindly administered in a flexible- dose design using doses of 10, 15, 20, and 30 mg / 9 hours to achieve an optimal regimen over 5 weeks, followed by a 2-week maintenance period using the optimal transdermal system dose for each patient. Symptoms of ADHD were evaluated by the ADHD-Rating Scale (RS)-IV. DAYTRANA was statistically significantly superior to placebo as measured by the mean change from baseline for the ADHD-RS-IV total Reference ID: 5487488 score. Although this study was not designed specifically to evaluate dose response, in general there did not appear to be any additional effectiveness accomplished by increasing the transdermal system dose from 20 mg / 9 hours to 30 mg / 9 hours. In Study 3, conducted in the outpatient setting, DAYTRANA or placebo was blindly administered in a flexible- dose design using doses of 10, 15, 20, and 30 mg / 9 hours during a 5-week dose-optimization phase, followed by a 2-week maintenance period using the optimal transdermal system dose for each patient. Symptoms of ADHD were evaluated using the ADHD-Rating Scale (RS)-IV. DAYTRANA was statistically significantly superior to placebo as measured by the mean change from baseline in the ADHD-RS-IV total score. 16 HOW SUPPLIED/STORAGE AND HANDLING DAYTRANA is supplied in a sealed tray containing 30 individually pouched transdermal systems. See the chart below for information regarding available strengths. Nominal Dose Dosage Transdermal Methylphenidate Transdermal NDC Number Delivered (mg) Rate* System Content per Systems Over 9 Hours (mg/hr) Size (cm2) Transdermal System** (mg) Per Carton 10 1.1 12.5 27.5 30 68968-5552-3 15 1.6 18.75 41.3 30 68968-5553-3 20 2.2 25 55 30 68968-5554-3 30 3.3 37.5 82.5 30 68968-5555-3 *Nominal in vivo delivery rate per hour in children and adolescents when applied to the hip, based on a 9-hour wear period. **Methylphenidate content in each transdermal system. Store at 25° C (77° F); excursions permitted to 15-30° C (59-86° F) [see USP Controlled Room Temperature]. Do not store transdermal systems unpouched. Do not store transdermal systems in refrigerators or freezers. Once the sealed tray is opened, use contents within 2 months. Apply the transdermal system immediately upon removal from the individual protective pouch. For transdermal use only. See the Patient Counseling Information (17) for specific disposal instructions for unused or expired DAYTRANA. 17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of DAYTRANA, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2), Overdosage (10)]. Advise patients to store DAYTRANA in a safe place, preferably locked, and instruct patients to not give DAYTRANA to anyone else. Special Disposal Instructions Advise patients that there are special disposal instructions for unused or expired DAYTRANA [see Warnings and Precautions (5.1)]. Instruct patients to find a take back location to dispose of unused or expired DAYTRANA. If a take back program is unavailable, instruct them to: 1. Remove DAYTRANA from its pouch, separate it from its liner, fold it in half with the adhesive sides touching each other, and immediately flush it down the toilet, and Reference ID: 5487488 2. Place the pouch and liner in a container, close the container, and throw out the container in the trash (advise patients not to flush the pouch and liner down the toilet). Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with DAYTRANA use. Instruct patients to contact a healthcare provider immediately if they develop symptoms, such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)]. Priapism Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.6)]. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud’s phenomenon] [see Warnings and Precautions (5.7)] • Instruct patients beginning treatment with DAYTRANA about the risk of peripheral vasculopathy, including Raynaud’s Phenomenon, and in associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. • Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. • Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while using DAYTRANA. • Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Long-Term Suppression of Growth in Pediatric Patients Advise patients that DAYTRANA may cause slowing of growth including weight loss [see Warnings and (5.8)]. Chemical Leukoderma Advise patients of the possibility of a persistent loss of skin pigmentation at, around and distant from the application site. Advise patients to immediately inform their healthcare provider if changes in skin pigmentation occur [see Warnings and Precautions (5.9)]. Increased Intraocular Pressure (IOP) and Glaucoma Advise patients that IOP and glaucoma may occur during treatment with DAYTRANA [see Warnings and Precautions (5.14)]. Motor and Verbal Tics, and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with DAYTRANA. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions (5.15)]. Important Preparation and Administration Instructions [see Dosage and Administration (2.3)] • Parents and patients should be informed to apply DAYTRANA to a clean, dry site on the hip, which is not oily, damaged, or irritated. The site of application must be alternated daily. DAYTRANA should not be applied to the waistline, or where tight clothing may rub it. • If patients or caregivers experience difficulty separating the transdermal system from the release liner or observe tearing and/or other damage to the transdermal system during removal from the liner, the transdermal system should be discarded according to the directions provided in this label, and a new transdermal system should be applied [see Dosage and Administration (2.3)]. Patients or caregivers Reference ID: 5487488 should inspect the release liner to ensure that no adhesive containing medication has transferred to the liner. If adhesive transfer has occurred, the transdermal system should be discarded. • DAYTRANA should be applied 2 hours before the desired effect. DAYTRANA should be removed approximately 9 hours after it is applied, although the effects from the transdermal system will last for several more hours. DAYTRANA may be removed earlier than 9 hours if a shorter duration of effect is desired or late day side effects appear. • The parent or caregiver should be encouraged to use the administration chart included with each carton of DAYTRANA to monitor application and removal time, and method of disposal. The Medication Guide included at the end of this insert also includes a timetable to calculate when to remove DAYTRANA, based on the 9 hour application time. • Patients or caregivers should avoid touching the adhesive side of the transdermal system during application, in order to avoid absorption of methylphenidate. If they do touch the adhesive side of the transdermal system, they should immediately wash their hands after application. • In the event that a DAYTRANA does not fully adhere to the skin upon application, or is partially or fully detached during wear time, the transdermal system should be discarded according to the directions provided in this label, and a new transdermal system should be applied [see Dosage and Administration (2.3)]. If a transdermal system is replaced, the total recommended wear time for that day should remain 9 hours, regardless of the number of transdermal systems used. • DAYTRANA should not be applied or re-applied with dressings, tape, or other common adhesives. • Exposure to water during bathing, swimming, or showering can affect DAYTRANA adherence. • Do not cut transdermal systems. Only intact transdermal systems should be applied. • If there is an unacceptable duration of appetite loss or insomnia in the evening, taking the transdermal system off earlier may be attempted before decreasing the transdermal system dose. • Skin redness or itching is common with DAYTRANA and small bumps on the skin may also occur in some patients. If any swelling or blistering occurs the DAYTRANA should not be worn and the patient should be seen by the prescriber. Patients or caregivers should not apply hydrocortisone or other solutions, creams, ointments, or emollients immediately prior to DAYTRANA application, since the effect on transdermal system adhesion and methylphenidate absorption has not been established. The potential adverse effects of topical corticosteroid use during treatment with DAYTRANA are unknown. Recommended Storage Instructions Transdermal systems should be stored at 25 degrees Celsius (77 degrees Fahrenheit) with excursions permitted that do not exceed 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit) [see How Supplied/Storage and Handling (16)]. Patients or caregivers should be advised not to store DAYTRANA in the refrigerator or freezer. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including DAYTRANA, during pregnancy [see Use in Specific Populations (8.1)]. Manufactured for: Noven Therapeutics, LLC, Miami, FL 33186. By: Noven Pharmaceuticals, Inc., Miami, FL 33186. For more information, call 1-877-567-7857 or visit www.daytrana.com. DOT Matrix™ is a trademark of Noven Pharmaceuticals, Inc. DAYTRANA® is a registered trademark of Noven Therapeutics, LLC. © 2023 Noven Pharmaceuticals, Inc. 102086-22 Reference ID: 5487488 MEDICATION GUIDE DAYTRANA® (day-TRON-ah) (methylphenidate transdermal system) CII Important: DAYTRANA is for use on the skin only. What is the most important information I should know about DAYTRANA? DAYTRANA may cause serious side effects, including: • Abuse, misuse, and addiction. DAYTRANA has a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of DAYTRANA, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of DAYTRANA or when it is used in ways that are not approved, such as snorting or injection. o Your healthcare provider should check your child’s risk for abuse, misuse, and addiction before starting treatment with DAYTRANA and will monitor your child during treatment. o DAYTRANA may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. o Do not give DAYTRANA to anyone else. See “What is DAYTRANA?” for more information. o Keep DAYTRANA in a safe place and properly dispose of any unused medicine. See “How should I store DAYTRANA?” for more information. o Tell your healthcare provider if your child has ever abused or been dependent on alcohol, prescription medicines, or street drugs. • Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or other serious heart disease. Your child’s healthcare provider should check your child carefully for blood pressure and heart problems before starting treatment with and while you are using DAYTRANA. Tell your child’s healthcare provider if your child has any heart problems, heart disease or heart defects. Remove the DAYTRANA transdermal system (patch) and call your child’s healthcare provider or go to the nearest emergency room right away if your child has any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with DAYTRANA. • Increased blood pressure and heart rate. Your child’s healthcare provider should check your child’s blood pressure and heart rate regularly during treatment with DAYTRANA. • Mental (psychiatric) problems, including: o new or worse behavior or thought problems o new or worse bipolar illness o new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or manic symptoms Tell your child’s healthcare provider about any mental problems your child has or about a family history of suicide, bipolar illness, or depression. Call your child’s healthcare provider right away if your child has any new or worsening mental symptoms or problems during treatment with DAYTRANA, especially hearing voices, seeing, or believing things that are not real, or new manic symptoms. What is DAYTRANA? DAYTRANA is a central nervous system (CNS) stimulant prescription medication used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 to 17 years of age. DAYTRANA may help increase attention and decrease impulsiveness and hyperactivity in children with ADHD. It is not known if DAYTRANA is safe and effective in children younger than 6 years. Reference ID: 5487488 DAYTRANA is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep DAYTRANA in a safe place to protect it from theft. Never give your DAYTRANA to anyone else because it may cause death or harm them. Selling or giving away DAYTRANA may harm others and is against the law. Do not use DAYTRANA if your child: • is allergic to methylphenidate or any of the ingredients in DAYTRANA. See the end of this Medication Guide for a complete list of ingredients in DAYTRANA. • is taking, or has stopped taking withing the past 14 days, a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI) Before using DAYTRANA, tell your child’s healthcare provider about all of your child’s medical conditions, including if your child: • has heart problems, heart disease, heart defects, or high blood pressure • has mental problems including psychosis, mania, bipolar illness, or depression, or has a family history of suicide bipolar illness, or depression • has seizures or have had an abnormal brain wave test (EEG) • has circulation problems in fingers or toes • has skin problems such as eczema or psoriasis, or have skin reactions to soaps, lotions, make-up, or adhesives (glues) • has a history of vitiligo or a family history of vitiligo • has eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) • has or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome • is pregnant or plans to become pregnant. It is not known if DAYTRANA will harm the unborn baby. Tell your child’s healthcare provider if your child becomes pregnant during treatment with DAYTRANA. o There is a pregnancy registry for females who are exposed to DAYTRANA during pregnancy. The purpose of the registry is to collect information about the health of women exposed to DAYTRANA and their baby. If your child becomes pregnant during treatment with DAYTRANA, talk to your child’s healthcare provider about registering with the National Pregnancy Registry of Psychostimulants at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhd-medications/. • is breast feeding or plan to breast feed. DAYTRANA passes into breast milk. Talk to your child’s healthcare provider about the best way to feed the baby during treatment with DAYTRANA. • a history of vitiligo and/or a family history of vitiligo Tell your child’s healthcare provider about all of the medicines your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. DAYTRANA and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with DAYTRANA. Your child’s healthcare provider will decide if DAYTRANA can be taken with other medicines. Especially tell your child’s healthcare provider if your child takes: • blood pressure medicines (anti-hypertensive) Know the medicines that your child takes. Keep a list of your child’s medicines with you to show your child’s healthcare provider and pharmacist when your child gets a new medicine. Do not start any new medicine while using DAYTRANA without first talking to your child’s healthcare provider. Reference ID: 5487488 How should DAYTRANA be used? • See the detailed “Instructions for Use” at the end of this Medication Guide for information about the right way to apply, remove, and dispose of DAYTRANA. • Use DAYTRANA exactly as prescribed by your child’s healthcare provider. • Your child’s healthcare provider may change the dose if needed. • Apply DAYTRANA to the hip area 2 hours before an effect is needed and remove DAYTRANA within 9 hours after it is applied. Do not wear DAYTRANA longer than 9 hours a day. • If DAYTRANA falls off, a new patch may be applied to a different area of the same hip. • If you forget to apply DAYTRANA at your usual scheduled time each day, you may apply the patch later in the day. The patch should be removed at the usual time of day to lower the chance of side effects later in the day. • If your child has loss of appetite or trouble sleeping in the evening, ask your child’s healthcare provider if your child can take the patch off earlier in the day. • Contact with water while bathing, swimming, or showering can make the patch not stick well. • Do not use bandages, tape, or other household adhesives (glue) to hold the patch onto the skin. If your child uses too much DAYTRANA transdermal systems call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What should your child avoid while using DAYTRANA? • After applying the DAYTRANA patch, avoid exposing the application site to direct external heat sources, such as hair dryers, heating pads, electric blankets, heated water beds or other heat sources. Exposure to heat can cause too much medicine to pass into the body and cause serious side effects. What are the possible side effects of DAYTRANA? DAYTRANA may cause serious side effects, including: • See "What is the most important information I should know about DAYTRANA?" • Seizures. Your child’s healthcare provider may stop treatment with DAYTRANA if your child has a seizure. • Painful and prolonged erections (priapism). Priapism that may require surgery has happened in people who take products that contain methylphenidate. If your child develops priapism, get medical help right away. • Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon). Signs and symptoms may include: o fingers or toes may feel numb, cool, or painful o fingers and toes may change color from pale, to blue, to red Tell your child’s healthcare provider if your child has any numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes. Call your healthcare provider right away if your child has any signs of unexplained wounds appearing on fingers or toes during treatment with DAYTRANA. • Slowing of growth (height and weight) in children. Your child should have their height and weight checked often during treatment with DAYTRANA. Your healthcare provider may stop your child’s DAYTRANA treatment if they are not growing or gaining weight as expected. • Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. Reference ID: 5487488 • New or worsening tics or worsening Tourette’s syndrome. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with DAYTRANA. • Loss of skin color. DAYTRANA may cause a persistent loss of skin-color where the patch is applied or around the patch application site. Loss of skin-color, in some cases, has been reported at locations on the skin far from any application site. The loss of skin-color may be permanent even after removing the patch or DAYTRANA is stopped. Call your healthcare provider right away if your child has changes in skin-color. DAYTRANA treatment may be stopped if your child has changes in skin color. • Allergic skin rash (contact sensitization). Stop using DAYTRANA and tell your child’s healthcare provider right away if your child develops swelling or blisters at or around the application site. Your child may have a skin allergy to DAYTRANA. People who have skin allergies to DAYTRANA may develop an allergy to all medicines that contain methylphenidate, even methylphenidate medicines taken by mouth. The most common side effects of DAYTRANA in children 6 to 12 years old include: • decreased appetite • vomiting • changes in mood • trouble sleeping • weight loss • trouble eating • nausea • tics The most common side effects of DAYTRANA in children 13 to 17 years old include: • decreased appetite • weight loss • stomach pain • nausea • dizziness • trouble eating • trouble sleeping DAYTRANA may also cause skin problems where it is applied (redness, small bumps, itching) Your child’s doctor may do certain blood tests while your child uses DAYTRANA. These are not all the possible side effects of DAYTRANA.. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA­ 1088. How should I store DAYTRANA? • Store DAYTRANA at room temperature between 68° F to 77° F (20° C to 25° C). • Store DAYTRANA in a safe place, like a locked cabinet. • Do not store DAYTRANA in the refrigerator or freezer. • Keep DAYTRANA in their unopened pouches until you are ready to use them. • Use or throw away the patches within 2 months after you open the sealed tray. • Dispose of remaining, unused, or expired DAYTRANA by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, each unused patch should be removed from its individual pouch, separated from the protective liner, folded in half so that the sticky sides stick together, and flushed down the toilet. Put the pouch and liner in a container with a lid, close the container and throw away the container in the household trash. Do not flush the pouch and liner down the toilet. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep DAYTRANA and all medicines out of the reach of children. General information about the safe and effective use of DAYTRANA. Reference ID: 5487488 Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DAYTRANA for a condition for which it was not prescribed. Do not give DAYTRANA to other people, even if they have the same symptoms. It may harm them and it is against the law. You can ask your pharmacist or healthcare provider for information about DAYTRANA that is written for healthcare professionals. What are the ingredients in DAYTRANA? Active ingredient: methylphenidate Inactive ingredients: acrylic adhesive, silicone adhesive Manufactured by: Noven Pharmaceuticals, Inc., Miami, FL 33186 DAYTRANA® is a trademark of Noven Therapeutics, LLC. For more information, go to www.daytrana.com, or call 1-877-567-7857. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised 11/2024 Reference ID: 5487488 INSTRUCTIONS FOR USE DAYTRANA® (day-TRON-ah) (methylphenidate transdermal system) CII 1. DAYTRANA Dosing Chart Each carton of DAYTRANA contains a DAYTRANA Dosing Chart to help you keep track of your DAYTRANA transdermal system (patch) including: • when you apply patch to the skin on your hip each morning • when you remove the patch • how and where you threw DAYTRANA away To use the DAYTRANA Dosing Chart, follow these instructions: • Each day, when a new patch is applied to your hip, write down the date and time that you applied the patch. • Use the DAYTRANA schedule below so you can decide when to remove the patch. For example, if the patch is applied to the skin at 6:00 a.m., remove the patch at 3:00 p.m. on the same day. After you remove and throw away the patch, write down the time you removed the patch and how and where you threw it away. • If the patch you placed on your child is missing, ask your child: • when the patch came off • how the patch came off • where the patch is DAYTRANA Schedule for 9 Hour Dosing If you put the patch on at: On the same day, remove the patch at: 5:00 a.m. 2:00 p.m. 6:00 a.m. 3:00 p.m. 7:00 a.m. 4:00 p.m. 8:00 a.m. 5:00 p.m. 9:00 a.m. 6:00 p.m. 10:00 a.m. 7:00 p.m. 11:00 a.m. 8:00 p.m. 12:00 p.m. 9:00 p.m. 2. Where to apply DAYTRANA • Apply patch to your hip area. Do not put the patch near your waist. Clothing and movement may make your patch rub off (See Figure A). • Use your other hip when you apply a new patch the next morning. Make sure there is no redness, small bumps or itching at the site where the patch is going to be applied. Reference ID: 5487488 outside backing !1' Figure A 3. Before you apply DAYTRANA Make sure your skin: • Is clean (freshly washed), dry, and cool • Does not have any powder, oil, or lotion • Does not have any cuts and irritation (rashes, inflammation, redness, or other skin problems). 4. How to apply DAYTRANA • Open the sealed tray and throw away the small packet (drying agent). • Each patch is sealed in its own protective pouch. • Carefully cut the protective pouch open with scissors, being careful not to cut the patch. Do not use patches that have been cut or damaged in any way (See Figure B). Figure B • Remove the patch from the protective pouch. • Look at the patch to make sure it is not damaged. The patch should separate easily from the protective liner. Throw away the patch if the protective liner is hard to remove. DAYTRANA has 3 layers. The 3 layers are pictured below. The pictures show both sides of the patch: Figure C Figure D Reference ID: 5487488 Layers: • Protective liner: The protective liner is the layer that you remove before you put the patch on (See Figure C). • Adhesive with medicine: The adhesive with medicine is the layer that sticks to your skin (See Figure C). • Outside backing: The outside backing is the layer that you see after you put the patch on your skin. The word "Daytrana" is printed on this layer (See Figure D). • Apply the patch right away after you remove the patch from protective pouch. • Hold the patch with the hard protective liner facing you. The word DAYTRANA will appear backwards. • Gently bend the patch along the faint line and slowly peel half the liner, which covers the sticky surface of the patch (See Figure E). Figure E • Avoid touching the sticky side of the patch with your fingers. • If you accidentally touch the sticky side of the patch, apply the patch, then wash your hands right away so that the medicine does not go into the skin on your hands. • Using the other half of the protective liner as a handle, apply the sticky side of the patch to the selected area of the child's hip (See Figure F). Figure F • Press the sticky side of the patch firmly into place and smooth it down. • While you are still holding the sticky side down, gently fold back the other half of the patch. • Hold an edge of the remaining protective liner and slowly peel it off (See Figure G). Reference ID: 5487488 Figure G • After the protective liner is removed, there should not be any adhesive (glue) sticking to the liner. Figure H • Press the entire patch firmly into place with the palm of your hand over the patch for about 30 seconds (See Figure H). • Make sure that the patch firmly sticks to your skin. • Gently rub the edges of the patch with your fingers to make sure the patch sticks to your skin. • Wash your hands after you apply your patch. • Write the time you applied your patch on the dosing chart on the carton. Use the dosing schedule so you know what time you should remove your patch. 5. How to remove and throw away DAYTRANA • When you remove the patch, peel it off slowly. If the patch is too sticky on your skin and you need something to help you remove it: o Gently apply an oil-based product (petroleum jelly, olive oil, or mineral oil) to the patch edges. Gently spread the oil underneath the patch edges. o Apply an oil-based product or lotion to your skin if any adhesive (glue) remains after you remove your patch. This will gently loosen and remove any adhesive that is left over. o If you still cannot easily remove the patch, ask your doctor or pharmacist about what to do for this problem. • Fold the used patch in half and press it together firmly so that the sticky side sticks to itself. Flush the used patch down the toilet. • Do not flush the protective pouches or the protective liners down the toilet. These items should be thrown away in a container with a lid. • Wash your hands after you handle the patch. • After you remove the patch and throw the patch away, write down the time on the dosing chart. Reference ID: 5487488 • Safely throw away any unused patches that are left over from the prescription as soon as they are no longer needed. To safely throw away the patches: o Remove the leftover patches from their protective pouches and remove the protective liners. o Either fold the patches in half with the sticky sides together, and flush the patches down the toilet, or o Dispose of remaining, unused, or expired DAYTRANA by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, each unused patch should be removed from its individual pouch, separated from the protective liner, folded in half so that the sticky sides stick together, and flushed down the toilet. Put the pouch and liner in a container with a lid, close the container and throw away the container in the household trash. Do not flush the pouch and liner down the toilet. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Manufactured for: Noven Therapeutics, LLC, Miami, FL 33186. By: Noven Pharmaceuticals, Inc., Miami, FL 33186. © 2023 Noven Pharmaceuticals, Inc. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 102086-22 Reference ID: 5487488
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2025-02-12T15:47:25.486659
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use WEGOVY safely and effectively. See full prescribing information for WEGOVY. WEGOVY (semaglutide) injection, for subcutaneous use Initial U.S. Approval: 2017 WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • In rodents, semaglutide causes thyroid C-cell tumors at clinically relevant exposures. It is unknown whether WEGOVY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined (5.1, 13.1). • WEGOVY is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors (4, 5.1). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Indications and Usage (1) 03/2024 Dosing and Administration (2.2) 11/2024 Warnings and Precautions, Hypoglycemia (5.4) 03/2024 Warning and Precautions, Severe Gastrointestinal Adverse Reactions (5.6) 11/2024 Warnings and Precaution, Pulmonary Aspiration During General Anesthesia or Deep Sedation (5.11) 11/2024 ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ WEGOVY is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated in combination with a reduced calorie diet and increased physical activity: • to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with established cardiovascular disease and either obesity or overweight (1). • to reduce excess body weight and maintain weight reduction long term in: o Adults and pediatric patients aged 12 years and older with obesity o Adults with overweight in the presence of at least one weight-related comorbid condition (1). Limitations of Use: • Coadministration with other semaglutide-containing products or with any other GLP-1 receptor agonist is not recommended (1). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Administer WEGOVY once weekly as an adjunct to diet and increased physical activity, on the same day each week, at any time of day, with or without meals (2.1). • Inject subcutaneously in the abdomen, thigh, or upper arm (2.1). • In patients with type 2 diabetes, monitor blood glucose prior to starting and during WEGOVY treatment (2.1). • Initiate at 0.25 mg once weekly for 4 weeks. Then follow the dosage escalation schedule, titrating every 4 weeks to achieve the maintenance dosage (2.2, 2.3). • The maintenance dosage of WEGOVY is either 2.4 mg (recommended) or 1.7 mg once weekly (2.2). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Injection: prefilled, single-dose pen that delivers doses of 0.25 mg, 0.5 mg, 1 mg, 1.7 mg or 2.4 mg (3). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Personal or family history of MTC or in patients with MEN2 (4). • Known hypersensitivity to semaglutide or any of the excipients in WEGOVY (4). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, including WEGOVY. Discontinue promptly if pancreatitis is suspected. (5.2). • Acute Gallbladder Disease: Has occurred in clinical trials. If cholelithiasis is suspected, gallbladder studies and clinical follow-up are indicated (5.3). • Hypoglycemia: Concomitant use with insulin or an insulin secretagogue may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dose of insulin or insulin secretagogue may be necessary. Inform all patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia (5.4). • Acute Kidney Injury: Has occurred. Monitor renal function when initiating or escalating doses of WEGOVY in patients reporting severe adverse gastrointestinal reactions or in those with renal impairment reporting severe adverse gastrointestinal reactions (5.5). • Severe Gastrointestinal Adverse Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. WEGOVY is not recommended in patients with severe gastroparesis. (5.6). • Hypersensitivity Reactions: Anaphylactic reactions and angioedema have been reported postmarketing. Discontinue WEGOVY if suspected and promptly seek medical advice (5.7). • Diabetic Retinopathy Complications in Patients with Type 2 Diabetes: Has been reported in trials with semaglutide. Patients with a history of diabetic retinopathy should be monitored (5.8). • Heart Rate Increase: Monitor heart rate at regular intervals (5.9). • Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts. Discontinue WEGOVY if symptoms develop (5.10). • Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. (5.11). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Most common adverse reactions (incidence ≥5%) in adults or pediatric patients aged 12 years and older are: nausea, diarrhea, vomiting, constipation, abdominal pain, headache, fatigue, dyspepsia, dizziness, abdominal distension, eructation, hypoglycemia in patients with type 2 diabetes, flatulence, gastroenteritis, gastroesophageal reflux disease, and nasopharyngitis (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-833-934-6891 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS----------------------------------­ WEGOVY delays gastric emptying. May impact absorption of concomitantly administered oral medications. Use with caution (7.2). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Pregnancy: May cause fetal harm. When pregnancy is recognized, discontinue WEGOVY (8.1). • Females and Males of Reproductive Potential: Discontinue WEGOVY at least 2 months before a planned pregnancy because of the long half-life of semaglutide (8.3). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2024 Reference ID: 5487292 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF THYROID C-CELL TUMORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Monitoring and Administration Instructions 2.2 Recommended Dosage in Adults and Pediatric Patients Aged 12 Years and Older 2.3 Recommendations Regarding Missed Dose 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors 5.2 Acute Pancreatitis 5.3 Acute Gallbladder Disease 5.4 Hypoglycemia 5.5 Acute Kidney Injury 5.6 Severe Gastrointestinal Adverse Reactions 5.7 Hypersensitivity Reactions 5.8 Diabetic Retinopathy Complications in Patients with Type 2 Diabetes 5.9 Heart Rate Increase 5.10 Suicidal Behavior and Ideation 5.11 Pulmonary Aspiration During General Anesthesia or Deep Sedation 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Use with Insulin or an Insulin Secretagogue (e.g., Sulfonylurea) 7.2 Oral Medications 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Cardiovascular Outcomes Trial in Adult Patients with Cardiovascular Disease and Either Obesity or Overweight 14.2 Weight Reduction and Long-term Maintenance Studies in Adults with Obesity or Overweight 14.3 Weight Reduction and Long-Term Maintenance Study in Pediatric Patients Aged 12 Years and Older with Obesity 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5487292 FULL PRESCRIBING INFORMATION WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether WEGOVY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1), Nonclinical Toxicology (13.1)]. • WEGOVY is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications (4)]. Counsel patients regarding the potential risk for MTC with the use of WEGOVY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with WEGOVY [see Contraindications (4), Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE WEGOVY is indicated in combination with a reduced calorie diet and increased physical activity: • to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with established cardiovascular disease and either obesity or overweight. • to reduce excess body weight and maintain weight reduction long term in: o Adults and pediatric patients aged 12 years and older with obesity o Adults with overweight in the presence of at least one weight-related comorbid condition. Limitations of Use • WEGOVY contains semaglutide. Coadministration with other semaglutide-containing products or with any other GLP-1 receptor agonist is not recommended. 2 DOSAGE AND ADMINISTRATION 2.1 Important Monitoring and Administration Instructions • In patients with type 2 diabetes mellitus, monitor blood glucose prior to starting WEGOVY and during WEGOVY treatment [see Warnings and Precautions (5.4)]. • Prior to initiation of WEGOVY, train patients on proper injection technique. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations. • Inspect WEGOVY visually prior to each injection. Only use if solution is clear, colorless, and contains no particles. • Administer WEGOVY in combination with a reduced-calorie diet and increased physical activity. • Administer WEGOVY once weekly, on the same day each week, at any time of day, with or without meals. • Inject WEGOVY subcutaneously in the abdomen, thigh, or upper arm. The time of day and the injection site can be changed without dose adjustment. 2.2 Recommended Dosage in Adults and Pediatric Patients Aged 12 Years and Older Dosage Initiation and Escalation Reference ID: 5487292 • Initiate WEGOVY with a dosage of 0.25 mg injected subcutaneously once weekly. Follow the dosage initiation and escalation in Table 1 to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.6), Adverse Reactions (6.1)]. • If patients do not tolerate a dose during dosage escalation, consider delaying dosage escalation for 4 weeks. Table 1. Recommended Dosage Escalation in Adults and Pediatric Patients Aged 12 Years and Older Treatment Weeks Once weekly Subcutaneous Dosage Initiation 1 through 4 0.25 mg Escalation 5 through 8 0.5 mg 9 through 12 1 mg 13 through 16 1.7 mg Maintenance 17 and onward 1.7 mg or 2.4 mg Maintenance Dosage The maintenance dosage of WEGOVY is either 2.4 mg (recommended) or 1.7 mg once weekly. Consider treatment response and tolerability when selecting the maintenance dosage [see Adverse Reactions (6.1), Clinical Studies (14.2, 14.3)]. 2.3 Recommendations Regarding Missed Dose • If one dose is missed and the next scheduled dose is more than 2 days away (48 hours), administer WEGOVY as soon as possible. If one dose is missed and the next scheduled dose is less than 2 days away (48 hours), do not administer the dose. Resume dosing on the regularly scheduled day of the week. • If 2 or more consecutive doses are missed, resume dosing as scheduled or, if needed, reinitiate WEGOVY and follow the dose escalation schedule, which may reduce the occurrence of gastrointestinal symptoms associated with reinitiation of treatment. 3 DOSAGE FORMS AND STRENGTHS Injection: clear, colorless solution available in 5 prefilled, disposable, single-dose pens: • 0.25 mg/0.5 mL • 0.5 mg/0.5 mL • 1 mg/0.5 mL • 1.7 mg/0.75 mL • 2.4 mg/0.75 mL 4 CONTRAINDICATIONS WEGOVY is contraindicated in the following conditions: • A personal or family history of MTC or in patients with MEN 2 [see Warnings and Precautions (5.1)]. • A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in WEGOVY. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with WEGOVY [see Warnings and Precautions (5.7)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures [see Nonclinical Toxicology (13.1)]. It is unknown whether WEGOVY causes thyroid C-cell tumors, including MTC, in humans, as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. Reference ID: 5487292 Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. WEGOVY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of WEGOVY and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with WEGOVY. Such monitoring may increase the risk of unnecessary procedures, due to the low-test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values greater than 50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including WEGOVY [see Adverse Reactions (6)]. After initiation of WEGOVY, observe patients carefully for signs and symptoms of acute pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, and which may or may not be accompanied by vomiting). If acute pancreatitis is suspected, discontinue WEGOVY and initiate appropriate management. 5.3 Acute Gallbladder Disease Treatment with WEGOVY is associated with an increased occurrence of cholelithiasis and cholecystitis. The incidence of cholelithiasis and cholecystitis was higher in WEGOVY-treated pediatric patients aged 12 years and older than in WEGOVY-treated adults. In randomized clinical trials in adult patients, cholelithiasis was reported by 1.6% of WEGOVY-treated patients and 0.7% of placebo-treated patients. Cholecystitis was reported by 0.6% of WEGOVY-treated adult patients and 0.2% of placebo-treated patients. In a clinical trial in pediatric patients aged 12 years and older, cholelithiasis was reported by 3.8% of WEGOVY-treated patients and 0% placebo-treated patients. Cholecystitis was reported by 0.8% of WEGOVY-treated pediatric patients and 0% placebo-treated patients [see Adverse Reactions (6.1)]. Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in WEGOVY-treated patients than in placebo-treated patients, even after accounting for the degree of weight loss. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. 5.4 Hypoglycemia WEGOVY lowers blood glucose and can cause hypoglycemia. In a trial of adult patients with type 2 diabetes and body mass index (BMI) greater than or equal to 27 kg/m2, hypoglycemia (defined as a plasma glucose less than 54 mg/dL) was reported in 6.2% of WEGOVY-treated patients versus 2.5% of placebo-treated patients. One episode of severe hypoglycemia (requiring the assistance of another person) was reported in one WEGOVY-treated patient versus no placebo-treated patients. Patients with diabetes mellitus taking WEGOVY in combination with insulin or an insulin secretagogue (e.g., sulfonylurea) may have an increased risk of hypoglycemia, including severe hypoglycemia. Hypoglycemia has been observed in patients treated with semaglutide at doses of 0.5 and 1 mg in combination with insulin. The use of WEGOVY (semaglutide 2.4 mg or 1.7 mg once weekly) in patients with type 1 diabetes mellitus or in combination with insulin has not been evaluated. Reference ID: 5487292 Inform patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. In patients with diabetes, monitor blood glucose prior to starting WEGOVY and during WEGOVY treatment. When initiating WEGOVY, consider reducing the dose of concomitantly administered insulin or insulin secretagogue (such as sulfonylureas) to reduce the risk of hypoglycemia [see Drug Interactions (7)]. 5.5 Acute Kidney Injury There have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which have in some cases required hemodialysis, in patients treated with semaglutide. Patients with renal impairment may be at greater risk of acute kidney injury, but some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, or diarrhea, leading to volume depletion [see Adverse Reactions (6)]. Monitor renal function when initiating or escalating doses of WEGOVY in patients reporting severe adverse gastrointestinal reactions. Monitor renal function in patients with renal impairment reporting any adverse reactions that could lead to volume depletion. 5.6 Severe Gastrointestinal Adverse Reactions Use of WEGOVY has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6.1)]. In WEGOVY clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving WEGOVY (4.1%) than placebo (0.9%). WEGOVY is not recommended in patients with severe gastroparesis. 5.7 Hypersensitivity Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported with WEGOVY. If hypersensitivity reactions occur, discontinue use of WEGOVY, treat promptly per standard of care, and monitor until signs and symptoms resolve. WEGOVY is contraindicated in patients with a prior serious hypersensitivity reaction to semaglutide or to any of the excipients in WEGOVY [see Adverse Reactions (6.2)]. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with WEGOVY. 5.8 Diabetic Retinopathy Complications in Patients with Type 2 Diabetes In a trial of adult patients with type 2 diabetes and BMI greater than or equal to 27 kg/m2, diabetic retinopathy was reported by 4% of WEGOVY-treated patients and 2.7% placebo-treated patients. In a 2-year trial with semaglutide 0.5 mg and 1 mg once-weekly injection in adult patients with type 2 diabetes and high cardiovascular risk, diabetic retinopathy complications (which was a 4-component adjudicated endpoint) occurred in patients treated with semaglutide injection (3%) compared to placebo (1.8%). The absolute risk increase for diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline (semaglutide injection 8.2%, placebo 5.2%) than among patients without a known history of diabetic retinopathy (semaglutide injection 0.7%, placebo 0.4%). Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been studied. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy. Reference ID: 5487292 5.9 Heart Rate Increase Treatment with WEGOVY was associated with increases in resting heart rate. Mean increases in resting heart rate of 1 to 4 beats per minute (bpm) were observed in WEGOVY-treated adult patients compared to placebo in clinical trials. More adult patients treated with WEGOVY compared with placebo had maximum changes from baseline at any visit of 10 to 19 bpm (41% versus 34%, respectively) and 20 bpm or more (26% versus 16%, respectively). In a clinical trial in pediatric patients aged 12 years and older with normal baseline heart rate, more patients treated with WEGOVY compared to placebo had maximum changes in heart rate of 20 bpm or more (54% versus 39%) [see Adverse Reactions (6.1)]. Monitor heart rate at regular intervals consistent with usual clinical practice. Instruct patients to inform their healthcare providers of palpitations or feelings of a racing heartbeat while at rest during WEGOVY treatment. If patients experience a sustained increase in resting heart rate, discontinue WEGOVY. 5.10 Suicidal Behavior and Ideation Suicidal behavior and ideation have been reported in clinical trials with other weight management products. Monitor patients treated with WEGOVY for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue WEGOVY in patients who experience suicidal thoughts or behaviors. Avoid WEGOVY in patients with a history of suicidal attempts or active suicidal ideation. 5.11 Pulmonary Aspiration During General Anesthesia or Deep Sedation WEGOVY delays gastric emptying [see Clinical Pharmacology (12.2)]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking WEGOVY, including whether modifying preoperative fasting recommendations or temporarily discontinuing WEGOVY could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking WEGOVY. 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-Cell Tumors [see Warnings and Precautions (5.1)] • Acute Pancreatitis [see Warnings and Precautions (5.2)] • Acute Gallbladder Disease [see Warnings and Precautions (5.3)] • Hypoglycemia [see Warnings and Precautions (5.4)] • Acute Kidney Injury [see Warnings and Precautions (5.5)] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.6)] • Hypersensitivity Reactions [see Warnings and Precautions (5.7)] • Diabetic Retinopathy Complications in Patients with Type 2 Diabetes [see Warnings and Precautions (5.8)] • Heart Rate Increase [see Warnings and Precautions (5.9)] • Suicidal Behavior and Ideation [see Warnings and Precautions (5.10)] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.11)] Reference ID: 5487292 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials in Adults with Obesity or Overweight WEGOVY 2.4 mg Subcutaneous Weekly Dosage WEGOVY was evaluated for safety in 3 randomized, double-blind, placebo-controlled trials that included 2,116 adult patients with obesity or overweight treated with 2.4 mg WEGOVY for up to 68 weeks and a 7 week off- drug follow-up period [see Clinical Studies (14.2)]. Baseline characteristics included a mean age of 48 years, 71% female, 72% White, 14% Asian, 9% Black or African American, and 5% reported as other or unknown; and 85% were not Hispanic or Latino ethnicity, 13% were Hispanic or Latino ethnicity, and 2% reported as unknown. The baseline characteristics were 42% with hypertension, 19% with type 2 diabetes, 43% with dyslipidemia, 28% with a BMI greater than 40 kg/m2, and 4% with cardiovascular disease. In these clinical trials, 6.8% of patients treated with 2.4 mg WEGOVY and 3.2% of patients treated with placebo permanently discontinued treatment as a result of adverse reactions. The most common adverse reactions leading to discontinuation were nausea (1.8% versus 0.2%), vomiting (1.2% versus 0%), and diarrhea (0.7% versus 0.1%) for WEGOVY and placebo, respectively. Adverse reactions reported in clinical trials in adults and greater than or equal to 2% of WEGOVY-treated patients and more frequently than in placebo-treated patients are shown in Table 2. Table 2. Adverse Reactions (≥2% and Greater Than Placebo) in WEGOVY-treated Adults with Obesity or Overweight Placebo N=1,261 % WEGOVY 2.4 mg N=2,116 % Nausea 16 44 Diarrhea 16 30 Vomiting 6 24 Constipation 11 24 Abdominal Paina 10 20 Headache 10 14 Fatigueb 5 11 Dyspepsia 3 9 Dizziness 4 8 Abdominal Distension 5 7 Eructation <1 7 Hypoglycemia in T2DMc 2 6 Flatulence 4 6 Gastroenteritis 4 6 Gastroesophageal Reflux Disease 3 5 Gastritisd 1 4 Gastroenteritis Viral 3 4 Hair Loss 1 3 Dysesthesiae 1 2 a Includes abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain, abdominal tenderness, abdominal discomfort and epigastric discomfort b Includes fatigue and asthenia c Defined as blood glucose <54 mg/dL with or without symptoms of hypoglycemia or severe hypoglycemia (requiring the assistance of another person) in patients with type 2 diabetes not on concomitant insulin (Study 3, WEGOVY N=403, Placebo Reference ID: 5487292 N=402). See text below for further information regarding hypoglycemia in patients with and without type 2 diabetes. T2DM = type 2 diabetes mellitus d Includes chronic gastritis, gastritis, gastritis erosive, and reflux gastritis e Includes paresthesia, hyperesthesia, burning sensation, allodynia, dysesthesia, skin burning sensation, pain of skin, and sensitive skin In a cardiovascular outcomes trial, 8,803 patients were exposed to WEGOVY for a median of 37.3 months and 8,801 patients were exposed to placebo for a median of 38.6 months [see Clinical Studies (14.1)]. Safety data collection was limited to serious adverse events (including death), adverse events leading to discontinuation, and adverse events of special interest. Sixteen percent (16%) of WEGOVY-treated patients and 8% of placebo- treated patients, respectively, discontinued study drug due to an adverse event. Additional information from this trial is included in subsequent sections below when relevant. Adverse Reactions in a Clinical Trial of Pediatric Patients Aged 12 Years and Older with Obesity WEGOVY was evaluated in a 68-week, double-blind, randomized, parallel group, placebo-controlled, multi- center trial in 201 pediatric patients aged 12 years and older with obesity [see Clinical Studies (14.3)]. Baseline characteristics included a mean age of 15.4 years; 38% of patients were male; 79% were White, 8% were Black or African American, 2% were Asian, and 11% were of other or unknown race; and 11% were of Hispanic or Latino ethnicity. The mean baseline body weight was 107.5 kg, and mean BMI was 37 kg/m2. Table 3 shows adverse reactions reported in greater than or equal to 3% of WEGOVY-treated pediatric patients and more frequently than in the placebo group from a study in pediatric patients aged 12 years and older. Table 3. Adverse Reactions (≥3% and Greater than Placebo) in WEGOVY-Treated Pediatric Patients Aged 12 Years and Older with Obesity Placebo N=67 % WEGOVY 2.4 mg N=133 % Nausea 18 42 Vomiting 10 36 Diarrhea 19 22 Headache 16 17 Abdominal Pain 6 15 Nasopharyngitis 10 12 Dizziness 3 8 Gastroenteritis 3 7 Constipation 2 6 Gastroesophageal Reflux Disease 2 4 Sinusitis 2 4 Urinary tract infection 2 4 Ligament sprain 2 4 Anxiety 2 4 Hair Loss 0 4 Cholelithiasis 0 4 Eructation 0 4 Influenza 0 3 Rash 0 3 Urticaria 0 3 Reference ID: 5487292 Other Adverse Reactions in Adults and/or Pediatric Patients Acute Pancreatitis In WEGOVY clinical trials in adults, acute pancreatitis was confirmed by adjudication in 4 WEGOVY-treated patients (0.2 cases per 100 patient years) versus 1 in placebo-treated patients (less than 0.1 cases per 100 patient years). One additional case of acute pancreatitis was confirmed in a patient treated with WEGOVY in another clinical trial. Acute Gallbladder Disease In WEGOVY clinical trials in adults, cholelithiasis was reported by 1.6% of WEGOVY-treated patients and 0.7% of placebo-treated patients. Cholecystitis was reported by 0.6% of WEGOVY-treated adult patients and 0.2% of placebo-treated patients. In a clinical trial in pediatric patients aged 12 years and older [see Clinical Studies (14.3)], cholelithiasis was reported by 3.8% of WEGOVY-treated patients and 0% placebo-treated patients. Cholecystitis was reported by 0.8% of WEGOVY-treated pediatric patients and 0% placebo-treated patients. Hypoglycemia Patients with Type 2 Diabetes In a trial of adult patients with type 2 diabetes and BMI greater than or equal to 27 kg/m2, clinically significant hypoglycemia (defined as a plasma glucose less than 54 mg/dL) was reported in 6.2% of WEGOVY-treated patients versus 2.5% of placebo-treated patients. A higher rate of clinically significant hypoglycemic episodes was reported with WEGOVY (semaglutide 2.4 mg) versus semaglutide 1 mg (10.7 vs. 7.2 episodes per 100 patient years of exposure, respectively); the rate in the placebo-treated group was 3.2 episodes per 100 patient years of exposure. In addition, one episode of severe hypoglycemia requiring intravenous glucose was reported in a WEGOVY-treated patient versus none in placebo-treated patients. The risk of hypoglycemia was increased when WEGOVY was used with a sulfonylurea. Patients without Type 2 Diabetes Episodes of hypoglycemia have been reported with GLP-1 receptor agonists in adult patients without type 2 diabetes mellitus. In WEGOVY clinical trials in adult patients without type 2 diabetes mellitus, there was no systematic capturing or reporting of hypoglycemia. In a cardiovascular outcomes trial in adult patients without type 2 diabetes, 3 episodes of serious hypoglycemia were reported in WEGOVY-treated patients versus 1 episode in placebo. Patients with a history of bariatric surgery (a risk factor for hypoglycemia) had more events of serious hypoglycemia while taking WEGOVY (2.3%, 2/87) than placebo (0%, 0/97). Acute Kidney Injury Acute kidney injury occurred in clinical trials in 7 adult patients (0.4 cases per 100 patient years) receiving WEGOVY versus 4 patients (0.2 cases per 100 patient years of exposure) receiving placebo. Some of these adverse reactions occurred in association with gastrointestinal adverse reactions or dehydration. In addition, 2 patients treated with WEGOVY had acute kidney injury with dehydration in other clinical trials. The risk of renal adverse reactions with WEGOVY was increased in adult patients with a history of renal impairment (trials included 65 patients with a history of moderate or severe renal impairment at baseline), and occurred more frequently during dose titration. Retinal Disorders in Patients with Type 2 Diabetes In a trial of adult patients with type 2 diabetes and BMI greater than or equal to 27 kg/m2, retinal disorders were reported by 6.9% of patients treated with WEGOVY (semaglutide 2.4 mg), 6.2% of patients treated with semaglutide 1 mg, and 4.2% of patients treated with placebo. The majority of events were reported as diabetic retinopathy (4%, 2.7%, and 2.7%, respectively) and non-proliferative retinopathy (0.7%, 0%, and 0%, respectively). Reference ID: 5487292 Increase in Heart Rate Mean increases in resting heart rate of 1 to 4 beats per minute (bpm) were observed with routine clinical monitoring in WEGOVY-treated adult patients compared to placebo in clinical trials. In trials in which adult patients were randomized prior to dose-escalation, more patients treated with WEGOVY, compared with placebo, had maximum changes from baseline at any visit of 10 to 19 bpm (41% versus 34%, respectively) and 20 bpm or more (26% versus 16%, respectively). In a clinical trial in pediatric patients aged 12 years and older with normal baseline heart rate, more patients treated with WEGOVY compared to placebo had maximum changes in heart rate of 20 bpm or more (54% versus 39%). Hypotension and Syncope Adverse reactions related to hypotension (hypotension, orthostatic hypotension, and decreased blood pressure) were reported in 1.3% of WEGOVY-treated adult patients versus 0.4% of placebo-treated patients and syncope was reported in 0.8% of WEGOVY-treated patients versus 0.2% of placebo-treated patients. Some reactions were related to gastrointestinal adverse reactions and volume loss associated with WEGOVY. Hypotension and orthostatic hypotension were more frequently seen in patients on concomitant antihypertensive therapy. In a clinical trial in pediatric patients aged 12 years and older, hypotension was reported in 2.3% of WEGOVY- treated patients versus 0% in placebo-treated patients. Appendicitis Appendicitis (including perforated appendicitis) occurred in 10 (0.5%) WEGOVY-treated adult patients and 2 (0.2%) patients receiving placebo. Gastrointestinal Adverse Reactions In clinical trials in adults, 73% of WEGOVY-treated patients and 47% of patients receiving placebo reported gastrointestinal adverse reactions, including severe reactions that were reported more frequently among patients receiving WEGOVY (4.1%) than placebo (0.9%). The most frequently reported reactions were nausea (44% vs. 16%), vomiting (25% vs. 6%), and diarrhea (30% vs. 16%). Other reactions that occurred at a higher incidence among WEGOVY-treated adult patients included dyspepsia, abdominal pain, abdominal distension, eructation, flatulence, gastroesophageal reflux disease, gastritis, hemorrhoids, and hiccups. These reactions were most frequently reported during dosage escalation. In the pediatric clinical trial, 62% of WEGOVY-treated patients and 42% of placebo-treated patients reported gastrointestinal adverse reactions. The most frequently reported reactions were nausea (42% vs. 18%), vomiting (36% vs. 10%), and diarrhea (22% vs. 19%). Other gastrointestinal-related reactions that occurred at a higher incidence than placebo among WEGOVY-treated pediatric patients included abdominal pain, constipation, eructation, gastroesophageal reflux disease, dyspepsia, and flatulence. Permanent discontinuation of treatment as a result of a gastrointestinal adverse reaction occurred in 4.3% of WEGOVY-treated adult patients versus 0.7% of placebo-treated patients. In a pediatric clinical trial, 2.3% of patients treated with WEGOVY versus 1.5% of patients who received placebo discontinued treatment as a result of gastrointestinal adverse reactions. Injection Site Reactions In clinical trials in adults, 1.4% of WEGOVY-treated patients and 1% of patients receiving placebo experienced injection site reactions (including injection site pruritus, erythema, inflammation, induration, and irritation). Hypersensitivity Reactions Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported with WEGOVY. In a pediatric clinical trial, rash was reported in 3% of WEGOVY-treated patients and 0% of placebo-treated patients, and urticaria was reported in 3% of WEGOVY-treated patients and 0% of placebo-treated patients. Reference ID: 5487292 In adult clinical trials, allergic reactions occurred in 16% (8/50) of WEGOVY-treated patients with anti­ semaglutide antibodies and in 7% (114/1659) of WEGOVY-treated patients who did not develop anti­ semaglutide antibodies [see Clinical Pharmacology (12.6)]. Fractures In the cardiovascular outcomes trial in adults, more fractures of the hip and pelvis were reported on WEGOVY than on placebo in female patients: 1% (24/2448) vs. 0.2% (5/2424), and in patients ages 75 years and older: 2.4% (17/703) vs. 0.6% (4/663), respectively. Urolithiasis In a cardiovascular outcomes trial, 1.2% of WEGOVY-treated patients and 0.8% of patients receiving placebo reported urolithiasis, including serious reactions that were reported more frequently among patients receiving WEGOVY (0.6%) than placebo (0.4%). Dysgeusia In clinical trials in adults, 1.7% of WEGOVY-treated patients and 0.5% of placebo-treated patients reported dysgeusia. Laboratory Abnormalities Amylase and Lipase Adult and pediatric patients treated with WEGOVY had a mean increase from baseline in amylase of 15 to 16% and lipase of 39%. These changes were not observed in the placebo group. The clinical significance of elevations in lipase or amylase with WEGOVY is unknown in the absence of other signs and symptoms of pancreatitis. Liver Enzymes In a pediatric clinical trial, increases in alanine aminotransferase (ALT) greater than or equal to 5 times the upper limit of normal were observed in 4 (3%) WEGOVY-treated patients compared with 0% of placebo- treated patients. In some patients, increases in ALT and AST were associated with other confounding factors (such as gallstones). In the cardiovascular outcomes trial in adults, increases in total bilirubin greater than or equal to 3 times the upper limit of normal were observed in 0.3% (30/8585) of WEGOVY-treated patients versus 0.2% (14/8579) of placebo-treated patients. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of WEGOVY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: acute pancreatitis and necrotizing pancreatitis, sometimes resulting in death; ileus Hypersensitivity: anaphylaxis, angioedema, rash, urticaria Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation Renal and Urinary Disorders: acute kidney injury DRUG INTERACTIONS 7.1 Concomitant Use with Insulin or an Insulin Secretagogue (e.g., Sulfonylurea) WEGOVY lowers blood glucose and can cause hypoglycemia. The risk of hypoglycemia is increased when WEGOVY is used in combination with insulin or insulin secretagogues (e.g., sulfonylureas). The addition of WEGOVY in patients treated with insulin has not been evaluated. Reference ID: 5487292 7 8 When initiating WEGOVY, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4), Adverse Reactions (6.1)]. 7.2 Oral Medications WEGOVY causes a delay of gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials with semaglutide 1 mg, semaglutide did not affect the absorption of orally administered medications [see Clinical Pharmacology (12.3)]. Nonetheless, monitor the effects of oral medications concomitantly administered with WEGOVY. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to semaglutide during pregnancy. Pregnant women exposed to WEGOVY and healthcare providers are encouraged to contact Novo Nordisk at 1-877-390-2760 or www.wegovypregnancyregistry.com. Risk Summary Based on animal reproduction studies, there may be potential risks to the fetus from exposure to semaglutide during pregnancy. Additionally, weight loss offers no benefit to a pregnant patient and may cause fetal harm. When a pregnancy is recognized, advise the pregnant patient of the risk to a fetus, and discontinue WEGOVY (see Clinical Considerations). Available pharmacovigilance data and data from clinical trials with WEGOVY use in pregnant patients are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In pregnant rats administered semaglutide during organogenesis, embryofetal mortality, structural abnormalities and alterations to growth occurred at maternal exposures below the maximum recommended human dose (MRHD) based on AUC. In rabbits and cynomolgus monkeys administered semaglutide during organogenesis, early pregnancy losses and structural abnormalities were observed at below the MRHD (rabbit) and greater than or equal to 2-fold the MRHD (monkey). These findings coincided with a marked maternal body weight loss in both animal species (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those who already have overweight or obesity, because of the obligatory weight gain that occurs in maternal tissues during pregnancy. Data Animal Data In a combined fertility and embryofetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.04-, 0.1-, and 0.4-fold the MRHD) were administered to males for 4 weeks prior to and throughout mating and to females for 2 weeks prior to mating, and throughout organogenesis to Gestation Day 17. In parental animals, pharmacologically mediated reductions in body weight gain and food consumption were observed at all dose levels. In the offspring, reduced growth and fetuses with visceral (heart blood vessels) and skeletal (cranial bones, vertebra, ribs) abnormalities were observed at the human exposure. Reference ID: 5487292 In an embryofetal development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or 0.0075 mg/kg/day (0.01-, 0.1-, and 0.9-fold the MRHD) were administered throughout organogenesis from Gestation Day 6 to 19. Pharmacologically mediated reductions in maternal body weight gain and food consumption were observed at all dose levels. Early pregnancy losses and increased incidences of minor visceral (kidney, liver) and skeletal (sternebra) fetal abnormalities were observed at greater than or equal to 0.0025 mg/kg/day, at clinically relevant exposures. In an embryofetal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (0.4-, 2-, and 6-fold the MRHD) were administered throughout organogenesis, from Gestation Day 16 to 50. Pharmacologically mediated, marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with the occurrence of sporadic abnormalities (vertebra, sternebra, ribs) at greater than or equal to 0.075 mg/kg twice weekly (greater than or equal to 2 times human exposure). In a pre- and postnatal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (0.2-, 1-, and 3-fold the MRHD) were administered from Gestation Day 16 to 140. Pharmacologically mediated marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with an increase in early pregnancy losses and led to delivery of slightly smaller offspring at greater than or equal to 0.075 mg/kg twice weekly (greater than or equal to 1-time human exposure). 8.2 Lactation Risk Summary There are no data on the presence of semaglutide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Semaglutide was present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WEGOVY and any potential adverse effects on the breastfed infant from WEGOVY or from the underlying maternal condition. Data In lactating rats, semaglutide was detected in milk at levels 3- to12-fold lower than in maternal plasma. 8.3 Females and Males of Reproductive Potential Because of the potential for fetal harm, discontinue WEGOVY in patients at least 2 months before they plan to become pregnant to account for the long half-life of semaglutide [see Use in Specific Populations (8.1)]. 8.4 Pediatric Use The safety and effectiveness of WEGOVY as an adjunct to a reduced calorie diet and increased physical activity for weight reduction and long-term maintenance have been established in pediatric patients aged 12 years and older with obesity. Use of WEGOVY for this indication is supported by a 68-week, double-blind, placebo-controlled clinical trial in 201 pediatric patients aged 12 years and older with a BMI corresponding to ≥95th percentile for age and sex [see Clinical Studies (14.3)] and from studies in adult patients with obesity [see Clinical Studies (14.2)]. Use of the 1.7 mg once weekly maintenance dosage of WEGOVY in pediatric patients is also supported by additional exposure-efficacy and safety analyses in pooled adult and pediatric patients. Adverse reactions with WEGOVY treatment in pediatric patients aged 12 years and older were generally similar to those reported in adults. Pediatric patients aged 12 years and older treated with WEGOVY had greater incidences of cholelithiasis, cholecystitis, hypotension, rash, and urticaria compared to adults treated with WEGOVY [see Adverse Reactions (6.1)]. Reference ID: 5487292 There are insufficient data in pediatric patients with type 2 diabetes treated with WEGOVY for obesity to determine if there is an increased risk of hypoglycemia with WEGOVY treatment similar to that reported in adults. Inform patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. In pediatric patients aged 12 years and older with type 2 diabetes, monitor blood glucose prior to starting WEGOVY and during WEGOVY treatment. When initiating WEGOVY in pediatric patients aged 12 years and older with type 2 diabetes, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4)]. The safety and effectiveness of WEGOVY have not been established in pediatric patients less than 12 years of age. 8.5 Geriatric Use In the WEGOVY clinical trials for weight reduction and long-term maintenance, 233 (9%) WEGOVY-treated patients were aged 65 to 75 years and 23 (1%) WEGOVY-treated patients were aged 75 years and older [see Clinical Studies (14.2)]. In a cardiovascular outcomes trial, 2656 (30%) WEGOVY-treated patients were aged 65 to 75 years and 703 (8%) WEGOVY-treated patients were aged 75 years and older [see Clinical Studies (14.1)]. No overall difference in effectiveness was observed between patients aged 65 years and older and younger adult patients. In the cardiovascular outcomes trial, patients aged 75 years and older reported more fractures of the hip and pelvis on WEGOVY than on placebo. Patients aged 75 years and older (WEGOVY­ treated and placebo-treated) reported more serious adverse reactions overall compared to younger adult patients [see Adverse Reactions (6.1)]. 8.6 Renal Impairment The recommended dosage of WEGOVY in patients with renal impairment is the same as those with normal renal function. In a study in patients with renal impairment, including end-stage renal disease, no clinically relevant change in semaglutide pharmacokinetics was observed [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment The recommended dosage of WEGOVY in patients with hepatic impairment is the same as those with normal hepatic function. In a study in patients with different degrees of hepatic impairment, no clinically relevant change in semaglutide pharmacokinetics was observed [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Overdoses have been reported with other GLP-1 receptor agonists. Effects have included severe nausea, severe vomiting, and severe hypoglycemia. In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. In the event of an overdose of WEGOVY, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the long half-life of WEGOVY of approximately 1 week. 11 DESCRIPTION WEGOVY (semaglutide) injection, for subcutaneous use, contains semaglutide, a human GLP-1 receptor agonist (or GLP-1 analog). The peptide backbone is produced by yeast fermentation. The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid. Furthermore, semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4). A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid. The molecular formula is C187H291N45O59 and the molecular weight is 4113.58 g/mol. Reference ID: 5487292 0 Figure 1. Structural Formula of Semaglutide WEGOVY is a sterile, aqueous, clear, colorless solution. Each 0.5 mL single-dose pen contains a solution of WEGOVY containing 0.25 mg, 0.5 mg or 1 mg of semaglutide; and each 0.75 mL single-dose pen contains a solution of WEGOVY containing 1.7 or 2.4 mg of semaglutide. Each 1 mL of WEGOVY contains the following inactive ingredients: disodium phosphate dihydrate, 1.42 mg; sodium chloride, 8.25 mg; and water for injection. WEGOVY has a pH of approximately 7.4. Hydrochloric acid or sodium hydroxide may be added to adjust pH. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1. GLP-1 is a physiological regulator of appetite and caloric intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. Animal studies show that semaglutide distributed to and activated neurons in brain regions involved in regulation of food intake. The exact mechanism of cardiovascular risk reduction has not been established. 12.2 Pharmacodynamics Semaglutide lowers body weight with greater fat mass loss than lean mass loss. Semaglutide decreases calorie intake. The effects are likely mediated by affecting appetite. Semaglutide stimulates insulin secretion and reduces glucagon secretion in a glucose-dependent manner. These effects can lead to a reduction of blood glucose. Gastric Emptying Semaglutide delays gastric emptying. Cardiac Electrophysiology (QTc) The effect of semaglutide on cardiac repolarization was tested in a thorough QTc trial. Semaglutide did not prolong QTc intervals at doses up to 1.5 mg at steady state. 12.3 Pharmacokinetics Absorption Absolute bioavailability of semaglutide is 89%. Maximum concentration of semaglutide is reached 1 to 3 days post dose. Reference ID: 5487292 1111 i-1 ~ I i.J I 1e11 I ~ i.J N 1111 I 11+i ~ 1-..i 0.50 1.0 2.0 Similar exposure was achieved with subcutaneous administration of semaglutide in the abdomen, thigh, or upper arm. The average semaglutide steady state concentration following subcutaneous administration of WEGOVY was approximately 75 nmol/L in patients with either obesity (BMI greater than or equal to 30 kg/m2) or overweight (BMI greater than or equal to 27 kg/m2). The steady state exposure of WEGOVY increased proportionally with doses up to 2.4 mg once weekly. Distribution The mean volume of distribution of semaglutide following subcutaneous administration in patients with obesity or overweight is approximately 12.5 L. Semaglutide is extensively bound to plasma albumin (greater than 99%) which results in decreased renal clearance and protection from degradation. Elimination The apparent clearance of semaglutide in patients with obesity or overweight is approximately 0.05 L/h. With an elimination half-life of approximately 1 week, semaglutide will be present in the circulation for about 5 to 7 weeks after the last dose of 2.4 mg. Metabolism The primary route of elimination for semaglutide is metabolism following proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain. Excretion The primary excretion routes of semaglutide-related material are via the urine and feces. Approximately 3% of the dose is excreted in the urine as intact semaglutide. Specific Populations The effects of intrinsic factors on the pharmacokinetics of semaglutide are shown in Figure 2. Figure 2. Impact of intrinsic factors on semaglutide exposure Intrinsic factor Relative exposure (Cavg) Ratio and 90% CI Sex Male Age group 65−<75 years >=75 years Race Black or African American Asian American Indian or Alaska Native Ethnicity Hispanic or Latino Body weight 74 kg 143 kg Renal function Mild Moderate Injection site Thigh Upper arm Data are steady-state dose-normalized average semaglutide exposures relative to a reference subject profile (non-Hispanic or Latino ethnicity, white female aged 18 to less than 65 years, with a body weight of 110 kg and normal renal function, who injected in the abdomen). Body weight categories (74 and 143 kg) represent the 5% and 95% percentiles in the dataset. Patients with Renal Impairment Renal impairment did not impact the exposure of semaglutide in a clinically relevant manner. The pharmacokinetics of semaglutide were evaluated following a single dose of 0.5 mg semaglutide in a study of Reference ID: 5487292 0.5 2 patients with different degrees of renal impairment (mild, moderate, severe, or ESRD) compared with subjects with normal renal function. The pharmacokinetics were also assessed in subjects with overweight (BMI 27 to 29.9 kg/m2) or obesity (BMI greater than or equal to 30 kg/m2) and mild to moderate renal impairment, based on data from clinical trials. Patients with Hepatic Impairment Hepatic impairment did not impact the exposure of semaglutide. The pharmacokinetics of semaglutide were evaluated following a single dose of 0.5 mg semaglutide in a study of patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function. Drug Interactions Studies In vitro studies have shown very low potential for semaglutide to inhibit or induce CYP enzymes, or to inhibit drug transporters. The delay of gastric emptying with semaglutide may influence the absorption of concomitantly administered oral medications [see Drug Interactions (7.2)]. The potential effect of semaglutide on the absorption of co- administered oral medications was studied in trials at semaglutide 1 mg steady-state exposure. No clinically relevant drug-drug interactions with semaglutide (Figure 3) were observed based on the evaluated medications. In a separate study, no apparent effect on the rate of gastric emptying was observed with semaglutide 2.4 mg. Figure 3. Impact of semaglutide 1 mg on the pharmacokinetics of co-administered medications Co-administered Relative exposure medication Ratio and 90% CI AUC0-12h Metformin Cmax AUC0-168h S-warfarin Cmax AUC0-168h R-warfarin Cmax AUC0-120h Digoxin Cmax AUC0-72h Atorvastatin Cmax AUC0-24h Ethinylestradiol Cmax AUC0-24h Levonorgestrel Cmax Relative exposure in terms of AUC and Cmax for each medication when given with semaglutide compared to without semaglutide. Metformin and oral contraceptive drug (ethinylestradiol/levonorgestrel) were assessed at steady state. Warfarin (S-warfarin/R­ warfarin), digoxin and atorvastatin were assessed after a single dose. Abbreviations: AUC: area under the curve, Cmax: maximum concentration, CI: confidence interval. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of semaglutide or of other semaglutide products. During the 68-week treatment periods in Studies 2 and 3 [see Clinical Studies (14.2)], 50/1709 (3%) of WEGOVY-treated patients developed anti-semaglutide antibodies. Of these 50 WEGOVY-treated patients, 28 patients (2% of the total WEGOVY-treated study population) developed antibodies that cross-reacted with native GLP-1. No identified clinically significant effect of anti-semaglutide antibodies on pharmacokinetics for Reference ID: 5487292 WEGOVY was observed. There is insufficient evidence to characterize the effects of anti-semaglutide antibodies on pharmacodynamics or effectiveness of semaglutide. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in CD-1 mice, subcutaneous doses of 0.3, 1 and 3 mg/kg/day (2-, 8-, and 22­ fold the maximum recommended human dose [MRHD] of 2.4 mg/week, based on AUC) were administered to the males, and 0.1, 0.3 and 1 mg/kg/day (0.6-, 2-, and 5-fold MRHD) were administered to the females. A statistically significant increase in thyroid C-cell adenomas and a numerical increase in C-cell carcinomas were observed in males and females at all dose levels (greater than or equal to 0.6 times human exposure). In a 2-year carcinogenicity study in Sprague Dawley rats, subcutaneous doses of 0.0025, 0.01, 0.025 and 0.1 mg/kg/day were administered (below quantification, 0.2-, 0.4-, and 2-fold the exposure at the MRHD). A statistically significant increase in thyroid C-cell adenomas was observed in males and females at all dose levels, and a statistically significant increase in thyroid C-cell carcinomas was observed in males at greater than or equal to 0.01 mg/kg/day, at clinically relevant exposures. Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies [see Boxed Warning, Warnings and Precautions (5.1)]. Semaglutide was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity [Ames] human lymphocyte chromosome aberration, rat bone marrow micronucleus). In a combined fertility and embryo-fetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.04-, 0.1-, and 0.4-fold the MRHD) were administered to male and female rats. Males were dosed for 4 weeks prior to mating, and females were dosed for 2 weeks prior to mating and throughout organogenesis until Gestation Day 17. No effects were observed on male fertility. In females, an increase in estrus cycle length was observed at all dose levels, together with a small reduction in numbers of corpora lutea at greater than or equal to 0.03 mg/kg/day. These effects were likely an adaptive response secondary to the pharmacological effect of semaglutide on food consumption and body weight. 14 CLINICAL STUDIES 14.1 Cardiovascular Outcomes Trial in Adult Patients with Cardiovascular Disease and Either Obesity or Overweight Overview of Clinical Trial Study 1 (NCT03574597) was a multi-national, multi-center, placebo-controlled, double-blind trial to determine the effect of WEGOVY relative to placebo on major adverse cardiovascular events (MACE) when added to current standard of care, which included management of CV risk factors and individualized healthy lifestyle counseling (including diet and physical activity). The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. All patients were 45 years or older, with an initial BMI of 27 kg/m2 or greater and established cardiovascular disease (prior myocardial infarction, prior stroke, or peripheral arterial disease). Patients with a history of type 1 or type 2 diabetes were excluded. Concomitant CV therapies could be adjusted, at the discretion of the investigator, to ensure participants were treated according to the current standard of care for patients with established cardiovascular disease. In this trial, 17,604 patients were randomized to WEGOVY or placebo. At baseline, the mean age was 62 years (range 45-93), 72% were male, 84% were White, 4% were Black or African American, and 8% were Asian, and 10% were Hispanic or Latino. Mean baseline body weight was 97 kg and mean BMI was 33 kg/m2. At baseline, prior myocardial infarction was reported in 76% of randomized individuals, prior stroke in 23%, and peripheral arterial disease in 9%. Heart failure was reported in 24% of patients. At baseline, cardiovascular disease and Reference ID: 5487292 10 - ,• -- --- 8 ________ ,,.------ 6 .. -, .. - 4 .---------------- 2 .,, .... -.. --- -- 0 0 6 12 18 24 30 36 42 48 54 8803 8695 8561 8427 8254 7229 5777 4126 1734 71 8801 8652 8487 8326 8164 7101 5660 4015 1672 59 risk factors were managed with lipid-lowering therapy (90%), platelet aggregation inhibitors (86%), angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (74%), and beta blockers (70%). A total of 10% had moderate renal impairment (eGFR 30 to <60 mL/min/1.73m2) and 0.4% had severe renal impairment eGFR <30 mL/min/1.73m2. Results In total, 96.9% of patients completed the trial, and vital status was available for 99.4% of patients. The median follow-up duration was 41.8 months. A total of 31% of WEGOVY-treated patients and 27% of placebo-treated patients permanently discontinued study drug. For the primary analysis, a Cox proportional hazards model was used to test for superiority. Type 1 error was controlled across multiple tests. WEGOVY significantly reduced the risk for first occurrence of MACE. The estimated hazard ratio (95% CI) was 0.80 (0.72, 0.90) (see Figure 4 and Table 4). Figure 4. Cumulative Incidence Function: Time to First Occurrence of MACE in Study 1 Placebo WEGOVY HR: 0.80 95% CI[0.72 - 0.90] Time from randomization (months) Patients at risk WEGOVY Placebo Data from the in-trial period. Cumulative incidence estimates are based on time from randomization to first EAC-confirmed cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke with non-CV death modeled as competing risk using the Aalen-Johansen estimator. Patients without events of interest were censored at the end of their in-trial observation period. Time from randomization to first cardiovascular death, non­ fatal myocardial infarction, or non-fatal stroke was analyzed using a Cox proportional hazards model with treatment as categorical fixed factor. The hazard ratio and confidence interval are adjusted for the group sequential design using the likelihood ratio ordering. HR: Hazard ratio; CI: confidence interval; CV: cardiovascular The treatment effect for the primary composite endpoint, its components, and other relevant endpoints in Study 1 are shown in Table 4. Table 4. Treatment Effect for MACE and Other Events in Study 1 Patients with Event (%) Patients with events n (%) Placebo N=8,801 WEGOVY N=8,803 Hazard Ratio (95% CI) Primary composite endpoint Composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke1 701 (8%) 569 (6.5%) 0.80 (0.72; 0.90)*2 Key secondary endpoints Cardiovascular death3 262 (3%) 223 (2.5%) 0.85 (0.71; 1.01) All-cause death4 458 (5.2%) 375 (4.3%) 0.81 (0.71; 0.93) Other secondary endpoints Fatal or non-fatal myocardial infarction5 334 (3.8%) 243 (2.8%) 0.72 (0.61; 0.85) Fatal or non-fatal stroke5 178 (2%) 160 (1.8%) 0.89 (0.72; 1.11) * p-value < 0.001, one-sided p-value Reference ID: 5487292 1 Primary endpoint 2 Adjusted for group sequential design using the likelihood ratio ordering. 3 Cardiovascular death was the first confirmatory secondary endpoint in the testing hierarchy and superiority was not confirmed. 4 Confirmatory secondary endpoint. Not statistically significant based on the prespecified testing hierarchy. 5 Not included in the prespecified testing hierarchy for controlling type-I error. NOTE: Time to first event was analyzed in a Cox proportional hazards model with treatment as factor. For patients with multiple events, only the first event contributed to the composite endpoint. Table 5. Mean Changes in Anthropometry and Cardiometabolic Parameters at Week 104 in Study 11,2 PLACEBO WEGOVY Baseline Change from Baseline (LSMean) Baseline Change from Baseline (LSMean) Difference from Placebo (LSMean) Body Weight (kg) 96.8 -0.93 96.5 -9.43 -8.53 Waist Circumference (cm) 111.4 -1 111.3 -7.6 -6.5 Systolic Blood Pressure (mmHg) 131 -0.5 131 -3.8 -3.3 Diastolic Blood Pressure (mmHg) 79 -0.5 79 -1 -0.5 Heart Rate 69 0.7 69 3.8 3.1 HbA1c (%) 5.8 0 5.8 -0.3 -0.3 Baseline % Change from Baseline (LSMean) Baseline % Change from Baseline (LSMean) Relative difference from placebo (%) (LSMean) Total Cholesterol (mg/dL)4 156 -1.9 155.5 -4.6 -2.8 LDL Cholesterol (mg/dL)4 78.5 -3.1 78.5 -5.3 -2.2 HDL Cholesterol (mg/dL)4 44.2 0.6 44.1 4.9 4.2 Triglycerides (mg/dL)4 139.5 -3.2 138.6 -18.3 -15.6 1 Parameters listed in the table were not included in the pre-specified hierarchical testing. 2 Responses were analysed using an ANCOVA with treatment as fixed factor and baseline value as covariate. Before analysis, missing data were multiple imputed. The imputation model (linear regression) was done separately for each treatment arm and included baseline value as a covariate and was fitted to all subjects with a measurement regardless of treatment status at week 104. 3 For body weight the ‘change from baseline’ and ‘difference to placebo’ the unit is percentage change from baseline. 4 Baseline value is the geometric mean. The reduction of MACE with WEGOVY was not impacted by age, sex, race, ethnicity, BMI at baseline, or level of renal function impairment. 14.2 Weight Reduction and Long-term Maintenance Studies in Adults with Obesity or Overweight Overview of Clinical Studies in Adults The safety and efficacy of WEGOVY for weight reduction and long-term maintenance of body weight in conjunction with a reduced calorie diet and increased physical activity were studied in three 68-week, randomized, double-blind, placebo-controlled trials; one 68-week, randomized, double-blind, placebo withdrawal trial; and one 68-week, randomized, double-blind trial that investigated 2 different doses of WEGOVY versus placebo. In Studies 2 (NCT#03548935), 3 (NCT#03552757), and 4 (NCT#03611582), WEGOVY or matching placebo was escalated to 2.4 mg subcutaneous weekly during a 16-week period followed by 52 weeks on maintenance dose. In Study 5 (NCT#03548987), WEGOVY was escalated during a 20-week run-in period, and patients who reached a WEGOVY 2.4 mg subcutaneous weekly dosage after the run-in period were randomized to either continued treatment with WEGOVY or placebo for 48 weeks. In Study 6 (NCT#03811574), WEGOVY was escalated to 1.7 mg or 2.4 mg subcutaneous weekly dosages or placebo over 12 to 16 weeks followed by 52 weeks on either maintenance dose. In Studies 2, 3 and 5, all patients received instruction for a reduced calorie diet (approximately 500 kcal/day deficit) and increased physical activity counseling (recommended to a minimum of 150 min/week) that began Reference ID: 5487292 with the first dose of study medication or placebo and continued throughout the trial. In Study 4, patients received an initial 8-week low-calorie diet (total energy intake 1,000 to 1,200 kcal/day) followed by 60 weeks of a reduced calorie diet (1200-1800 kcal/day) and increased physical activity (100 mins/week with gradual increase to 200 mins/week). Study 2 was a 68-week trial that enrolled 1,961 patients with obesity (BMI greater than or equal to 30 kg/m2) or with overweight (BMI 27 to 29.9 kg/m2) and at least one weight-related comorbid condition, such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. Patients were randomized in a 2:1 ratio to either WEGOVY or placebo. At baseline, mean age was 46 years (range 18 to 86), 74% were female, 75% were White, 13% were Asian and 6% were Black or African American. A total of 12% were Hispanic or Latino ethnicity. Mean baseline body weight was 105.3 kg and mean BMI was 37.9 kg/m2. Study 3 was a 68-week trial that enrolled 807 patients with type 2 diabetes and BMI greater than or equal to 27 kg/m2. Patients included in the trial had HbA1c 7-10% and were treated with either: diet and exercise alone or 1 to 3 oral anti-diabetic drugs (metformin, sulfonylurea, glitazone or sodium-glucose co-transporter 2 inhibitor). Patients were randomized in a 1:1 ratio to receive either WEGOVY or placebo. At baseline, the mean age was 55 years (range 19 to 84), 51% were female, 62% were White, 26% were Asian and 8% were Black or African American. A total of 13% were Hispanic or Latino ethnicity. Mean baseline body weight was 99.8 kg and mean BMI was 35.7 kg/m2. Study 4 was a 68-week trial that enrolled 611 patients with obesity (BMI greater than or equal to 30 kg/m2) or with overweight (BMI 27 to 29.9 kg/m2) and at least one weight-related comorbid condition such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. The patients were randomized in a 2:1 ratio to receive either WEGOVY or placebo. At baseline, the mean age was 46 years, 81% were female, 76% were White, 19% were Black or African American and 2% were Asian. A total of 20% were Hispanic or Latino ethnicity. Mean baseline body weight was 105.8 kg and mean BMI was 38 kg/m2. Study 5 was a 68-week trial that enrolled 902 patients with obesity (BMI greater than or equal to 30 kg/m2) or with overweight (BMI 27 to 29.9 kg/m2) and at least one weight-related comorbid condition such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. Mean body weight at baseline for the 902 patients was 106.8 kg and mean BMI was 38.3 kg/m². All patients received WEGOVY during the run-in period of 20 weeks that included 16 weeks of dose escalation. Trial product was permanently discontinued before randomization in 99 of 902 patients (11%); the most common reason was adverse reactions (n=48, 5.3%); 803 patients reached WEGOVY 2.4 mg and were then randomized in a 2:1 ratio to either continue on WEGOVY or receive placebo. Among the 803 randomized patients, the mean age was 46 years, 79% were female, 84% were White, 13% were Black or African American, and 2% Asian. A total of 8% were Hispanic or Latino ethnicity. Mean body weight at randomization (week 20) was 96.1 kg and mean BMI at randomization (week 20) was 34.4 kg/m2. Study 6 was a 68-week trial that enrolled 401 East-Asian patients (Japan and South Korea) with BMI greater than or equal to 35 kg/m2 and at least one weight-related comorbid condition or with BMI 27 to 34.9 kg/m2 and at least two weight-related comorbid conditions. The patients were randomized 2:1:1 to receive WEGOVY 2.4 mg, WEGOVY 1.7 mg, or placebo. At baseline, the mean age was 51 years, 63% were male, and all patients were Asian. Mean baseline body weight was 87.5 kg and mean BMI was 31.9 kg/m2. At baseline, 24.7% of patients had type 2 diabetes mellitus. Results The proportions of patients who discontinued study drug in Studies 2, 3, and 4 was 16% for the WEGOVY- treated group and 19.1% for the placebo-treated group, and 6.8% of patients treated with WEGOVY and 3.2% of patients treated with placebo discontinued treatment due to an adverse reaction [see Adverse Reactions (6.1)]. In Study 5, the proportions of patients who discontinued study drug were 5.8% and 11.6% for WEGOVY Reference ID: 5487292 and placebo, respectively. In Study 6, the proportions of patients who discontinued study drug were 7.9%, 6.5%, and 3% for WEGOVY 1.7 mg, WEGOVY 2.4 mg, and placebo, respectively. For Studies 2, 3 and 4, the primary efficacy parameters were mean percent change in body weight and the percentages of patients achieving greater than or equal to 5% weight loss from baseline to week 68. After 68 weeks, treatment with WEGOVY resulted in a statistically significant reduction in body weight compared with placebo. Greater proportions of patients treated with WEGOVY achieved 5%, 10% and 15% weight loss than those treated with placebo as shown in Table 6. Table 6. Changes in Body Weight at Week 68 in Studies 2, 3, and 4 Study 2 (Obesity or overweight with comorbidity) Study 3 (Type 2 diabetes with obesity or overweight) Study 4 (Obesity or overweight with comorbidity undergoing intensive lifestyle therapy) Intention-to-Treat1 PLACEBO N=655 WEGOVY N=1306 PLACEBO N=403 WEGOVY N=404 PLACEBO N=204 WEGOVY N=407 Body Weight Baseline mean (kg) 105.2 105.4 100.5 99.9 103.7 106.9 % change from baseline (LSMean) -2.4 -14.9 -3.4 -9.6 -5.7 -16 % difference from placebo (LSMean) (95% CI) -12.4 (-13.3; -11.6)* -6.2 (-7.3; -5.2)* -10.3 (-11.8; -8.7)* % of Patients losing greater than or equal to 5% body weight 31.1 83.5 30.2 67.4 47.8 84.8 % difference from placebo (LSMean) (95% CI) 52.4 (48.1; 56.7)* 37.2 (30.7; 43.8)* 37 (28.9; 45.2)* % of Patients losing greater than or equal to 10% body weight 12 66.1 10.2 44.5 27.1 73 % difference from placebo (LSMean) (95% CI) 54.1 (50.4; 57.9)* 34.3 (28.4; 40.2)* 45.9 (38; 53.7)* % of Patients losing greater than or equal to 15% body weight 4.8 47.9 4.3 25.1 13.2 53.4 % difference from placebo (LSMean) (95% CI) 43.1 (39.8; 46.3)* 20.7 (15.7; 25.8)* 40.2 (33.1; 47.3)* LSMean = least squares mean; CI = confidence interval 1 The intent-to-treat population includes all randomized patients. In Study 2, at week 68, the body weight was missing for 7.2% and 11.9% of patients randomized to WEGOVY and placebo, respectively. In Study 3, at week 68, the body weight was missing for 4% and 6.7% of patients randomized to WEGOVY and placebo, respectively. In Study 4, at week 68, the body weight was missing for 8.4% and 7.4% of patients randomized to WEGOVY and placebo, respectively. Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI). * p<0.0001 (unadjusted 2-sided) for superiority. For Study 5, the primary efficacy parameter was mean percent change in body weight from randomization (week 20) to week 68. From randomization (week 20) to week 68, treatment with WEGOVY resulted in a statistically significant reduction in body weight compared with placebo (Table 7). Because patients who discontinued WEGOVY during titration and those who did not reach the 2.4 mg weekly dose were not eligible for the randomized treatment period, the results may not reflect the experience of patients in the general population who are first starting WEGOVY. Reference ID: 5487292 Table 7. Changes in Body Weight at Week 68 in Study 5 (Obesity or overweight with comorbidity after 20-week run-in) WEGOVY N=8031 Body Weight (only randomized patients) Mean at week 0 (kg) 107.2 PLACEBO N=268 WEGOVY N=535 Body Weight Mean at week 20 (SD) (kg) 95.4 (22.7) 96.5 (22.5) % change from week 20 at week 68 (LSMean) 6.9 -7.9 % difference from placebo (LSMean) (95% CI) -14.8 (-16; -13.5)* LSMean = least squares mean; CI = confidence interval 1 902 patients were enrolled at week 0 with a mean baseline body weight of 106.8 kg. The intent-to-treat population includes all randomized patients. At week 68, the body weight was missing for 2.8% and 6.7% of patients randomized to WEGOVY and placebo, respectively. Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI). * p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. For Study 6, the primary efficacy parameters were mean percent change in body weight and the percentage of patients achieving greater than or equal to 5% weight loss from baseline to week 68. After 68 weeks, treatment with WEGOVY 1.7 mg and 2.4 mg resulted in a statistically significant reduction in body weight compared with placebo. Greater proportions of patients treated with WEGOVY achieved 5%, 10%, and 15% weight loss than those treated with placebo as shown in Table 8. Table 8. Changes in Body Weight at Week 68 in Study 6 in East-Asian Patients (WEGOVY 1.7 mg) Study 6 (BMI ≥35 kg/m2 with at least one comorbidity or BMI 27-34.9 kg/m2 with at least two comorbidities) Intention-to-treat1 PLACEBO N=101 WEGOVY 1.7 mg N=101 WEGOVY 2.4 mg N=199 Body Weight Baseline mean (kg) 90.2 86.1 86.9 % change from baseline (LSMean) -2.1 -9.6 -13.2 % difference from placebo (LSMean) (95% CI) -7.5 (-9.6; -5.4)* -11.1 (-12.9; -9.2)* % of Patients losing greater than or equal to 5% body weight 19.4 72.8 84 % difference from placebo (LSMean) (95% CI) 53.3 (41; 65.6)* 64.5 (54.8; 74.3)* % of Patients losing greater than or equal to 10% body weight 4.5 39.1 59.9 % difference from placebo (LSMean) (95% CI) 34.5 (23.9; 45.1)* 55.4 (47.3; 63.6)* % of Patients losing greater than or equal to 15% body weight 2.6 20.8 38.2 % difference from placebo (LSMean) (95% CI) 18.2 (9.8; 26.7)* 35.6 (27.9; 43.3)* LSMean = least squares mean; CI = confidence interval 1 The intent-to-treat population includes all randomized patients. At baseline, 24.7% of patients had type 2 diabetes mellitus. At week 68, the body weight was missing for 3%, 3%, and 1% of patients randomized to WEGOVY 1.7 mg, WEGOVY 2.4 mg, and placebo, respectively. Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI). * p<0.0001 (unadjusted 2-sided) for superiority. Reference ID: 5487292 100 90 80 ~ e.., 70 >, ~ ;;; 60 g. "' 50 <.; " .f 40 ~ 30 = 8 20 v_ .. , •" / I I I I I V I I I I I I I V I ' / I I ' / , ,· 10 / 0 -40 -- . , I-_ ...... -30 -20 -10 0 10 20 Change in body weight (%) -- WEGOVY - - - - Placebo 100 90 I~ -- -- ----- ~ 80 G' 70 C: ., 60 ::, O"' ., <.i:. 50 J: / , J i I I I I I I ., I > 40 ] ::, 30 E ::, 20 u 10 0 I I I ,' I I I I / I ,, /_ .. ~-I'"' -40 -30 -20 -10 0 10 20 30 40 30 40 A reduction in body weight was observed with WEGOVY irrespective of age, sex, race, ethnicity, BMI at baseline, body weight (kg) at baseline, and level of renal function impairment. The cumulative frequency distributions of change in body weight are shown in Figure 5 and Figure 6 for Studies 2 and 3. One way to interpret this figure is to select a change in body weight of interest on the horizontal axis and note the corresponding proportions of patients (vertical axis) in each treatment group who achieved at least that degree of weight loss. For example, note that the vertical line arising from -10% in Study 2 intersects the WEGOVY and placebo curves at approximately 66%, and 12%, respectively, which correspond to the values shown in Table 6. Figure 5. Change in body weight (%) from baseline to week 68 (Study 2) Observed data from in-trial period including imputed data for missing observations (RD-MI). Figure 6. Change in body weight (%) from baseline to week 68 (Study 3) Change in body weight (%) WEGOVY Placebo Observed data from in-trial period including imputed data for missing observations (RD-MI). The time courses of weight loss with WEGOVY and placebo from baseline through week 68 are depicted in Figure 7, Figure 8 and Figure 9. Reference ID: 5487292 0 -2 ~ -4 ~ Jc: -6 bl) ·;;:; -8 3: >-. -10 -0 0 ..0 -12 .!: "' -14 bl) = "' -= -16 u -18 -20 0 -2 ~ ~ -4 - ~ -6 ·;;:; 3: -8 >-. -0 -10 0 ..0 = -12 "' bl) = -14 "' 6 -16 -18 -20 ------ ------------- - - - - - ' ~ -2.8 -2.4 --- -- - - _._ ---- - -•- -- - - -- -14.9 -15.6 . 0 4 8 12 16 20 28 36 44 52 60 68 1306 1281 1248 1203 1212 1306 655 641 603 549 577 655 ------------------------ ' 0 4 407 204 0 -2 -4 -6 -8 -10 -12 -14 -16 -18 -20 ' ' -5.8 ~ A--- ' ' ------- -~ ,,,,,_ .. - -------- -16.5 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 396 385 367 373 197 194 183 189 ... ... - --- - --- - ________ .. __ _ .. ~ -....... -.._ ....___. --+- --. 0 4 8 12 16 20 28 36 44 52 60 68 101 199 101 99 198 101 --+- 98 197 100 97 191 99 98 101 193 199 100 101 -5.7 . .-16.0 407 204 0 --------- ....... --------------- -~ -2 -.... __ .....,. _____ _ ---------.------- -3.3 -3.4 ~ -4 ~ Jc: -6 bl) ·;;:; -8 3: -9.6 >-. -9.9 -0 -10 0 ..0 .!: -12 "' -14 bl) = "' -= -16 u -18 -20 0 4 8 12 16 20 28 36 44 52 60 68 404 397 392 381 388 404 403 394 383 367 376 403 - _ _,, __ 0 - - - - - -1- ------------------ I -2 I ~ e -4 -5.0 Jc: _. -5.4 -6 bl) ___ ..... ·;;:; -· A-- 3: -8 --- >-. -- -0 -10 0 _..- ..0 .!: -12 "' bl) -14 = "' -= -16 u .-17.4 -17.7 -18 -20 0 4 8 12 16 20 24 28 36 44 52 60 68 803 803 535 521 520 535 268 254 250 268 Figure 7. Change from baseline (%) in body weight (Study 2 on left and Study 3 on right) RD-MI RD-MI WEGOVY Weeks WEGOVY Weeks Placebo Placebo WEGOVY Placebo WEGOVY Placebo Observed values for patients completing each scheduled visit, and estimates with multiple imputations from retrieved dropouts (RD-MI) Figure 8. Change from baseline (%) in body weight (Study 4 on left and Study 5a on right) RD-MI RD-MI WEGOVY Weeks WEGOVY Weeks Placebo Placebo WEGOVY Placebo WEGOVY Placebo Change in body weight (%) Observed values for patients completing each scheduled visit, and estimates with multiple imputations from retrieved dropouts (RD-MI) a Change from week 0 was not a primary endpoint in study 5. Dotted line indicates time of randomization. Randomized patients (shown) do not include 99 patients that discontinued during the 20-week run-in period. Figure 9. Change in body weight (%) from baseline to week 68 (Study 6 in East-Asian Patients) -1.9 -2.1 -9.6 -9.9 -13.2 -13.4 RD-MI WEGOVY 1.7 mg WEGOVY 2.4 mg Weeks Placebo WEGOVY 1.7 mg WEGOVY 2.4 mg Placebo Reference ID: 5487292 Observed values for patients completing each scheduled visit and estimates with multiple imputations from retrieved dropouts (RD­ MI). At baseline, 24.7% of patients had type 2 diabetes mellitus. Effect of WEGOVY on Anthropometry and Cardiometabolic Parameters in Adults Changes in waist circumference and cardiometabolic parameters with WEGOVY are shown in Table 9 for Studies 2, 3, and 4; in Table 10 for Study 5; and in Table 11 for Study 6. Table 9. Changes in Anthropometry and Cardiometabolic Parameters at Week 68 in Studies 2, 3, and 4 Study 2 (Obesity or overweight with comorbidity) Study 3 (Type 2 diabetes with obesity or overweight) Study 4 (Obesity or overweight with comorbidity undergoing intensive lifestyle therapy) Intention-to-Treat PLACEBO N=655 WEGOVY N=1306 PLACEBO N=403 WEGOVY N=404 PLACEBO N=204 WEGOVY N=407 Waist Circumference (cm) Baseline 114.8 114.6 115.5 114.5 111.8 113.6 Changes from baseline (LSMean1) -4.1 -13.5 -4.5 -9.4 -6.3 -14.6 Difference from placebo (LSMean) -9.4 -4.9 -8.3 Systolic Blood Pressure (mmHg) Baseline 127 126 130 130 124 124 Changes from baseline (LSMean1) -1.1 -6.2 -0.5 -3.9 -1.6 -5.6 Difference from placebo (LSMean) -5.1 -3.4 -3.9 Diastolic Blood Pressure (mmHg)2 Baseline Changes from baseline (LSMean1) Difference from placebo (LSMean) 80 -0.4 80 -2.8 -2.4 80 -0.9 80 -1.6 -0.7 81 -0.8 80 -3 -2.2 Heart Rate2,3 Baseline 72 72 76 75 71 71 Changes from baseline (LSMean) -0.7 3.5 -0.2 2.5 2.1 3.1 Difference from placebo (LSMean) 4.3 2.7 1 HbA1c (%)2 Baseline 5.7 5.7 8.1 8.1 5.8 5.7 Changes from baseline (LSMean1) -0.2 -0.4 -0.4 -1.6 -0.3 -0.5 Difference from placebo (LSMean) -0.3 -1.2 -0.2 Total Cholesterol (mg/dL)2,4 Baseline 192.1 189.6 170.8 170.8 188.7 185.4 Percent Change from baseline (LSMean1) 0.1 -3.3 -0.5 -1.4 2.1 -3.9 Relative difference from placebo (LSMean) -3.3 -0.9 -5.8 LDL Cholesterol (mg/dL)2,4 Baseline 112.5 110.3 90.1 90.1 111.8 107.7 Percent Change from baseline (LSMean1) 1.3 -2.5 0.1 0.5 2.6 -4.7 Relative difference from placebo (LSMean) -3.8 0.4 -7.1 Reference ID: 5487292 Study 2 (Obesity or overweight with comorbidity) Study 3 (Type 2 diabetes with obesity or overweight) Study 4 (Obesity or overweight with comorbidity undergoing intensive lifestyle therapy) Intention-to-Treat PLACEBO N=655 WEGOVY N=1306 PLACEBO N=403 WEGOVY N=404 PLACEBO N=204 WEGOVY N=407 HDL (mg/dL)2,4 Baseline Percent Change from baseline (LSMean1) Relative difference from placebo (LSMean) 49.5 1.4 49.4 5.2 3.8 43.8 4.1 44.7 6.9 2.7 50.9 5 51.6 6.5 1.5 Triglycerides (mg/dL)2,4 Baseline Percent Change from baseline (LSMean1) Relative difference from placebo (LSMean) 127.9 -7.3 126.2 -21.9 -15.8 159.5 -9.4 154.9 -22 -13.9 110.9 -6.5 107.9 -22.5 -17 Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI) 1 Model based estimates based on an analysis of covariance model including treatment (and stratification factors for Study 3 only) as a factor and baseline value as a covariate 2 Not included in the pre-specified hierarchical testing (except HbA1c for Study 3) 3 Model based estimates based on a mixed model for repeated measures including treatment (and stratification factors for Study 3 only) as a factor and baseline values as a covariate 4 Baseline value is the geometric mean Table 10. Mean Changes in Anthropometry and Cardiometabolic Parameters in Study 5 (Obesity or overweight with comorbidity after 20-week run-in)1 PLACEBO N=268 WEGOVY N=535 Randomization (week 20) Change from Randomization (week 20) to week 68 (LSMean1) Randomization (week 20) Change from Randomization (week 20) to week 68 (LSMean1) Difference from placebo (LSMean) Waist Circumference (cm) 104.7 3.3 105.5 -6.4 -9.7 Systolic Blood Pressure (mmHg) 121 4.4 121 0.5 -3.9 Diastolic Blood Pressure (mmHg)2 78 0.9 78 0.3 -0.5 Heart Rate2,3 76 -5.3 76 -2 3.3 HbA1c (%)2 5.4 0.1 5.4 -0.1 -0.2 Randomization (week 20) % Change from Randomization (week 20) (LSMean1) Randomization (week 20) % Change from Randomization (week 20) (LSMean1) Relative difference from placebo (LSMean) Total Cholesterol (mg/dL)2,4 175.1 11.4 175.9 4.9 -5.8 LDL Cholesterol (mg/dL)2,4 109.1 7.6 108.7 1.1 -6.1 HDL Cholesterol (mg/dL)2,4 43.6 17.8 44.5 18.2 0.3 Triglycerides (mg/dL)2,4 95.3 14.8 98.1 -5.6 -17.8 Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI) 1 Model based estimates based on an analysis of covariance model including treatment as a factor and baseline value as a covariate 2 Not included in the pre-specified hierarchical testing 3 Model based estimates based on a mixed model for repeated measures including treatment as a factor and baseline values as a covariate 4 Baseline value is the geometric mean Reference ID: 5487292 Table 11. Mean Changes in Anthropometry and Cardiometabolic Parameters at Week 68 in Study 6 in East-Asian Patients (WEGOVY 1.7 mg) Study 6 (BMI ≥35 kg/m2 with at least one comorbidity or BMI 27 to 34.9 kg/m2 with at least two comorbidities) Intention-to-treat PLACEBO N=101 WEGOVY 1.7 mg N=101 WEGOVY 2.4 mg N=199 Waist circumference (cm) Baseline Change from baseline (LSMean1) Difference from placebo (LSMean) 103.8 -1.8 101.4 -7.7 -5.9 103.8 -11 -9.3 Systolic blood pressure (mmHg)2 Baseline Change from baseline (LSMean1) Difference from placebo (LSMean) 133 -5.3 135 -10.8 -5.4 133 -10.8 -5.5 Diastolic blood pressure (mmHg)2 Baseline Change from baseline (LSMean1) Difference from placebo (LSMean) 86 -2.2 85 -4.6 -2.4 83 -5.3 -3.1 Heart Rate2, 3 Baseline Change from baseline (LSMean) Difference from placebo (LSMean) 73 2.4 73 4.4 2 73 6.3 3.9 HbA1c (%)2 Baseline Change from baseline (LSMean1) Difference from placebo (LSMean) 6.4 0 6.4 -0.9 -0.9 6.4 -0.9 -0.9 Total Cholesterol (mg/dL)2,4 Baseline Percent change from baseline (LSMean1) Relative difference from placebo (LSMean) 203.1 0.8 203.3 -6.6 -7.3 197.2 -8.7 -9.4 LDL Cholesterol (mg/dL)2,4 Baseline Percent change from baseline (LSMean1) Relative difference from placebo (LSMean) 123.3 -3.8 120.1 -10.1 -6.5 116.5 -14.6 -11.2 HDL Cholesterol (mg/dL)2,4 Baseline Percent change from baseline (LSMean1) Relative difference from placebo (LSMean) 48.7 5.9 50.2 6.7 0.7 50.8 9.2 3.1 Triglyceride (mg/dL)2,4 Baseline Percent change from baseline (LSMean1) Relative difference from placebo (LSMean) 134.2 5.5 138.8 -19.5 -23.7 127.1 -21.2 -25.3 Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI). At baseline, 24.7% of patients had type 2 diabetes mellitus. 1 Model based estimates based on an analysis of covariance model including treatment and type 2 diabetes status as factors and baseline value as a covariate 2 Not included in the pre-specified hierarchical testing 3 Model based estimates based on a mixed model for repeated measures including treatment and type 2 diabetes status as factors and baseline values as a covariate 4 Baseline value is the geometric mean 14.3 Weight Reduction and Long-Term Maintenance Study in Pediatric Patients Aged 12 Years and Older with Obesity Overview of Clinical Trial in Pediatric Patients WEGOVY was evaluated in a 68-week, double-blind, randomized, parallel group, placebo-controlled, multi- center trial in 201 pubertal pediatric patients aged 12 years and older with BMI corresponding to ≥95th percentile standardized for age and sex (Study 7) (NCT#04102189). After a 12-week lifestyle run-in period (including dietary recommendations and physical activity counseling), patients were randomized 2:1 to WEGOVY once weekly or placebo once weekly. WEGOVY or matching placebo was escalated to 2.4 mg or Reference ID: 5487292 maximally tolerated dose during a 16-week period followed by 52 weeks on maintenance dose. Of WEGOVY- treated patients who completed the trial, 86.7% were on the 2.4 mg dosage at the end of the trial; for 5% of patients, 1.7 mg was the maximum tolerated dosage. The mean age was 15 years; 38% of patients were male; 79% were White, 8% were Black or African American, 2% were Asian, and 11% were of other or unknown race; and 11% were of Hispanic or Latino ethnicity. The mean baseline body weight was 108 kg, and mean BMI was 37 kg/m2. Results The proportions of patients who discontinued study drug were 10% for the WEGOVY-treated group and 10% for the placebo-treated group. The primary endpoint was percent change in BMI from baseline to week 68. After 68 weeks, treatment with WEGOVY resulted in a statistically significant reduction in percent BMI compared with placebo. Greater proportions of patients treated with WEGOVY achieved ≥5% reduction in baseline BMI than those treated with placebo as shown in Table 12. Table 12. Changes in Weight and BMI at Week 68 in Pediatric Patients with Obesity Aged 12 Years and Older in Study 7 Intention-to-Treata PLACEBO N=67 WEGOVY N=134 BMI Baseline mean (kg/m2) 35.7 37.7 % change from baseline in BMI (LSMean) 0.6 -16.1 % difference from placebo (LSMean) (95% CI) -16.7 (-20.3; -13.2)* % of Patients with greater than or equal to 5% reduction in baseline BMIb 19.7 77.1 % difference from placebo (LSMean) 57.4 % of Patients with greater than or equal to 10% reduction in baseline BMIb 7.7 65.1 % difference from placebo (LSMean) 57.5 % of Patients with greater than or equal to 15% reduction in baseline BMIb 4 57.8 % difference from placebo (LSMean) 53.9 Body Weightb Baseline mean (kg) 102.6 109.9 % change from baseline (LSMean)a 2.7 -14.7 % difference from placebo (LSMean) -17.4 LSMean = least squares mean; CI = confidence interval a The intention-to-treat population includes all randomized patients. Missing data were imputed using available data according to value and timing of last available observation on treatment and endpoint’s baseline value from retrieved subjects (RD-MI). At week 68, the BMI was missing for 2.2% and 7.5% of patients randomized to WEGOVY and placebo, respectively. bParameters not included in the pre-specified hierarchical testing. * p<0.0001 (unadjusted 2-sided) for superiority. The time course of change in BMI with WEGOVY and placebo from baseline through week 68 is depicted in Figure 10. The cumulative frequency distribution of change in BMI is shown in Figure 11. Reference ID: 5487292 ,,-.. 4 2 0 ~ '-' -2 ::s -4 o:l -6 .5 (1) -8 o/) s:: -10 "' 0 -12 -14 -16 -18 100 90 80 70 60 50 40 30 20 10 0 0 134 67 ______,..r 12 119 56 _,..,..,.r' -50 -40 .,r / 28 131 63 r I ___ .J- j ; -- -30 -20 44 ~ _, 52 131 62 J ; / ,, r I : J r I r" / 68 131 134 62 67 ~ ~--..J I I .1 r ,- J J J C ,, J -10 0 10 20 Figure 10. Change from Baseline (%) in BMI in Pediatric Patients with Obesity Aged 12 Years and Older in Study 7 0.6 -0.1 -16.2 -16.1 RD-MI WEGOVY Weeks Placebo WEGOVY Placebo Observed values for patients completing each scheduled visit, and estimates with multiple imputations from retrieved dropouts (RD-MI) Figure 11. Change in BMI (%) from Baseline to Week 68 in Pediatric Patients with Obesity Aged 12 Years and Older in Study 7 Cumulative frequency (%) Change in BMI (%) WEGOVY Placebo Observed data from in-trial period including imputed data for missing observations (RD-MI) Effect of WEGOVY on Anthropometry and Cardiometabolic Parameters in Pediatric Patients with Obesity Aged 12 Years and Older Changes in waist circumference and cardiometabolic parameters with WEGOVY are shown in Table 13 for the study in pediatric patients aged 12 years and older. Reference ID: 5487292 Table 13. Mean Changes in Anthropometry and Cardiometabolic Parameters in Pediatric Patients with Obesity Aged 12 Years and Older in Study 71 PLACEBO N=67 WEGOVY N=134 Baseline Change from Baseline (LSMean) Baseline Change from Baseline (LSMean) Difference from placebo (LSMean) Waist Circumference (cm)2 107.3 -0.6 111.9 -12.7 -12.1 Systolic Blood Pressure (mmHg)2 120 -0.8 120 -2.7 -1.9 Diastolic Blood Pressure (mmHg)2 73 -0.8 73 -1.4 -0.6 Heart Rate3 76 -2.3 79 1.2 3.5 HbA1c (%)2,4 5.4 -0.1 5.5 -0.4 -0.2 Baseline % Change from Baseline (LSMean) Baseline % Change from Baseline (LSMean) Relative difference from placebo (LSMean) Total Cholesterol (mg/dL)2,5 160.1 -1.3 159.4 -8.3 -7.1 LDL Cholesterol (mg/dL)2,5 91.7 -3.6 89.8 -9.9 -6.6 HDL Cholesterol (mg/dL)2,5 43.3 3.2 43.7 8 4.7 Triglycerides (mg/dL)2,5 108 2.6 111.3 -28.4 -30.2 1 Parameters listed in the table were not included in the pre-specified hierarchical testing. 2 Missing data were imputed using available data according to value and timing of last available observation on treatment and endpoint’s baseline value from retrieved subjects (RD-MI). Model based estimates based on an analysis of covariance model including treatment and stratification groups (gender, Tanner stage group) and the interaction between stratification groups as factors and baseline value as a covariate. 3 Model based estimates based on a mixed model for repeated measures including treatment as a factor and baseline value as a covariate all nested within visit. 4 For patients without type 2 diabetes at randomization (N=129 for WEGOVY-treated patients and N=64 for placebo-treated patients). 5 Baseline value is the geometric mean. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied WEGOVY injection is a clear, colorless solution in a prefilled, disposable, single-dose pen-injector with an integrated needle. It is supplied in cartons containing 4 pen-injectors in the following packaging configurations: Total Strength per Total Volume NDC 0.25 mg/0.5 mL 0169-4525-14 0.5 mg/0.5 mL 0169-4505-14 1 mg/0.5 mL 0169-4501-14 1.7 mg/0.75 mL 0169-4517-14 2.4 mg/0.75 mL 0169-4524-14 Recommended Storage Store the WEGOVY single-dose pen in the refrigerator from 2°C to 8°C (36°F to 46°F). If needed, prior to cap removal, the pen can be kept from 8°C to 30°C (46°F to 86°F) up to 28 days. Do not freeze. Protect WEGOVY from light. WEGOVY must be kept in the original carton until time of administration. Discard the WEGOVY pen after use. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Risk of Thyroid C-cell Tumors Inform patients that semaglutide causes thyroid C-cell tumors in rodents and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, or dyspnea) to their physician [see Boxed Warning, Warnings and Precautions (5.1)]. Reference ID: 5487292 Acute Pancreatitis Inform patients of the potential risk for acute pancreatitis and its symptoms: severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting. Instruct patients to discontinue WEGOVY promptly and contact their physician if pancreatitis is suspected [see Warnings and Precautions (5.2)]. Acute Gallbladder Disease Inform patients of the risk of acute gallbladder disease. Advise patients that substantial or rapid weight loss can increase the risk of gallbladder disease, but that gallbladder disease may also occur in the absence of substantial or rapid weight loss. Instruct patients to contact their healthcare provider for appropriate clinical follow-up if gallbladder disease is suspected [see Warnings and Precautions (5.3)]. Hypoglycemia Inform patients of the risk of hypoglycemia and educate patients on the signs and symptoms of hypoglycemia. Advise patients with diabetes mellitus on glycemic lowering therapy that they may have an increased risk of hypoglycemia when using WEGOVY and to report signs and/or symptoms of hypoglycemia to their healthcare provider [see Warnings and Precautions (5.4)]. Dehydration and Renal Impairment Advise patients treated with WEGOVY of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs [see Warnings and Precautions (5.5)]. Severe Gastrointestinal Adverse Reactions Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.6)]. Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of semaglutide, the active ingredient in WEGOVY. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking WEGOVY and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.7)]. Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Inform patients with type 2 diabetes to contact their physician if changes in vision are experienced during treatment with WEGOVY [see Warnings and Precautions (5.8)]. Heart Rate Increase Instruct patients to inform their healthcare providers of palpitations or feelings of a racing heartbeat while at rest during WEGOVY treatment [see Warnings and Precautions (5.9)]. Suicidal Behavior and Ideation Advise patients to report emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Inform patients that if they experience suicidal thoughts or behaviors, they should stop taking WEGOVY [see Warnings and Precautions (5.10)]. Pulmonary Aspiration During General Anesthesia or Deep Sedation Inform patients that WEGOVY may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to Reference ID: 5487292 inform healthcare providers prior to any planned surgeries or procedures if they are taking WEGOVY [see Warnings and Precautions (5.11)]. Pregnancy WEGOVY may cause fetal harm. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise patients who are exposed to WEGOVY during pregnancy to contact Novo Nordisk at 1-877­ 390-2760 or www.wegovypregnancyregistry.com [see Use in Specific Populations (8.1)]. Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd Denmark For additional information about WEGOVY contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-833-934-6891 Version: 6 WEGOVY® is a registered trademark of Novo Nordisk A/S. PATENT INFORMATION: http://www.novonordisk-us.com/products/product-patents.html © 2024 Novo Nordisk Reference ID: 5487292 MEDICATION GUIDE WEGOVY® (wee-GOH-vee) (semaglutide) injection, for subcutaneous use Read this Medication Guide and Instructions for Use before you start using WEGOVY and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about WEGOVY? WEGOVY may cause serious side effects, including: • Possible thyroid tumors, including cancer. Tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer. In studies with rodents, WEGOVY and medicines that work like WEGOVY caused thyroid tumors, including thyroid cancer. It is not known if WEGOVY will cause thyroid tumors or a type of thyroid cancer called medullary thyroid carcinoma (MTC) in people. • Do not use WEGOVY if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC), or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). What is WEGOVY? • WEGOVY is an injectable prescription medicine: • to reduce the risk of major cardiovascular events such as death, heart attack, or stroke in adults with known heart disease and with either obesity or overweight... • that may help adults and children aged 12 years and older with obesity, or some adults with excess weight (overweight) who also have weight-related medical problems to lose weight and keep the weight off. • WEGOVY should be used with a reduced calorie meal plan and increased physical activity. • WEGOVY contains semaglutide and should not be used with other semaglutide-containing products or other GLP-1 receptor agonist medicines. • It is not known if WEGOVY is safe and effective for use in children under 12 years of age. Do not use WEGOVY if: • you or any of your family have ever had a type of thyroid cancer called MTC or if you have an endocrine system condition called MEN 2. • you have had a serious allergic reaction to semaglutide or any of the ingredients in WEGOVY. See the end of this Medication Guide for a complete list of ingredients in WEGOVY. Before using WEGOVY, tell your healthcare provider if you have any other medical conditions, including if you: • have or have had problems with your pancreas or kidneys. • have type 2 diabetes and a history of diabetic retinopathy. • have or have had depression or suicidal thoughts, or mental health issues. • are pregnant or plan to become pregnant. WEGOVY may harm your unborn baby. You should stop using WEGOVY 2 months before you plan to become pregnant. o Pregnancy Exposure Registry: There is a pregnancy exposure registry for women who use WEGOVY during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry or you may contact Novo Nordisk at 1-877-390-2760. • are breastfeeding or plan to breastfeed. It is not known if WEGOVY passes into your breast milk. You should talk with your healthcare provider about the best way to feed your baby while using WEGOVY. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. WEGOVY may affect the way some medicines work and some medicines may affect the way WEGOVY works. Tell your healthcare provider if you are taking other medicines to treat diabetes, including sulfonylureas or insulin. WEGOVY slows stomach emptying and can affect medicines that need to pass through the stomach quickly. Reference ID: 5487292 Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use WEGOVY? • Read the Instructions for Use that comes with WEGOVY. • Use WEGOVY exactly as your healthcare provider tells you to. • Your healthcare provider should show you how to use WEGOVY before you use it for the first time. • Use WEGOVY with a reduced-calorie diet and increased physical activity. • WEGOVY is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm. Do not inject WEGOVY into a muscle (intramuscularly) or vein (intravenously). • Change (rotate) your injection site with each injection. Do not use the same site for each injection. • Use WEGOVY 1 time each week, on the same day each week, at any time of the day. • If you need to change the day of the week, you may do so as long as your last dose of WEGOVY was given 2 or more days before. • If you miss a dose of WEGOVY and the next scheduled dose is more than 2 days away (48 hours), take the missed dose as soon as possible. If you miss a dose of WEGOVY and the next schedule dose is less than 2 days away (48 hours), do not administer the dose. Take your next dose on the regularly scheduled day. • If you miss doses of WEGOVY for 2 or more weeks, take your next dose on the regularly scheduled day or call your healthcare provider to talk about how to restart your treatment. • You can take WEGOVY with or without food. • If you take too much WEGOVY, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. Advice is also available online at poisonhelp.org. What are the possible side effects of WEGOVY? WEGOVY may cause serious side effects, including: • See “What is the most important information I should know about WEGOVY?” • inflammation of your pancreas (pancreatitis). Stop using WEGOVY and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back. • gallbladder problems. WEGOVY may cause gallbladder problems including gallstones. Some gallbladder problems need surgery. Call your healthcare provider if you have any of the following symptoms: o pain in your upper stomach (abdomen) o yellowing of skin or eyes (jaundice) o fever o clay-colored stools • increased risk of low blood sugar (hypoglycemia) in patients with type 2 diabetes, especially those who also take medicines to treat type 2 diabetes mellitus such as an insulin or a sulfonylureas. Low blood sugar in patients with type 2 diabetes who receive WEGOVY can be both a serious and common side effect. Talk to your healthcare provider about how to recognize and treat low blood sugar. You should check your blood sugar before you start taking WEGOVY and while you take WEGOVY. Signs and symptoms of low blood sugar may include: o dizziness or light-headedness o sweating o shakiness o blurred vision o slurred speech o weakness o anxiety o hunger o headache o irritability or mood changes o confusion or drowsiness o fast heartbeat o feeling jittery • kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration. • severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use WEGOVY. Tell your healthcare provider if you have stomach problems that are severe or will not go away. • serious allergic reactions. Stop using WEGOVY and get medical help right away, if you have any symptoms of a serious allergic reaction including: o swelling of your face, lips, tongue or throat o severe rash or itching o very rapid heartbeat Reference ID: 5487292 o problems breathing or swallowing o fainting or feeling dizzy • change in vision in people with type 2 diabetes. Tell your healthcare provider if you have changes in vision during treatment with WEGOVY. • increased heart rate. WEGOVY can increase your heart rate while you are at rest. Your healthcare provider should check your heart rate while you take WEGOVY. Tell your healthcare provider if you feel your heart racing or pounding in your chest and it lasts for several minutes. • depression or thoughts of suicide. You should pay attention to any mental changes, especially sudden changes in your mood, behaviors, thoughts, or feelings. Call your healthcare provider right away if you have any mental changes that are new, worse, or worry you. • food or liquid getting into the lungs during surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). WEGOVY may increase the chance of food getting into your lungs during surgery or other procedures. Tell all your healthcare providers that you are taking WEGOVY before you are scheduled to have surgery or other procedures. The most common side effects of WEGOVY in adults or children aged 12 years and older may include: • nausea • stomach (abdomen) pain • dizziness • gas • diarrhea • headache • feeling bloated • stomach flu • vomiting • tiredness (fatigue) • belching • heartburn • constipation • upset stomach • low blood sugar in people • runny nose or sore throat with type 2 diabetes Talk to your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of WEGOVY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of WEGOVY. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use WEGOVY for a condition for which it was not prescribed. Do not give WEGOVY to other people, even if they have the same condition that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about WEGOVY that is written for health professionals. What are the ingredients in WEGOVY? Active Ingredient: semaglutide Inactive Ingredients: disodium phosphate dihydrate, 1.42 mg; sodium chloride, 8.25 mg; water for injection; and hydrochloric acid or sodium hydroxide may be added to adjust pH. Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark WEGOVY® is a registered trademark of Novo Nordisk A/S. PATENT Information: http://novonordisk-us.com/products/product-patents.html © 2024 Novo Nordisk For more information, go to startWegovy.com or call 1-833-Wegovy-1. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 11/2024 Reference ID: 5487292 0.25 mg/ 0.5 ml 0.5 mg/ 0.5 ml 1 mg /0.5 ml 1.7 mg/ 0.75 ml 2.4 mg/ 0.75 ml Instructions for Use WEGOVY® (semaglutide) injection WEGOVY comes in five strengths: Before you use your WEGOVY pen for the first time, talk to your healthcare provider or your caregiver about how to prepare and inject WEGOVY correctly. Pull out to get started Important information Read this Instructions for Use before you start using WEGOVY. This information does not replace talking to your healthcare provider about your medical condition or treatment. · Your WEGOVY pen is for 1 time use only. The WEGOVY pen is for subcutaneous (under the skin) use only. · The dose of WEGOVY is already set on your pen. · The needle is covered by the needle cover and the needle will not be seen. · Do not remove the pen cap until you are ready to inject. · Do not touch or push on the needle cover. You could get a needle stick injury. · Your WEGOVY injection will start when the needle cover is pressed firmly against your skin. · Do not remove the pen from your skin before the yellow bar in the pen window has stopped moving. The medicine may appear on the skin or squirt from the needle and you may not get your full dose of WEGOVY if: • the pen is removed too early or • you have not pressed the pen firmly against the skin for the entire injection. · If the yellow bar does not start moving or stops during the injection, contact your healthcare provider or Novo Nordisk at startWegovy.com or call Novo Nordisk Inc. at 1-833-934-6891. · The needle cover will lock when the pen is removed from your skin. You cannot stop the injection and restart it later. · People who are blind or have vision problems should not use the WEGOVY pen without help from a person trained to use the WEGOVY pen. How do I store WEGOVY? · Store the WEGOVY pen in the refrigerator between 36°F to 46°F (2°C to 8°C). · If needed, before removing the pen cap, WEGOVY can be stored from 46°F to 86°F (8°C to 30°C) in the original carton for up to 28 days. · Keep WEGOVY in the original carton to protect it from light. · Do not freeze. · Throw away the pen if WEGOVY has been frozen, has been exposed to light or temperatures above 86°F(30°C), or has been out of the refrigerator for 28 days or longer. Keep WEGOVY and all medicines out of the reach of children. Reference ID: 5487292 . Ill II wegovy® (scmaglutidc) injection wegovye (scmagl111ide) i1tjection WEGOVY pen parts Before use After use Expiration date (on the back) Check that WEGOVY has not expired. Always check you have the medicine and dose that your healthcare provider prescribed. Either: 0 25 mg / 0.5 mL 0.5 mg / 0.5 mL 1 mg / 0.5 mL 1.7 mg / 0.75 mL 2.4 mg / 0.75 mL Pen window Pen window Check that Check that WEGOVY is clear the yellow bar and colorless. Air has stopped bubbles are normal. moving to They do not affect make sure you your dose. received your Needle cover full dose. Needle is hidden Needle cover inside. locks after use. Pen cap Remove it just before you are ready to inject. How to use your WEGOVY pen Do not use your WEGOVY pen without receiving training from your healthcare provider. Make sure that you or your caregiver know how to give an injection with the pen before you start your treatment. Reference ID: 5487292 "' '\ Read and follow the instructions so that you use your WEGOVY pen correctly: Preparation Step 1. Prepare for your injection. • Supplies you will need to give your WEGOVY injection: o WEGOVY pen o 1 alcohol swab or soap and water o 1 gauze pad or cotton ball o 1 sharps disposable container for used WEGOVY pens • Wash your hands. • Check your WEGOVY pen. Do not use your WEGOVY pen if: o The pen appears to have been used or any part of the pen appears broken, for example if it has been dropped. o The WEGOVY medicine is not clear and colorless through the pen window. o The expiration date (EXP) has passed. Contact Novo Nordisk at 1-833-934-6891 if your WEGOVY pen fails any of these checks. Step 2. Choose your injection site. • Your healthcare provider can help you choose the injection site that is best for you • You may inject into your upper leg (front of the thighs), lower stomach (keep 2 inches away from your belly button) or upper arm. • Do not inject into an area where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. • You may inject in the same body area each week, but make sure it is not in the same spot each time. Clean the injection site with an alcohol swab or soap and water. Do not touch the injection site after cleaning. Allow the skin to dry before injecting. Reference ID: 5487292 0 ,, ' - l ._j -.., ...... I I Upper arms Stomach Upper legs Injection Step 3. Remove pen cap. • Pull the pen cap straight off your pen. Step 4. Inject WEGOVY. • Push the pen firmly against your skin and keep applying pressure until the yellow bar has stopped moving. If the yellow bar does not start moving, press the pen more firmly against your skin. • You will hear 2 clicks during the injection. • Click 1: the injection has started. • Click 2: the injection is ongoing. • If you have problems with the injection, refer to the “Troubleshooting” section. Reference ID: 5487292 - / .,,,........_ 0 Troubleshooting Needle inside Pen cap Throw away pen The injection takes about 5-10 seconds. Click 1 The injection starts. Click 2 Keep applying pressure until the yellow bar has stopped moving. Yellow bar has stopped moving. The injection is complete. Lift the pen slowly. Step 5. Throw away (dispose of) pen. Safely dispose of the WEGOVY pen right away after each use. See “How do I throw away (dispose of) WEGOVY pens?” • What if blood appears after injection? If blood appears at the injection site, press the site lightly with a gauze pad or cotton ball. • If you have problems injecting, change to a more firm injection site, such as upper leg, or upper arm or consider standing up while injecting into the lower stomach. • If medicine appears on the skin or squirts from the needle, make sure the next time you inject to keep applying pressure until the yellow bar has stopped moving. Then you can lift the pen slowly from your skin. Reference ID: 5487292 Medicine How do I throw away (dispose of) WEGOVY pens? Put the used WEGOVY pen in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the pen in your household trash. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: · made of a heavy-duty plastic, · able to be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, · upright and stable during use, · leak-resistant, and · properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific sharps disposal in the state that you live in, go to the FDA’s website at http://www.fda.gov/safesharpsdisposal. · Do not reuse the pen. · Do not recycle the pen or sharps disposal container, or throw them into household trash. Important: Keep your WEGOVY pen, sharps disposal container and all medicines out of the reach of children. How do I care for my pen? Protect your pen · Do not drop your pen or knock it against hard surfaces. · Do not expose your pen to any liquids. · If you think that your pen may be damaged, do not try to fix it. Use a new one. · Keep the pen cap on until you are ready to inject. Your pen will no longer be sterile if you store an unused pen without the cap, if you pull the pen cap off and put it on again, or if the pen cap is missing. This could lead to an infection. If you have any questions about WEGOVY, go to startWegovy.com or call Novo Nordisk Inc. at 1-833­ Wegovy-1 Manufactured by: Novo Nordisk A/S Novo Allé DK-2880 Bagsvaerd, Denmark For information about WEGOVY, go to startWegovy.com or contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-833-Wegovy-1 Version: 2 WEGOVY® is a registered trademark of Novo Nordisk A/S. Reference ID: 5487292 PATENT Information: http://novonordisk-us.com/products/product-patents.html © 2022 Novo Nordisk This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: August 2022 Reference ID: 5487292
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2025-02-12T15:47:25.555246
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_______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IFEX safely and effectively. See full prescribing information for IFEX. IFEX (ifosfamide) for injection, intravenous use Initial U.S. Approval: 1988 WARNING: MYELOSUPPRESSION, ENCEPHALOPATHY, NEPHROTOXICITY and UROTOXICITY See full prescribing information for complete boxed warning. • Myelosuppression can be severe and lead to fatal infections (5.1) • Encephalopathy can be severe and may result in death (5.2) • Nephrotoxicity can be severe and result in renal failure. Hemorrhagic cystitis can be severe. (5.3) ----------------------------RECENT MAJOR CHANGES-------------------------­ Boxed Warning 12/2024 Dosage and Administration (2.1, 2.2, 2.3) 12/2024 Warnings and Precautions (5) 12/2024 ----------------------------INDICATIONS AND USAGE--------------------------­ IFEX is an alkylating drug indicated for use in adults in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. (1) ----------------------DOSAGE AND ADMINISTRATION-----------------------­ • Administer IFEX with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day to reduce the incidence or severity of bladder toxicity. (2.1, 5.3) • Administer mesna with IFEX to reduce the incidence or severity of hemorrhagic cystitis. (2.1, 5.3) • Administer IFEX as a slow intravenous infusion (at least 30 minutes) at a dose of 1.2 grams per m2 per day for 5 consecutive days. Repeat every 3 weeks or after recovery from hematologic toxicity. (2.2) • Individualize the dose and dosing schedule of IFEX based on patient risk factors and adverse reactions. (2.2) • See Full Prescribing Information for instructions on preparation and administration. (2.3) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ • For injection: Single dose vials: 1 gram, 3 grams (3) -------------------------------CONTRAINDICATIONS-----------------------------­ • Known hypersensitivity to administration of ifosfamide. (4) • Urinary outflow obstruction. (4) -----------------------WARNINGS AND PRECAUTIONS---------------------­ • Myelosuppression: Monitor blood counts prior to treatment, during treatment, and as clinically indicated. (5.1) • Encephalopathy: Monitor for signs and symptoms of CNS toxicity during and after IFEX treatment. Dose interruption or permanent discontinuation may be required based on individual safety and tolerability. (5.2) • Nephrotoxicity and Urotoxicity: Monitor signs and symptoms. Monitor serum and urine chemistries. (2.1, 5.3) • Cardiotoxicity: Arrhythmias, other ECG changes, and cardiomyopathy can occur and result in death. Cardiotoxicity is dose dependent and the risk is increased in patients with preexisting cardiac, treatment with other cardiotoxic agents, radiation, and renal impairment. (5.4) • Pulmonary toxicity: Interstitial pneumonitis, pulmonary fibrosis, and pulmonary toxicity with fatal outcomes can occur. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated. (5.5) • Secondary malignancies can occur. (5.6) • Veno-occlusive Liver Disease can occur. (5.7) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. (5.8, 8.1, 8.3) • Infertility: Can impair male and female reproductive function. (5.9) • Anaphylactic/anaphylactoid reactions have been reported. (5.10) ------------------------------ADVERSE REACTIONS------------------------------­ The most common (≥ 10%) adverse reactions were alopecia, nausea/vomiting, hematuria, leukopenia, anemia, CNS toxicity, infection. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at phone: 1 866 888 2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS---------------------------­ • CYP3A4 Inducers: Monitor for increased toxicity when used in combination with CYP3A4 inducers. (7.1) • CYP3A4 Inhibitors: Use in combination with CYP3A4 inhibitors could decrease the effectiveness of ifosfamide. (7.2) -----------------------USE IN SPECIFIC POPULATIONS--------------------­ • Lactation: Advise not to breastfeed. (8.2) • Renal impairment: Closely monitor for adverse reactions and consider dosage modifications. (8.6) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: MYELOSUPPRESSION, ENCEPHALITIS, and UROTOXICITY 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions 2.2 Recommended Dosage 2.3 Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression 5.2 Encephalopathy 5.3 Nephrotoxicity and Urotoxicity 5.4 Cardiotoxicity 5.5 Pulmonary Toxicity 5.6 Secondary Malignancies 5.7 Veno-occlusive Liver Disease 5.8 Embryo-Fetal Toxicity 5.9 Infertility 5.10 Anaphylactic/Anaphylactoid Reactions and Cross-sensitivity 5.11 Impairment of Wound Healing 6. ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Inducers of CYP3A4 7.2 Inhibitors of CYP3A4 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.3 Pediatric Use 8.4 Geriatric Use 8.5 Use in Patients with Renal Impairment 8.6 Use in Patients with Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Reference ID: 5487945 *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5487945 FULL PRESCRIBING INFORMATION WARNING: MYELOSUPPRESSION, ENCEPHALOPATHY, NEPHROTOXICITY and UROTOXICITY • Myelosuppression can be severe and lead to fatal infections. Monitor blood counts prior to and at intervals after each treatment cycle [see Warnings and Precautions (5.1)]. • Encephalopathy can be severe and may result in death. Monitor for CNS toxicity and discontinue treatment for encephalopathy [see Warnings and Precautions (5.2)]. • Nephrotoxicity can be severe and result in renal failure. Hemorrhagic cystitis can be severe and can be reduced by the prophylactic use of mesna [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE IFEX is indicated for use in adults in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions Administer IFEX with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day to reduce the incidence or severity of bladder toxicity. Administer IFEX with mesna to reduce the incidence or severity of hemorrhagic cystitis [see Warnings and Precautions (5.3)]. 2.2 Recommended Dosage The recommended dosage of IFEX is 1.2 grams per m2 per day administered as a slow intravenous infusion (lasting at least 30 minutes) for 5 consecutive days. Treatment is repeated every 3 weeks or after recovery from hematologic toxicity. Individualize the dose and dosing schedule of IFEX based on patient risk factors and adverse reactions. 2.3 Preparation and Administration IFEX is a hazardous drug. Follow applicable special handling and disposal procedures.1 Skin reactions associated with accidental exposure to IFEX may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and solutions containing IFEX. If IFEX solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Prepare IFEX for intravenous use by adding Sterile Water for Injection, USP or Bacteriostatic Water for Injection, USP (benzyl alcohol or parabens preserved) to the vial and shaking to dissolve. Before administration, the substance must be completely dissolved. Use the quantity of diluents shown in Table 1 below to reconstitute the product: Reference ID: 5487945 Table 1: IFEX Quantities for Dilution and Final Concentrations Dosage Strength Quantity of Diluent Final Concentration 1 gram 20 mL 50 mg per mL 3 grams 60 mL 50 mg per mL Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6 to 20 mg/mL in the following fluids: • 5% Dextrose Injection, USP • 0.9% Sodium Chloride Injection, USP • Lactated Ringer’s Injections, USP • Sterile Water for Injection, USP Because essentially identical stability results were obtained for Sterile Water admixtures as for the other admixtures (5% Dextrose Injection, 0.9% Sodium Chloride Injection, and Lactated Ringer’s Injection), the use of large volume parenteral glass bottles, VIAFLEX bags or PAB bags that contain intermediate concentrations or mixtures of excipients (e.g., 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection) is also acceptable. Refrigerate constituted or constituted and further diluted solutions of IFEX and use within 24 hours. Benzyl-alcohol-containing solutions can reduce the stability of ifosfamide. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 3 DOSAGE FORMS AND STRENGTHS For injection: white, crystalline powder available in: • 1 gram single-dose vial for reconstitution • 3 gram single-dose vial for reconstitution 4 CONTRAINDICATIONS IFEX is contraindicated in patients with: • Known hypersensitivity to administration of ifosfamide. • Urinary outflow obstruction. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression IFEX can cause myelosuppression that results in severe or fatal infections including sepsis or septic shock. Ifosfamide-induced myelosuppression includes leukopenia, neutropenia, thrombocytopenia (with bleeding events), and anemia. The nadir of the leukocyte count usually occurs during the second week after administration of IFEX. The risk of myelosuppression is dose-dependent and increased in patients with reduced renal function, bone marrow metastases, prior radiation, and concomitant or prior therapy with other cytotoxic agents. Reference ID: 5487945 Monitor complete blood counts, including leukocytes, neutrophils, platelets, and hemoglobin prior to each administration of IFEX, at appropriate intervals during treatment, and as clinically indicated. Myelosuppression may require dosage delays. Avoid administration of IFEX to patients with a WBC count below 2000/µL, a platelet count below 50,000/µL, or when signs or symptoms of active infection or severe immunosuppression are present. 5.2 Encephalopathy IFEX can cause encephalopathy which may be fatal. Signs and symptoms may include confusion, somnolence, coma, hallucination, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, and seizures. Risk factors include high ifosfamide dosage, hypoalbuminemia, impaired renal function, poor performance status, bulky abdominal-pelvic disease, nephrotoxic treatments including cisplatin, CNS active drugs, or alcohol use. Signs and symptoms may occur or recur within hours to days after administration of IFEX. Continue supportive care until complete resolution of CNS signs and symptoms. Monitor for signs and symptoms of encephalopathy during and after IFEX treatment. Dose interruption or permanent discontinuation may be required based on individual safety and tolerability. Consider methylene blue for treatment of encephalopathy. 5.3 Nephrotoxicity and Urotoxicity IFEX can cause severe or fatal nephrotoxicity and urotoxicity including glomerular or tubular dysfunction, tubular necrosis, renal parenchymal necrosis, acute renal failure, chronic renal failure, and hemorrhagic cystitis (requiring blood transfusion). Tubular damage may occur up to years after cessation of IFEX treatment. The risk of nephrotoxicity is increased in patients with renal impairment or reduced nephron reserve. Hemorrhagic cystitis is dose-dependent and the risk is increased with past or concomitant radiation of the bladder or busulfan treatment. Evaluate glomerular and tubular kidney function before treatment with IFEX, during IFEX treatment, and as clinically indicated. Monitor serum and urine chemistries (including phosphorus and potassium) and urinary sediment for the presence of erythrocytes or other signs of nephrotoxicity. Signs and symptoms may include a decrease in glomerular filtration rate, increased serum creatinine, proteinuria, enzymuria, cylindruria, aminoaciduria, phosphaturia, glycosuria, osteomalacia, tubular acidosis, Fanconi syndrome, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Before starting treatment, exclude or correct any urinary tract obstructions [see Contraindications (4)]. During or immediately after administration, provide oral or intravenous fluid to force dieresis to reduce the risk of urinary tract toxicity. Administer mesna with IFEX to reduce the incidence and severity of urotoxicity [see Dosage and Administration (2.1)]. Obtain a urinalysis prior to each dose of IFEX. Avoid administration of IFEX in patients with active urinary tract infections. If microscopic hematuria (greater than 10 RBCs per high power field) is present, then withhold administration of IFEX until complete resolution. Further administration of IFEX should be given Reference ID: 5487945 with vigorous oral or parenteral hydration. Dosage interruption or permanent discontinuation may be required based on individual safety and tolerability. 5.4 Cardiotoxicity IFEX can cause severe or fatal cardiotoxicity including any of the following: • Supraventricular or ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia • Decreased QRS voltage and ST-segment or T-wave changes • Toxic cardiomyopathy leading to heart failure with congestion and hypotension • Pericardial effusion, fibrinous pericarditis, and epicardial fibrosis Cardiotoxic effects are dose-dependent and the risk is increased in patients with cardiac disease, prior or concomitant treatment with other cardiotoxic agents, radiation of the cardiac region, and renal impairment. 5.5 Pulmonary Toxicity IFEX can cause severe or fatal pulmonary toxicities including interstitial pneumonitis, pulmonary fibrosis, and respiratory failure. Monitor for signs and symptoms of pulmonary toxicity and treat as clinically indicated. 5.6 Secondary Malignancies The incidence of secondary malignancies is increased in patients treated with IFEX-containing regimens. Cases of myelodysplastic syndrome, acute leukemias, lymphomas, thyroid cancers, and sarcomas have occurred and may develop several years after chemotherapy has been discontinued. 5.7 Veno-occlusive Liver Disease Veno-occlusive liver disease has been reported with chemotherapy that included ifosfamide. 5.8 Embryo-Fetal Toxicity Based on mechanism of action and human and animal data, IFEX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy. Ifosfamide is genotoxic and mutagenic in male and female germ cells. Embryotoxic and teratogenic effects have been observed in mice, rats and rabbits at doses 0.05 to 0.075 times the human dose. Advise pregnant women and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1)]. Verify the pregnancy status of females of reproductive potential prior to initiation of IFEX. Advise females of reproductive potential to use effective contraception during treatment with IFEX and for up to 12 months after completion of therapy. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IFEX and for 6 months after completion of therapy [see Use in Specific Populations (8.1, 8.3)]. Reference ID: 5487945 5.9 Infertility Male and female reproductive function and fertility may be impaired in patients treated with IFEX. Ifosfamide interferes with oogenesis and spermatogenesis. Amenorrhea, azoospermia; and sterility in both sexes have been reported. Development of sterility appears to depend on the dose of ifosfamide, duration of therapy, and state of gonadal function at the time of treatment. Sterility may be irreversible in some patients. Advise patients on the potential risks for infertility [see Use in Specific Populations (8.3 and 8.4)]. 5.10 Anaphylactic/Anaphylactoid Reactions and Cross-sensitivity Anaphylactic/anaphylactoid reactions have been reported in association with ifosfamide. Cross-sensitivity between oxazaphosphorine cytotoxic agents has been reported. 5.11 Impairment of Wound Healing Ifosfamide may interfere with normal wound healing. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted from widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse reactions in Table 2 below are based on 30 publications describing clinical experience with fractionated administration of ifosfamide as a single agent with a total dose of 4 to 12 g/m2 per course. Table 2: Adverse Reactions in Patients Treated with Single Agent IFEX Adverse Reaction Single Agent IFEX % (number of patients) Skin and Subcutaneous Tissue Disorders Alopecia 90% (540/603) Dermatitis 0.08% (1/1317) Papular rash 0.08% (1/1317) Gastrointestinal Disorders Nausea/Vomiting 47% (443/964) Diarrhea 0.7% (9/1317) Stomatitis 0.3% (4/1317) Reference ID: 5487945 Adverse Reaction Single Agent IFEX % (number of patients) Renal and Urinary Disorders Hemorrhagic cystitis1 Hematuria - without mesna 44% (282/640) - with mesna 21% (33/155) Macrohematuria - without mesna 11% (66/594) - with mesna 5% (5/97) Renal dysfunction2 -­ Renal structural damage3 -­ Blood and Lymphatic System Disorders Leukopenia4 (any) -- Leukopenia <1 x 103/µL 44% (267/614) Anemia6 38% (202/533) Thrombocytopenia5 (any) -- Thrombocytopenia, 50 x 103/µL 4.8% (35/729) Nervous System Disorders Central nervous system toxicity7,8 15% (154/1001) Peripheral neuropathy 0.4% (5/1317) Infections and Infestations Infection 10% (112/1128) General Disorders and Administration Site Conditions Phlebitis9 2.8% (37/1317) Neutropenic fever10 1% (13/1317) Fatigue 0.3% (4/1317) Reference ID: 5487945 Adverse Reaction Single Agent IFEX % (number of patients) Malaise Unable to calculate Hepatobiliary Disorders Hepatotoxicity11 1.8% (22/1190) Metabolism and Nutrition Disorders Anorexia 1.1% (15/1317) Cardiac Disorders Cardiotoxicity12 0.5% (7/1317) Vascular Disorders Hypotension13 0.3% (4/1317) 1 Includes dysuria and pollakiuria 2 Includes acute renal failure, irreversible renal failure (fatal outcomes) serum creatinine increased, BUN increased, creatinine clearance decreased, metabolic acidosis, anuria, oliguria, glycosuria, hyponatremia, uremia, creatinine clearance increased 3 Includes acute tubular necrosis, renal parenchymal damage, enzymuria, cylindruria, proteinuria. 4 Includes neutropenia, granulocytopenia, lymphopenia, and pancytopenia 5 Includes severe or fatal bleeding 6 Includes anemia and decrease in hemoglobin/hematocrit 7 Includes coma and death 8 Includes abnormal behavior, affect lability aggression, agitation, anxiety, aphasia, asthenia, ataxia, cerebellar syndrome, cerebral function deficiency, cognitive disorder, coma, confusional state, convulsions, cranial nerve dysfunction, depressed state of consciousness, depression, disorientation, dizziness, electroencephalogram abnormal, encephalopathy, flat affect, hallucinations, headache, ideation, lethargy, memory impairment, mood change, motor dysfunction, muscle spasms, myoclonus, progressive loss of brainstem reflexes, psychotic reaction, restlessness, somnolence, tremor, urinary incontinence 9 Includes phlebitis and irritation of the venous walls 10 Includes granulocytopenic fever 11 Includes increased serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyltransferase (GGT) and lactate dehydrogenase (LDH) 12 Includes severe or fatal congestive heart failure, tachycardia, pulmonary edema 13 Includes shock and death 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of IFEX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic Disorders: agranulocytosis, febrile bone marrow aplasia, bone marrow failure, disseminated intravascular coagulation, hemolytic anemia, hemolytic febrile uremic syndrome, methemoglobinemia, neonatal anemia Reference ID: 5487945 Cardiac Disorders: cardiac arrest*, cardiac failure*, arrhythmia*, cardiomyopathy*, cardiotoxicity, cardiac shock, ejection fraction decreased*, myocardial infarction*, myocarditis*, ventricular fibrillation*, ventricular tachycardia*, angina pectoris, atrial fibrillation, atrial flutter, bradycardia, bundle branch block left, bundle branch block right, congestive cardiomyopathy, electrocardiogram ST – segment abnormal, electrocardiogram QRD complex abnormal, electrocardiogram T-wave inversion, myocardial depression, myocardial hemorrhage, left ventricular failure, premature atrial contractions, palpitations, pericardial effusion, pericarditis, supraventricular extrasystoles, ventricular extrasystoles Congenital Disorders: fetal growth retardation Ear Disorders: deafness, hypoacusis, tinnitus, vertigo Endocrine Disorder: SIADH Eye Disorders: conjunctivitis, eye irritation, vision blurred, visual impairment Gastrointestinal Disorders: abdominal pain, cecitis, colitis, constipation, enterocolitis, ileus, gastrointestinal hemorrhage, mucosal ulceration, pancreatitis, salivary hypersecretion General Disorders and Administrative Site Conditions: multi-organ failure*, chest pain, chills, injection/infusion site reactions (including erythema, inflammation, pain, pruritus, swelling, tenderness), edema, general physical deterioration, mucosal inflammation, pain, pyrexia Hepatobiliary Disorders: hepatic failure*, hepatitis fulminant* cholestasis, cytolytic hepatitis, portal vein thrombosis, veno-occlusive liver disease Immune System Disorders: anaphylactic reaction, angioedema, hypersensitivity reaction, immunosuppression, urticaria Infections: The following manifestations have been associated with myelosuppression and immunosuppression caused by ifosfamide: increased risk for and severity of infections†, pneumonias†, sepsis and septic shock (including fatal outcomes), as well as reactivation of latent infections, including viral hepatitis†, Pneumocystis jiroveci†, herpes zoster, Strongyloides, progressive multifocal leukoencephalopathy†, and other viral and fungal infections. † Severe immunosuppression has led to serious, sometimes fatal, infections Metabolic and Nutrition Disorders: hypocalcemia, hypokalemia, hypophosphatemia, hyperglycemia, metabolic acidosis, polydipsia, tumor lysis syndrome Musculoskeletal and Connective Tissue Disorders: arthralgia, growth retardation, myalgia, muscle twitching, osteomalacia, pain in extremity, rhabdomyolysis, rickets Neoplasms: secondary malignancies*, acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, myelodysplastic syndrome, Non-Hodgkin’s lymphoma, renal cell carcinoma, sarcomas, thyroid cancer Nervous System Disorders: seizure*, asterixis, dysarthria, dysesthesia, extrapyramidal disorder, fecal incontinence, gait disturbance hypothesia, leukoencephalopathy, movement disorder, neuralgia, paresthesia, Reference ID: 5487945 polyneuropathy, reversible posterior leukoencephalopathy syndrome. Ifosfamide has been reintroduced after neurotoxicity. While some patients did not experience neurotoxicity, others had recurrent, including fatal, events. Psychiatric Disorders: amnesia, bradyphrenia, catatonia, delirium, delusion, echolalia, logorrhea, mania mental status change, mutism, paranoia, panic attack, perseveration Renal and Urinary Disorders: aminoaciduria, diabetes insipidus, enuresis, Fanconi syndrome, feeling of residual urine, nephrogenic phosphaturia, polyuria, tubulointerstitial nephritis Reproductive System and Breast Disorders: amenorrhea, azoospermia, decreased blood estrogen, impairment of spermatogenesis, increased blood gonadotrophin, infertility, oligospermia, ovarian disorder, ovarian failure, ovulation disorder, premature menopause Respiratory, Thoracic, and Mediastinal Disorders: acute respiratory distress syndrome*, pulmonary fibrosis*, pneumonitis*/interstitial lung disease*, pulmonary edema*, pulmonary hypertension*, respiratory failure*, alveolitis allergic, bronchospasm, cough, dyspnea, hypoxia, pleural effusion Skin and Subcutaneous Disorders: erythema, facial swelling, hyperhidrosis, macular rash, nail disorder, palmar-plantar erythrodysesthesia syndrome, petechiae, pruritus, radiation recall dermatitis, rash, skin hyperpigmentation, skin necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis Vascular Disorders: capillary leak syndrome, deep vein thrombosis, flushing, hypertension, pulmonary embolism, vasculitis * Includes fatal outcomes 7 DRUG INTERACTIONS 7.1 Inducers of CYP3A4 CYP3A4 inducers may increase the metabolism of ifosfamide to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. Closely monitor patients taking ifosfamide with CYP3A4 inducers for toxicities and consider dose adjustment. 7.2 Inhibitors of CYP3A4 CYP3A4 inhibitors may decrease the metabolism of ifosfamide to its active alkylating metabolites, perhaps decreasing the effectiveness of ifosfamide treatment. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on mechanism of action [see Clinical Pharmacology (12.1)], and human and animal data (see Data), IFEX can cause fetal harm when administered to a pregnant woman. Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide-containing chemotherapy regimens during pregnancy. Reference ID: 5487945 In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Animal studies indicate that ifosfamide is capable of causing gene mutations and chromosomal damage in vivo. In pregnant mice, resorptions increased and anomalies were present at day 19 after a 30 mg/m2 dose of ifosfamide was administered on day 11 of gestation. Embryo-lethal effects were observed in rats following the administration of 54 mg/m2 doses of ifosfamide from the 6th through the 15th day of gestation and embryotoxic effects were apparent after dams received 18 mg/m2 doses over the same dosing period. Ifosfamide is embryotoxic to rabbits receiving 88 mg/m2/day doses from the 6th through the 18th day after mating. The number of anomalies was also significantly increased over the control group. 8.2 Lactation Risk Summary Ifosfamide is excreted in breast milk. Because of the potential for serious adverse events, and the tumorigenicity shown for ifosfamide in animal studies, advise women not to breastfeed during treatment with IFEX and for one week after the last dose. 8.3 Females and Males of Reproductive Potential IFEX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating IFEX [see Use in Specific Populations (8.1)]. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with IFEX and for 12 months after the last dose. Males Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with IFEX and for 6 months after the last dose [see Nonclinical Toxicology (13.1)]. Infertility Females Amenorrhea has been reported in patients treated with ifosfamide. The risk of permanent chemotherapy induced amenorrhea increases with age. Males Men treated with ifosfamide may develop oligospermia or azoospermia. Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Sexual function and libido are generally unimpaired in these patients. Some degree of testicular atrophy may occur. Patients treated with ifosfamide have subsequently fathered children. Reference ID: 5487945 Females and Males Based on animal studies, IFEX may impair fertility in females and males of reproductive potential. The reversibility of these effects is unknown [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. Renal rickets and growth retardation in pediatric patients treated with ifosfamide have been reported. IFEX may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential and may have an increased risk of developing premature menopause. IFEX may cause abnormal secondary sexual characteristic development in prepubertal males. Sterility, azoospermia, and testicular atrophy have been reported in male patients. Azoospermia may be reversible in some patients, but may not occur for several years after cessation of IFEX therapy. 8.5 Geriatric Use Clinical studies of IFEX did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. A study of patients 40 to 71 years of age indicated that elimination half-life appears to increase with advancing age [see Pharmacokinetics (12.3)]. This apparent increase in half-life appeared to be related to increases in volume of distribution of ifosfamide with age. No significant changes in total plasma clearance or renal or non-renal clearance with age were reported. Ifosfamide and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, closely monitor for adverse reactions and monitor renal function as clinically indicated. 8.6 Use in Patients with Renal Impairment Ifosfamide and its metabolites are known to be excreted by the kidneys and may accumulate in plasma with decreased renal function. Closely monitor patients with renal impairment for adverse reactions and consider dosage modifications. Ifosfamide and its metabolites are dialyzable. 8.7 Use in Patients with Hepatic Impairment Ifosfamide is extensively metabolized in the liver and forms both efficacious and toxic metabolites. Closely monitor patients with impaired hepatic function for adverse reactions during treatment with IFEX. 10 OVERDOSAGE No specific antidote for IFEX is known. Patients who receive an overdose should be closely monitored for the development of toxicities. Serious consequences of overdosage include manifestations of dose-dependent toxicities such as CNS toxicity, nephrotoxicity, myelosuppression, and mucositis [see Warnings and Precautions (5)]. Reference ID: 5487945 Management of overdosage would include general supportive measures to sustain the patient through any period of toxicity that might occur, including appropriate state-of-the-art treatment for any concurrent infection, myelosuppression, or other toxicity. Ifosfamide as well as ifosfamide metabolites are dialyzable. Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with overdose. 11 DESCRIPTION IFEX (ifosfamide for injection, USP) single-dose vials for constitution and administration by intravenous infusion each contain 1 gram or 3 grams of sterile ifosfamide. Ifosfamide is a alkylating drug chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide. Ifosfamide is 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2­ oxazaphosphorine 2-oxide. The molecular formula is C7H15Cl2N2O2P and its molecular weight is 261.1. Ifosfamide is a white crystalline powder soluble in water. There are no excipients in the formulation. Each vial contains 1 gram or 3 grams of sterile ifosfamide alone. Its structural formula is: 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of action Ifosfamide is a prodrug that requires metabolic activation by hepatic cytochrome P450 isoenzymes to exert its cytotoxic activity. Activation occurs by hydroxylation at the ring carbon atom forming the unstable intermediate 4-hydroxyifosfamide and its ring-opened aldo tautomer, which decomposes to yield the cytotoxic and urotoxic compound acrolein and an alkylating isophosphoramide mustard. The exact mechanism of action of ifosfamide has not been determined, but its cytotoxic action is primarily through DNA crosslinks caused by alkylation by the isophosphoramide mustard at guanine N-7 positions. The formation of inter- and intra-strand cross-links in the DNA results in cell death. 12.3 Pharmacokinetics Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8 to 5.0 g/m2, the plasma concentrations decay biphasically and the mean terminal elimination half-life is about 15 hours. At doses of 1.6 to 2.4 g/m2/day, the plasma decay is monoexponential and the terminal elimination half-life is about 7 hours. Ifosfamide exhibits time-dependent pharmacokinetics in humans. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, a decrease in the median elimination half-life from 7.2 hour on Day 1 to 4.6 hours on Day 5 occurred with a concomitant increase in the median clearance from 66 mL/min on Day 1 to 115 mL/min on Day 5. There was no significant change in the volume of distribution on Day 5 compared with Day 1. Reference ID: 5487945 Distribution Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 1 and 0.72 L/kg on Day 5. Ifosfamide shows little plasma protein binding. Ifosfamide and its active metabolites are extensively bound by red blood cells. Ifosfamide is not a substrate for P-glycoprotein. Metabolism Ifosfamide is extensively metabolized in humans through two metabolic pathways: ring oxidation ("activation") to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde. Small quantities (nmol/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma. Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients. Excretion After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in urine as metabolites, with about 61% of the dose excreted as parent compound. At doses of 1.6 to 2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours. Two different dechloroethylated derivatives of ifosfamide, 4-carboxyifosfamide, thiodiacetic acid and cysteine conjugates of chloroacetic acid have been identified as the major urinary metabolites of ifosfamide in humans and only small amounts of 4-hydroxyifosfamide and acrolein are present. Specific Populations Pediatric Patients Population PK analysis was performed on plasma data from 32 pediatric patients various malignant diseases aged between 1 and 18 years. Patients received a total of 45 courses of ifosfamide at doses of 1.2, 2.0 and 3.0 g/m2 given intravenously over 1 or 3 hours on 1, 2, or 3 days. The mean±standard error population estimates for the initial clearance and volume of distribution of ifosfamide were 2.4±0.33 L/h/m2 and 21±1.6 L/m2 with an interindividual variability of 43% and 32%, respectively. Effect of Age A study of 20 patients between 40 to 71 years of age receiving 1.5 g/m2 of ifosfamide daily for 3 or 5 days indicated that elimination half-life appears to increase with age. The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age. No significant changes in total plasma clearance or renal clearance with age were reported. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Ifosfamide has been shown to be carcinogenic in rats when administered by intraperitoneal injection at 6 mg/kg (37 mg/m2, or about 3% of the daily human dose on a mg/m2 basis) 3 times a week for 52 weeks. Female rats had a significantly higher incidence of uterine leiomyosarcomas and mammary fibroadenomas than vehicle controls. The mutagenic potential of ifosfamide has been documented in bacterial systems in vitro and mammalian cells in vivo. In vivo, ifosfamide has induced mutagenic effects in mice and Drosophila melanogaster germ Reference ID: 5487945 cells, and has induced a significant increase in dominant lethal mutations in male mice as well as recessive sex-linked lethal mutations in Drosophila. Ifosfamide was administered to male and female beagle dogs at doses of 1.00 or 4.64 mg/kg/day (20 or 93 mg/m2) orally 6 days a week for 26 weeks. Male dogs at 4.64 mg/kg (about 7.7% of the daily clinical dose on a mg/m2 basis) had testicular atrophy with degeneration of the seminiferous tubular epithelium. In a second study, male and female rats were given 0, 25, 50, or 100 mg/kg (0, 150, 300, or 600 mg/m2) ifosfamide intraperitoneally once every 3 weeks for 6 months. Decreased spermatogenesis was observed in most male rats given 100 mg/kg (about half the daily clinical dose on a mg/m2 basis). 14 CLINICAL STUDIES Patients with refractory testicular cancer (n=59) received a combination of ifosfamide, cisplatin, and either etoposide (VePesid) or vinblastine (VIP) as third-line therapy or later. The selection of etoposide or vinblastine (“V” in the VIP regimen) was guided by the therapeutic effect achieved with prior regimens. The contribution of ifosfamide to the VIP combination was determined in patients treated with cisplatin­ etoposide prior to ifosfamide- cisplatin-etoposide or those who received cisplatin-vinblastine prior to ifosfamide-cisplatin-vinblastine. A total of 59 patients received a third-line salvage regimen which consisted of ifosfamide 1.2 g/m2/day intravenously on days 1 to 5, cisplatin 20 mg/m2/day intravenously on days 1 to 5, and either etoposide 75 mg/m2/day intravenously on days 1 to 5 or vinblastine 0.22 mg/kg intravenously on day 1. Efficacy results with the VIP regimen were compared to data pooled from six single agent phase II trials conducted between August 1980 and October 1985 including a total of 90 patients of whom 65 were eligible as controls of this study. Twenty-three patients in the VIP regimen became free of disease with VIP alone or VIP plus surgery, whereas a single patient in the historical control group achieved complete response. The median survival time exceeded two years in the VIP group versus less than one year in the control group. Performance status ≥ 80, embryonal carcinoma and minimal disease were favorable prognostic factors for survival. In all prognostic categories, the difference between VIP and historical controls remained highly significant. Table 3: Efficacy Results Number. (%) of Patients VIP Control p-value Total Patients 59 (100) 65 (100) Disease-free Chemotherapy alone Chemotherapy plus surgery 23 (39) 1 (2) 15 (25) 1 (2) 8 (14) 0 < 0.001 < 0.001 Overall Response 32 (54) 2 (3) < 0.001 Time to progression (weeks) Median Range 19 4 1 – 205+ 1 – 29 < 0.001a Disease-free interval (weeks) Median Range 114 29 13 – 205+ -­ Survival (weeks) Reference ID: 5487945 Median 53 10 < 0.001a Range 1 – 205+ 1 – 123+ a: Gehan-Breslow and Mantel-Cox tests In a study, 50 fully evaluable patients with germ cell testicular cancer were treated with IFEX in combination with cisplatin and either vinblastine or etoposide after failing (47 of 50 patients) at least two prior chemotherapy regimens consisting of cisplatin/vinblastine/bleomycin, (PVB), cisplatin/vinblastine/actinomycin D/bleomycin/cyclophosphamide, (VAB6), or the combination of cisplatin and etoposide. Patients were selected for remaining cisplatin sensitivity because they had previously responded to a cisplatin containing regimen and had not progressed while on the cisplatin containing regimen or within 3 weeks of stopping it. Patients served as their own control based on the premise that long term complete responses could not be achieved by retreatment with a regimen to which they had previously responded and subsequently relapsed. Ten of 50 fully evaluable patients were still alive 2 to 5 years after treatment. Four of the 10 long term survivors were rendered free of cancer by surgical resection after treatment with the ifosfamide regimen; median survival for the entire group of 50 fully evaluable patients was 53 weeks. 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html 16 HOW SUPPLIED/STORAGE AND HANDLING IFEX (ifosfamide for injection, USP) is available in single-dose vials as follows: IFEX (ifosfamide for injection) NDC 0338-3991-01 1-gram Single-Dose Vial NDC 0338-3993-01 3-gram Single-Dose Vial Store at controlled room temperature 20°C to 25°C (68°F to 77°F). Protect from temperatures above 30°C (86°F). 17 PATIENT COUNSELING INFORMATION Myelosuppression • Advise patients that treatment with IFEX may cause myelosuppression which can be severe and lead to infections and fatal outcomes. • Inform patients of the risks associated with the use of IFEX and plan for regular blood monitoring during therapy [see Boxed Warning, Warnings and Precautions (5.1)]. • Inform patients to report fever or other symptoms of an infection [see Boxed Warning, Warnings and Precautions (5.1), Adverse Reactions (6.2)]. • Advise patients on the risks of bleeding and anemia [see Warnings and Precautions (5.1, 5.8), Adverse Reactions (6.2)], Use in Specific Populations (8.1)]. Encephalopathy • Advise patients on the risk of encephalopathy and other neurotoxic effects with fatal outcome [see Boxed Warning, Warnings and Precautions (5.2)]. • Inform patients that IFEX may impair the ability to operate an automobile or other heavy machinery [see Boxed Warning, Warnings and Precautions (5.2)]. Reference ID: 5487945 Nephrotoxicity and Urotoxicity • Advise patients on the risk of bladder and kidney toxicity. • Advise patients of the need to increase fluid intake and frequent voiding to prevent accumulation in the bladder [see Warnings and Precautions (5.3)]. Cardiotoxicity • Advise patients on the risk of cardiotoxicity and fatal outcome. • Advise patients to report preexisting cardiac disease and manifestations of cardiotoxicity [see Warnings and Precautions (5.4), Adverse Reactions (6.2)]. Pulmonary Toxicity • Advise patients on the risk of pulmonary toxicity leading to respiratory failure with fatal outcome. • Inform patients to report signs and symptoms of pulmonary toxicity [see Warnings and Precautions (5.5)]. Secondary Malignancies • Advise patients on the risk of secondary malignancies due to therapy [see Warnings and Precautions (5.6)]. Veno-occlusive Liver Disease • Advise patients on the risk of veno-occlusive liver disease [see Warnings and Precautions (5.7)]. Embryo-Fetal Toxicity • Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential to use effective contraception during treatment with IFEX and for 12 months after the last dose [see Use in Specific Populations (8.3)]. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IFEX and for 6 months after the last dose [see Use in Specific Populations (8.3)]. Lactation • Advise women not to breastfeed during treatment with IFEX and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Infertility • Advise females and males of reproductive potential that IFEX may cause temporary or permanent infertility [see Use in Specific Populations (8.3)]. Skin and Subcutaneous Tissue Disorders • Advise patients on the risk of alopecia, wound healing, and other serious skin and subcutaneous tissue disorders [see Warnings and Precautions (5.11), Adverse Reactions (6.2)]. Gastrointestinal Disorders • Advise patients that the therapy may cause gastrointestinal disorders and alcohol may increase nausea and vomiting [see Adverse Reactions (6.2)]. • Advise patients on the risk of stomatitis and the importance of proper oral hygiene [see Adverse Reactions (6.2)]. Reference ID: 5487945 Eye Disorders • Advise patients on the risk of eye disorders such as visual impairment, blurred vision, and eye irritation [see Adverse Reactions (6.2)]. Ear and Labyrinth Disorders • Advise patients on the risk of ear and labyrinth disorders such as deafness, vertigo, and tinnitus [see Adverse Reactions (6.2)]. Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1-800 ANA DRUG (1-800-262-3784) Made in Germany Baxter, Ifex and Viaflex are trademarks of Baxter International Inc. PAB is a trademark of B Braun HA-30-02-445 Reference ID: 5487945
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NDA 020648/S-009 Page 4 of 8 Revised 10 mg Pharmacist Card Reference ID: 3364931 NDA 020648/S-009 Page 5 of 8 Revised 20 mg Pharmacist Card Reference ID: 3364931 NDA 020648/S-009 Page 6 of 8 Sidesert for Diastat AcuDial 10 mg and 20 mg Reference ID: 3364931 NDA 020648/S-009 Page 7 of 8 Assembly Instruction Diagram (non-adhesive band/tab label) Reference ID: 3364931
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AXTLE safely and effectively. See full prescribing information for AXTLE. AXTLETM (pemetrexed) for Injection, for intravenous use Initial U.S. Approval: 2004 ------------------------------INDICATIONS AND USAGE---------------------------­ AXTLE is a folate analog metabolic inhibitor indicated: • in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. (1.1) • as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.1) • as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. (1.1) Limitations of Use: AXTLE is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. (1.1) • initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. (1.2) -----------------------DOSAGE AND ADMINISTRATION ------------------------­ • The recommended dose of AXTLE, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. (2.1, 2.2,) • Initiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning 7 days prior to the first dose of AXTLE and continue until 21 days after the last dose of AXTLE. (2.4) • Administer vitamin B12, 1 mg intramuscularly, 1 week prior to the first dose of AXTLE and every 3 cycles. (2.4) • Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after AXTLE administration. (2.4) ----------------------DOSAGE FORMS AND STRENGTHS-------------------­ For Injection: 100 mg or 500 mg pemetrexed equivalent to 118.3 mg or 591.5 mg pemetrexed dipotassium as lyophilized powder in single-dose vial (3) -------------------------------CONTRAINDICATIONS--------------------------------­ History of severe hypersensitivity reaction to pemetrexed. (4) ------------------------WARNINGS AND PRECAUTIONS ------------------------­ • Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer AXTLE when the absolute neutrophil count is less than 1500 cells/mm3 and platelets are less than 100,000 cells/mm3. Initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of AXTLE. (2.4, 5.1) • Renal Failure: Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min. (2.3, 5.2) • Bullous and Exfoliative Skin Toxicity: Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. (5.3) • Interstitial Pneumonitis: Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed. (5.4) • Radiation Recall: Can occur in patients who received radiation weeks to years previously; permanently discontinue for signs of radiation recall. (5.5) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (5.7, 8.1, 8.3) -------------------------------ADVERSE REACTIONS ------------------------------­ • The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent are fatigue, nausea, and anorexia. (6.1) • The most common adverse reactions (incidence ≥20%) of pemetrexed when administered with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Avyxa Pharma, LLC at 1-888-520-0954 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS -------------------------------­ Ibuprofen increased risk of pemetrexed toxicity in patients with mild to moderate renal impairment. Modify the ibuprofen dosage as recommended for patients with a creatinine clearance between 45 mL/min and 79 mL/min. (2.5, 5.6, 7) ------------------------ USE IN SPECIFIC POPULATIONS ----------------------­ Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 12/2024 Reference ID: 5488378 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC) 1.2 Mesothelioma 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage for Non-Squamous NSCLC 2.2 Recommended Dosage for Mesothelioma 2.3 Renal Impairment 2.4 Premedication and Concomitant Medications to Mitigate Toxicity 2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving AXTLE 2.6 Dosage Modifications for Adverse Reactions 2.7 Preparation for Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation 5.2 Renal Failure 5.3 Bullous and Exfoliative Skin Toxicity 5.4 Interstitial Pneumonitis 5.5 Radiation Recall 5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment 5.7 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Patients with Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Non-squamous NSCLC 14.2 Mesothelioma 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5488378 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC) AXTLE is indicated for: • in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. • as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. • as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. Limitations of Use: AXTLE is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies (14.1)]. 1.2 Mesothelioma AXTLE is indicated, in combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage for Non-Squamous NSCLC • The recommended dose of AXTLE when administered with cisplatin for initial treatment of locally advanced or metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes administered prior to cisplatin on Day 1 of each 21­ day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity. • The recommended dose of AXTLE for maintenance treatment of non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity after four cycles of platinum-based first-line chemotherapy. • The recommended dose of AXTLE for treatment of recurrent non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. 2.2 Recommended Dosage for Mesothelioma • The recommended dose of AXTLE, when administered with cisplatin, in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. 2.3 Renal Impairment • AXTLE dosing recommendations are provided for patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater [see Dosage and Reference ID: 5488378 Administration (2.1, 2.2)]. There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min [see Use in Specific Populations (8.6)]. 2.4 Premedication and Concomitant Medications to Mitigate Toxicity Vitamin Supplementation • Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 7 days before the first dose of AXTLE and continuing until 21 days after the last dose of AXTLE [see Warnings and Precautions (5.1)]. • Administer vitamin B12, 1 mg intramuscularly, 1 week prior to the first dose of AXTLE and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with AXTLE [see Warnings and Precautions (5.1)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Corticosteroids • Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each AXTLE administration. 2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving AXTLE In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen as follows [see Warnings and Precautions (5.6), Drug Interactions (7) and Clinical Pharmacology (12.3)]: • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of AXTLE. • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. 2.6 Dosage Modifications for Adverse Reactions Obtain complete blood count on Days 1, 8, and 15 of each cycle. Assess creatinine clearance prior to each cycle. Do not administer AXTLE if the creatinine clearance is less than 45 mL/min. Delay initiation of the next cycle of AXTLE until: • recovery of non-hematologic toxicity to Grade 0-2, • absolute neutrophil count (ANC) is 1500 cells/mm3 or higher, and • platelet count is 100,000 cells/mm3 or higher. Upon recovery, modify the dosage of AXTLE in the next cycle as specified in Table 1. For dosing modifications for cisplatin, refer to the prescribing information. Table 1: Recommended Dosage Modifications for Adverse Reactionsa Toxicity in Most Recent Treatment Cycle AXTLE Dose Modification for Next Cycle Myelosuppressive toxicity [see Warnings and Precautions (5.1)] ANC less than 500/mm³ and platelets greater than or equal to 50,000/mm³ OR Platelet count less than 50,000/mm3 without bleeding. 75% of previous dose Platelet count less than 50,000/mm3 with bleeding 50% of previous dose Reference ID: 5488378 Recurrent Grade 3 or 4 myelosuppression after 2 dose reductions Discontinue Non-hematologic toxicity Any Grade 3 or 4 toxicities EXCEPT mucositis or neurologic toxicity OR Diarrhea requiring hospitalization 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose Renal toxicity [see Warnings and Precautions (5.2)] Withhold until creatinine clearance is 45 mL/min or greater Grade 3 or 4 neurologic toxicity Permanently discontinue Recurrent Grade 3 or 4 non-hematologic toxicity after 2 dose reductions Permanently discontinue Severe and life-threatening Skin Toxicity [see Warnings and Precautions (5.3)] Permanently discontinue Interstitial Pneumonitis [see Warnings and Precautions (5.4)] Permanently discontinue a National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2) 2.7 Preparation for Administration • AXTLE is a hazardous drug. Follow applicable special handling and disposal procedures.1 • Calculate the dose of AXTLE and determine the number of vials needed. • Reconstitute AXTLE to achieve a concentration of 25 mg/mL as follows: • Reconstitute each 100-mg vial with 4.2 mL of 5% Dextrose Injection, USP (preservative-free) • Reconstitute each 500-mg vial with 20 mL of 5% Dextrose Injection, USP (preservative-free) • Do not use calcium-containing solutions for reconstitution. • Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow. FURTHER DILUTION IS REQUIRED prior to administration. • Store reconstituted, preservative-free product under refrigerated conditions [2-8°C (36­ 46°F)] for no longer than 24 hours from the time of reconstitution. Discard vial after 24 hours. • Inspect reconstituted product visually for particulate matter and discoloration prior to further dilution. If particulate matter is observed, discard vial. • Withdraw the calculated dose of AXTLE from the vial(s) and discard vial with any unused portion. • Further dilute AXTLE with 5% Dextrose Injection, USP to achieve a total volume of 100 mL for intravenous infusion. • Store diluted, reconstituted product under refrigerated conditions [2-8°C (36-46°F)] for no more than 24 hours from the time of reconstitution. Discard after 24 hours. 3 DOSAGE FORMS AND STRENGTHS For injection: 100 mg or 500 mg pemetrexed equivalent to 118.3 mg or 591.5 mg pemetrexed Reference ID: 5488378 dipotassium as a sterile preservative free white to light-yellow or green-yellow lyophilized powder in single-dose vials for reconstitution. 4 CONTRAINDICATIONS AXTLE is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse Reactions (6.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation AXTLE can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation. In Study JMCH, incidences of Grade 3-4 neutropenia (38% versus 23%), thrombocytopenia (9% versus 5%), febrile neutropenia (9% versus 0.6%), and neutropenic infection (6% versus 0) were higher in patients who received pemetrexed plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout pemetrexed plus cisplatin treatment. Initiate supplementation with oral folic acid and intramuscular vitamin B12 prior to the first dose of AXTLE; continue vitamin supplementation during treatment and for 21 days after the last dose of AXTLE to reduce the severity of hematologic and gastrointestinal toxicity of AXTLE [see Dosage and Administration (2.4)]. Obtain a complete blood count at the beginning of each cycle. Do not administer AXTLE until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce AXTLE in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles [see Dosage and Administration (2.6)]. In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the pemetrexed arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm [see Adverse Reactions (6.1)]. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%. 5.2 Renal Failure AXTLE can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which patients received pemetrexed with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received pemetrexed as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI [see Adverse Reactions (6.1)]. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with AXTLE. Withhold AXTLE in patients with a creatinine clearance of less than 45 mL/minute [see Dosage and Administration (2.3)]. Reference ID: 5488378 5.3 Bullous and Exfoliative Skin Toxicity Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/Toxic epidermal necrolysis can occur with AXTLE. Permanently discontinue AXTLE for severe and life-threatening bullous, blistering or exfoliating skin toxicity. 5.4 Interstitial Pneumonitis Serious interstitial pneumonitis, including fatal cases, can occur with AXTLE treatment. Withhold AXTLE for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue AXTLE. 5.5 Radiation Recall Radiation recall can occur with AXTLE in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue AXTLE for signs of radiation recall. 5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment Exposure to pemetrexed is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of AXTLE. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of AXTLE. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for pemetrexed adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity [see Dosage and Administration (2.5), Drug Interactions (7), and Clinical Pharmacology (12.3)]. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, AXTLE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with AXTLE and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with AXTLE and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Warnings and Precautions (5.1)] • Renal failure [see Warnings and Precautions (5.2)] • Bullous and exfoliative skin toxicity [see Warning and Precautions (5.3)] • Interstitial pneumonitis [see Warnings and Precautions (5.4)] • Radiation recall [see Warnings and Precautions (5.5)] Reference ID: 5488378 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. Non-Squamous NSCLC Initial Treatment in Combination with Cisplatin The safety of pemetrexed was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC. Patients received either pemetrexed 500 mg/m2 intravenously and cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle (n=839) or gemcitabine 1250 mg/m2 intravenously on Days 1 and 8 and cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle (n=830). All patients were fully supplemented with folic acid and vitamin B12. Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of 2 or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed plus cisplatin in 839 patients in Study JMDB. Median age was 61 years (range 26-83 years); 70% of patients were men; 78% were White,16% were Asian, 2.9% were Hispanic or Latino, 2.1% were Black or African American, and <1% were other ethnicities; 36% had an ECOG PS 0. Patients received a median of 5 cycles of pemetrexed. Table 2 provides the frequency and severity of adverse reactions that occurred in ≥5% of 839 patients receiving pemetrexed in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in Table 2. Table 2: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDB Adverse Reactiona Pemetrexed/Cisplatin (N=839) Gemcitabine/Cisplatin (N=830) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All adverse reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 Thrombocytopenia 10 4 27 13 Renal Reference ID: 5488378 Adverse Reactiona Pemetrexed/Cisplatin (N=839) Gemcitabine/Cisplatin (N=830) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Elevated creatinine 10 1 7 1 Clinical Constitutional symptoms Fatigue 43 7 45 5 Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/pharyngitis 14 1 12 0 Diarrhea 12 1 13 2 Dyspepsia/heartburn 5 0 6 0 Neurology Sensory neuropathy 9 0 12 1 Taste disturbance 8 0 9 0 Dermatology/Skin Alopecia 12 0 21 1 Rash/Desquamation 7 0 8 1 a NCI CTCAE version 2.0. The following additional adverse reactions of pemetrexed were observed. Incidence 1% to <5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal — renal failure Eye Disorder — conjunctivitis Incidence <1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy Maintenance Treatment Following First-line Non-Pemetrexed Containing Platinum-Based Chemotherapy In Study JMEN, the safety of pemetrexed was evaluated in a randomized (2:1), placebo- controlled, multicenter trial conducted in patients with non-progressive locally advanced or metastatic NSCLC following four cycles of a first-line, platinum-based chemotherapy regimen. Patients received either pemetrexed 500 mg/m2 or matching placebo intravenously every 21 days until disease progression or unacceptable toxicity. Patients in both study arms were fully supplemented with folic acid and vitamin B12. Study JMEN excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine Reference ID: 5488378 clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti- inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed in 438 patients in Study JMEN. Median age was 61 years (range 26-83 years), 73% of patients were men; 65% were White, 31% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 39% had an ECOG PS 0. Patients received a median of 5 cycles of pemetrexed and a relative dose intensity of pemetrexed of 96%. Approximately half the patients (48%) completed at least six, 21-day cycles and 23% completed ten or more 21-day cycles of pemetrexed. Table 3 provides the frequency and severity of adverse reactions reported in ≥5% of the 438 pemetrexed-treated patients in Study JMEN. Table 3: Adverse Reactions Occurring in ≥5% Patients Receiving Pemetrexed in Study JMEN Adverse Reactiona Pemetrexed (N=438) Placebo (N=218) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All adverse reactions 66 16 37 4 Laboratory Hematologic Anemia 15 3 6 1 Neutropenia 6 3 0 0 Hepatic Increased ALT 10 0 4 0 Increased AST 8 0 4 0 Clinical Constitutional symptoms Fatigue 25 5 11 1 Gastrointestinal Nausea 19 1 6 1 Anorexia 19 2 5 0 Vomiting 9 0 1 0 Mucositis/stomatitis 7 1 2 0 Diarrhea 5 1 3 0 Infection 5 2 2 0 Neurology Sensory neuropathy 9 1 4 0 Dermatology/Skin Rash/desquamation 10 0 3 0 a NCI CTCAE version 3.0 The requirement for transfusions (9.5% versus 3.2%), primarily red blood cell transfusions, and for erythropoiesis stimulating agents (5.9% versus 1.8%) were higher in the pemetrexed arm compared to the placebo arm. The following additional adverse reactions were observed in patients who received pemetrexed. Reference ID: 5488378 Incidence 1% to <5% Dermatology/Skin — alopecia, pruritis/itching Gastrointestinal — constipation General Disorders — edema, fever Hematologic — thrombocytopenia Eye Disorder — ocular surface disease (including conjunctivitis), increased lacrimation Incidence <1% Cardiovascular — supraventricular arrhythmia Dermatology/Skin — erythema multiforme General Disorders — febrile neutropenia, allergic reaction/hypersensitivity Neurology — motor neuropathy Renal — renal failure Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy The safety of pemetrexed was evaluated in PARAMOUNT, a randomized (2:1), placebo- controlled study conducted in patients with non-squamous NSCLC with non-progressive (stable or responding disease) locally advanced or metastatic NSCLC following four cycles of pemetrexed in combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive pemetrexed 500 mg/m2 or matching placebo intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Patients in both study arms received folic acid and vitamin B12 supplementation. PARAMOUNT excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti- inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed in 333 patients in PARAMOUNT. Median age was 61 years (range 32 to 83 years); 58% of patients were men; 94% were White, 4.8% were Asian, and <1% were Black or African American; 36% had an ECOG PS 0. The median number of maintenance cycles was 4 for pemetrexed and placebo arms. Dose reductions for adverse reactions occurred in 3.3% of patients in the pemetrexed arm and 0.6% in the placebo arm. Dose delays for adverse reactions occurred in 22% of patients in the pemetrexed arm and 16% in the placebo arm. Table 4 provides the frequency and severity of adverse reactions reported in ≥5% of the 333 pemetrexed-treated patients in PARAMOUNT. Table 4: Adverse Reactions Occurring in ≥5% of Patients Receiving Pemetrexed in PARAMOUNT Adverse Reactiona Pemetrexed (N=333) Placebo (N=167) All Grades (%) Grade 3-4 (%) All Grades (%) Grades 3-4 (%) All adverse reactions 53 17 34 4.8 Laboratory Hematologic Anemia 15 4.8 4.8 0.6 Reference ID: 5488378 Neutropenia 9 3.9 0.6 0 Clinical Constitutional symptoms Fatigue 18 4.5 11 0.6 Gastrointestinal Nausea 12 0.3 2.4 0 Vomiting 6 0 1.8 0 Mucositis/stomatitis 5 0.3 2.4 0 General disorders Edema 5 0 3.6 0 a NCI CTCAE version 3.0 The requirement for red blood cell (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0%) were higher in the pemetrexed arm compared to the placebo arm. The following additional Grade 3 or 4 adverse reactions were observed more frequently in the pemetrexed arm. Incidence 1% to <5% Blood/Bone Marrow — thrombocytopenia General Disorders — febrile neutropenia Incidence <1% Cardiovascular — ventricular tachycardia, syncope General Disorders — pain Gastrointestinal — gastrointestinal obstruction Neurologic — depression Renal — renal failure Vascular — pulmonary embolism Treatment of Recurrent Disease After Prior Chemotherapy The safety of pemetrexed was evaluated in Study JMEI, a randomized (1:1), open-label, active- controlled trial conducted in patients who had progressed following platinum-based chemotherapy. Patients received pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 intravenously on Day 1 of each 21-day cycle. All patients on the pemetrexed arm received folic acid and vitamin B12 supplementation. Study JMEI excluded patients with an ECOG PS of 3 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to discontinue aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed in 265 patients in Study JMEI. Median age was 58 years (range 22 to 87 years); 73% of patients were men; 70% were White, 24% were Asian, 2.6% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 19% had an ECOG PS 0. Reference ID: 5488378 Table 5 provides the frequency and severity of adverse reactions reported in ≥5% of the 265 pemetrexed-treated patients in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the Table 5 below. Table 5: Adverse Reactions Occurring in ≥5% of Fully Supplemented Patients Receiving Pemetrexed in Study JMEI Adverse Reactiona Pemetrexed (N=265) Docetaxel (N=276) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Laboratory Hematologic Anemia 19 4 22 4 Neutropenia 11 5 45 40 Thrombocytopenia 8 2 1 0 Hepatic Increased ALT 8 2 1 0 Increased AST 7 1 1 0 Clinical Gastrointestinal Nausea 31 3 17 2 Anorexia 22 2 24 3 Vomiting 16 2 12 1 Stomatitis/pharyngitis 15 1 17 1 Diarrhea 13 0 24 3 Constipation 6 0 4 0 Constitutional symptoms Fatigue 34 5 36 5 Fever 8 0 8 0 Dermatology/Skin Rash/desquamation 14 0 6 0 Pruritus 7 0 2 0 Alopecia 6 1 38 2 a NCI CTCAE version 2.0. The following additional adverse reactions were observed in patients assigned to receive pemetrexed. Incidence 1% to <5% Body as a Whole — abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection Dermatology/Skin — erythema multiforme Neurology — motor neuropathy, sensory neuropathy Incidence <1% Cardiovascular — supraventricular arrhythmias Renal — renal failure Reference ID: 5488378 Mesothelioma The safety of pemetrexed was evaluated in Study JMCH, a randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy for MPM. Patients received pemetrexed 500 mg/m2 intravenously in combination with cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle or cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle administered until disease progression or unacceptable toxicity. Safety was assessed in 226 patients who received at least one dose of pemetrexed in combination with cisplatin and 222 patients who received at least one dose of cisplatin alone. Among 226 patients who received pemetrexed in combination with cisplatin, 74% (n=168) received full supplementation with folic acid and vitamin B12 during study therapy, 14% (n=32) were never supplemented, and 12% (n=26) were partially supplemented. Study JMCH excluded patients with Karnofsky Performance Scale (KPS) of less than 70, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs were also excluded from the study. The data described below reflect exposure to pemetrexed in 168 patients that were fully supplemented with folic acid and vitamin B12. Median age was 60 years (range 19 to 85 years); 82% were men; 92% were White, 5% were Hispanic or Latino, 3.0% were Asian, and <1% were other ethnicities; 54% had KPS of 90-100. The median number of treatment cycles administered was 6 in the pemetrexed/cisplatin fully supplemented group and 2 in the pemetrexed/cisplatin never supplemented group. Patients receiving pemetrexed in the fully supplemented group had a relative dose intensity of 93% of the protocol-specified pemetrexed dose intensity. The most common adverse reaction resulting in dose delay was neutropenia. Table 6 provides the frequency and severity of adverse reactions ≥5% in the subgroup of pemetrexed-treated patients who were fully vitamin supplemented in Study JMCH. Study JMCH was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the table below. Table 6: Adverse Reactions Occurring in ≥5% of Fully Supplemented Subgroup of Patients Receiving Pemetrexed/Cisplatin in Study JMCHa Adverse Reactionb Pemetrexed /cisplatin (N=168) Cisplatin (N=163) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Laboratory Hematologic Neutropenia 56 23 13 3 Anemia 26 4 10 0 Thrombocytopenia 23 5 9 0 Renal Elevated creatinine 11 1 10 1 Decreased creatinine clearance 16 1 18 2 Clinical Eye Disorder Conjunctivitis 5 0 1 0 Reference ID: 5488378 Adverse Reactionb Pemetrexed /cisplatin (N=168) Cisplatin (N=163) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Gastrointestinal Nausea 82 12 77 6 Vomiting 57 11 50 4 Stomatitis/pharyngitis 23 3 6 0 Anorexia 20 1 14 1 Diarrhea 17 4 8 0 Constipation 12 1 7 1 Dyspepsia 5 1 1 0 Constitutional Symptoms Fatigue 48 10 42 9 Metabolism and Nutrition Dehydration 7 4 1 1 Neurology Sensory neuropathy 10 0 10 1 Taste disturbance 8 0 6 0 Dermatology/Skin Rash 16 1 5 0 Alopecia 11 0 6 0 a In Study JMCH, 226 patients received at least one dose of pemetrexed in combination with cisplatin and 222 patients received at least one dose of cisplatin. Table 6 provides the ADRs for subgroup of patients treated with pemetrexed in combination with cisplatin (168 patients) or cisplatin alone (163 patients) who received full supplementation with folic acid and vitamin B12 during study therapy. b NCI CTCAE version 2.0 The following additional adverse reactions were observed in patients receiving pemetrexed plus cisplatin: Incidence 1% to <5% Body as a Whole — febrile neutropenia, infection, pyrexia Dermatology/Skin — urticaria General Disorders — chest pain Metabolism and Nutrition — increased AST, increased ALT, increased GGT Renal — renal failure Incidence <1% Cardiovascular — arrhythmia Neurology — motor neuropathy Exploratory Subgroup Analyses based on Vitamin Supplementation Table 7 provides the results of exploratory analyses of the frequency and severity of NCI CTCAE Grade 3 or 4 adverse reactions reported in more pemetrexed-treated patients who did not receive vitamin supplementation (never supplemented) as compared with those who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in Study JMCH (fully-supplemented). Reference ID: 5488378 Table 7: Exploratory Subgroup Analysis of Selected Grade 3/4 Adverse Reactions Occurring in Patients Receiving Pemetrexed in Combination with Cisplatin with or without Full Vitamin Supplementation in Study JMCHa Grade 3-4 Adverse Reactions Fully Supplemented Patients N=168 (%) Never Supplemented Patients N=32 (%) Neutropenia 23 38 Thrombocytopenia 5 9 Vomiting 11 31 Febrile neutropenia 1 9 Infection with Grade 3/4 neutropenia 0 6 Diarrhea 4 9 a NCI CTCAE version 2.0 The following adverse reactions occurred more frequently in patients who were fully vitamin supplemented than in patients who were never supplemented: • hypertension (11% versus 3%), • chest pain (8% versus 6%), • thrombosis/embolism (6% versus 3%). Additional Experience Across Clinical Trials Sepsis, with or without neutropenia, including fatal cases: 1% Severe esophagitis, resulting in hospitalization: <1% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of pemetrexed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System — immune-mediated hemolytic anemia Gastrointestinal — colitis, pancreatitis General Disorders and Administration Site Conditions — edema Injury, poisoning, and procedural complications — radiation recall Respiratory — interstitial pneumonitis Skin — Serious and fatal bullous skin conditions, Stevens-Johnson syndrome, and toxic epidermal necrolysis 7 DRUG INTERACTIONS Effects of Ibuprofen on Pemetrexed Ibuprofen increases exposure (AUC) of pemetrexed [see Clinical Pharmacology (12.3)]. In patients with creatinine clearance between 45 mL/min and 79 mL/min: • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of AXTLE [see Dosage and Administration (2.5)]. • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. Reference ID: 5488378 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, AXTLE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on pemetrexed use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m2 [see Data]. Advise pregnant women of the potential risk to a fetus [see Use in Special Populations (8.3)]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m2. At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight). 8.2 Lactation Risk Summary There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from pemetrexed, advise women not to breastfeed during treatment with AXTLE and for one week after last dose. 8.3 Females and Males of Reproductive Potential Based on animal data, pemetrexed can cause malformations and developmental delays when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating AXTLE [see Use in Specific Populations (8.1)]. Contraception Females Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with AXTLE and for 6 months after the last dose. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with AXTLE and for 3 months after the last dose [see Nonclinical Toxicology (13.1)]. Reference ID: 5488378 Infertility Males AXTLE may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of AXTLE in pediatric patients have not been established. The safety and pharmacokinetics of pemetrexed were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors (NCT00070473 N=32 and NCT00520936 N=72). Patients in both studies received concomitant vitamin B12 and folic acid supplementation and dexamethasone. No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults. Single-dose pharmacokinetics of pemetrexed were evaluated in 22 patients age 4 to 18 years enrolled in NCT00070473 were within range of values in adults. 8.5 Geriatric Use Of the 3,946 patients enrolled in clinical studies of pemetrexed, 34% were 65 and over and 4% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials. [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)]. 8.6 Patients with Renal Impairment Pemetrexed is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to pemetrexed compared with patients with normal renal function [Warnings and Precautions (5.2, 5.6) and Clinical Pharmacology (12.3)]. No dose is recommended for patients with creatinine clearance less than 45 mL/min [see Dosage and Administration (2.3)]. 10 OVERDOSAGE No drugs are approved for the treatment of pemetrexed overdose. Based on animal studies, administration of leucovorin may mitigate the toxicities of pemetrexed overdosage. It is not known whether pemetrexed is dialyzable. 11 DESCRIPTION Pemetrexed is a folate analog metabolic inhibitor. The drug substance is pemetrexed dipotassium heptahydrate, has the chemical name L-glutamic acid, N-[4-[2-(2-amino-4,7­ dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, dipotassium salt, heptahydrate. It is a white to off-white powder having blue or green tinge with a molecular formula of C20H19K2N5O6 .7 H2O and a molecular weight of 629.49. Pemetrexed dipotassium is freely soluble in water. The reported pKaS are 3.6 and 4.5. The structural formula of pemetrexed dipotassium heptahydrate is as follows: Reference ID: 5488378 N H AXTLE is supplied as a sterile white to light-yellow or green-yellow lyophilized powder or cake for intravenous infusion available in single-dose vials. Each 100-mg or 500-mg vial of AXTLE contains 100 mg pemetrexed equivalent to 118.3 mg pemetrexed dipotassium and 106 mg mannitol or 500 mg pemetrexed equivalent to 591.5 mg pemetrexed dipotassium and 500 mg mannitol, respectively. Hydrochloric acid may have been added to adjust the pH. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. 12.2 Pharmacodynamics Pemetrexed inhibited the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) and showed synergistic effects when combined with cisplatin. Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with the systemic exposure to pemetrexed and supplementation with folic acid and vitamin B12. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles. 12.3 Pharmacokinetics Absorption The pharmacokinetics of pemetrexed when pemetrexed was administered as a single agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with increase of dose. The pharmacokinetics of pemetrexed did not change over multiple treatment cycles. Distribution Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicated that pemetrexed is 81% bound to plasma proteins. Reference ID: 5488378 Elimination The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). As renal function decreases, the clearance of pemetrexed decreases and exposure (AUC) of pemetrexed increases. Metabolism Pemetrexed is not metabolized to an appreciable extent. Excretion Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. In vitro studies indicated that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that is involved in the active secretion of pemetrexed. Specific Populations Age (26 to 80 years) and sex had no clinically meaningful effect on the systemic exposure of pemetrexed based on population pharmacokinetic analyses. Racial Groups The pharmacokinetics of pemetrexed were similar in Whites and Blacks or African Americans. Insufficient data are available for other ethnic groups. Patients with Hepatic Impairment Pemetrexed has not been formally studied in patients with hepatic impairment. No effect of elevated AST, ALT, or total bilirubin on the PK of pemetrexed was observed in clinical studies. Patients with Renal Impairment Pharmacokinetic analyses of pemetrexed included 127 patients with impaired renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. Third-Space Fluid The pemetrexed plasma concentrations in patients with various solid tumors with stable, mild to moderate third-space fluid were comparable to those observed in patients without third space fluid collections. The effect of severe third space fluid on pharmacokinetics is not known. Drug Interaction Studies Drugs Inhibiting OAT3 Transporter Ibuprofen, an OAT3 inhibitor, administered at 400 mg four times a day decreased the clearance of pemetrexed and increased its exposure (AUC) by approximately 20% in patients with normal renal function (creatinine clearance >80 mL/min). In Vitro Studies Reference ID: 5488378 Pemetrexed is a substrate for OAT3. Ibuprofen, an OAT3 inhibitor inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iµ]/IC50 ratio of 0.38. In vitro data predict that at clinically relevant concentrations, other NSAIDs (naproxen, diclofenac, celecoxib) would not inhibit the uptake of pemetrexed by OAT3 and would not increase the AUC of pemetrexed to a clinically significant extent. [see Drug Interactions (7)]. Pemetrexed is a substrate for OAT4. In vitro, ibuprofen and other NSAIDs (naproxen, diclofenac, celecoxib) are not inhibitors of OAT4 at clinically relevant concentrations. Aspirin Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. Cisplatin Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed. Vitamins Neither folic acid nor vitamin B12 affect the pharmacokinetics of pemetrexed. Drugs Metabolized by Cytochrome P450 Enzymes In vitro studies suggest that pemetrexed does not inhibit the clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in an in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, Chinese Hamster Ovary cell assay). Pemetrexed administered intraperitoneally at doses of ≥0.1 mg/kg/day to male mice (approximately 0.0006 times the recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy. 14 CLINICAL STUDIES 14.1 Non-Squamous NSCLC Initial Treatment in Combination with Cisplatin The efficacy of pemetrexed was evaluated in Study JMDB (NCT00087711), a multi-center, randomized (1:1), open-label study conducted in 1725 chemotherapy-naive patients with Stage IIIb/IV NSCLC. Patients were randomized to receive pemetrexed with cisplatin or gemcitabine with cisplatin. Randomization was stratified by Eastern Cooperative Oncology Group Performance Status (ECOG PS 0 versus 1), gender, disease stage, basis for pathological diagnosis (histopathological/cytopathological), history of brain metastases, and investigative center. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle. Cisplatin was administered intravenously at a dose of 75 mg/m2 approximately 30 minutes after pemetrexed administration on Day 1 of each cycle, gemcitabine was administered at a dose of 1250 mg/m2 on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m2 approximately 30 minutes after administration of Reference ID: 5488378 gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles; patients in both arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.4)]. The primary efficacy outcome measure was overall survival. A total of 1725 patients were enrolled with 862 patients randomized to pemetrexed in combination with cisplatin and 863 patients to gemcitabine in combination with cisplatin. The median age was 61 years (range 26-83 years), 70% were male, 78% were White, 17% were Asian, 2.9% were Hispanic or Latino, and 2.1% were Black or African American, and <1% were other ethnicities. Among patients for whom ECOG PS (n=1722) and smoking history (n=1516) were collected, 65% had an ECOG PS of 1, 36% had an ECOG PS of 0, and 84% were smokers. For tumor characteristics, 73% had non-squamous NSCLC and 27% had squamous NSCLC; 76% had Stage IV disease. Among 1252 patients with non-squamous NSCLC histology, 68% had a diagnosis of adenocarcinoma, 12% had large cell histology and 20% had other histologic subtypes. Efficacy results in Study JMDB are presented in Table 8 and Figure 1. Table 8: Efficacy Results in Study JMDB Efficacy Parameter Pemetrexed plus Cisplatin (N=862) Gemcitabine plus Cisplatin (N=863) Overall Survival Median (months) (95% CI) 10.3 (9.8-11.2) 10.3 (9.6-10.9) Hazard ratio (HR)a,b (95% CI) 0.94 (0.84-1.05) Progression-Free Survival Median (months) (95% CI) 4.8 (4.6-5.3) 5.1 (4.6-5.5) Hazard ratio (HR)a,b (95% CI) 1.04 (0.94-1.15) Overall Response Rate (95% CI) 27.1% (24.2-30.1) 24.7% (21.8-27.6) a Unadjusted for multiple comparisons. b Adjusted for gender, stage, basis of diagnosis, and performance status. Reference ID: 5488378 1.0 0.9 0.8 ~ 0.7 :.a (V 0.6 ..0 0 ,._ a. 0.5 7ii > 0.4 ·s: ,._ ::, 0.3 (/) 0.2 0.1 0.0 0 - Pemetrexed + Clsplalln (PC) ••• •• • Gemcltablne + Clsplalln (GC) 3 6 9 Patients at Risk PC GC 862 863 737 731 598 590 458 456 12 15 18 Survival Time (months) 341 327 235 209 146 139 21 88 78 24 45 34 27 10 14 30 0 0 Figure 1: Kaplan-Meier Curves for Overall Survival in Study JMDB In pre-specified analyses assessing the impact of NSCLC histology on overall survival, clinically relevant differences in survival according to histology were observed. These subgroup analyses are shown in Table 9 and Figures 2 and 3. This difference in treatment effect for pemetrexed based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in Studies JMEN and JMEI. Table 9: Overall Survival in NSCLC Histologic Subgroups in Study JMDB Histologic Subgroups Pemetrexed plus Cisplatin (N=862) Gemcitabine plus Cisplatin (N=863) Non-squamous NSCLC (N=1252) Median (months) (95% CI) 11.0 (10.1-12.5) 10.1 (9.3-10.9) HRa,b (95% CI) 0.84 (0.74-0.96) Adenocarcinoma (N=847) Median (months) (95% CI) 12.6 (10.7-13.6) 10.9 (10.2-11.9) HRa,b (95% CI) 0.84 (0.71-0.99) Large Cell (N=153) Median (months) (95% CI) 10.4 (8.6-14.1) 6.7 (5.5-9.0) HRa,b (95% CI) 0.67 (0.48-0.96) Non-squamous, not otherwise specified (N=252) Reference ID: 5488378 ~ .c I'll .c e Q. iii > ~ ::::, fl) 1.0 0.8 0.6 0.4 0.2 0.0 0 - Pemetreced + Clsplatln (PC) ------ Gemcltablne+ Clsplatln (GC) 3 6 9 Patients at Risk PC GC 618 634 533 542 437 435 341 339 12 15 18 Survlval Time (months) 264 240 188 151 118 101 I I 21 72 55 .. ~· - - ............ w ... • ...................... . 24 37 26 27 8 10 30 0 0 Median (months) (95% CI) 8.6 (6.8-10.2) 9.2 (8.1-10.6) HRa,b (95% CI) 1.08 (0.81-1.45) Squamous Cell (N=473) Median (months) (95% CI) 9.4 (8.4-10.2) 10.8 (9.5-12.1) HRa,b (95% CI) 1.23 (1.00-1.51) a Unadjusted for multiple comparisons. b Adjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological). Figure 2: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMDB Reference ID: 5488378 1.0 0.8 0.6 0.4 0.2 - Peme1rexed + Clsplalln (PC) 0.0 • • • • • • Gemchablne + Clsplatln (GC) 0 3 6 9 Patients at Risk PC GC 244 229 204 189 161 155 117 117 12 1S 18 survival Time (months) 77 87 47 58 28 38 21 16 23 24 8 8 27 2 4 30 0 0 Figure 3: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMDB Maintenance Treatment Following First-line Non-Pemetrexed Containing Platinum-Based Chemotherapy The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was evaluated in Study JMEN (NCT00102804), a multicenter, randomized (2:1), double-blind, placebo-controlled study conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously every 21 days or placebo until disease progression or intolerable toxicity. Patients in both study arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.4)]. Randomization was carried out using a minimization approach [Pocock and Simon (1975)] using the following factors: gender, ECOG PS (0 versus 1), response to prior chemotherapy (complete or partial response versus stable disease), history of brain metastases (yes versus no), non-platinum component of induction therapy (docetaxel versus gemcitabine versus paclitaxel), and disease stage (IIIb versus IV). The major efficacy outcome measures were progression-free survival based on assessment by independent review and overall survival; both were measured from the date of randomization in Study JMEN. A total of 663 patients were enrolled with 441 patients randomized to pemetrexed and 222 patients randomized to placebo. The median age was 61 years (range 26-83 years); 73% were male; 65% were White, 32% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 60% had an ECOG PS of 1; and 73% were current or former smokers. Median time from initiation of platinum-based chemotherapy to randomization was 3.3 months (range 1.6 to 5.1 months) and 49% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 81% had Stage IV disease, 73% had non-squamous NSCLC and 27% had squamous NSCLC. Among the 481 patients with Reference ID: 5488378 1.0 0.9 0.8 ~ 0.7 .c I'll 0.6 .c 0 ... c.. 0.5 "ii _;:: 0.4 > ... ::J CJ) 0.3 0.2 0.1 0.0 0 ·­ - Pemetrexed •····· Placebo 3 6 Patients at Risk .. • . '• .. 9 ... .. , .. ·• ..... .. 12 Pemetrexed 441 396 340 27 4 221 Placebo 222 200 160 119 93 •., ..... ·--........ 15 ···-..... 18 .......... ... 21 ......... ....................................... 24 27 30 Survival Time (months) 179 76 141 60 97 40 63 29 45 20 29 13 • ............................ . 33 19 6 36 11 4 39 2 0 42 0 0 non-squamous NSCLC, 68% had adenocarcinoma, 4% had large cell, and 28% had other histologies. Efficacy results are presented in Table 10 and Figure 4. Table 10: Efficacy Results in Study JMEN Efficacy Parameter Pemetrexed Placebo Overall survival N=441 N=222 Median (months) (95% CI) 13.4 (11.9-15.9) 10.6 (8.7-12.0) Hazard ratioa (95% CI) 0.79 (0.65-0.95) p-value p=0.012 Progression-free survival per independent review N=387 N=194 Median (months) (95% CI) 4.0 (3.1-4.4) 2.0 (1.5-2.8) Hazard ratioa (95% CI) 0.60 (0.49-0.73) p-value p<0.00001 a Hazard ratios are adjusted for multiplicity but not for stratification variables. Figure 4: Kaplan-Meier Curves for Overall Survival in Study JMEN The results of pre-specified subgroup analyses by NSCLC histology are presented in Table 11 and Figures 5 and 6. Reference ID: 5488378 I I I I I I I I I I I I Table 11: Efficacy Results in Study JMEN by Histologic Subgroup Efficacy Parameter Overall Survival Progression-Free Survival Per Independent Review Pemetrexed (N=441) Placebo (N=222) Pemetrexed (N=387) Placebo (N=194) Non-squamous NSCLC (n=481) Median (months) 15.5 10.3 4.4 1.8 HRa (95% CI) 0.70 (0.56-0.88) 0.47 (0.37-0.60) Adenocarcinoma (n=328) Median (months 16.8 11.5 4.6 2.7 HRa (95% CI) 0.73 (0.56-0.96) 0.51 (0.38-0.68) Large cell carcinoma (n=20) Median (months) 8.4 7.9 4.5 1.5 HRa (95% CI) 0.98 (0.36-2.65) 0.40 (0.12-1.29) Otherb (n=133) Median (months) 11.3 7.7 4.1 1.6 HRa (95% CI) 0.61 (0.40-0.94) 0.44 (0.28-0.68) Squamous cell NSCLC (n=182) Median (months) 9.9 10.8 2.4 2.5 HRa (95% CI) 1.07 (0.77-1.50) 1.03 (0.71-1.49) a Hazard ratios are not adjusted for multiplicity b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma. Reference ID: 5488378 ? :0 <'G .0 e 0.. 1.0 .. 0.8 0.6 ·-•· .... •-...... .. ••· ... .. .. •· .. '••··. • ............ _. iii .i:: > .... 0.4 -.. , ::s (/) 0.2 0.0 0 - Pemetrexed •••••• Placebo 3 6 Patients at Risk Pemetrexed 325 302 265 Placebo 156 140 112 0.8 .. '• ., 9 216 80 ~ :0 • ·-· ... i! 0.6 e 0.. iii .i:: 04 2: • ::, (/) 0.2 0.0 0 - Pemetrexed •••••• Placebo 3 6 Patients at Risk Pemetrexed 116 94 75 Placebo 66 60 48 •, .. ... 9 58 39 12 178 63 ·, 12 43 30 •••··· .... ----.. ·---.. ---.. -.. ··-····----·--':.., •.• , ....................... . 15 18 21 24 27 30 33 36 Survival Time (months) 141 117 82 51 38 25 15 9 52 42 28 20 11 7 4 3 15 18 21 24 27 30 33 36 Survival Time (months) 38 24 15 12 7 4 4 2 24 18 12 9 9 6 2 39 42 2 0 0 0 39 42 0 0 0 0 Figure 5: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMEN Figure 6: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMEN Reference ID: 5488378 I I I Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was also evaluated in PARAMOUNT (NCT00789373), a multi-center, randomized (2:1), double-blind, placebo-controlled study conducted in patients with Stage IIIb/IV non-squamous NSCLC who had completed four cycles of pemetrexed in combination with cisplatin and achieved a complete response (CR) or partial response (PR) or stable disease (SD). Patients were required to have an ECOG PS of 0 or 1. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously every 21 days or placebo until disease progression. Randomization was stratified by response to pemetrexed in combination with cisplatin induction therapy (CR or PR versus SD), disease stage (IIIb versus IV), and ECOG PS (0 versus 1). Patients in both arms received folic acid, vitamin B12, and dexamethasone. The main efficacy outcome measure was investigator-assessed progression-free survival (PFS) and an additional efficacy outcome measure was overall survival (OS); PFS and OS were measured from the time of randomization. A total of 539 patients were enrolled with 359 patients randomized to pemetrexed and 180 patients randomized to placebo. The median age was 61 years (range 32 to 83 years); 58% were male; 95% were White, 4.5% were Asian, and <1% were Black or African American; 67% had an ECOG PS of 1; 78% were current or former smokers; and 43% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 91% had Stage IV disease, 87% had adenocarcinoma, 7% had large cell, and 6% had other histologies. Efficacy results for PARAMOUNT are presented in Table 12 and Figure 7. Table 12: Efficacy Results in PARAMOUNT Efficacy Parameter Pemetrexed (N=359) Placebo (N=180) Overall survival Median (months) (95% CI) 13.9 (12.8-16.0) 11.0 (10.0-12.5) Hazard ratio (HR)a (95% CI) 0.78 (0.64-0.96) p-value p=0.02 Progression-free survivalb Median (months) (95% CI) 4.1 (3.2-4.6) 2.8 (2.6-3.1) Hazard ratio (HR)a (95% CI) 0.62 (0.49-0.79) p-value p<0.0001 a Hazard ratios are adjusted for multiplicity but not for stratification variables. b Based on investigator’s assessment. Reference ID: 5488378 1.0 0.9 0.8 -~ 0.7 ·•. ··-. :c cu 0.6 ..0 0 ... a. 0.5 cu . 2: 0.4 C: ::s 0.3 en 0.2 0.1 - Pemetrexed •••••• Placebo 0.0 0 3 Patients at Risk Pemetrexed 359 333 Placebo 180 169 6 272 131 .. ·-... -.... 9 •·. .. 235 103 .. ... ... 12 200 78 ··--­--... ·---.. ... -·-••• ·--. ·-... • . . -... -..... -- 15 18 21 Survival Time (months) 166 65 138 49 105 35 24 79 23 --...... .. .............. .. , 27 43 12 30 15 8 33 2 3 36 0 0 Figure 7: Kaplan-Meier Curves for Overall Survival in PARAMOUNT Treatment of Recurrent Disease After Prior Chemotherapy The efficacy of pemetrexed was evaluated in Study JMEI (NCT00004881), a multicenter, randomized (1:1), open-label study conducted in patients with Stage III or IV NSCLC that had recurred or progressed following one prior chemotherapy regimen for advanced disease. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 as a 1-hour intravenous infusion once every 21 days. Patients randomized to pemetrexed also received folic acid and vitamin B12. The study was designed to show that overall survival with pemetrexed was non-inferior to docetaxel, as the major efficacy outcome measure, and that overall survival was superior for patients randomized to pemetrexed compared to docetaxel, as a secondary outcome measure. A total of 571 patients were enrolled with 283 patients randomized to pemetrexed and 288 patients randomized to docetaxel. The median age was 58 years (range 22 to 87 years); 72% were male; 71% were White, 24% were Asian, 2.8% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 88% had an ECOG PS of 0 or 1. With regard to tumor characteristics, 75% had Stage IV disease; 53% had adenocarcinoma, 30% had squamous histology; 8% large cell; and 9% had other histologic subtypes of NSCLC. The efficacy results in the overall population and in subgroup analyses based on histologic subtype are provided in Tables 13 and 14, respectively. Study JMEI did not show an improvement in overall survival in the intent-to-treat population. In subgroup analyses, there was no evidence of a treatment effect on survival in patients with squamous NSCLC; the absence of a treatment effect in patients with NSCLC of squamous histology was also observed Studies JMDB and JMEN [see Clinical Studies (14.1)]. Reference ID: 5488378 I I I I I I I I I I Table 13: Efficacy Results in Study JMEI Efficacy Parameter Pemetrexed (N=283) Docetaxel (N=288) Overall survival Median (months) (95% CI) 8.3 (7.0-9.4) 7.9 (6.3-9.2) Hazard ratioa (95% CI) 0.99 (0.82-1.20) Progression-free survival Median (months) (95% CI) 2.9 (2.4-3.1) 2.9 (2.7-3.4) Hazard ratioa (95% CI) 0.97 (0.82-1.16) Overall response rate (95% CI) 8.5% (5.2-11.7) 8.3% (5.1-11.5) a Hazard ratios are not adjusted for multiplicity or for stratification variables. Table 14: Exploratory Efficacy Analyses by Histologic Subgroup in Study JMEI Histologic Subgroups Pemetrexed (N=283) Docetaxel (N=288) Non-squamous NSCLC (N=399) Median (months) (95% CI) 9.3 (7.8-9.7) 8.0 (6.3-9.3) HRa (95% CI) 0.89 (0.71-1.13) Adenocarcinoma (N=301) Median (months) (95% CI) 9.0 (7.6-9.6) 9.2 (7.5-11.3) HRa (95% CI) 1.09 (0.83-1.44) Large Cell (N=47) Median (months) (95% CI) 12.8 (5.8-14.0) 4.5 (2.3-9.1) HRa (95% CI) 0.38 (0.18-0.78) Otherb (N=51) Median (months) (95% CI) 9.4 (6.0-10.1) 7.9 (4.0-8.9) HRa (95% CI) 0.62 (0.32-1.23) Squamous NSCLC (N=172) Median (months) (95% CI) 6.2 (4.9-8.0) 7.4 (5.6-9.5) HRa (95% CI) 1.32 (0.93-1.86) a Hazard ratio unadjusted for multiple comparisons. b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma. Reference ID: 5488378 14.2 Mesothelioma The efficacy of pemetrexed was evaluated in Study JMCH (NCT00005636), a multicenter, randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy. Patients were randomized (n=456) to receive pemetrexed 500 mg/m2 intravenously over 10 minutes followed 30 minutes later by cisplatin 75 mg/m2 intravenously over two hours on Day 1 of each 21-day cycle or to receive cisplatin 75 mg/m2 intravenously over 2 hours on Day 1 of each 21-day cycle; treatment continued until disease progression or intolerable toxicity. The study was modified after randomization and treatment of 117 patients to require that all patients receive folic acid 350 mcg to 1000 mcg daily beginning 1 to 3 weeks prior to the first dose of pemetrexed and continuing until 1 to 3 weeks after the last dose, vitamin B12 1000 mcg intramuscularly 1 to 3 weeks prior to first dose of pemetrexed and every 9 weeks thereafter, and dexamethasone 4 mg orally, twice daily, for 3 days starting the day prior to each pemetrexed dose. Randomization was stratified by multiple baseline variables including KPS, histologic subtype (epithelial, mixed, sarcomatoid, other), and gender. The major efficacy outcome measure was overall survival and additional efficacy outcome measures were time to disease progression, overall response rate, and response duration. A total of 448 patients received at least one dose of protocol-specified therapy; 226 patients were randomized to and received at least one dose of pemetrexed plus cisplatin, and 222 patients were randomized to and received cisplatin. Among the 226 patients who received cisplatin with pemetrexed, 74% received full supplementation with folic acid and vitamin B12 during study therapy, 14% were never supplemented, and 12% were partially supplemented. Across the study population, the median age was 61 years (range: 20 to 86 years); 81% were male; 92% were White, 5% were Hispanic or Latino, 3.1% were Asian, and <1% were other ethnicities; and 54% had a baseline KPS score of 90-100% and 46% had a KPS score of 70­ 80%. With regard to tumor characteristics, 46% had Stage IV disease, 31% Stage III, 15% Stage II, and 7% Stage I disease at baseline; the histologic subtype of mesothelioma was epithelial in 68% of patients, mixed in 16%, sarcomatoid in 10% and other histologic subtypes in 6%. The baseline demographics and tumor characteristics of the subgroup of fully supplemented patients was similar to the overall study population. The efficacy results from Study JMCH are summarized in Table 15 and Figure 8. Table 15: Efficacy Results in Study JMCH Efficacy Parameter All Randomized and Treated Patients (N=448) Fully Supplemented Patients (N=331) Pemetrexed /Cisplatin (N=226) Cisplatin (N=222) Pemetrexed /Cisplatin (N=168) Cisplatin (N=163) Median overall survival (months) 12.1 9.3 13.3 10.0 (95% CI) (10.0-14.4) (7.8-10.7) (11.4-14.9) (8.4-11.9) Hazard ratioa 0.77 0.75 Log rank p-value 0.020 NAb a Hazard ratios are not adjusted for stratification variables. b Not a pre-specified analysis. Reference ID: 5488378 1.0 0.9 0.8 -~ 0.7 :5 ., 0.6 .0 e o.s 0. j -~ 0.4 ::, (/) 0.3 0.2 0.1 0.0 0 Patients at Risk Pemetrexed .. ClsplaUn 226 Clsplatln 222 - Pemetrexed + Clsplatln • ••••• Clsplatln 3 201 195 6 166 153 9 128 104 -.... ·-... _ 12 ···---. •••••••• ••••••••••.............. •,-.. -.-.. ----, ..... ...... 15 18 21 24 Survival Time (months) 84 63 50 31 32 21 17 14 8 3 27 4 30 0 0 Figure 8: Kaplan-Meier Curves for Overall Survival in Study JMCH Based upon prospectively defined criteria (modified Southwest Oncology Group methodology) the objective tumor response rate for pemetrexed plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the pemetrexed plus cisplatin arm compared to the control arm. 15 REFERENCES 1. “OSHA Hazardous Drugs.” OSHA. [https://www.osha.gov/hazardous-drugs] 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied AXTLETM, is a sterile preservative free white-to-light yellow or green-yellow lyophilized powder supplied in single-dose vials for reconstitution for intravenous infusion. NDC 83831-111-01: 100 mg single-dose vial containing pemetrexed equivalent to 118.3 mg pemetrexed dipotassium with aluminum flip-off seals with grey color button individually packaged in a carton. NDC 83831-112-01: 500 mg single-dose vial containing pemetrexed equivalent to 591.5 mg pemetrexed dipotassium with aluminum flip-off seals with red color button individually packaged in a carton. Storage and Handling Store at controlled room temperature, 20°-25°C (68°-77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. AXTLE is a hazardous drug. Follow applicable special handling and disposal procedures.1 Reference ID: 5488378 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Premedication and Concomitant Medication: Instruct patients to take folic acid as directed and to keep appointments for vitamin B12 injections to reduce the risk of treatment-related toxicity. Instruct patients of the requirement to take corticosteroids to reduce the risks of treatment- related toxicity [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)]. Myelosuppression: Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, fever, bleeding, or symptoms of anemia [see Warnings and Precautions (5.1)]. Renal Failure: Inform patients of the risks of renal failure, which may be exacerbated in patients with dehydration arising from severe vomiting or diarrhea. Instruct patients to immediately contact their healthcare provider for a decrease in urine output [see Warnings and Precautions (5.2)]. Bullous and Exfoliative Skin Disorders: Inform patients of the risks of severe and exfoliative skin disorders. Instruct patients to immediately contact their healthcare provider for development of bullous lesions or exfoliation in the skin or mucous membranes [see Warnings and Precautions (5.3)]. Interstitial Pneumonitis: Inform patients of the risks of pneumonitis. Instruct patients to immediately contact their healthcare provider for development of dyspnea or persistent cough [see Warnings and Precautions (5.4)]. Radiation Recall: Inform patients who have received prior radiation of the risks of radiation recall. Instruct patients to immediately contact their healthcare provider for development of inflammation or blisters in an area that was previously irradiated [see Warnings and Precautions (5.5)]. Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment: Advise patients with mild to moderate renal impairment of the risks associated with concomitant ibuprofen use and instruct them to avoid use of all ibuprofen containing products for 2 days before, the day of, and 2 days following administration of AXTLE [see Dosage and Administration (2.5), Warnings and Precautions (5.6), and Drug Interactions (7)]. Embryo-Fetal Toxicity: Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1,)]. Advise females of reproductive potential to use effective contraception during treatment with AXTLE and for 6 months after the last dose. Advise females to inform their prescriber of a known or suspected pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with AXTLE and for 3 months after the last dose [see Warnings and Precautions (5.7) and Use in Specific Populations (8.3)]. Lactation: Advise women not to breastfeed during treatment with AXTLE and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Reference ID: 5488378 AVYXA Manufactured for: Avyxa Pharma, LLC New Jersey 07054, USA Made in India Reference ID: 5488378 PATIENT INFORMATION AXTLETM (AXE-tul) (pemetrexed) for Injection for intravenous use What is AXTLE? AXTLE is a prescription medicine used to treat: • a kind of lung cancer called non-squamous non-small cell lung cancer (NSCLC). AXTLE is used: o as the first treatment in combination with cisplatin when your lung cancer has spread (advanced NSCLC). o alone as maintenance treatment after you have received 4 cycles of chemotherapy that contains platinum for first treatment of your advanced NSCLC and your cancer has not progressed. • alone when your lung cancer has returned or spread after prior chemotherapy. AXTLE is not for use for the treatment of people with squamous cell non-small cell lung cancer. • a kind of cancer called malignant pleural mesothelioma. This cancer affects the lining of the lungs and chest wall. AXTLE is used in combination with cisplatin as the first treatment for malignant pleural mesothelioma that cannot be removed by surgery or you are not able to have surgery. AXTLE has not been shown to be safe and effective in children. Do not take AXTLE: if you have had a severe allergic reaction to any medicine that contains pemetrexed. Before taking AXTLE, tell your healthcare provider about all of your medical conditions, including if you: • have kidney problems. • have had radiation therapy. • are pregnant or plan to become pregnant. AXTLE can harm your unbornbaby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with AXTLE. You should use effective birth control (contraception) during treatment with AXTLE and for 6 months after the last dose. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with AXTLE. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with AXTLE and for 3 months after the last dose. • are breastfeeding or plan to breastfeed. It is not known if AXTLE passes into breast milk. Do not breastfeed during treatment with AXTLE and for 1 week after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Tell your healthcare provider if you have kidney problems and take a medicine that contains ibuprofen. You should avoid taking ibuprofen for 2 days before, the day of, and 2 days after receiving treatment with AXTLE. Reference ID: 5488378 How is AXTLE given? • It is very important to take folic acid and vitamin B12 during your treatment with AXTLE to lower your risk of harmful side effects. o Take folic acid exactly as prescribed by your healthcare provider 1 time a day, beginning 7 days (1 week) before your first dose of AXTLE and continue taking folic acid until 21 days (3 weeks) after your last dose of AXTLE. o Your healthcare provider will give you vitamin B12 injections during treatment with AXTLE. You will get your first vitamin B12 injection 7 days (1 week) before your first dose of AXTLE, and then every 3 cycles. • Your healthcare provider will prescribe a medicine called corticosteroid for you to take 2 times a day for 3 days, beginning the day before each treatment with AXTLE . • AXTLE is given to you by intravenous (IV) infusion into your vein. The infusion is given over 10 minutes. • AXTLE is usually given once every 21 days (3weeks). What are the possible side effects of AXTLE? AXTLE can cause serious side effects, including: • Low blood cell counts. Low blood cell counts can be severe, including low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and low red blood cell counts (anemia). Your healthcare provider will do blood tests to check your blood cell counts regularly during your treatment with AXTLE. Tell your healthcare provider right away if you have any signs of infection, fever, bleeding, or severe tiredness during your treatment with AXTLE. • Kidney problems, including kidney failure. AXTLE can cause severe kidney problems that can lead to death. Severe vomiting or diarrhea can lead to loss of fluids (dehydration) which may cause kidney problems to become worse. Tell your healthcare provider right away if you have a decrease in amount of urine. • Severe skin reactions. Severe skin reactions that may lead to death can happen with AXTLE. Tell your healthcare provider right away if you develop blisters, skin sores, skin peeling, or painful sores, or ulcers in your mouth, nose, throat or genital area. • Lung problems (pneumonitis). AXTLE can cause serious lung problems that can lead to death. Tell your healthcare provider right away if you get any new or worsening symptoms of shortness of breath, cough, or fever. • Radiation recall. Radiation recall is a skin reaction that can happen in people who have received radiationtreatment in the past and are treated with AXTLE. Tell your healthcare provider if you get swelling, blistering, or a rash that looks like a sunburn in an area that was previously treated with radiation. The most common side effects of AXTLE when given alone are: • tiredness • nausea • loss of appetite The most common side effects of AXTLE when given with cisplatin are: • vomiting • low white blood cell counts (neutropenia) • swelling or sores in your mouth or sore throat • low platelet counts (thrombocytopenia) • constipation • low red blood cell counts (anemia) AXTLE may cause fertility problems in males. This may affect your ability to father a child. It is not known if these effects are reversible. Talk to your healthcare provider if this is a concern for you. Your healthcare provider will do blood tests to check for side effects during treatment with AXTLE. Your healthcare provider may change your dose of AXTLE, delay treatment, or stop treatment if you have certain side effects. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Reference ID: 5488378 AVYXA These are not all the side effects of AXTLE. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of AXTLE. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about AXTLE that is written for health professionals. What are the ingredients in AXTLE? Active ingredient: pemetrexed Inactive ingredients: mannitol. Hydrochloric acid may have been added to adjust pH. Manufactured for: Avyxa Pharma, LLC New Jersey 07054, USA Made in India For more information, call 1-888-520-0954. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: December 2024 Reference ID: 5488378
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2025-02-12T15:47:26.535434
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AXTLE safely and effectively. See full prescribing information for AXTLE. AXTLETM (pemetrexed) for Injection, for intravenous use Initial U.S. Approval: 2004 ------------------------------INDICATIONS AND USAGE---------------------------­ AXTLE is a folate analog metabolic inhibitor indicated: • in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. (1.1) • as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.1) • as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. (1.1) Limitations of Use: AXTLE is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. (1.1) • initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. (1.2) -----------------------DOSAGE AND ADMINISTRATION ------------------------­ • The recommended dose of AXTLE, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. (2.1, 2.2,) • Initiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning 7 days prior to the first dose of AXTLE and continue until 21 days after the last dose of AXTLE. (2.4) • Administer vitamin B12, 1 mg intramuscularly, 1 week prior to the first dose of AXTLE and every 3 cycles. (2.4) • Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after AXTLE administration. (2.4) ----------------------DOSAGE FORMS AND STRENGTHS-------------------­ For Injection: 100 mg or 500 mg pemetrexed equivalent to 118.3 mg or 591.5 mg pemetrexed dipotassium as lyophilized powder in single-dose vial (3) -------------------------------CONTRAINDICATIONS--------------------------------­ History of severe hypersensitivity reaction to pemetrexed. (4) ------------------------WARNINGS AND PRECAUTIONS ------------------------­ • Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer AXTLE when the absolute neutrophil count is less than 1500 cells/mm3 and platelets are less than 100,000 cells/mm3. Initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of AXTLE. (2.4, 5.1) • Renal Failure: Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min. (2.3, 5.2) • Bullous and Exfoliative Skin Toxicity: Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. (5.3) • Interstitial Pneumonitis: Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed. (5.4) • Radiation Recall: Can occur in patients who received radiation weeks to years previously; permanently discontinue for signs of radiation recall. (5.5) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (5.7, 8.1, 8.3) -------------------------------ADVERSE REACTIONS ------------------------------­ • The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent are fatigue, nausea, and anorexia. (6.1) • The most common adverse reactions (incidence ≥20%) of pemetrexed when administered with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Avyxa Pharma, LLC at 1-888-520-0954 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS -------------------------------­ Ibuprofen increased risk of pemetrexed toxicity in patients with mild to moderate renal impairment. Modify the ibuprofen dosage as recommended for patients with a creatinine clearance between 45 mL/min and 79 mL/min. (2.5, 5.6, 7) ------------------------ USE IN SPECIFIC POPULATIONS ----------------------­ Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 12/2024 Reference ID: 5488378 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC) 1.2 Mesothelioma 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage for Non-Squamous NSCLC 2.2 Recommended Dosage for Mesothelioma 2.3 Renal Impairment 2.4 Premedication and Concomitant Medications to Mitigate Toxicity 2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving AXTLE 2.6 Dosage Modifications for Adverse Reactions 2.7 Preparation for Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation 5.2 Renal Failure 5.3 Bullous and Exfoliative Skin Toxicity 5.4 Interstitial Pneumonitis 5.5 Radiation Recall 5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment 5.7 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Patients with Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Non-squamous NSCLC 14.2 Mesothelioma 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5488378 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC) AXTLE is indicated for: • in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. • as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. • as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. Limitations of Use: AXTLE is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies (14.1)]. 1.2 Mesothelioma AXTLE is indicated, in combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage for Non-Squamous NSCLC • The recommended dose of AXTLE when administered with cisplatin for initial treatment of locally advanced or metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes administered prior to cisplatin on Day 1 of each 21­ day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity. • The recommended dose of AXTLE for maintenance treatment of non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity after four cycles of platinum-based first-line chemotherapy. • The recommended dose of AXTLE for treatment of recurrent non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. 2.2 Recommended Dosage for Mesothelioma • The recommended dose of AXTLE, when administered with cisplatin, in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. 2.3 Renal Impairment • AXTLE dosing recommendations are provided for patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater [see Dosage and Reference ID: 5488378 Administration (2.1, 2.2)]. There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min [see Use in Specific Populations (8.6)]. 2.4 Premedication and Concomitant Medications to Mitigate Toxicity Vitamin Supplementation • Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 7 days before the first dose of AXTLE and continuing until 21 days after the last dose of AXTLE [see Warnings and Precautions (5.1)]. • Administer vitamin B12, 1 mg intramuscularly, 1 week prior to the first dose of AXTLE and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with AXTLE [see Warnings and Precautions (5.1)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Corticosteroids • Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each AXTLE administration. 2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving AXTLE In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen as follows [see Warnings and Precautions (5.6), Drug Interactions (7) and Clinical Pharmacology (12.3)]: • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of AXTLE. • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. 2.6 Dosage Modifications for Adverse Reactions Obtain complete blood count on Days 1, 8, and 15 of each cycle. Assess creatinine clearance prior to each cycle. Do not administer AXTLE if the creatinine clearance is less than 45 mL/min. Delay initiation of the next cycle of AXTLE until: • recovery of non-hematologic toxicity to Grade 0-2, • absolute neutrophil count (ANC) is 1500 cells/mm3 or higher, and • platelet count is 100,000 cells/mm3 or higher. Upon recovery, modify the dosage of AXTLE in the next cycle as specified in Table 1. For dosing modifications for cisplatin, refer to the prescribing information. Table 1: Recommended Dosage Modifications for Adverse Reactionsa Toxicity in Most Recent Treatment Cycle AXTLE Dose Modification for Next Cycle Myelosuppressive toxicity [see Warnings and Precautions (5.1)] ANC less than 500/mm³ and platelets greater than or equal to 50,000/mm³ OR Platelet count less than 50,000/mm3 without bleeding. 75% of previous dose Platelet count less than 50,000/mm3 with bleeding 50% of previous dose Reference ID: 5488378 Recurrent Grade 3 or 4 myelosuppression after 2 dose reductions Discontinue Non-hematologic toxicity Any Grade 3 or 4 toxicities EXCEPT mucositis or neurologic toxicity OR Diarrhea requiring hospitalization 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose Renal toxicity [see Warnings and Precautions (5.2)] Withhold until creatinine clearance is 45 mL/min or greater Grade 3 or 4 neurologic toxicity Permanently discontinue Recurrent Grade 3 or 4 non-hematologic toxicity after 2 dose reductions Permanently discontinue Severe and life-threatening Skin Toxicity [see Warnings and Precautions (5.3)] Permanently discontinue Interstitial Pneumonitis [see Warnings and Precautions (5.4)] Permanently discontinue a National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2) 2.7 Preparation for Administration • AXTLE is a hazardous drug. Follow applicable special handling and disposal procedures.1 • Calculate the dose of AXTLE and determine the number of vials needed. • Reconstitute AXTLE to achieve a concentration of 25 mg/mL as follows: • Reconstitute each 100-mg vial with 4.2 mL of 5% Dextrose Injection, USP (preservative-free) • Reconstitute each 500-mg vial with 20 mL of 5% Dextrose Injection, USP (preservative-free) • Do not use calcium-containing solutions for reconstitution. • Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow. FURTHER DILUTION IS REQUIRED prior to administration. • Store reconstituted, preservative-free product under refrigerated conditions [2-8°C (36­ 46°F)] for no longer than 24 hours from the time of reconstitution. Discard vial after 24 hours. • Inspect reconstituted product visually for particulate matter and discoloration prior to further dilution. If particulate matter is observed, discard vial. • Withdraw the calculated dose of AXTLE from the vial(s) and discard vial with any unused portion. • Further dilute AXTLE with 5% Dextrose Injection, USP to achieve a total volume of 100 mL for intravenous infusion. • Store diluted, reconstituted product under refrigerated conditions [2-8°C (36-46°F)] for no more than 24 hours from the time of reconstitution. Discard after 24 hours. 3 DOSAGE FORMS AND STRENGTHS For injection: 100 mg or 500 mg pemetrexed equivalent to 118.3 mg or 591.5 mg pemetrexed Reference ID: 5488378 dipotassium as a sterile preservative free white to light-yellow or green-yellow lyophilized powder in single-dose vials for reconstitution. 4 CONTRAINDICATIONS AXTLE is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse Reactions (6.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation AXTLE can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation. In Study JMCH, incidences of Grade 3-4 neutropenia (38% versus 23%), thrombocytopenia (9% versus 5%), febrile neutropenia (9% versus 0.6%), and neutropenic infection (6% versus 0) were higher in patients who received pemetrexed plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout pemetrexed plus cisplatin treatment. Initiate supplementation with oral folic acid and intramuscular vitamin B12 prior to the first dose of AXTLE; continue vitamin supplementation during treatment and for 21 days after the last dose of AXTLE to reduce the severity of hematologic and gastrointestinal toxicity of AXTLE [see Dosage and Administration (2.4)]. Obtain a complete blood count at the beginning of each cycle. Do not administer AXTLE until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce AXTLE in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles [see Dosage and Administration (2.6)]. In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the pemetrexed arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm [see Adverse Reactions (6.1)]. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%. 5.2 Renal Failure AXTLE can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which patients received pemetrexed with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received pemetrexed as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI [see Adverse Reactions (6.1)]. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with AXTLE. Withhold AXTLE in patients with a creatinine clearance of less than 45 mL/minute [see Dosage and Administration (2.3)]. Reference ID: 5488378 5.3 Bullous and Exfoliative Skin Toxicity Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/Toxic epidermal necrolysis can occur with AXTLE. Permanently discontinue AXTLE for severe and life-threatening bullous, blistering or exfoliating skin toxicity. 5.4 Interstitial Pneumonitis Serious interstitial pneumonitis, including fatal cases, can occur with AXTLE treatment. Withhold AXTLE for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue AXTLE. 5.5 Radiation Recall Radiation recall can occur with AXTLE in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue AXTLE for signs of radiation recall. 5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment Exposure to pemetrexed is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of AXTLE. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of AXTLE. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for pemetrexed adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity [see Dosage and Administration (2.5), Drug Interactions (7), and Clinical Pharmacology (12.3)]. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, AXTLE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with AXTLE and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with AXTLE and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Warnings and Precautions (5.1)] • Renal failure [see Warnings and Precautions (5.2)] • Bullous and exfoliative skin toxicity [see Warning and Precautions (5.3)] • Interstitial pneumonitis [see Warnings and Precautions (5.4)] • Radiation recall [see Warnings and Precautions (5.5)] Reference ID: 5488378 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. Non-Squamous NSCLC Initial Treatment in Combination with Cisplatin The safety of pemetrexed was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC. Patients received either pemetrexed 500 mg/m2 intravenously and cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle (n=839) or gemcitabine 1250 mg/m2 intravenously on Days 1 and 8 and cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle (n=830). All patients were fully supplemented with folic acid and vitamin B12. Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of 2 or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed plus cisplatin in 839 patients in Study JMDB. Median age was 61 years (range 26-83 years); 70% of patients were men; 78% were White,16% were Asian, 2.9% were Hispanic or Latino, 2.1% were Black or African American, and <1% were other ethnicities; 36% had an ECOG PS 0. Patients received a median of 5 cycles of pemetrexed. Table 2 provides the frequency and severity of adverse reactions that occurred in ≥5% of 839 patients receiving pemetrexed in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in Table 2. Table 2: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDB Adverse Reactiona Pemetrexed/Cisplatin (N=839) Gemcitabine/Cisplatin (N=830) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All adverse reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 Thrombocytopenia 10 4 27 13 Renal Reference ID: 5488378 Adverse Reactiona Pemetrexed/Cisplatin (N=839) Gemcitabine/Cisplatin (N=830) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Elevated creatinine 10 1 7 1 Clinical Constitutional symptoms Fatigue 43 7 45 5 Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/pharyngitis 14 1 12 0 Diarrhea 12 1 13 2 Dyspepsia/heartburn 5 0 6 0 Neurology Sensory neuropathy 9 0 12 1 Taste disturbance 8 0 9 0 Dermatology/Skin Alopecia 12 0 21 1 Rash/Desquamation 7 0 8 1 a NCI CTCAE version 2.0. The following additional adverse reactions of pemetrexed were observed. Incidence 1% to <5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal — renal failure Eye Disorder — conjunctivitis Incidence <1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy Maintenance Treatment Following First-line Non-Pemetrexed Containing Platinum-Based Chemotherapy In Study JMEN, the safety of pemetrexed was evaluated in a randomized (2:1), placebo- controlled, multicenter trial conducted in patients with non-progressive locally advanced or metastatic NSCLC following four cycles of a first-line, platinum-based chemotherapy regimen. Patients received either pemetrexed 500 mg/m2 or matching placebo intravenously every 21 days until disease progression or unacceptable toxicity. Patients in both study arms were fully supplemented with folic acid and vitamin B12. Study JMEN excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine Reference ID: 5488378 clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti- inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed in 438 patients in Study JMEN. Median age was 61 years (range 26-83 years), 73% of patients were men; 65% were White, 31% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 39% had an ECOG PS 0. Patients received a median of 5 cycles of pemetrexed and a relative dose intensity of pemetrexed of 96%. Approximately half the patients (48%) completed at least six, 21-day cycles and 23% completed ten or more 21-day cycles of pemetrexed. Table 3 provides the frequency and severity of adverse reactions reported in ≥5% of the 438 pemetrexed-treated patients in Study JMEN. Table 3: Adverse Reactions Occurring in ≥5% Patients Receiving Pemetrexed in Study JMEN Adverse Reactiona Pemetrexed (N=438) Placebo (N=218) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All adverse reactions 66 16 37 4 Laboratory Hematologic Anemia 15 3 6 1 Neutropenia 6 3 0 0 Hepatic Increased ALT 10 0 4 0 Increased AST 8 0 4 0 Clinical Constitutional symptoms Fatigue 25 5 11 1 Gastrointestinal Nausea 19 1 6 1 Anorexia 19 2 5 0 Vomiting 9 0 1 0 Mucositis/stomatitis 7 1 2 0 Diarrhea 5 1 3 0 Infection 5 2 2 0 Neurology Sensory neuropathy 9 1 4 0 Dermatology/Skin Rash/desquamation 10 0 3 0 a NCI CTCAE version 3.0 The requirement for transfusions (9.5% versus 3.2%), primarily red blood cell transfusions, and for erythropoiesis stimulating agents (5.9% versus 1.8%) were higher in the pemetrexed arm compared to the placebo arm. The following additional adverse reactions were observed in patients who received pemetrexed. Reference ID: 5488378 Incidence 1% to <5% Dermatology/Skin — alopecia, pruritis/itching Gastrointestinal — constipation General Disorders — edema, fever Hematologic — thrombocytopenia Eye Disorder — ocular surface disease (including conjunctivitis), increased lacrimation Incidence <1% Cardiovascular — supraventricular arrhythmia Dermatology/Skin — erythema multiforme General Disorders — febrile neutropenia, allergic reaction/hypersensitivity Neurology — motor neuropathy Renal — renal failure Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy The safety of pemetrexed was evaluated in PARAMOUNT, a randomized (2:1), placebo- controlled study conducted in patients with non-squamous NSCLC with non-progressive (stable or responding disease) locally advanced or metastatic NSCLC following four cycles of pemetrexed in combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive pemetrexed 500 mg/m2 or matching placebo intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Patients in both study arms received folic acid and vitamin B12 supplementation. PARAMOUNT excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti- inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed in 333 patients in PARAMOUNT. Median age was 61 years (range 32 to 83 years); 58% of patients were men; 94% were White, 4.8% were Asian, and <1% were Black or African American; 36% had an ECOG PS 0. The median number of maintenance cycles was 4 for pemetrexed and placebo arms. Dose reductions for adverse reactions occurred in 3.3% of patients in the pemetrexed arm and 0.6% in the placebo arm. Dose delays for adverse reactions occurred in 22% of patients in the pemetrexed arm and 16% in the placebo arm. Table 4 provides the frequency and severity of adverse reactions reported in ≥5% of the 333 pemetrexed-treated patients in PARAMOUNT. Table 4: Adverse Reactions Occurring in ≥5% of Patients Receiving Pemetrexed in PARAMOUNT Adverse Reactiona Pemetrexed (N=333) Placebo (N=167) All Grades (%) Grade 3-4 (%) All Grades (%) Grades 3-4 (%) All adverse reactions 53 17 34 4.8 Laboratory Hematologic Anemia 15 4.8 4.8 0.6 Reference ID: 5488378 Neutropenia 9 3.9 0.6 0 Clinical Constitutional symptoms Fatigue 18 4.5 11 0.6 Gastrointestinal Nausea 12 0.3 2.4 0 Vomiting 6 0 1.8 0 Mucositis/stomatitis 5 0.3 2.4 0 General disorders Edema 5 0 3.6 0 a NCI CTCAE version 3.0 The requirement for red blood cell (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0%) were higher in the pemetrexed arm compared to the placebo arm. The following additional Grade 3 or 4 adverse reactions were observed more frequently in the pemetrexed arm. Incidence 1% to <5% Blood/Bone Marrow — thrombocytopenia General Disorders — febrile neutropenia Incidence <1% Cardiovascular — ventricular tachycardia, syncope General Disorders — pain Gastrointestinal — gastrointestinal obstruction Neurologic — depression Renal — renal failure Vascular — pulmonary embolism Treatment of Recurrent Disease After Prior Chemotherapy The safety of pemetrexed was evaluated in Study JMEI, a randomized (1:1), open-label, active- controlled trial conducted in patients who had progressed following platinum-based chemotherapy. Patients received pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 intravenously on Day 1 of each 21-day cycle. All patients on the pemetrexed arm received folic acid and vitamin B12 supplementation. Study JMEI excluded patients with an ECOG PS of 3 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to discontinue aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed in 265 patients in Study JMEI. Median age was 58 years (range 22 to 87 years); 73% of patients were men; 70% were White, 24% were Asian, 2.6% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 19% had an ECOG PS 0. Reference ID: 5488378 Table 5 provides the frequency and severity of adverse reactions reported in ≥5% of the 265 pemetrexed-treated patients in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the Table 5 below. Table 5: Adverse Reactions Occurring in ≥5% of Fully Supplemented Patients Receiving Pemetrexed in Study JMEI Adverse Reactiona Pemetrexed (N=265) Docetaxel (N=276) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Laboratory Hematologic Anemia 19 4 22 4 Neutropenia 11 5 45 40 Thrombocytopenia 8 2 1 0 Hepatic Increased ALT 8 2 1 0 Increased AST 7 1 1 0 Clinical Gastrointestinal Nausea 31 3 17 2 Anorexia 22 2 24 3 Vomiting 16 2 12 1 Stomatitis/pharyngitis 15 1 17 1 Diarrhea 13 0 24 3 Constipation 6 0 4 0 Constitutional symptoms Fatigue 34 5 36 5 Fever 8 0 8 0 Dermatology/Skin Rash/desquamation 14 0 6 0 Pruritus 7 0 2 0 Alopecia 6 1 38 2 a NCI CTCAE version 2.0. The following additional adverse reactions were observed in patients assigned to receive pemetrexed. Incidence 1% to <5% Body as a Whole — abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection Dermatology/Skin — erythema multiforme Neurology — motor neuropathy, sensory neuropathy Incidence <1% Cardiovascular — supraventricular arrhythmias Renal — renal failure Reference ID: 5488378 Mesothelioma The safety of pemetrexed was evaluated in Study JMCH, a randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy for MPM. Patients received pemetrexed 500 mg/m2 intravenously in combination with cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle or cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle administered until disease progression or unacceptable toxicity. Safety was assessed in 226 patients who received at least one dose of pemetrexed in combination with cisplatin and 222 patients who received at least one dose of cisplatin alone. Among 226 patients who received pemetrexed in combination with cisplatin, 74% (n=168) received full supplementation with folic acid and vitamin B12 during study therapy, 14% (n=32) were never supplemented, and 12% (n=26) were partially supplemented. Study JMCH excluded patients with Karnofsky Performance Scale (KPS) of less than 70, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs were also excluded from the study. The data described below reflect exposure to pemetrexed in 168 patients that were fully supplemented with folic acid and vitamin B12. Median age was 60 years (range 19 to 85 years); 82% were men; 92% were White, 5% were Hispanic or Latino, 3.0% were Asian, and <1% were other ethnicities; 54% had KPS of 90-100. The median number of treatment cycles administered was 6 in the pemetrexed/cisplatin fully supplemented group and 2 in the pemetrexed/cisplatin never supplemented group. Patients receiving pemetrexed in the fully supplemented group had a relative dose intensity of 93% of the protocol-specified pemetrexed dose intensity. The most common adverse reaction resulting in dose delay was neutropenia. Table 6 provides the frequency and severity of adverse reactions ≥5% in the subgroup of pemetrexed-treated patients who were fully vitamin supplemented in Study JMCH. Study JMCH was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the table below. Table 6: Adverse Reactions Occurring in ≥5% of Fully Supplemented Subgroup of Patients Receiving Pemetrexed/Cisplatin in Study JMCHa Adverse Reactionb Pemetrexed /cisplatin (N=168) Cisplatin (N=163) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Laboratory Hematologic Neutropenia 56 23 13 3 Anemia 26 4 10 0 Thrombocytopenia 23 5 9 0 Renal Elevated creatinine 11 1 10 1 Decreased creatinine clearance 16 1 18 2 Clinical Eye Disorder Conjunctivitis 5 0 1 0 Reference ID: 5488378 Adverse Reactionb Pemetrexed /cisplatin (N=168) Cisplatin (N=163) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Gastrointestinal Nausea 82 12 77 6 Vomiting 57 11 50 4 Stomatitis/pharyngitis 23 3 6 0 Anorexia 20 1 14 1 Diarrhea 17 4 8 0 Constipation 12 1 7 1 Dyspepsia 5 1 1 0 Constitutional Symptoms Fatigue 48 10 42 9 Metabolism and Nutrition Dehydration 7 4 1 1 Neurology Sensory neuropathy 10 0 10 1 Taste disturbance 8 0 6 0 Dermatology/Skin Rash 16 1 5 0 Alopecia 11 0 6 0 a In Study JMCH, 226 patients received at least one dose of pemetrexed in combination with cisplatin and 222 patients received at least one dose of cisplatin. Table 6 provides the ADRs for subgroup of patients treated with pemetrexed in combination with cisplatin (168 patients) or cisplatin alone (163 patients) who received full supplementation with folic acid and vitamin B12 during study therapy. b NCI CTCAE version 2.0 The following additional adverse reactions were observed in patients receiving pemetrexed plus cisplatin: Incidence 1% to <5% Body as a Whole — febrile neutropenia, infection, pyrexia Dermatology/Skin — urticaria General Disorders — chest pain Metabolism and Nutrition — increased AST, increased ALT, increased GGT Renal — renal failure Incidence <1% Cardiovascular — arrhythmia Neurology — motor neuropathy Exploratory Subgroup Analyses based on Vitamin Supplementation Table 7 provides the results of exploratory analyses of the frequency and severity of NCI CTCAE Grade 3 or 4 adverse reactions reported in more pemetrexed-treated patients who did not receive vitamin supplementation (never supplemented) as compared with those who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in Study JMCH (fully-supplemented). Reference ID: 5488378 Table 7: Exploratory Subgroup Analysis of Selected Grade 3/4 Adverse Reactions Occurring in Patients Receiving Pemetrexed in Combination with Cisplatin with or without Full Vitamin Supplementation in Study JMCHa Grade 3-4 Adverse Reactions Fully Supplemented Patients N=168 (%) Never Supplemented Patients N=32 (%) Neutropenia 23 38 Thrombocytopenia 5 9 Vomiting 11 31 Febrile neutropenia 1 9 Infection with Grade 3/4 neutropenia 0 6 Diarrhea 4 9 a NCI CTCAE version 2.0 The following adverse reactions occurred more frequently in patients who were fully vitamin supplemented than in patients who were never supplemented: • hypertension (11% versus 3%), • chest pain (8% versus 6%), • thrombosis/embolism (6% versus 3%). Additional Experience Across Clinical Trials Sepsis, with or without neutropenia, including fatal cases: 1% Severe esophagitis, resulting in hospitalization: <1% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of pemetrexed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System — immune-mediated hemolytic anemia Gastrointestinal — colitis, pancreatitis General Disorders and Administration Site Conditions — edema Injury, poisoning, and procedural complications — radiation recall Respiratory — interstitial pneumonitis Skin — Serious and fatal bullous skin conditions, Stevens-Johnson syndrome, and toxic epidermal necrolysis 7 DRUG INTERACTIONS Effects of Ibuprofen on Pemetrexed Ibuprofen increases exposure (AUC) of pemetrexed [see Clinical Pharmacology (12.3)]. In patients with creatinine clearance between 45 mL/min and 79 mL/min: • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of AXTLE [see Dosage and Administration (2.5)]. • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. Reference ID: 5488378 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, AXTLE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on pemetrexed use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m2 [see Data]. Advise pregnant women of the potential risk to a fetus [see Use in Special Populations (8.3)]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m2. At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight). 8.2 Lactation Risk Summary There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from pemetrexed, advise women not to breastfeed during treatment with AXTLE and for one week after last dose. 8.3 Females and Males of Reproductive Potential Based on animal data, pemetrexed can cause malformations and developmental delays when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating AXTLE [see Use in Specific Populations (8.1)]. Contraception Females Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with AXTLE and for 6 months after the last dose. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with AXTLE and for 3 months after the last dose [see Nonclinical Toxicology (13.1)]. Reference ID: 5488378 Infertility Males AXTLE may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of AXTLE in pediatric patients have not been established. The safety and pharmacokinetics of pemetrexed were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors (NCT00070473 N=32 and NCT00520936 N=72). Patients in both studies received concomitant vitamin B12 and folic acid supplementation and dexamethasone. No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults. Single-dose pharmacokinetics of pemetrexed were evaluated in 22 patients age 4 to 18 years enrolled in NCT00070473 were within range of values in adults. 8.5 Geriatric Use Of the 3,946 patients enrolled in clinical studies of pemetrexed, 34% were 65 and over and 4% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials. [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)]. 8.6 Patients with Renal Impairment Pemetrexed is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to pemetrexed compared with patients with normal renal function [Warnings and Precautions (5.2, 5.6) and Clinical Pharmacology (12.3)]. No dose is recommended for patients with creatinine clearance less than 45 mL/min [see Dosage and Administration (2.3)]. 10 OVERDOSAGE No drugs are approved for the treatment of pemetrexed overdose. Based on animal studies, administration of leucovorin may mitigate the toxicities of pemetrexed overdosage. It is not known whether pemetrexed is dialyzable. 11 DESCRIPTION Pemetrexed is a folate analog metabolic inhibitor. The drug substance is pemetrexed dipotassium heptahydrate, has the chemical name L-glutamic acid, N-[4-[2-(2-amino-4,7­ dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, dipotassium salt, heptahydrate. It is a white to off-white powder having blue or green tinge with a molecular formula of C20H19K2N5O6 .7 H2O and a molecular weight of 629.49. Pemetrexed dipotassium is freely soluble in water. The reported pKaS are 3.6 and 4.5. The structural formula of pemetrexed dipotassium heptahydrate is as follows: Reference ID: 5488378 N H AXTLE is supplied as a sterile white to light-yellow or green-yellow lyophilized powder or cake for intravenous infusion available in single-dose vials. Each 100-mg or 500-mg vial of AXTLE contains 100 mg pemetrexed equivalent to 118.3 mg pemetrexed dipotassium and 106 mg mannitol or 500 mg pemetrexed equivalent to 591.5 mg pemetrexed dipotassium and 500 mg mannitol, respectively. Hydrochloric acid may have been added to adjust the pH. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. 12.2 Pharmacodynamics Pemetrexed inhibited the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) and showed synergistic effects when combined with cisplatin. Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with the systemic exposure to pemetrexed and supplementation with folic acid and vitamin B12. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles. 12.3 Pharmacokinetics Absorption The pharmacokinetics of pemetrexed when pemetrexed was administered as a single agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with increase of dose. The pharmacokinetics of pemetrexed did not change over multiple treatment cycles. Distribution Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicated that pemetrexed is 81% bound to plasma proteins. Reference ID: 5488378 Elimination The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). As renal function decreases, the clearance of pemetrexed decreases and exposure (AUC) of pemetrexed increases. Metabolism Pemetrexed is not metabolized to an appreciable extent. Excretion Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. In vitro studies indicated that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that is involved in the active secretion of pemetrexed. Specific Populations Age (26 to 80 years) and sex had no clinically meaningful effect on the systemic exposure of pemetrexed based on population pharmacokinetic analyses. Racial Groups The pharmacokinetics of pemetrexed were similar in Whites and Blacks or African Americans. Insufficient data are available for other ethnic groups. Patients with Hepatic Impairment Pemetrexed has not been formally studied in patients with hepatic impairment. No effect of elevated AST, ALT, or total bilirubin on the PK of pemetrexed was observed in clinical studies. Patients with Renal Impairment Pharmacokinetic analyses of pemetrexed included 127 patients with impaired renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. Third-Space Fluid The pemetrexed plasma concentrations in patients with various solid tumors with stable, mild to moderate third-space fluid were comparable to those observed in patients without third space fluid collections. The effect of severe third space fluid on pharmacokinetics is not known. Drug Interaction Studies Drugs Inhibiting OAT3 Transporter Ibuprofen, an OAT3 inhibitor, administered at 400 mg four times a day decreased the clearance of pemetrexed and increased its exposure (AUC) by approximately 20% in patients with normal renal function (creatinine clearance >80 mL/min). In Vitro Studies Reference ID: 5488378 Pemetrexed is a substrate for OAT3. Ibuprofen, an OAT3 inhibitor inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iµ]/IC50 ratio of 0.38. In vitro data predict that at clinically relevant concentrations, other NSAIDs (naproxen, diclofenac, celecoxib) would not inhibit the uptake of pemetrexed by OAT3 and would not increase the AUC of pemetrexed to a clinically significant extent. [see Drug Interactions (7)]. Pemetrexed is a substrate for OAT4. In vitro, ibuprofen and other NSAIDs (naproxen, diclofenac, celecoxib) are not inhibitors of OAT4 at clinically relevant concentrations. Aspirin Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. Cisplatin Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed. Vitamins Neither folic acid nor vitamin B12 affect the pharmacokinetics of pemetrexed. Drugs Metabolized by Cytochrome P450 Enzymes In vitro studies suggest that pemetrexed does not inhibit the clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in an in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, Chinese Hamster Ovary cell assay). Pemetrexed administered intraperitoneally at doses of ≥0.1 mg/kg/day to male mice (approximately 0.0006 times the recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy. 14 CLINICAL STUDIES 14.1 Non-Squamous NSCLC Initial Treatment in Combination with Cisplatin The efficacy of pemetrexed was evaluated in Study JMDB (NCT00087711), a multi-center, randomized (1:1), open-label study conducted in 1725 chemotherapy-naive patients with Stage IIIb/IV NSCLC. Patients were randomized to receive pemetrexed with cisplatin or gemcitabine with cisplatin. Randomization was stratified by Eastern Cooperative Oncology Group Performance Status (ECOG PS 0 versus 1), gender, disease stage, basis for pathological diagnosis (histopathological/cytopathological), history of brain metastases, and investigative center. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle. Cisplatin was administered intravenously at a dose of 75 mg/m2 approximately 30 minutes after pemetrexed administration on Day 1 of each cycle, gemcitabine was administered at a dose of 1250 mg/m2 on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m2 approximately 30 minutes after administration of Reference ID: 5488378 gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles; patients in both arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.4)]. The primary efficacy outcome measure was overall survival. A total of 1725 patients were enrolled with 862 patients randomized to pemetrexed in combination with cisplatin and 863 patients to gemcitabine in combination with cisplatin. The median age was 61 years (range 26-83 years), 70% were male, 78% were White, 17% were Asian, 2.9% were Hispanic or Latino, and 2.1% were Black or African American, and <1% were other ethnicities. Among patients for whom ECOG PS (n=1722) and smoking history (n=1516) were collected, 65% had an ECOG PS of 1, 36% had an ECOG PS of 0, and 84% were smokers. For tumor characteristics, 73% had non-squamous NSCLC and 27% had squamous NSCLC; 76% had Stage IV disease. Among 1252 patients with non-squamous NSCLC histology, 68% had a diagnosis of adenocarcinoma, 12% had large cell histology and 20% had other histologic subtypes. Efficacy results in Study JMDB are presented in Table 8 and Figure 1. Table 8: Efficacy Results in Study JMDB Efficacy Parameter Pemetrexed plus Cisplatin (N=862) Gemcitabine plus Cisplatin (N=863) Overall Survival Median (months) (95% CI) 10.3 (9.8-11.2) 10.3 (9.6-10.9) Hazard ratio (HR)a,b (95% CI) 0.94 (0.84-1.05) Progression-Free Survival Median (months) (95% CI) 4.8 (4.6-5.3) 5.1 (4.6-5.5) Hazard ratio (HR)a,b (95% CI) 1.04 (0.94-1.15) Overall Response Rate (95% CI) 27.1% (24.2-30.1) 24.7% (21.8-27.6) a Unadjusted for multiple comparisons. b Adjusted for gender, stage, basis of diagnosis, and performance status. Reference ID: 5488378 1.0 0.9 0.8 ~ 0.7 :.a (V 0.6 ..0 0 ,._ a. 0.5 7ii > 0.4 ·s: ,._ ::, 0.3 (/) 0.2 0.1 0.0 0 - Pemetrexed + Clsplalln (PC) ••• •• • Gemcltablne + Clsplalln (GC) 3 6 9 Patients at Risk PC GC 862 863 737 731 598 590 458 456 12 15 18 Survival Time (months) 341 327 235 209 146 139 21 88 78 24 45 34 27 10 14 30 0 0 Figure 1: Kaplan-Meier Curves for Overall Survival in Study JMDB In pre-specified analyses assessing the impact of NSCLC histology on overall survival, clinically relevant differences in survival according to histology were observed. These subgroup analyses are shown in Table 9 and Figures 2 and 3. This difference in treatment effect for pemetrexed based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in Studies JMEN and JMEI. Table 9: Overall Survival in NSCLC Histologic Subgroups in Study JMDB Histologic Subgroups Pemetrexed plus Cisplatin (N=862) Gemcitabine plus Cisplatin (N=863) Non-squamous NSCLC (N=1252) Median (months) (95% CI) 11.0 (10.1-12.5) 10.1 (9.3-10.9) HRa,b (95% CI) 0.84 (0.74-0.96) Adenocarcinoma (N=847) Median (months) (95% CI) 12.6 (10.7-13.6) 10.9 (10.2-11.9) HRa,b (95% CI) 0.84 (0.71-0.99) Large Cell (N=153) Median (months) (95% CI) 10.4 (8.6-14.1) 6.7 (5.5-9.0) HRa,b (95% CI) 0.67 (0.48-0.96) Non-squamous, not otherwise specified (N=252) Reference ID: 5488378 ~ .c I'll .c e Q. iii > ~ ::::, fl) 1.0 0.8 0.6 0.4 0.2 0.0 0 - Pemetreced + Clsplatln (PC) ------ Gemcltablne+ Clsplatln (GC) 3 6 9 Patients at Risk PC GC 618 634 533 542 437 435 341 339 12 15 18 Survlval Time (months) 264 240 188 151 118 101 I I 21 72 55 .. ~· - - ............ w ... • ...................... . 24 37 26 27 8 10 30 0 0 Median (months) (95% CI) 8.6 (6.8-10.2) 9.2 (8.1-10.6) HRa,b (95% CI) 1.08 (0.81-1.45) Squamous Cell (N=473) Median (months) (95% CI) 9.4 (8.4-10.2) 10.8 (9.5-12.1) HRa,b (95% CI) 1.23 (1.00-1.51) a Unadjusted for multiple comparisons. b Adjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological). Figure 2: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMDB Reference ID: 5488378 1.0 0.8 0.6 0.4 0.2 - Peme1rexed + Clsplalln (PC) 0.0 • • • • • • Gemchablne + Clsplatln (GC) 0 3 6 9 Patients at Risk PC GC 244 229 204 189 161 155 117 117 12 1S 18 survival Time (months) 77 87 47 58 28 38 21 16 23 24 8 8 27 2 4 30 0 0 Figure 3: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMDB Maintenance Treatment Following First-line Non-Pemetrexed Containing Platinum-Based Chemotherapy The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was evaluated in Study JMEN (NCT00102804), a multicenter, randomized (2:1), double-blind, placebo-controlled study conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously every 21 days or placebo until disease progression or intolerable toxicity. Patients in both study arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.4)]. Randomization was carried out using a minimization approach [Pocock and Simon (1975)] using the following factors: gender, ECOG PS (0 versus 1), response to prior chemotherapy (complete or partial response versus stable disease), history of brain metastases (yes versus no), non-platinum component of induction therapy (docetaxel versus gemcitabine versus paclitaxel), and disease stage (IIIb versus IV). The major efficacy outcome measures were progression-free survival based on assessment by independent review and overall survival; both were measured from the date of randomization in Study JMEN. A total of 663 patients were enrolled with 441 patients randomized to pemetrexed and 222 patients randomized to placebo. The median age was 61 years (range 26-83 years); 73% were male; 65% were White, 32% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 60% had an ECOG PS of 1; and 73% were current or former smokers. Median time from initiation of platinum-based chemotherapy to randomization was 3.3 months (range 1.6 to 5.1 months) and 49% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 81% had Stage IV disease, 73% had non-squamous NSCLC and 27% had squamous NSCLC. Among the 481 patients with Reference ID: 5488378 1.0 0.9 0.8 ~ 0.7 .c I'll 0.6 .c 0 ... c.. 0.5 "ii _;:: 0.4 > ... ::J CJ) 0.3 0.2 0.1 0.0 0 ·­ - Pemetrexed •····· Placebo 3 6 Patients at Risk .. • . '• .. 9 ... .. , .. ·• ..... .. 12 Pemetrexed 441 396 340 27 4 221 Placebo 222 200 160 119 93 •., ..... ·--........ 15 ···-..... 18 .......... ... 21 ......... ....................................... 24 27 30 Survival Time (months) 179 76 141 60 97 40 63 29 45 20 29 13 • ............................ . 33 19 6 36 11 4 39 2 0 42 0 0 non-squamous NSCLC, 68% had adenocarcinoma, 4% had large cell, and 28% had other histologies. Efficacy results are presented in Table 10 and Figure 4. Table 10: Efficacy Results in Study JMEN Efficacy Parameter Pemetrexed Placebo Overall survival N=441 N=222 Median (months) (95% CI) 13.4 (11.9-15.9) 10.6 (8.7-12.0) Hazard ratioa (95% CI) 0.79 (0.65-0.95) p-value p=0.012 Progression-free survival per independent review N=387 N=194 Median (months) (95% CI) 4.0 (3.1-4.4) 2.0 (1.5-2.8) Hazard ratioa (95% CI) 0.60 (0.49-0.73) p-value p<0.00001 a Hazard ratios are adjusted for multiplicity but not for stratification variables. Figure 4: Kaplan-Meier Curves for Overall Survival in Study JMEN The results of pre-specified subgroup analyses by NSCLC histology are presented in Table 11 and Figures 5 and 6. Reference ID: 5488378 I I I I I I I I I I I I Table 11: Efficacy Results in Study JMEN by Histologic Subgroup Efficacy Parameter Overall Survival Progression-Free Survival Per Independent Review Pemetrexed (N=441) Placebo (N=222) Pemetrexed (N=387) Placebo (N=194) Non-squamous NSCLC (n=481) Median (months) 15.5 10.3 4.4 1.8 HRa (95% CI) 0.70 (0.56-0.88) 0.47 (0.37-0.60) Adenocarcinoma (n=328) Median (months 16.8 11.5 4.6 2.7 HRa (95% CI) 0.73 (0.56-0.96) 0.51 (0.38-0.68) Large cell carcinoma (n=20) Median (months) 8.4 7.9 4.5 1.5 HRa (95% CI) 0.98 (0.36-2.65) 0.40 (0.12-1.29) Otherb (n=133) Median (months) 11.3 7.7 4.1 1.6 HRa (95% CI) 0.61 (0.40-0.94) 0.44 (0.28-0.68) Squamous cell NSCLC (n=182) Median (months) 9.9 10.8 2.4 2.5 HRa (95% CI) 1.07 (0.77-1.50) 1.03 (0.71-1.49) a Hazard ratios are not adjusted for multiplicity b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma. Reference ID: 5488378 ? :0 <'G .0 e 0.. 1.0 .. 0.8 0.6 ·-•· .... •-...... .. ••· ... .. .. •· .. '••··. • ............ _. iii .i:: > .... 0.4 -.. , ::s (/) 0.2 0.0 0 - Pemetrexed •••••• Placebo 3 6 Patients at Risk Pemetrexed 325 302 265 Placebo 156 140 112 0.8 .. '• ., 9 216 80 ~ :0 • ·-· ... i! 0.6 e 0.. iii .i:: 04 2: • ::, (/) 0.2 0.0 0 - Pemetrexed •••••• Placebo 3 6 Patients at Risk Pemetrexed 116 94 75 Placebo 66 60 48 •, .. ... 9 58 39 12 178 63 ·, 12 43 30 •••··· .... ----.. ·---.. ---.. -.. ··-····----·--':.., •.• , ....................... . 15 18 21 24 27 30 33 36 Survival Time (months) 141 117 82 51 38 25 15 9 52 42 28 20 11 7 4 3 15 18 21 24 27 30 33 36 Survival Time (months) 38 24 15 12 7 4 4 2 24 18 12 9 9 6 2 39 42 2 0 0 0 39 42 0 0 0 0 Figure 5: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMEN Figure 6: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMEN Reference ID: 5488378 I I I Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was also evaluated in PARAMOUNT (NCT00789373), a multi-center, randomized (2:1), double-blind, placebo-controlled study conducted in patients with Stage IIIb/IV non-squamous NSCLC who had completed four cycles of pemetrexed in combination with cisplatin and achieved a complete response (CR) or partial response (PR) or stable disease (SD). Patients were required to have an ECOG PS of 0 or 1. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously every 21 days or placebo until disease progression. Randomization was stratified by response to pemetrexed in combination with cisplatin induction therapy (CR or PR versus SD), disease stage (IIIb versus IV), and ECOG PS (0 versus 1). Patients in both arms received folic acid, vitamin B12, and dexamethasone. The main efficacy outcome measure was investigator-assessed progression-free survival (PFS) and an additional efficacy outcome measure was overall survival (OS); PFS and OS were measured from the time of randomization. A total of 539 patients were enrolled with 359 patients randomized to pemetrexed and 180 patients randomized to placebo. The median age was 61 years (range 32 to 83 years); 58% were male; 95% were White, 4.5% were Asian, and <1% were Black or African American; 67% had an ECOG PS of 1; 78% were current or former smokers; and 43% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 91% had Stage IV disease, 87% had adenocarcinoma, 7% had large cell, and 6% had other histologies. Efficacy results for PARAMOUNT are presented in Table 12 and Figure 7. Table 12: Efficacy Results in PARAMOUNT Efficacy Parameter Pemetrexed (N=359) Placebo (N=180) Overall survival Median (months) (95% CI) 13.9 (12.8-16.0) 11.0 (10.0-12.5) Hazard ratio (HR)a (95% CI) 0.78 (0.64-0.96) p-value p=0.02 Progression-free survivalb Median (months) (95% CI) 4.1 (3.2-4.6) 2.8 (2.6-3.1) Hazard ratio (HR)a (95% CI) 0.62 (0.49-0.79) p-value p<0.0001 a Hazard ratios are adjusted for multiplicity but not for stratification variables. b Based on investigator’s assessment. Reference ID: 5488378 1.0 0.9 0.8 -~ 0.7 ·•. ··-. :c cu 0.6 ..0 0 ... a. 0.5 cu . 2: 0.4 C: ::s 0.3 en 0.2 0.1 - Pemetrexed •••••• Placebo 0.0 0 3 Patients at Risk Pemetrexed 359 333 Placebo 180 169 6 272 131 .. ·-... -.... 9 •·. .. 235 103 .. ... ... 12 200 78 ··--­--... ·---.. ... -·-••• ·--. ·-... • . . -... -..... -- 15 18 21 Survival Time (months) 166 65 138 49 105 35 24 79 23 --...... .. .............. .. , 27 43 12 30 15 8 33 2 3 36 0 0 Figure 7: Kaplan-Meier Curves for Overall Survival in PARAMOUNT Treatment of Recurrent Disease After Prior Chemotherapy The efficacy of pemetrexed was evaluated in Study JMEI (NCT00004881), a multicenter, randomized (1:1), open-label study conducted in patients with Stage III or IV NSCLC that had recurred or progressed following one prior chemotherapy regimen for advanced disease. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 as a 1-hour intravenous infusion once every 21 days. Patients randomized to pemetrexed also received folic acid and vitamin B12. The study was designed to show that overall survival with pemetrexed was non-inferior to docetaxel, as the major efficacy outcome measure, and that overall survival was superior for patients randomized to pemetrexed compared to docetaxel, as a secondary outcome measure. A total of 571 patients were enrolled with 283 patients randomized to pemetrexed and 288 patients randomized to docetaxel. The median age was 58 years (range 22 to 87 years); 72% were male; 71% were White, 24% were Asian, 2.8% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 88% had an ECOG PS of 0 or 1. With regard to tumor characteristics, 75% had Stage IV disease; 53% had adenocarcinoma, 30% had squamous histology; 8% large cell; and 9% had other histologic subtypes of NSCLC. The efficacy results in the overall population and in subgroup analyses based on histologic subtype are provided in Tables 13 and 14, respectively. Study JMEI did not show an improvement in overall survival in the intent-to-treat population. In subgroup analyses, there was no evidence of a treatment effect on survival in patients with squamous NSCLC; the absence of a treatment effect in patients with NSCLC of squamous histology was also observed Studies JMDB and JMEN [see Clinical Studies (14.1)]. Reference ID: 5488378 I I I I I I I I I I Table 13: Efficacy Results in Study JMEI Efficacy Parameter Pemetrexed (N=283) Docetaxel (N=288) Overall survival Median (months) (95% CI) 8.3 (7.0-9.4) 7.9 (6.3-9.2) Hazard ratioa (95% CI) 0.99 (0.82-1.20) Progression-free survival Median (months) (95% CI) 2.9 (2.4-3.1) 2.9 (2.7-3.4) Hazard ratioa (95% CI) 0.97 (0.82-1.16) Overall response rate (95% CI) 8.5% (5.2-11.7) 8.3% (5.1-11.5) a Hazard ratios are not adjusted for multiplicity or for stratification variables. Table 14: Exploratory Efficacy Analyses by Histologic Subgroup in Study JMEI Histologic Subgroups Pemetrexed (N=283) Docetaxel (N=288) Non-squamous NSCLC (N=399) Median (months) (95% CI) 9.3 (7.8-9.7) 8.0 (6.3-9.3) HRa (95% CI) 0.89 (0.71-1.13) Adenocarcinoma (N=301) Median (months) (95% CI) 9.0 (7.6-9.6) 9.2 (7.5-11.3) HRa (95% CI) 1.09 (0.83-1.44) Large Cell (N=47) Median (months) (95% CI) 12.8 (5.8-14.0) 4.5 (2.3-9.1) HRa (95% CI) 0.38 (0.18-0.78) Otherb (N=51) Median (months) (95% CI) 9.4 (6.0-10.1) 7.9 (4.0-8.9) HRa (95% CI) 0.62 (0.32-1.23) Squamous NSCLC (N=172) Median (months) (95% CI) 6.2 (4.9-8.0) 7.4 (5.6-9.5) HRa (95% CI) 1.32 (0.93-1.86) a Hazard ratio unadjusted for multiple comparisons. b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma. Reference ID: 5488378 14.2 Mesothelioma The efficacy of pemetrexed was evaluated in Study JMCH (NCT00005636), a multicenter, randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy. Patients were randomized (n=456) to receive pemetrexed 500 mg/m2 intravenously over 10 minutes followed 30 minutes later by cisplatin 75 mg/m2 intravenously over two hours on Day 1 of each 21-day cycle or to receive cisplatin 75 mg/m2 intravenously over 2 hours on Day 1 of each 21-day cycle; treatment continued until disease progression or intolerable toxicity. The study was modified after randomization and treatment of 117 patients to require that all patients receive folic acid 350 mcg to 1000 mcg daily beginning 1 to 3 weeks prior to the first dose of pemetrexed and continuing until 1 to 3 weeks after the last dose, vitamin B12 1000 mcg intramuscularly 1 to 3 weeks prior to first dose of pemetrexed and every 9 weeks thereafter, and dexamethasone 4 mg orally, twice daily, for 3 days starting the day prior to each pemetrexed dose. Randomization was stratified by multiple baseline variables including KPS, histologic subtype (epithelial, mixed, sarcomatoid, other), and gender. The major efficacy outcome measure was overall survival and additional efficacy outcome measures were time to disease progression, overall response rate, and response duration. A total of 448 patients received at least one dose of protocol-specified therapy; 226 patients were randomized to and received at least one dose of pemetrexed plus cisplatin, and 222 patients were randomized to and received cisplatin. Among the 226 patients who received cisplatin with pemetrexed, 74% received full supplementation with folic acid and vitamin B12 during study therapy, 14% were never supplemented, and 12% were partially supplemented. Across the study population, the median age was 61 years (range: 20 to 86 years); 81% were male; 92% were White, 5% were Hispanic or Latino, 3.1% were Asian, and <1% were other ethnicities; and 54% had a baseline KPS score of 90-100% and 46% had a KPS score of 70­ 80%. With regard to tumor characteristics, 46% had Stage IV disease, 31% Stage III, 15% Stage II, and 7% Stage I disease at baseline; the histologic subtype of mesothelioma was epithelial in 68% of patients, mixed in 16%, sarcomatoid in 10% and other histologic subtypes in 6%. The baseline demographics and tumor characteristics of the subgroup of fully supplemented patients was similar to the overall study population. The efficacy results from Study JMCH are summarized in Table 15 and Figure 8. Table 15: Efficacy Results in Study JMCH Efficacy Parameter All Randomized and Treated Patients (N=448) Fully Supplemented Patients (N=331) Pemetrexed /Cisplatin (N=226) Cisplatin (N=222) Pemetrexed /Cisplatin (N=168) Cisplatin (N=163) Median overall survival (months) 12.1 9.3 13.3 10.0 (95% CI) (10.0-14.4) (7.8-10.7) (11.4-14.9) (8.4-11.9) Hazard ratioa 0.77 0.75 Log rank p-value 0.020 NAb a Hazard ratios are not adjusted for stratification variables. b Not a pre-specified analysis. Reference ID: 5488378 1.0 0.9 0.8 -~ 0.7 :5 ., 0.6 .0 e o.s 0. j -~ 0.4 ::, (/) 0.3 0.2 0.1 0.0 0 Patients at Risk Pemetrexed .. ClsplaUn 226 Clsplatln 222 - Pemetrexed + Clsplatln • ••••• Clsplatln 3 201 195 6 166 153 9 128 104 -.... ·-... _ 12 ···---. •••••••• ••••••••••.............. •,-.. -.-.. ----, ..... ...... 15 18 21 24 Survival Time (months) 84 63 50 31 32 21 17 14 8 3 27 4 30 0 0 Figure 8: Kaplan-Meier Curves for Overall Survival in Study JMCH Based upon prospectively defined criteria (modified Southwest Oncology Group methodology) the objective tumor response rate for pemetrexed plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the pemetrexed plus cisplatin arm compared to the control arm. 15 REFERENCES 1. “OSHA Hazardous Drugs.” OSHA. [https://www.osha.gov/hazardous-drugs] 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied AXTLETM, is a sterile preservative free white-to-light yellow or green-yellow lyophilized powder supplied in single-dose vials for reconstitution for intravenous infusion. NDC 83831-111-01: 100 mg single-dose vial containing pemetrexed equivalent to 118.3 mg pemetrexed dipotassium with aluminum flip-off seals with grey color button individually packaged in a carton. NDC 83831-112-01: 500 mg single-dose vial containing pemetrexed equivalent to 591.5 mg pemetrexed dipotassium with aluminum flip-off seals with red color button individually packaged in a carton. Storage and Handling Store at controlled room temperature, 20°-25°C (68°-77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. AXTLE is a hazardous drug. Follow applicable special handling and disposal procedures.1 Reference ID: 5488378 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Premedication and Concomitant Medication: Instruct patients to take folic acid as directed and to keep appointments for vitamin B12 injections to reduce the risk of treatment-related toxicity. Instruct patients of the requirement to take corticosteroids to reduce the risks of treatment- related toxicity [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)]. Myelosuppression: Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, fever, bleeding, or symptoms of anemia [see Warnings and Precautions (5.1)]. Renal Failure: Inform patients of the risks of renal failure, which may be exacerbated in patients with dehydration arising from severe vomiting or diarrhea. Instruct patients to immediately contact their healthcare provider for a decrease in urine output [see Warnings and Precautions (5.2)]. Bullous and Exfoliative Skin Disorders: Inform patients of the risks of severe and exfoliative skin disorders. Instruct patients to immediately contact their healthcare provider for development of bullous lesions or exfoliation in the skin or mucous membranes [see Warnings and Precautions (5.3)]. Interstitial Pneumonitis: Inform patients of the risks of pneumonitis. Instruct patients to immediately contact their healthcare provider for development of dyspnea or persistent cough [see Warnings and Precautions (5.4)]. Radiation Recall: Inform patients who have received prior radiation of the risks of radiation recall. Instruct patients to immediately contact their healthcare provider for development of inflammation or blisters in an area that was previously irradiated [see Warnings and Precautions (5.5)]. Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment: Advise patients with mild to moderate renal impairment of the risks associated with concomitant ibuprofen use and instruct them to avoid use of all ibuprofen containing products for 2 days before, the day of, and 2 days following administration of AXTLE [see Dosage and Administration (2.5), Warnings and Precautions (5.6), and Drug Interactions (7)]. Embryo-Fetal Toxicity: Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1,)]. Advise females of reproductive potential to use effective contraception during treatment with AXTLE and for 6 months after the last dose. Advise females to inform their prescriber of a known or suspected pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with AXTLE and for 3 months after the last dose [see Warnings and Precautions (5.7) and Use in Specific Populations (8.3)]. Lactation: Advise women not to breastfeed during treatment with AXTLE and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Reference ID: 5488378 AVYXA Manufactured for: Avyxa Pharma, LLC New Jersey 07054, USA Made in India Reference ID: 5488378 PATIENT INFORMATION AXTLETM (AXE-tul) (pemetrexed) for Injection for intravenous use What is AXTLE? AXTLE is a prescription medicine used to treat: • a kind of lung cancer called non-squamous non-small cell lung cancer (NSCLC). AXTLE is used: o as the first treatment in combination with cisplatin when your lung cancer has spread (advanced NSCLC). o alone as maintenance treatment after you have received 4 cycles of chemotherapy that contains platinum for first treatment of your advanced NSCLC and your cancer has not progressed. • alone when your lung cancer has returned or spread after prior chemotherapy. AXTLE is not for use for the treatment of people with squamous cell non-small cell lung cancer. • a kind of cancer called malignant pleural mesothelioma. This cancer affects the lining of the lungs and chest wall. AXTLE is used in combination with cisplatin as the first treatment for malignant pleural mesothelioma that cannot be removed by surgery or you are not able to have surgery. AXTLE has not been shown to be safe and effective in children. Do not take AXTLE: if you have had a severe allergic reaction to any medicine that contains pemetrexed. Before taking AXTLE, tell your healthcare provider about all of your medical conditions, including if you: • have kidney problems. • have had radiation therapy. • are pregnant or plan to become pregnant. AXTLE can harm your unbornbaby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with AXTLE. You should use effective birth control (contraception) during treatment with AXTLE and for 6 months after the last dose. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with AXTLE. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with AXTLE and for 3 months after the last dose. • are breastfeeding or plan to breastfeed. It is not known if AXTLE passes into breast milk. Do not breastfeed during treatment with AXTLE and for 1 week after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Tell your healthcare provider if you have kidney problems and take a medicine that contains ibuprofen. You should avoid taking ibuprofen for 2 days before, the day of, and 2 days after receiving treatment with AXTLE. Reference ID: 5488378 How is AXTLE given? • It is very important to take folic acid and vitamin B12 during your treatment with AXTLE to lower your risk of harmful side effects. o Take folic acid exactly as prescribed by your healthcare provider 1 time a day, beginning 7 days (1 week) before your first dose of AXTLE and continue taking folic acid until 21 days (3 weeks) after your last dose of AXTLE. o Your healthcare provider will give you vitamin B12 injections during treatment with AXTLE. You will get your first vitamin B12 injection 7 days (1 week) before your first dose of AXTLE, and then every 3 cycles. • Your healthcare provider will prescribe a medicine called corticosteroid for you to take 2 times a day for 3 days, beginning the day before each treatment with AXTLE . • AXTLE is given to you by intravenous (IV) infusion into your vein. The infusion is given over 10 minutes. • AXTLE is usually given once every 21 days (3weeks). What are the possible side effects of AXTLE? AXTLE can cause serious side effects, including: • Low blood cell counts. Low blood cell counts can be severe, including low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and low red blood cell counts (anemia). Your healthcare provider will do blood tests to check your blood cell counts regularly during your treatment with AXTLE. Tell your healthcare provider right away if you have any signs of infection, fever, bleeding, or severe tiredness during your treatment with AXTLE. • Kidney problems, including kidney failure. AXTLE can cause severe kidney problems that can lead to death. Severe vomiting or diarrhea can lead to loss of fluids (dehydration) which may cause kidney problems to become worse. Tell your healthcare provider right away if you have a decrease in amount of urine. • Severe skin reactions. Severe skin reactions that may lead to death can happen with AXTLE. Tell your healthcare provider right away if you develop blisters, skin sores, skin peeling, or painful sores, or ulcers in your mouth, nose, throat or genital area. • Lung problems (pneumonitis). AXTLE can cause serious lung problems that can lead to death. Tell your healthcare provider right away if you get any new or worsening symptoms of shortness of breath, cough, or fever. • Radiation recall. Radiation recall is a skin reaction that can happen in people who have received radiationtreatment in the past and are treated with AXTLE. Tell your healthcare provider if you get swelling, blistering, or a rash that looks like a sunburn in an area that was previously treated with radiation. The most common side effects of AXTLE when given alone are: • tiredness • nausea • loss of appetite The most common side effects of AXTLE when given with cisplatin are: • vomiting • low white blood cell counts (neutropenia) • swelling or sores in your mouth or sore throat • low platelet counts (thrombocytopenia) • constipation • low red blood cell counts (anemia) AXTLE may cause fertility problems in males. This may affect your ability to father a child. It is not known if these effects are reversible. Talk to your healthcare provider if this is a concern for you. Your healthcare provider will do blood tests to check for side effects during treatment with AXTLE. Your healthcare provider may change your dose of AXTLE, delay treatment, or stop treatment if you have certain side effects. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Reference ID: 5488378 AVYXA These are not all the side effects of AXTLE. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of AXTLE. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about AXTLE that is written for health professionals. What are the ingredients in AXTLE? Active ingredient: pemetrexed Inactive ingredients: mannitol. Hydrochloric acid may have been added to adjust pH. Manufactured for: Avyxa Pharma, LLC New Jersey 07054, USA Made in India For more information, call 1-888-520-0954. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: December 2024 Reference ID: 5488378
custom-source
2025-02-12T15:47:26.818617
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BIZENGRI® safely and effectively. See full prescribing information for BIZENGRI. BIZENGRI (zenocutuzumab-zbco) injection, for intravenous use Initial U.S. Approval: 2024 WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Embryo-Fetal Toxicity: Exposure to BIZENGRI during pregnancy can cause embryo-fetal harm. Advise patients of this risk and the need for effective contraception [see Warnings and Precautions (5.4), Use on Specific Populations (8.1, 8.3)]. ----------------------------INDICATIONS AND USAGE--------------------------­ BIZENGRI® is a bispecific HER2- and HER3-directed antibody indicated for the treatment of: • Adults with advanced, unresectable or metastatic non-small cell lung cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy.* (1.1) • Adults with advanced, unresectable or metastatic pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy.* (1.2) *This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ---------------------DOSAGE AND ADMINISTRATION-----------------------­ • Select patients for treatment with BIZENGRI based on the presence of an NRG1 gene fusion. (2.1) • Evaluate left ventricular ejection fraction (LVEF) before initiating BIZENGRI. (2.2) • The recommended dosage of BIZENGRI is 750 mg every 2 weeks until disease progression or unacceptable toxicity. (2.3) • Administer premedications before each infusion to reduce the risk of infusion-related reactions. (2.4) • Administer as an intravenous infusion, after dilution, over 4 hours. (2.7) --------------------DOSAGE FORMS AND STRENGTHS--------------------­ Injection: 375 mg/18.75 mL (20 mg/mL) in a single-dose vial. (3) ----------------------------CONTRAINDICATIONS-----------------------------­ None. (4) ---------------------WARNINGS AND PRECAUTIONS-----------------------­ • Infusion-Related Reactions (IRR)/Hypersensitivity/Anaphylactic Reactions: Administer BIZENGRI in a setting with emergency resuscitation equipment and staff who are trained to monitor for IRRs and to administer emergency medications. Monitor for signs and symptoms of IRR. Interrupt infusion in patients with ≤ Grade 3 IRRs and administer symptomatic treatment as needed. Resume infusion at a reduced rate after resolution of symptoms. Immediately stop the infusion and permanently discontinue BIZENGRI for Grade 4 or life-threatening IRR or hypersensitivity/anaphylaxis. (5.1) • Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Permanently discontinue BIZENGRI in patients with ≥ Grade 2 ILD/pneumonitis. (5.2) • Left Ventricular Dysfunction: Assess LVEF before initiating BIZENGRI and at regular intervals during treatment as clinically indicated. Manage through treatment interruption or discontinuation. Permanently discontinue BIZENGRI in patients with symptomatic congestive heart failure (CHF). (5.3) ----------------------------ADVERSE REACTIONS------------------------------­ • The most common adverse reactions (≥ 10%) in patients were diarrhea musculoskeletal pain, fatigue, nausea, infusion-related reactions (IRR), dyspnea, rash, constipation, vomiting, abdominal pain, and edema. (6.1) • The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were increased GGT, decreased hemoglobin, decreased sodium, decreased platelets, increased AST, increased ALT, increased alkaline phosphatase, decreased magnesium, decreased phosphate, increased aPTT and increased bilirubin. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Merus N.V. at 1-844-637-8787 (MERUSUS) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ---------------------USE IN SPECIFIC POPULATIONS-----------------------­ Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of BIZENGRI. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: EMBRYO-FETAL TOXICITY 1 INDICATIONS AND USAGE 8 USE IN SPECIFIC POPULATIONS 1.1 Advanced Unresectable or Metastatic NRG1 Fusion- 8.1 Pregnancy Positive Non-Small Cell Lung Cancer 8.2 Lactation 1.2 Advanced Unresectable or Metastatic NRG1 Fusion- 8.3 Females and Males of Reproductive Potential Positive Pancreatic Adenocarcinoma 8.4 Pediatric Use 2 DOSAGE AND ADMINISTRATION 8.5 Geriatric Use 2.1 Patient Selection 11 DESCRIPTION 2.2 Recommended Evaluation Before Initiating BIZENGRI 12 CLINICAL PHARMACOLOGY 2.3 Recommended Dosage 12.1 Mechanism of Action 2.4 Recommended Premedications 12.2 Pharmacodynamics 2.5 Dosage Modifications for Adverse Reactions 12.3 Pharmacokinetics 2.6 Preparation 12.6 Immunogenicity 2.7 Administration 13 NONCLINICAL TOXICOLOGY 3 DOSAGE FORMS AND STRENGTHS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 4 CONTRAINDICATIONS 14 CLINICAL STUDIES 5 WARNINGS AND PRECAUTIONS 14.1 Advanced Unresectable or Metastatic NRG1 Fusion­ 5.1 Infusion-Related Reactions/Hypersensitivity/Anaphylactic Positive Non-Small Cell Lung Cancer Reactions 14.2 Advanced Unresectable or Metastatic NRG1 Fusion­ 5.2 Interstitial Lung Disease/Pneumonitis Positive Pancreatic Adenocarcinoma 5.3 Left Ventricular Dysfunction 16 HOW SUPPLIED/STORAGE AND HANDLING 5.4 Embryo-Fetal Toxicity 17 PATIENT COUNSELING INFORMATION 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience *Sections or subsections omitted from the full prescribing information are not listed. Page 1 of 21 Reference ID: 5489851 FULL PRESCRIBING INFORMATION WARNING: EMBRYO-FETAL TOXICITY Embryo-Fetal Toxicity: Exposure to BIZENGRI during pregnancy can cause embryo-fetal harm. Advise patients of this risk and the need for effective contraception [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)]. 1 INDICATIONS AND USAGE 1.1 Advanced Unresectable or Metastatic NRG1 Fusion-Positive Non-Small Cell Lung Cancer BIZENGRI is indicated for the treatment of adults with advanced unresectable or metastatic non- small cell lung cancer (NSCLC) harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). 1.2 Advanced Unresectable or Metastatic NRG1 Fusion-Positive Pancreatic Adenocarcinoma BIZENGRI is indicated for the treatment of adults with advanced unresectable or metastatic pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion with disease progression on or after prior systemic therapy. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients for treatment with BIZENGRI based on the presence of an NRG1 gene fusion in tumor specimens [see Clinical Studies (14.1, 14.2)]. An FDA-approved test for the detection of NRG1 gene fusions is not currently available. 2.2 Recommended Evaluation Before Initiating BIZENGRI Before initiating BIZENGRI, evaluate left ventricular ejection fraction (LVEF) [see Warnings and Precautions (5.3)]. Page 2 of 21 Reference ID: 5489851 2.3 Recommended Dosage • The recommended dosage of BIZENGRI is 750 mg as an intravenous (IV) infusion every 2 weeks until disease progression or unacceptable toxicity [see Dosage and Administration (2.7)]. • Administer premedications before each BIZENGRI infusion as recommended to reduce the risk of infusion-related reactions [see Dosage and Administration (2.4)]. 2.4 Recommended Premedications Prior to each infusion of BIZENGRI, administer premedications to reduce the risk of infusion- related reactions (IRRs) [see Warnings and Precautions (5.1)] (see Table 1). Table 1: Premedications Prior to BIZENGRI Infusions Medication Dose Route of Administration Corticosteroid1 Dexamethasone (10 mg) Oral or intravenous Antipyretic Acetaminophen (1,000 mg) Oral or intravenous H1 Antihistamine Dexchlorpheniramine (5 mg) or other anti-H1 equivalent Intravenous or oral 1 Optional after initial BIZENGRI infusion 2.5 Dosage Modifications for Adverse Reactions No dose reduction is recommended for BIZENGRI. The recommended dosage modifications of BIZENGRI for adverse reactions are provided in Table 2. Table 2: Recommended BIZENGRI Dosage Modifications and Management for Adverse Reactions Adverse Reaction Severity Dose Modifications and Management Infusion-related reactions (IRRs)/Hypersensitivity/Anaphy lactic Reactions [see Warnings and Precautions (5.1)] ≤ Grade 3 IRR • Interrupt BIZENGRI infusion if IRR is suspected and monitor patient until reaction symptoms resolve. • Provide symptomatic treatment as needed. • Resume the infusion at 50% of the infusion rate at which the reaction occurred. The infusion rate may be escalated if there are no additional symptoms. • Corticosteroid premedication can be used as necessary for subsequent BIZENGRI infusions [see Recommended Premedications (2.4)]. Page 3 of 21 Reference ID: 5489851 Grade 4 IRR or any grade hypersensitivity/ anaphylactic reaction • Permanently discontinue BIZENGRI. Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.2)] Grade 1 • Interrupt BIZENGRI until recovery. • Consider prompt initiation of corticosteroids when the diagnosis is suspected. • Resume treatment after resolution. ≥ Grade 2 • Permanently discontinue BIZENGRI. • Promptly treat with corticosteroids. Left Ventricular Dysfunction [see Warnings and Precautions (5.3)] LVEF is 45-49% and absolute decrease from baseline ≥10% or LVEF less than 45% • Interrupt BIZENGRI. • Repeat LVEF assessment within 3 weeks. • If LVEF is less than 45% or LVEF has not recovered to within 10% from baseline, permanently discontinue BIZENGRI. • If LVEF is 50% or greater or LVEF is 45-49% and recovered to within 10% of baseline, resume BIZENGRI and monitor LVEF every 12 weeks while on treatment and as clinically indicated. Symptomatic congestive heart failure (CHF) • Permanently discontinue BIZENGRI. Other Clinically Relevant Adverse Reactions [see Adverse Reactions (6.1)] Grade 3 or 4 • Withhold BIZENGRI until recovery to ≤ Grade 1 or baseline. • Provide symptomatic treatment as needed. • Resume treatment after resolution of symptoms. 2.6 Preparation Dilute and prepare BIZENGRI for intravenous infusion before administration. For the initial infusion, prepare BIZENGRI as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction. • Check that the BIZENGRI solution is clear to slightly opalescent, colorless to slightly yellow. Parenteral drug products should be inspected visually for particulate matter and Page 4 of 21 Reference ID: 5489851 discoloration prior to administration, whenever solution and container permit. Do not use if discoloration or visible particles are present. • Withdraw and then discard 37.5 mL 0.9% Sodium Chloride Injection from the 250 mL infusion bag. Only use infusion bags made of polyvinylchloride (PVC), polyolefin or polyolefin/polyamide coextruded plastic. • Withdraw a total of 37.5 mL of BIZENGRI from 2 vials and add it to the infusion bag. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial. • Gently invert the bag to mix the solution. Do not shake. • If not used immediately, store the diluted solution refrigerated at 2°C to 8°C (36°F to 46°F) and protect from light after preparation unless the infusion is initiated within 2 hours of preparation. 2.7 Administration • If the infusion time exceeds the recommended storage time, the infusion bag must be discarded and a new infusion bag prepared to continue the infusion. Diluted BIZENGRI solution must by administered within: o 6 hours from end of preparation of infusion solution stored at room temperature [15°C to 25°C (59°F to 77°F)] o 28 hours from end of preparation of infusion solution stored refrigerated [2°C to 8°C (36°F to 46°F)] • If the diluted BIZENGRI solution has been refrigerated, allow it to reach room temperature (approximately 30 minutes) prior to administration. • Administer diluted BIZENGRI solution [see Dosage and Administration (2.6)] by intravenous infusion using an infusion set made of either PVC, polyethylene (PE), polyurethane (PUR) or polybutadiene (PB) with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer). • Do not infuse BIZENGRI concomitantly in the same IV line with other agents. • Administer BIZENGRI infusion via a peripheral or central line. • Monitor patients closely for signs and symptoms of infusion-related reactions during BIZENGRI infusion and monitor patients for at least 1 hour following completion of the first BIZENGRI infusion and as clinically indicated [see Warnings and Precautions (5.1)]. Page 5 of 21 Reference ID: 5489851 • Administer intravenous infusion over 4 hours. 3 DOSAGE FORMS AND STRENGTHS Injection: 375 mg/18.75 mL (20 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Infusion-Related Reactions/Hypersensitivity/Anaphylactic Reactions BIZENGRI can cause serious and life-threatening infusion-related reactions (IRRs), hypersensitivity and anaphylactic reactions. Signs and symptoms of IRR may include chills, nausea, fever, and cough. In the eNRGy study, 13% of patients experienced IRRs, all were Grade 1 or 2; 91% occurred during the first infusion. The median time to onset was 63 minutes (range: 13 minutes to 240 minutes) from the start of infusion. Administer BIZENGRI in a setting with emergency resuscitation equipment and staff who are trained to monitor for IRRs and to administer emergency medications. Monitor patients closely for signs and symptoms of infusion reactions during infusion and for at least 1 hour following completion of first BIZENGRI infusion and as clinically indicated. Prior to the first BIZENGRI infusion, premedicate with a corticosteroid, an H1 antihistamine and acetaminophen to reduce the risk of IRRs [see Dosage and Administration (2.4)]. Corticosteroid premedication can be used as necessary for subsequent BIZENGRI infusions. Interrupt BIZENGRI infusion in patients with ≤ Grade 3 IRRs and administer symptomatic treatment as needed. Resume infusion at a reduced rate after resolution of symptoms [see Dosage and Administration (2.5)]. Immediately stop the infusion and permanently discontinue BIZENGRI for Grade 4 or life-threatening IRR or hypersensitivity/anaphylaxis reactions. 5.2 Interstitial Lung Disease/Pneumonitis BIZENGRI can cause serious and life-threatening interstitial lung disease (ILD)/pneumonitis. In the eNRGy study [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 2 (1.1%) patients treated with BIZENGRI. Grade 2 ILD/pneumonitis (Grade 2) resulting in permanent discontinuation of BIZENGRI occurred in 1 (0.6%) patient. Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold BIZENGRI in patients with suspected Page 6 of 21 Reference ID: 5489851 ILD/pneumonitis and administer corticosteroids as clinically indicated. Permanently discontinue BIZENGRI if ILD/pneumonitis ≥ Grade 2 is confirmed [see Dosage and Administration (2.5)]. 5.3 Left Ventricular Dysfunction BIZENGRI can cause left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease occurred with anti-HER2 therapies, including BIZENGRI. Treatment with BIZENGRI has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment. In the eNRGy study [see Adverse Reactions (6.1)], Grade 2 LVEF decrease [Grade 2 LVEF decrease (40%-50%; 10 - 19% drop from baseline)] occurred in 2% of evaluable patients. Cardiac failure without LVEF decrease occurred in 1.7% of patients including 1 (0.6%) fatal event. Before initiating BIZENGRI, evaluate LVEF and monitor at regular intervals during treatment as clinically indicated. For LVEF of less than 45% or less than 50% with absolute decrease from baseline of 10% or greater - is confirmed, permanently discontinue BIZENGRI. Permanently discontinue BIZENGRI in patients with symptomatic congestive heart failure (CHF) [see Dosage and Administration (2.5)]. 5.4 Embryo-Fetal Toxicity Based on its mechanism of action, BIZENGRI can cause fetal harm when administered to a pregnant woman. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Animal studies have demonstrated that inhibition of HER2 and/or HER3 results in impaired embryo-fetal development, including effects on cardiac, vascular and neuronal development, and embryolethality. Advise patients of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of BIZENGRI. Advise females of reproductive potential to use effective contraception during treatment with BIZENGRI and for 2 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Infusion-Related Reactions/Hypersensitivity/Anaphylaxis [see Warnings and Precautions (5.1)] • Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.3)] Page 7 of 21 Reference ID: 5489851 • Embryo-Fetal Toxicity [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to BIZENGRI as a single agent at 750 mg administered intravenously every 2 weeks until disease progression or unacceptable toxicity in 175 patients with NRG1 gene fusion positive tumors in the eNRGy study. Of these, there were 99 patients with NSCLC, 39 patients with pancreatic adenocarcinoma and 37 patients with other solid tumors [see Clinical Studies (14.1, 14.2)]. Among the 175 patients who received BIZENGRI, the median duration of exposure to BIZENGRI was 5.3 months (range: 0.1 to 36), including 45% of patients exposed for at least 6 months and 15% of patients exposed for at least 1 year. In this pooled safety population, the most common (≥ 10%) adverse reactions were diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions (IRR), dyspnea, rash, constipation, vomiting, abdominal pain, and edema. The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were increased GGT, decreased hemoglobin, decreased sodium, decreased platelets, increased AST, increased ALT, increased alkaline phosphatase, decreased magnesium, decreased phosphate, increased aPTT and increased bilirubin. NRG1 Gene Fusion Positive Unresectable or Metastatic NSCLC eNRGy Study The safety of BIZENGRI was evaluated in the eNRGy study in 99 patients with unresectable or metastatic NSCLC with NRG1 gene fusions [see Clinical Studies (14.1)]. Patients received BIZENGRI as a single agent at 750 mg intravenously every 2 weeks until disease progression or unacceptable toxicity. Among patients who received BIZENGRI, 47% were exposed for 6 months or longer and 17% were exposed for greater than one year. The median age was 66 years (range: 27 to 88), 54% were 65 years or older; 62% were female; 37% were White, 53% were Asian, 2% were Black or African American; and 1% were Hispanic or Latino. Serious adverse reactions occurred in 25% of patients who received BIZENGRI. Serious adverse reactions in ≥ 2% of patients included pneumonia (n=4) dyspnea and fatigue (n=2 each). Serious adverse reactions occurring in one patient each were: abdominal pain, acute kidney injury, ascites, bradycardia, carotid artery stenosis, cellulitis, acute cholecystitis, COVID-19, decreased appetite, dehydration, dizziness, dysphagia, hyponatremia, ileus, lymphadenitis, nausea, gastric obstruction, pericardial effusion, pneumonitis, pulmonary hypertension, sepsis, staphylococcal infection, tumor pain, urinary tract infection, viral infection and vomiting. Fatal adverse reactions occurred in 3 (3%) patients and included respiratory failure (n=2) and cardiac failure (n=1). Page 8 of 21 Reference ID: 5489851 Permanent discontinuation of BIZENGRI due to an adverse reaction occurred in 3% of patients. Adverse reactions resulting in permanent discontinuation of BIZENGRI included dyspnea, pneumonitis and sepsis (n=1 each). Dosage interruptions of BIZENGRI due to an adverse reaction, excluding temporary interruptions of BIZENGRI due to infusion-related reactions, occurred in 29% of patients. Adverse reactions leading to dosage interruptions in ≥2% of patients included dyspnea, COVID­ 19, arrhythmia, increased ALT, increased AST, and pneumonia. Table 3 summarizes the adverse reactions in the eNRGy study in patients with NRG1 gene fusion positive unresectable or metastatic NSCLC. Table 3: Adverse Reactions (≥10%) in Patients with NRG1 Gene Fusion Positive NSCLC Who Received BIZENGRI in the eNRGy Study Adverse Reaction1 BIZENGRI (N=99) All Grades % Grade 3 or 4 % Gastrointestinal disorders Diarrhea2 25 2 Nausea 10 1 Musculoskeletal and connective tissue disorders Musculoskeletal pain3 23 1 Respiratory, thoracic and mediastinal disorders Dyspnea4 18 5 Cough5 15 1 General disorders and administration site conditions Fatigue6 17 2 Edema7 11 0 Skin and subcutaneous tissue disorders Rash8 14 0 Injury, poisoning and procedural complications Infusion-related reactions 9 12 0 Metabolism and nutrition disorders Decreased appetite 11 1 1 Based on NCI CTCAE v4.03 and MedDRA v26.0 2 Includes post-procedural diarrhea 3 Includes back pain, pain in extremity, musculoskeletal chest pain, myalgia, arthralgia, non-cardiac chest pain, bone pain, musculoskeletal stiffness, neck pain, spinal pain. Page 9 of 21 Reference ID: 5489851 4 Includes dyspnea exertional 5 Includes productive cough 6 Includes asthenia 7 Includes breast edema, peripheral edema, face edema 8 Includes eczema, erythema, dermatitis, dermatitis contact, rash maculopapular, rash erythematous. 9 Includes chills, IRR, nausea, cough, diarrhea, back pain, body temperature increased, dyspnea, face edema, fatigue, non-cardiac chest pain, oropharyngeal discomfort, paresthesia, pyrexia, and vomiting. AEs that were considered IRRs were counted under the composite term ‘IRR’, irrespective of the reported PT. Clinically relevant adverse reactions in <10% of patients receiving BIZENGRI were stomatitis (7%), vomiting (8%), cardiac failure and pneumonitis (2% each). Table 4 summarizes the laboratory abnormalities in the eNRGy study in patients with NRG1 gene fusion positive unresectable or metastatic NSCLC. Table 4: Select Laboratory Abnormalities ≥ 20% that Worsened from Baseline in Patients with NRG1 Gene Fusion Positive NSCLC Who Received BIZENGRI in the eNRGy Study Laboratory Abnormality BIZENGRI1 All Grades % Grade 3 or 4 % Hematology Decreased hemoglobin 35 4.2 Chemistry Increased alanine aminotransferase 30 3.1 Decreased magnesium 28 4.3 Increased alkaline phosphatase 27 0 Decreased phosphate 26 1.1 Increased gamma-glutamyl transpeptidase 23 5 Increased aspartate aminotransferase 22 3.1 Decreased potassium 21 2.1 1 The denominator used to calculate the rate varied from 93 to 96 based on the number of patients with a baseline value and at least one post-treatment value. NRG1 Gene Fusion Positive Unresectable or Metastatic Pancreatic Adenocarcinoma eNRGy Study The safety of BIZENGRI was evaluated in the eNRGy study in 39 patients with unresectable or metastatic pancreatic adenocarcinoma with NRG1 gene fusions [see Clinical Studies (14.2)]. Patients received BIZENGRI as a single agent at 750 mg intravenously every 2 weeks until Page 10 of 21 Reference ID: 5489851 disease progression or unacceptable toxicity. Among patients who received BIZENGRI, 50% were exposed for 6 months or longer and 13% were exposed for greater than one year. The median age was 51 years (range: 21 to 74), 23% were 65 years or older; 49% were female; 82% were White, 13% were Asian, 2.6% were Black or African American; and 5% were Hispanic or Latino. Serious adverse reactions occurred in 23% of patients who received BIZENGRI. Serious adverse reactions occurring in one patient each were: anemia, thrombocytopenia, tachycardia, abdominal pain, hemorrhoidal hemorrhage, nausea, cholestatic jaundice, COVID-19, liver abscess, traumatic fracture, blood creatinine increased, back pain, myelodysplastic syndrome, and respiratory disorder. There were 2 fatal adverse reactions, one due to COVID-19 and one due to respiratory failure. Dosage interruptions of BIZENGRI due to an adverse reaction, excluding temporary interruptions of BIZENGRI due to infusion-related reactions, occurred in 33% of patients. Adverse reactions leading to dosage interruptions in ≥2% of patients included COVID-19, pneumonia, increased AST, neutropenia, abdominal pain, agitation, increased blood alkaline phosphatase, increased blood bilirubin, constipation, increased creatinine, hemorrhage, hyperbilirubinemia, cholestatic jaundice, tachycardia, traumatic fracture, and upper respiratory infection. Table 5 summarizes the adverse reactions in the eNRGy study in patients with NRG1 gene fusion positive pancreatic adenocarcinoma. Table 5: Adverse Reactions (≥10%) in Patients with NRG1 Gene Fusion Positive Pancreatic Adenocarcinoma Who Received BIZENGRI in the eNRGy Study Adverse Reaction1 BIZENGRI (N=39) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Diarrhea 36 5 Nausea 23 5 Vomiting 23 2.6 Abdominal pain 18 5 Constipation 15 0 Abdominal distension 13 0 Stomatitis 10 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain2 28 2.6 General disorders and administration site conditions Fatigue3 21 5 Page 11 of 21 Reference ID: 5489851 Edema4 13 0 Pyrexia 10 0 Infections and infestations COVID-19 18 0 Injury, poisoning and procedural complications Infusion-related reactions5 15 0 Vascular disorders Hemorrhage6 13 5 Psychiatric disorders Anxiety 10 0 Skin and subcutaneous tissue disorders Dry skin 10 0 1 Based on NCI CTCAE v4.03 and MedDRA v26.0 2 Includes back pain, pain in extremity, musculoskeletal chest pain, myalgia, arthralgia, non-cardiac chest pain, bone pain, musculoskeletal stiffness, neck pain, spinal pain 3 Includes asthenia 4 Includes peripheral edema, face edema, localized edema, peripheral swelling 5 Includes chills, IRR, nausea, cough, diarrhea, back pain, body temperature increased, dyspnea, face edema, fatigue, non-cardiac chest pain, oropharyngeal discomfort, paresthesia, pyrexia, and vomiting 6 Includes epistaxis, hematochezia, hematuria, hemorrhoidal hemorrhage Clinically relevant adverse reactions in <10% of patients receiving BIZENGRI were decreased appetite (5%), and rash (8%) [including dermatitis acneiform, erythema, dermatitis, dermatitis contact, rash maculopapular, rash erythematous]. Table 6 summarizes the laboratory abnormalities in the eNRGy study in patients with NRG1 gene fusion positive pancreatic adenocarcinoma. Table 6: Select Laboratory Abnormalities ≥ 20% That Worsened from Baseline in Patients with NRG1 Gene Fusion Positive Pancreatic Adenocarcinoma Who Received BIZENGRI in the eNRGy Study Laboratory Abnormality BIZENGRI1 (N=39) All Grades (%) Grade 3 or 4 (%) Chemistry Increased alanine aminotransferase 51 5 Increased aspartate aminotransferase 31 5 Increased bilirubin 31 5 Decreased phosphate 31 2.9 Increased alkaline phosphatase 28 8 Decreased sodium 28 10 Page 12 of 21 Reference ID: 5489851 Decreased albumin 26 0 Decreased potassium 26 2.6 Decreased magnesium 24 2.6 Increased gamma-glutamyl transpeptidase 23 15 Hematology Decreased platelets 26 10 Decreased hemoglobin 23 10 Decreased leukocytes 21 2.6 1 The denominator used to calculate the rate varied from 35 to 39, based on the number of patients with a baseline value and at least one post-treatment value. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, BIZENGRI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of BIZENGRI in pregnant women to inform a drug-associated risk. Animal studies have demonstrated that HER2 and/or HER3 deficiency results in embryo-fetal malformation, including effects on cardiac, vascular and neuronal development, and embryolethality (see Data). Human IgG1 is known to cross the placenta; therefore, BIZENGRI has the potential to be transmitted from the mother to the developing fetus. Advise patients of the potential risk to a fetus. There are clinical considerations if BIZENGRI is used in pregnant women, or if a patient becomes pregnant within 2 months after the last dose of BIZENGRI (see Clinical Considerations). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received BIZENGRI during pregnancy or within 2 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. Page 13 of 21 Reference ID: 5489851 Data Human Data There are no available data on the use of BIZENGRI in pregnant women. In literature reports in pregnant women receiving a HER2-directed antibody, cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported. These case reports described oligohydramnios in pregnant women who received HER2-directed antibody alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after use of a HER2-directed antibody was stopped. Animal Data There were no animal reproductive or developmental toxicity studies conducted with zenocutuzumab-zbco. A literature-based assessment of the effects on reproduction demonstrated that HER2 and HER3 are critically important in embryo-fetal development. HER2 knockout mice or mice expressing catalytically inactive HER2 die at mid-gestation due to cardiac dysfunction. HER2 knockout mice have also shown abnormal sympathetic nervous system development. In HER3-deficient mice, embryolethality occurred on embryonic day 13.5 due to cardiac and vascular defects, as well as abnormalities in other organs (neural crest, pancreas, stomach, and adrenal). In addition, HER3 is shown to be involved in mammary gland ductal morphogenesis in mice. Zenocutuzumab-zbco can cause embryo-fetal toxicity based on its mechanism of action. 8.2 Lactation Risk Summary There are no data on the presence of zenocutuzumab-zbco in human milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG1 is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to BIZENGRI are unknown. Consider the developmental and health benefits of breast feeding along with the mother’s clinical need for BIZENGRI treatment and any potential adverse effects on the breastfed child from BIZENGRI or from the underlying maternal condition. This consideration should also take into account the elimination half-life of zenocutuzumab-zbco and washout period of 2 months. 8.3 Females and Males of Reproductive Potential BIZENGRI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating BIZENGRI [see Use in Specific Populations (8.1)]. Page 14 of 21 Reference ID: 5489851 Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with BIZENGRI and for 2 months after the last dose. 8.4 Pediatric Use The safety and effectiveness of BIZENGRI have not been established in pediatric patients. 8.5 Geriatric Use Of the 175 patients with NRG1 gene fusion positive tumors in the eNRGy study treated with BIZENGRI at 750 mg every 2 weeks, 75 patients (43%) were 65 years of age or older and 26 patients (15%) were 75 years of age and older. No clinically important differences in safety or efficacy were observed between patients who were ≥65 years of age and younger patients. 11 DESCRIPTION Zenocutuzumab-zbco is a low-fucose humanized full-length immunoglobulin G1 (IgG1) bispecific HER2- and HER3-directed antibody. It has a molecular weight of approximately 146 kDa and is produced in a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology. BIZENGRI is a sterile, clear to slightly opalescent, colorless to slightly yellow, preservative-free injection for intravenous infusion in single-dose vials. The pH is 6.0. Each BIZENGRI vial contains 375 mg/18.75 mL zenocutuzumab-zbco at a concentration of 20 mg/mL. Each vial also contains the following inactive ingredients: histidine (34.9 mg), L-histidine hydrochloride monohydrate (51.1 mg), polysorbate 20 (3.7 mg), trehalose (1412 mg), and water for injection. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Zenocutuzumab-zbco is a bispecific antibody that binds to the extracellular domains of HER2 and HER3 expressed on the surface of cells, including tumor cells, inhibiting HER2:HER3 dimerization and preventing NRG1 binding to HER3. Zenocutuzumab-zbco decreased cell proliferation and signaling through the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway. In addition, zenocutuzumab-zbco mediates antibody- dependent cellular cytotoxicity (ADCC). Zenocutuzumab-zbco showed antitumor activity in mouse models of NRG1 fusion-positive lung and pancreatic cancers. 12.2 Pharmacodynamics The exposure-response relationship and time-course of pharmacodynamic response for zenocutuzumab-zbco have not been fully characterized. Page 15 of 21 Reference ID: 5489851 12.3 Pharmacokinetics Zenocutuzumab-zbco pharmacokinetic parameters are expressed as mean unless otherwise specified. Zenocutuzumab-zbco exposure increases proportionally over a dose range from 480 mg (0.6 times the approved recommended dosage) to 900 mg (1.2 times the approved recommended dosage). The median time to steady state of zenocutuzumab-zbco concentrations is 8 weeks and the median accumulation ratio is 1.6-fold at the approved recommended dosage. Distribution Zenocutuzumab-zbco volume of distribution is 6 L (CV 18%). Elimination The steady state zenocutuzumab-zbco half-life is 8 days (SD ±1.3 days) with a clearance of 22 mL/h (CV 37%). Metabolism Zenocutuzumab-zbco is expected to be metabolized into small peptides by catabolic pathways. Specific Populations No clinically significant differences in the pharmacokinetics of zenocutuzumab-zbco were observed based on age (22 to 88 years), sex, race [White or Asian], body weight (38 to 126 kg), albumin level (20 to 49 g/L), mild or moderate renal impairment (creatinine clearance (CLcr) 30 to 89 mL/min), and mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN). The pharmacokinetics of zenocutuzumab-zbco in patients with moderate to severe hepatic impairment (total bilirubin > 1.5 to 3 times ULN with any AST) or severe renal impairment (CLcr < 30 mL/min) is unknown. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparison of the incidence of anti-drug antibodies in the studies below with the incidence of anti-drug antibodies in other studies, including those of BIZENGRI or of other zenocutuzumab products. In patients who received BIZENGRI at the approved recommended dosage for up to 30 months, 7 of 153 (4.6%) patients developed anti-zenocutuzumab antibodies. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and efficacy of zenocutuzumab is unknown. Page 16 of 21 Reference ID: 5489851 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been performed to assess the carcinogenic or mutagenic potential of zenocutuzumab-zbco. Animal fertility studies have not been conducted with zenocutuzumab-zbco. 14 CLINICAL STUDIES 14.1 Advanced Unresectable or Metastatic NRG1 Fusion-Positive Non-Small Cell Lung Cancer The efficacy of BIZENGRI was evaluated in the eNRGy study (NCT02912949) a multicenter, open-label, multi-cohort clinical study. The study enrolled adult patients with advanced or metastatic NRG1 fusion-positive NSCLC who had disease progression following standard of care treatment for their disease. Identification of positive NRG1 gene fusion status was prospectively determined based on next generation sequencing (NGS) assays performed at local laboratories or central laboratories. Patients received BIZENGRI as an intravenous infusion, 750 mg every 2 weeks, until unacceptable toxicity or disease progression. Tumor assessments were performed every 8 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR) as determined by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Efficacy was evaluated in 64 patients with NRG1 fusion-positive NSCLC previously treated with systemic therapy enrolled in eNRGy. The trial population characteristics were: median age 63.5 years (range: 32 to 86) with 10% of patients ≥ 65 years of age; 64% female; 56% Asian, 33% White, 3.4% Black or African American, and 11% other races or not reported; none were Hispanic or Latino; baseline ECOG performance status of 0 or 1 (97%) or 2 (3%) and 98% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1 to 6); 95% had prior platinum chemotherapy and 64% had prior anti-PD-1/PD-L1 therapy. A total of 54 patients (84%) had an NRG1 gene fusion detected by RNA-based NGS that may include DNA sequencing and 9 (14%) had an NRG1 gene fusion detected by DNA-based NGS. Efficacy results are summarized in Table 7 and Table 8. Page 17 of 21 Reference ID: 5489851 Table 7: Efficacy Results for Advanced Unresectable or Metastatic NRG1 Fusion-Positive NSCLC in the eNRGy Study Efficacy Parameter BIZENGRI Previously Treated with Systemic Therapy (n = 64) Overall response rate1 (95% CI) 33% (22%, 46%) Complete response rate 1.6% Partial response rate 31% Duration of response Median (95% CI) (months) 7.4 (4.0, 16.6) Patients with DOR ≥6 months2 43% 1 Confirmed overall response rate assessed by BICR 2 Based on observed duration of response Table 8: Efficacy Results by NRG1 Gene Fusion Partner in NRG1 Fusion-Positive NSCLC Patients in the eNRGy Study NRG1 Partner1 BIZENGRI ORR DOR (n = 64) n (%) 95% CI Range (Months) CD74 37 12 (32) (18, 50) 1.8+; 20.3+ SLC3A2 14 5 (36) (13, 65) 3.6; 20.8+ SDC4 7 2 (29) (3.7, 71) 7.4; 16.6 CDH1 2 1 (50) (1.3, 99) 1.9+ FUT10 1 PD NA NA PVALB 1 PD NA NA ST14 1 PD NA NA VAMP2 1 PR NA 5.6 1 Fusion partners identified in this primary analysis set (n=64) may not represent all potential fusion partners. PR=partial response; PD=progressive disease; NA=not applicable; “+” indicates ongoing response­ 14.2 Advanced Unresectable or Metastatic NRG1 Fusion-Positive Pancreatic Adenocarcinoma The efficacy of BIZENGRI was evaluated in the eNRGy study (NCT02912949), a multicenter, open-label, multi-cohort clinical study. The study enrolled 30 adult patients with advanced or metastatic NRG1 fusion-positive pancreatic adenocarcinoma who had disease progression following standard of care treatment. Identification of an NRG1 gene fusion was prospectively determined in local laboratories using next generation sequencing (NGS). Patients received BIZENGRI as an intravenous infusion, 750 mg every 2 weeks, until unacceptable toxicity or disease progression. Tumor assessments were performed every 8 weeks. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR) as determined by a blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Page 18 of 21 Reference ID: 5489851 The trial population characteristics were: median age 49 years (range: 21 to 72) with 10% of patients ≥ 65 years of age; 43% female; 87% White, 7% Asian, 3.3% Black or African American, and 3.3% other races or not reported; 3.3% were Hispanic or Latino; baseline ECOG performance status of 0 (53%) or 1 (47%) and all patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 0 to 5); 97% had prior systemic therapy with FOLFIRINOX, gemcitabine/taxane-based therapy, or both. A total of 27 patients (90%) had an NRG1 gene fusion detected by RNA-based NGS that may include DNA sequencing and 3 (10%) had an NRG1 gene fusion detected by DNA-based NGS. Efficacy results are summarized in Table 9 and Table 10. Table 9: Efficacy Results for Advanced Unresectable or Metastatic NRG1 Fusion-Positive Pancreatic Adenocarcinoma in the eNRGy Study Efficacy Parameter BIZENGRI (n = 30) Overall response rate1 (95% CI) 40% (23%, 59%) Complete response rate 3.3% Partial response rate 37% Duration of response Range (months) 3.7, 16.6 Patients with DOR ≥6 months2 67% 1 Confirmed overall response rate assessed by BICR. 2 Based on observed duration of response Table 10: Efficacy Results by NRG1 Gene Fusion Partner in NRG1 Fusion-Positive Pancreatic Adenocarcinoma Patients in the eNRGy Study NRG1 Partner1 BIZENGRI (n = 30) ORR DOR n (%) 95% CI Range (Months) ATP1B1 14 7 (50) (23, 77) 3.7, 16.6 CD44 3 0 (0, 71) NA NOTCH2 3 1 (33) (0.8, 91) 7.4+ SLC4A4 3 2 (67) (9, 99) 7.5+, 15.2+ AGRN 1 PR NA 9.1+ APP 1 PR NA 3.7 CDH1 2 SD, SD NA NA SDC4 1 SD NA NA THBS1 1 PD NA NA VTCN1 1 SD NA NA 1 Fusion partners identified in this primary analysis set (n=30) may not represent all potential fusion partners. PR=partial response; PD=progressive disease; SD=stable disease; NA=not applicable; “+” indicates ongoing response Page 19 of 21 Reference ID: 5489851 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied BIZENGRI (zenocutuzumab-zbco) injection is a sterile, clear to slightly opalescent, colorless to slightly yellow, preservative-free solution for intravenous infusion. Each single-dose vial contains 375 mg/18.75 mL (20 mg/mL) BIZENGRI. Two vials (equivalent to 1 dose) are packed in a single carton. (NDC 83077-100-01 for individual vial and NDC 83077-100-02 for a single carton). Storage and Handling Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Infusion-Related Reactions/Hypersensitivity/Anaphylaxis Advise patients that BIZENGRI can cause serious and life-threatening infusion-related reactions (IRRs). Advise patients to alert their healthcare provider immediately for any signs or symptoms of IRRs during and following the infusion [see Warnings and Precautions (5.1)]. Interstitial Lung Disease (ILD)/Pneumonitis Inform patients that BIZENGRI can cause serious and life threatening ILD/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms [see Warnings and Precautions (5.2)]. Left Ventricular Dysfunction Inform patients that BIZENGRI can cause serious and life threatening left ventricular dysfunction. Advise patients to immediately contact their healthcare provider for new or worsening cardiovascular symptoms [see Warnings and Precautions (5.3)]. Embryo-Fetal Toxicity • Inform female patients of the potential risk to a fetus. Advise female patients to contact their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)]. • Advise females of reproductive potential to use effective contraception during treatment with BIZENGRI and for 2 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. Page 20 of 21 Reference ID: 5489851 Lactation Advise women not to breastfeed during treatment with BIZENGRI and for 2 months after the last dose [see Use in Specific Populations (8.2)]. Product of the USA Manufactured by: Merus N.V. Uppsalalaan 17, Utrecht, The Netherlands Distributed by: Merus US, Inc. Cambridge, MA 02142 BIZENGRI® is a registered trademark of Merus N.V. U.S. License Number XXXX ©2024 Merus N.V. All rights reserved. BIZENGRIPI.00X Page 21 of 21 Reference ID: 5489851 PATIENT INFORMATION BIZENGRI® (bi zen gree) (zenocutuzumab-zbco) injection, for intravenous use What is the most important information I should know about BIZENGRI? BIZENGRI may cause serious side effects, including: • Infusion-related, allergic and anaphylactic reactions. BIZENGRI may cause serious infusion-related and allergic reactions that can be life-threatening. Infusion-related reactions are also common during BIZENGRI treatment. Before each BIZENGRI infusion, your healthcare provider will give you medicines to help reduce your chance of getting infusion-related reactions. Your healthcare provider will monitor you for signs and symptoms during your infusion and for at least 1 hour after your first infusion and as needed. Tell your healthcare provider right away if you develop any of the following signs or symptoms during or after your BIZENGRI infusion: o chills or shaking o itching or rash o nausea, vomiting, or diarrhea o shortness of breath or wheezing o fever o chest discomfort o cough o feeling light-headed o sudden swelling of your face, tongue, o dizziness throat, or troubled swallowing o back or neck pain o throat tightness or discomfort o feeling of numbness or tingling • Lung problems. BIZENGRI may cause serious lung problems that may be life-threatening. If you develop lung problems, your healthcare provider may treat you with corticosteroid medicines. Tell your healthcare provider right away if you develop any new or worsening symptoms of lung problems, including: o trouble breathing o cough o shortness of breath o fever • Heart problems that may affect your heart’s ability to pump blood. BIZENGRI may cause serious and life- threatening heart problems that may lead to death. Your healthcare provider will check your heart function before you start treatment with BIZENGRI and as needed during your treatment. Tell your healthcare provider right away if you develop any new or worsening symptoms of heart problems, including: o shortness of breath o irregular heartbeat o coughing o sudden weight gain o tiredness o dizziness or feeling light-headed o swelling of your feet, ankles or legs o loss of consciousness Your healthcare provider will check you for these side effects during your treatment with BIZENGRI and may delay your treatment, slow the infusion rate, or completely stop your treatment with BIZENGRI if you develop severe side effects. • Harm to your unborn baby. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with BIZENGRI. Females who are able to become pregnant: o Your healthcare provider will do a pregnancy test before you start treatment with BIZENGRI. o Use effective birth control (contraception) during treatment and for 2 months after your last dose of BIZENGRI. See “What are the possible side effects of BIZENGRI?” for more information about side effects. What is BIZENGRI? BIZENGRI is a prescription medicine used to treat adults who have: • lung cancer called non-small cell lung cancer (NSCLC): o that has a neuregulin 1 (NRG1) gene fusion and cannot be removed by surgery or has spread to other parts of the body (advanced unresectable or metastatic), and o whose disease has worsened on or after prior cancer treatment. • pancreatic cancer called pancreatic adenocarcinoma: o that has a neuregulin 1 (NRG1) gene fusion and cannot be removed by surgery or has spread to other parts of the body (advanced unresectable or metastatic), and o whose disease has worsened on or after prior cancer treatment. It is not known if BIZENGRI is safe and effective in children. Before receiving BIZENGRI, tell your healthcare provider about all your medical conditions, including if you: • have lung or breathing problems other than your lung cancer. • have or have had any heart problems. • are breastfeeding or plan to breastfeed. It is not known if BIZENGRI passes into your breast milk. Do not breastfeed during treatment and for 2 months after your last dose of BIZENGRI. Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements. Reference ID: 5489851 How will I receive BIZENGRI? • BIZENGRI will be given to you by your healthcare provider as an intravenous (IV) infusion into your vein, usually over 4 hours. • BIZENGRI is usually given 1 time every 2 weeks. • Your healthcare provider will decide how many treatments you will need. What are the possible side effects of BIZENGRI? BIZENGRI may cause serious side effects, including: • See “What is the most important information I should know about BIZENGRI?” The most common side effects of BIZENGRI include: • diarrhea • rash • muscle or bone pain • constipation • tiredness • vomiting • nausea • stomach-area (abdominal) pain • shortness of breath • swelling of your breast, face, ankles or legs The most common severe abnormal blood test results with BIZENGRI include: • increased blood levels of liver enzymes • decreased blood level of sodium, and bilirubin magnesium, and phosphate • decreased red blood cell counts and • increase in the time that it takes your blood platelet counts to clot These are not all of the possible side effects of BIZENGRI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about safe and effective use of BIZENGRI: Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about BIZENGRI that is written for health professionals. What are the ingredients in BIZENGRI? Active ingredient: zenocutuzumab-zbco Inactive ingredients: histidine, L-histidine hydrochloride monohydrate, polysorbate 20, trehalose, and water for injection Product of the USA Manufactured by: Merus N.V. Uppsalalaan 17, Utrecht, The Netherlands Distributed by: Merus US, Inc. Cambridge, MA 02142 BIZENGRI® is a registered trademark of Merus N.V. U.S. License Number XXXX © copyright statement (i.e. 2024 Merus N.V.). All Rights Reserved. For more information, go to www.BIZENGRI.com or call 1-844-637-8777 (MERUSRS) This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: Dec/2024 Reference ID: 5489851
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2025-02-12T15:47:27.145916
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use LUTATHERA safely and effectively. See full prescribing information for LUTATHERA. LUTATHERA® (lutetium Lu 177 dotatate) injection, for intravenous use Initial U.S. Approval: 2018 ---------------------------RECENT MAJOR CHANGES--------------------------- Indications and Usage (1) 4/2024 Dosage and Administration (2.2, 2.5, 2.6) 4/2024 Warnings and Precautions (5.1) 4/2024 ----------------------------INDICATIONS AND USAGE--------------------------- LUTATHERA is a radiolabeled somatostatin analog indicated for the treatment of adult and pediatric patients 12 years and older with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors. (0) ------------------------DOSAGE AND ADMINISTRATION----------------------  Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA. (0)  Administer 7.4 GBq (200 mCi) every 8 weeks (± 1 week) for a total of 4 doses. (2.2)  Administer long-acting octreotide 30 mg intramuscularly 4 to 24 hours after each LUTATHERA dose and short-acting octreotide for symptomatic management. (0)  Continue long-acting octreotide 30 mg intramuscularly every 4 weeks after completing LUTATHERA until disease progression or for 18 months following treatment initiation. (0)  Administer antiemetics before recommended amino acid solution. (0)  Initiate recommended intravenous amino acid solution 30 minutes before LUTATHERA infusion; continue during and for at least 3 hours after LUTATHERA infusion. Do not decrease dose of amino acid solution if LUTATHERA dose is reduced. (0) ----------------------DOSAGE FORMS AND STRENGTHS--------------------- Injection: 370 MBq/mL (10 mCi/mL) in single-dose vial. (3) -------------------------------CONTRAINDICATIONS------------------------------ None. (0) ------------------------WARNINGS AND PRECAUTIONS-----------------------  Risk From Radiation Exposure: Minimize radiation exposure during and after treatment with LUTATHERA consistent with institutional good radiation safety practices and patient management procedures. (0, 0)  Myelosuppression: Monitor blood cell counts. Withhold dose, reduce dose, or permanently discontinue based on the severity. (2.4, 0)  Secondary Myelodysplastic Syndrome (MDS) and Leukemia: Median time to onset: MDS is 29 months; acute leukemia is 55 months. (0)  Renal Toxicity: Advise patients to hydrate and to urinate frequently before, on the day of and the day after administration of LUTATHERA. Monitor serum creatinine and calculated creatinine clearance. Withhold dose, reduce dose, or permanently discontinue based on the severity. (2.3, 2.4, 0)  Hepatotoxicity: Monitor transaminases, bilirubin, serum albumin and INR. (2.4, 5.5)  Hypersensitivity Reactions: Monitor patients closely for signs and symptoms of hypersensitivity reactions, including anaphylaxis. Permanently discontinue LUTATHERA based on severity. (2.3, 2.4, 5.6)  Neuroendocrine Hormonal Crisis: Monitor for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms. (5.7)  Embryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.8, 0, 0)  Risk of Infertility: LUTATHERA may cause infertility. (5.9, 0) -------------------------------ADVERSE REACTIONS------------------------------ Most common Grade 3-4 adverse reactions (≥ 4% with a higher incidence in LUTATHERA arm) are lymphopenia, increased GGT, vomiting, nausea, increased AST, increased ALT, hyperglycemia and hypokalemia. (0) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA- 1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------ Somatostatin Analogs: Discontinue long-acting analogs at least 4 weeks and short-acting octreotide at least 24 hours prior to each LUTATHERA dose. (0, 0) ------------------------USE IN SPECIFIC POPULATIONS----------------------- Lactation: Advise not to breastfeed. (0) See 0 for PATIENT COUNSELING INFORMATION. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Safety Instructions 2.2 Recommended Dosage 2.3 Premedications and Concomitant Medications 2.4 Dosage Modifications for Adverse Reactions 2.5 Preparation and Administration 2.6 Radiation Dosimetry 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk From Radiation Exposure 5.2 Myelosuppression 5.3 Secondary Myelodysplastic Syndrome and Leukemia 5.4 Renal Toxicity 5.5 Hepatotoxicity 5.6 Hypersensitivity Reactions 5.7 Neuroendocrine Hormonal Crisis 5.8 Embryo-Fetal Toxicity 5.9 Risk of Infertility 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Somatostatin Analogs 7.2 Glucocorticoids 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 11  DESCRIPTION 11.1 Physical Characteristics 11.2 External Radiation 12  CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13  NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14  CLINICAL STUDIES 14.1 Progressive, Well-Differentiated Advanced or Metastatic Somatostatin Receptor-Positive Midgut Carcinoid Tumors 14.2 Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors 16  HOW SUPPLIED/STORAGE AND HANDLING 17  PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE LUTATHERA is indicated for the treatment of adult and pediatric patients 12 years and older with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors. 2 DOSAGE AND ADMINISTRATION 2.1 Important Safety Instructions LUTATHERA is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5.1)]. Use waterproof gloves and effective radiation shielding when handling LUTATHERA. Radiopharmaceuticals, including LUTATHERA, should be used by or under the control of healthcare providers who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals. Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA [see Use in Specific Populations (8.1, 8.3)]. Monitor patients closely for signs and symptoms of hypersensitivity reactions during and following the LUTATHERA administration for a minimum of 2 hours in a setting where cardiopulmonary resuscitation medication and equipment are available [see Warnings and Precautions (5.6)]. 2.2 Recommended Dosage The recommended LUTATHERA dosage for adult and pediatric patients 12 years and older is 7.4 GBq (200 mCi) every 8 weeks (± 1 week) for a total of 4 doses. Administer premedications and concomitant medications as recommended [see Dosage and Administration (2.3)]. 2.3 Premedications and Concomitant Medications Somatostatin Analogs  Before initiating LUTATHERA treatment: Discontinue long-acting somatostatin analogs (e.g., long-acting octreotide) at least 4 weeks prior to initiating LUTATHERA. Administer short-acting octreotide as needed; discontinue at least 24 hours prior to initiating LUTATHERA [see Drug Interactions (7.1)].  During LUTATHERA treatment: Administer long-acting octreotide 30 mg intramuscularly between 4 to 24 hours after each LUTATHERA dose. Do not administer long-acting octreotide within 4 weeks prior to each subsequent LUTATHERA dose. Short-acting octreotide may be given for symptomatic management during LUTATHERA treatment but must be withheld at least 24 hours before each LUTATHERA dose.  Following LUTATHERA treatment: Continue long-acting octreotide 30 mg intramuscularly every 4 weeks after completing LUTATHERA until disease progression or for 18 months following treatment initiation at the discretion of the physician. Antiemetics Administer antiemetics before the recommended amino acid solution. Amino Acid Solution Initiate an intravenous infusion of a sterile amino acid solution containing L-lysine and L-arginine (Table 1) 30 minutes before the start of the LUTATHERA infusion. Use a three-way valve to administer the amino acid solution using the same venous access as LUTATHERA or administer the amino acid solution through a separate venous access in the patient’s other arm. Continue the amino acid solution infusion during and for at least 3 hours after completion of the LUTATHERA infusion. Do not decrease the dose of the amino acid solution if a reduced dose of LUTATHERA is administered [see Warnings and Precautions (5.4)]. Table 1. Amino Acid Solution Item Specification L-lysine HCl Between 18 and 25 ga L-arginine HCl Between 18 and 25 gb Volume 1 to 2 L Osmolality < 1200 mOsmol/kg aequivalent to 14.4 to 20 g L-lysine. bequivalent to 14.9 to 20.7 g L-arginine. Hypersensitivity Prophylaxis Premedicate patients who have had prior Grade 1 or 2 hypersensitivity reactions to LUTATHERA. Do not re- challenge patients who experience Grade 3 or 4 hypersensitivity reactions to LUTATHERA [see Warnings and Precautions (5.6)]. 2.4 Dosage Modifications for Adverse Reactions Recommended dose modifications of LUTATHERA for adverse reactions are provided in Table 2. Table 2. Recommended Dosage Modifications of LUTATHERA for Adverse Reactions Adverse reaction Severity of adverse reactiona Dose modification Thrombocytopenia [see Warnings and Precautions (5.2)] First occurrence of Grade 2, 3, or 4 Withhold dose until complete or partial resolution (Grade 0 to 1). Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 2, 3, or 4 thrombocytopenia, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for Grade 2 or higher thrombocytopenia requiring a dosing interval beyond 16 weeks. Recurrent Grade 2, 3, or 4 Permanently discontinue LUTATHERA. Anemia and Neutropenia [see Warnings and Precautions (5.2)] First occurrence of Grade 3 or 4 Withhold dose until complete or partial resolution (Grade 0, 1, or 2). Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 3 or 4 anemia or neutropenia, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for Grade 3 or higher anemia or neutropenia requiring a dosing interval beyond 16 weeks. Recurrent Grade 3 or 4 Permanently discontinue LUTATHERA. Adverse reaction Severity of adverse reactiona Dose modification Renal Toxicity [see Warnings and Precautions (5.4)] First occurrence of:  Creatinine clearance less than 40 mL/min; calculated using Cockcroft- Gault formula with actual body weight, or  40% increase from baseline serum creatinine, or  40% decrease from baseline creatinine clearance; calculated using Cockcroft- Gault formula with actual body weight. Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with resolution or return to baseline. If reduced dose does not result in renal toxicity, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for renal toxicity requiring a dosing interval beyond 16 weeks. Recurrent renal toxicity Permanently discontinue LUTATHERA. Hepatotoxicity [see Warnings and Precautions (5.5)] First occurrence of:  Bilirubinemia greater than 3 times the upper limit of normal (Grade 3 or 4), or  Serum albumin less than 30 g/L with international normalized ratio (INR) > 1.5. Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with resolution or return to baseline. If reduced LUTATHERA dose does not result in hepatotoxicity, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for hepatotoxicity requiring a dosing interval beyond 16 weeks. Recurrent hepatotoxicity Permanently discontinue LUTATHERA. Hypersensitivity Reactionsb [see Warnings and Precautions (5.6)] First occurrence of Grade 3 or 4 Permanently discontinue LUTATHERA. Any Other Adverse Reactionsc [see Adverse Reactions (6.1)] First occurrence of Grade 3 or 4 Withhold dose until complete or partial resolution (Grade 0 to 2). Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 3 or 4 toxicity, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for Grade 3 or higher adverse reactions requiring a dosing interval beyond 16 weeks. Recurrent Grade 3 or 4 Permanently discontinue LUTATHERA. aGrading of severity is defined in the most current Common Terminology Criteria for Adverse Events (CTCAE). bIncluding allergic reaction and anaphylaxis. cNo dose modification required for hematological toxicities Grade 3 or Grade 4 solely due to lymphopenia. 2.5 Preparation and Administration Preparation Instructions  Use aseptic technique and radiation shielding when handling or administering the LUTATHERA solution. Use tongs when handling the vial to minimize radiation exposure.  Inspect the product visually under a shielded screen for particulate matter and discoloration prior to administration. Discard the vial if particulates and/or discoloration are present.  Do not inject the LUTATHERA solution directly into any other intravenous solution.  Confirm the amount of radioactivity of LUTATHERA delivered to the patient with an appropriate dose calibrator prior to and after each LUTATHERA administration.  Dispose of any unused medicinal product or waste material in accordance with local and federal laws. Administration Instructions  Prior to administration, flush the intravenous catheter used for LUTATHERA administration with ≥ 10 mL of 0.9% Sodium Chloride Injection, USP to ensure patency and to minimize the risk of extravasation. Manage cases of extravasation as per institutional guidelines.  The gravity method, peristaltic pump method, or the syringe pump method may be used for the administration of the recommended dosage. Do not administer LUTATHERA as an intravenous bolus.  When using the gravity or peristaltic pump method, infuse LUTATHERA directly from its original container.  Use the peristaltic pump or syringe pump method when administering a reduced dose of LUTATHERA following a dosage modification for an adverse reaction. When using the gravity method for a reduced dose, adjust the LUTATHERA dose before the administration to avoid the delivery of an incorrect volume of LUTATHERA. Intravenous Methods of Administration Instructions for the Gravity Method  Insert a 2.5 cm, 20-gauge needle (short needle) into the LUTATHERA vial and connect via a catheter to 500 mL 0.9% Sodium Chloride Injection, USP (used to transport the LUTATHERA solution during the infusion). Ensure that the short needle does not touch the LUTATHERA solution in the vial and do not connect this short needle directly to the patient. Do not allow the 0.9% Sodium Chloride Injection, USP to flow into the LUTATHERA vial prior to the initiation of the LUTATHERA infusion and do not inject the LUTATHERA solution directly into the 0.9% Sodium Chloride Injection, USP.  Insert a second needle that is 9 cm, 18-gauge (long needle) into the LUTATHERA vial ensuring that this long needle touches and is secured to the bottom of the LUTATHERA vial during the entire infusion. Connect the long needle to the patient by an intravenous catheter that is pre-filled with 0.9% Sodium Chloride Injection, USP and that is used for the LUTATHERA infusion into the patient.  Use a clamp or an infusion pump to regulate the flow of the 0.9% Sodium Chloride Injection, USP via the short needle into the LUTATHERA vial at a rate of 50 mL/hour to 100 mL/hour for 5 to 10 minutes and then 200 mL/hour to 300 mL/hour for an additional 25 to 30 minutes (the 0.9% Sodium Chloride Injection, USP entering the vial through the short needle will carry the LUTATHERA solution from the vial to the patient via the intravenous catheter connected to the long needle over a total duration of 30 to 40 minutes).  During the infusion, ensure that the level of solution in the LUTATHERA vial remains constant.  Disconnect the vial from the long needle line and clamp the 0.9% Sodium Chloride Injection, USP line once the level of radioactivity is stable for at least five minutes.  Follow the infusion with an intravenous flush of 25 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient. Instructions for the Peristaltic Pump Method  Insert a filtered 2.5 cm, 20-gauge needle (short venting needle) into the LUTATHERA vial. Ensure that the short needle does not touch the LUTATHERA solution in the vial and do not connect this short needle directly to the patient or to the peristaltic pump.  Insert a second needle that is 9 cm, 18 gauge (long needle) into the LUTATHERA vial ensuring that the long needle touches and is secured to the bottom of the LUTATHERA vial during the entire infusion. Connect the long needle and a 0.9% Sodium Chloride Injection, USP to a 3-way stopcock valve via appropriate tubing.  Connect the output of the 3-way stopcock valve to tubing installed on the input side of the peristaltic pump according to manufacturer’s instructions.  Prime the line by opening the 3-way stopcock valve and pumping the LUTATHERA solution through the tubing until it reaches the exit of the valve.  Prime the intravenous catheter that will be connected to the patient by opening the 3-way stopcock valve to the 0.9% Sodium Chloride Injection, USP and pumping the 0.9% Sodium Chloride Injection, USP until it exits the end of the catheter tubing.  Connect the primed intravenous catheter to the patient and set the 3-way stopcock valve such that the LUTATHERA solution is in line with the peristaltic pump.  Infuse an appropriate volume of LUTATHERA solution over a 30-40 min period to deliver the desired radioactivity.  When the desired LUTATHERA radioactivity has been delivered, stop the peristaltic pump and then change the position of the 3-way stopcock valve so that the peristaltic pump is in line with the 0.9% Sodium Chloride Injection, USP. Restart the peristaltic pump and infuse an intravenous flush of 25 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient. Instructions for the Syringe Pump Method  Withdraw an appropriate volume of LUTATHERA solution to deliver the desired radioactivity by using a disposable syringe fitted with a syringe shield and a disposable sterile needle that is 9 cm, 18 gauge (long needle). To aid the withdrawal of the solution, a filtered 2.5 cm, 20-gauge needle (short venting needle) can be used to reduce the resistance from the pressurized vial. Ensure that the short needle does not touch the LUTATHERA solution in the vial.  Fit the syringe into the shielded pump and include a 3-way stopcock valve between the syringe and an intravenous catheter pre-filled with 0.9% Sodium Chloride Injection, USP and used for LUTATHERA administration to the patient.  Infuse an appropriate volume of LUTATHERA solution over a 30-40 min period to deliver the desired radioactivity.  When the desired LUTATHERA radioactivity has been delivered, stop the syringe pump and then change the position of the 3-way stopcock valve to flush the syringe with 25 mL of 0.9% Sodium Chloride Injection, USP. Restart the syringe pump.  After the flush of the syringe has been completed, perform an intravenous flush with 25 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient. 2.6 Radiation Dosimetry The maximum penetration of lutetium-177 in tissue is 2.2 mm and the mean penetration is 0.67 mm. The mean and standard deviation (SD) of the estimated radiation absorbed doses for adults receiving LUTATHERA are shown in Table 3. The mean and SD of the estimated radiation absorbed doses for pediatric patients 12 years and older receiving LUTATHERA are shown in Table 4. Table 3. Estimated Radiation Absorbed Dose for LUTATHERA in Adults in NETTER-1 Absorbed dose per unit activity (Gy/GBq) (N = 20) Calculated absorbed dose for 4 × 7.4 GBq (29.6 GBq cumulative activity) (Gy) Organ Mean SD Mean SD Adrenals 0.037 0.016 1.1 0.5 Brain 0.027 0.016 0.8 0.5 Breasts 0.027 0.015 0.8 0.4 Gallbladder wall 0.042 0.019 1.2 0.6 Heart wall 0.032 0.015 0.9 0.4 Kidneys 0.654 0.295 19.4 8.7 Livera 0.299 0.226 8.9 6.7 Lower large intestine wall 0.029 0.016 0.9 0.5 Lungs 0.031 0.015 0.9 0.4 Muscle 0.029 0.015 0.8 0.4 Osteogenic cells 0.151 0.268 4.5 7.9 Ovariesb 0.031 0.013 0.9 0.4 Pancreas 0.038 0.016 1.1 0.5 Red marrowc 0.035 0.029 1.0 0.8 Skin 0.027 0.015 0.8 0.4 Small intestine 0.031 0.015 0.9 0.5 Spleen 0.846 0.804 25.1 23.8 Stomach wall 0.032 0.015 0.9 0.5 Testesd 0.026 0.018 0.8 0.5 Thymus 0.028 0.015 0.8 0.5 Thyroid 0.027 0.016 0.8 0.5 Total body 0.052 0.027 1.6 0.8 Upper large intestine wall 0.032 0.015 0.9 0.4 Urinary bladder wall 0.437 0.176 12.8 5.3 Uterusb 0.032 0.013 1.0 0.4 aN = 18 (two patients excluded because the liver absorbed dose was biased by the uptake of the liver metastases). bN = 9 (female patients only). cRed marrow dosimetry estimates were determined using blood radioactivity. dN = 11 (male patients only). Table 4. Estimated Radiation Absorbed Dose for LUTATHERA in Pediatric Patients 12 Years and Older in NETTER-P Absorbed dose per unit activity (Gy/GBq) (N = 8a) Calculated absorbed dose for 4 × 7.4 GBq (29.6 GBq cumulative activity) (Gy) Organ Mean SD Mean SD Adrenals 0.045 0.011 1.3 0.3 Brain 0.021 0.006 0.6 0.2 Breastsb 0.018 0.006 0.5 0.2 Esophagus 0.024 0.006 0.7 0.2 Eyes 0.021 0.006 0.6 0.2 Gallbladder wall 0.031 0.011 0.9 0.3 Heart wall 0.024 0.006 0.7 0.2 Kidneys 0.773 0.288 22.9 8.5 Left colon 0.265 0.081 7.8 2.4 Liver 0.216 0.231 6.4 6.8 Lungs 0.024 0.006 0.7 0.2 Osteogenic cells 0.046 0.019 1.4 0.6 Ovariesb 0.026 0.007 0.8 0.2 Pancreas 0.027 0.007 0.8 0.2 Pituitaryc 1.053 0.348 31.2 10.3 Prostated 0.026 0.006 0.8 0.2 Rectum 0.272 0.085 8.0 2.5 Red marrow (blood)e 0.027 0.005 0.8 0.2 Red marrow (image) e 0.055 0.026 1.6 0.8 Right colon 0.152 0.045 4.5 1.3 Salivary glands 0.036 0.017 1.1 0.5 Small intestine 0.046 0.013 1.3 0.4 Spleen 0.733 0.304 21.7 9.0 Stomach wall 0.027 0.007 0.8 0.2 Testesd 0.021 0.005 0.6 0.2 Thymus 0.022 0.006 0.7 0.2 Thyroid 0.022 0.006 0.6 0.2 Total body 0.042 0.010 1.2 0.3 Urinary bladder wall 0.573 0.088 17.0 2.6 Uterusb 0.031 0.008 0.9 0.2 aData are pooled for 8 pediatric patients with somatostatin receptor-positive (SSTR+) tumors, including 4 patients with GEP-NETs. bN = 5 (female patients only). cN = 7 (3 GEP-NET, 4 SSTR+ tumors). Pituitary dosimetry estimates were only performed when pituitary uptake was clearly observed on the planar images. Due to the small size of the pituitary gland, availability for quantification only from planar images and interference from activity in the nasal mucosa, estimates can be associated with a large uncertainty. Pituitary gland absorbed dose estimate includes absorbed dose contributions from activity within the pituitary only, dose contributions from other tissues are not included. dN = 3 (male patients only). eRed marrow dosimetry estimates were determined either using blood radioactivity or by imaging and scaling of a representative region of the lumbar spine. 3 DOSAGE FORMS AND STRENGTHS Injection: 370 MBq/mL (10 mCi/mL) of lutetium Lu 177 dotatate as a clear and colorless to slightly yellow solution in a single-dose vial. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Risk From Radiation Exposure LUTATHERA contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. These risks of radiation associated with the use of LUTATHERA are greater in pediatric patients than in adults [see Use in Specific Populations (8.4)]. Radiation can be detected in the urine for up to 30 days following LUTATHERA administration. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with LUTATHERA consistent with institutional good radiation safety practices, patient management procedures, Nuclear Regulatory Commission patient-release guidance, and instructions to the patient for follow-up radiation protection at home [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. 5.2 Myelosuppression In NETTER-1, myelosuppression occurred more frequently in patients receiving LUTATHERA with long- acting octreotide compared to patients receiving high-dose long-acting octreotide (all Grades/Grade 3 or 4): anemia (81%/0) versus (54%/1%); thrombocytopenia (53%/1%) versus (17%/0); and neutropenia (26%/3%) versus (11%/0). In NETTER-1, platelet nadir occurred at a median of 5.1 months following the first dose. Of the 59 patients who developed thrombocytopenia, 68% had platelet recovery to baseline or normal levels. The median time to platelet recovery was 2 months. Fifteen of the nineteen patients in whom platelet recovery was not documented had post-nadir platelet counts. Among these 15 patients, 5 improved to Grade 1, 9 to Grade 2, and 1 to Grade 3. Monitor blood cell counts. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of myelosuppression [see Dosage and Administration (2.4)]. 5.3 Secondary Myelodysplastic Syndrome and Leukemia In NETTER-1, with a median follow-up time of 76 months in the main study, myelodysplastic syndrome (MDS) was reported in 2.3% of patients receiving LUTATHERA with long-acting octreotide compared to no patients receiving high-dose long-acting octreotide. In ERASMUS, 16 patients (2.0%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to onset was 29 months (9 to 45 months) for MDS and 55 months (32 to 125 months) for acute leukemia. 5.4 Renal Toxicity In ERASMUS, 8 patients (< 1%) developed renal failure 3 to 36 months following LUTATHERA. Two of these patients had underlying renal impairment or risk factors for renal failure (e.g., diabetes or hypertension) and required dialysis. Administer the recommended amino acid solution before, during and after LUTATHERA [see Dosage and Administration (2.3)] to decrease the reabsorption of lutetium Lu 177 dotatate through the proximal tubules and decrease the radiation dose to the kidneys. Advise patients to hydrate and to urinate frequently before, on the day of, and the day after administration of LUTATHERA. Monitor serum creatinine and calculated creatinine clearance. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of renal toxicity [see Dosage and Administration (2.4)]. Patients with baseline renal impairment may be at increased risk of toxicity due to increased radiation exposure [see Use in Specific Populations (8.6)]. 5.5 Hepatotoxicity In ERASMUS, 2 patients (< 1%) were reported to have hepatic tumor hemorrhage, edema, or necrosis, with one patient experiencing intrahepatic congestion and cholestasis. Patients with hepatic metastasis may be at increased risk of hepatotoxicity due to radiation exposure. Monitor transaminases, bilirubin, serum albumin, and international normalized ratio (INR) during treatment. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of hepatotoxicity [see Dosage and Administration (2.4)]. 5.6 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema, occurred in patients treated with LUTATHERA [see Adverse Reactions (6.2)]. Monitor patients closely for signs and symptoms of hypersensitivity reactions, including anaphylaxis, during and following LUTATHERA administration for a minimum of 2 hours in a setting where cardiopulmonary resuscitation medication and equipment are available. Discontinue the infusion upon the first observation of any signs or symptoms consistent with a severe hypersensitivity reaction and initiate appropriate therapy. Premedicate patients with a history of Grade 1 or 2 hypersensitivity reactions to LUTATHERA before subsequent doses [see Dosage and Administration (2.3)]. Permanently discontinue LUTATHERA in patients who experience Grade 3 or 4 hypersensitivity reactions [see Dosage and Administration (2.4)]. 5.7 Neuroendocrine Hormonal Crisis Neuroendocrine hormonal crises, manifesting with flushing, diarrhea, bronchospasm and hypotension, occurred in < 1% of patients in ERASMUS and typically occurred during or within 24 hours following the initial LUTATHERA dose. Two (< 1%) patients were reported to have hypercalcemia. Monitor patients for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms of tumor-related hormonal release. Administer intravenous somatostatin analogs, fluids, corticosteroids, and electrolytes as indicated. 5.8 Embryo-Fetal Toxicity Based on its mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on LUTATHERA use in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, radioactive emissions, including those from LUTATHERA, can cause fetal harm. Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA [see Dosage and Administration (2.1)]. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LUTATHERA and for 7 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LUTATHERA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. 5.9 Risk of Infertility LUTATHERA may cause infertility in males and females. The recommended cumulative dose of 29.6 GBq of LUTATHERA results in a radiation absorbed dose to the testes and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy [see Dosage and Administration (2.6), Use in Specific Populations (8.3)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:  Myelosuppression [see Warnings and Precautions (5.2)]  Secondary Myelodysplastic Syndrome and Leukemia [see Warnings and Precautions (5.3)]  Renal Toxicity [see Warnings and Precautions (5.4)]  Hepatotoxicity [see Warnings and Precautions (5.5)]  Hypersensitivity Reactions [see Warnings and Precautions (5.6)]  Neuroendocrine Hormonal Crisis [see Warnings and Precautions (5.7)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in WARNINGS AND PRECAUTIONS reflect exposure to LUTATHERA in 111 patients with advanced, progressive midgut neuroendocrine tumors (NETTER-1). Safety data in WARNINGS AND PRECAUTIONS were also obtained in an additional 22 patients in a non-randomized pharmacokinetic sub- study of NETTER-1 and in a subset of patients (811 of 1214) with advanced somatostatin receptor-positive tumors enrolled in ERASMUS [see Warnings and Precautions (5)]. Adult Population NETTER-1 The safety data of LUTATHERA with octreotide was evaluated in NETTER-1 [see Clinical Studies (14.1)]. Patients with progressive, somatostatin receptor-positive midgut carcinoid tumors received LUTATHERA 7.4 GBq (200 mCi) administered every 8 to 16 weeks concurrently with the recommended amino acid solution and with long-acting octreotide (30 mg administered by intramuscular injection within 24 hours of each LUTATHERA dose) (N = 111), or high-dose octreotide (defined as long-acting octreotide 60 mg by intramuscular injection every 4 weeks) (N = 112) [see Clinical Studies (14.1)]. Among patients receiving LUTATHERA with octreotide, 79% received a cumulative dose > 22.2 GBq (> 600 mCi) and 76% of patients received all four planned doses. Six percent (6%) of patients required a dose reduction and 13% of patients discontinued LUTATHERA. Five patients discontinued LUTATHERA for renal-related events and 4 discontinued for hematological toxicities. Table 5 and Table 6 summarize the incidence of adverse reactions and laboratory abnormalities, respectively. The most common Grade 3-4 adverse reactions occurring with a greater frequency among patients receiving LUTATHERA with octreotide compared to patients receiving high-dose octreotide include: lymphopenia (44%), increased gamma-glutamyltransferase (GGT) (20%), vomiting (7%), nausea and increased aspartate aminotransferase (AST) (5% each), and increased alanine aminotransferase (ALT), hyperglycemia and hypokalemia (4% each). Table 5. Adverse Reactions Occurring at Higher Incidence in Patients Receiving LUTATHERA with Long-Acting Octreotide Compared to High-Dose Long-Acting Octreotide (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4)a Adverse reactiona LUTATHERA with long- acting Octreotide (30 mg) (N = 111) Long-acting Octreotide (60 mg) (N = 112) All Grades % Grades 3-4 % All Grades % Grades 3-4 % Gastrointestinal disorders Nausea 65 5 12 2 Vomiting 53 7 10 0 Abdominal pain 26 3 19 3 Diarrhea 26 3 18 1 Constipation 10 0 5 0 General disorders Fatigue 38 1 26 2 Peripheral edema 16 0 9 1 Pyrexia 8 0 3 0 Metabolism and nutrition disorders Decreased appetite 21 0 11 3 Nervous system disorders  Headache  17  0  5  0  Dizziness  17  0  8  0  Dysgeusia  8  0  2  0  Vascular disorders  Flushing  14  1  9  0  Hypertension  12  2  7  2  Musculoskeletal and connective tissue disorders Back pain 13 2 10 0 Pain in extremity 11 0 5 0 Myalgia 5 0 0 0 Neck pain 5 0 0 0 Renal and urinary disorders          Renal failureb  13  3  4  1  Radiation-related urinary tract adverse reactionsc  8  0  3  0  Psychiatric disorders Anxiety 12 1 5 0 Skin and subcutaneous tissue disorders  Alopecia  12  0  2  0  Respiratory, thoracic and mediastinal disorders Cough 11 1 6 0 Cardiac disorders  Atrial fibrillation  5  1  0  0  aNational Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Only displays adverse reactions occurring at a higher incidence in LUTATHERA-treated patients [between arm difference of ≥ 5% (all Grades) or ≥ 2% (Grades 3-4)]. bIncludes the terms: Glomerular filtration rate decreased, acute kidney injury, acute prerenal failure, azotemia, renal disorder, renal failure, renal impairment. cIncludes the terms: Dysuria, micturition urgency, nocturia, pollakiuria, renal colic, renal pain, urinary tract pain and urinary incontinence. Table 6. Laboratory Abnormalities Occurring at Higher Incidence in Patients Receiving LUTATHERA with Long-Acting Octreotide Compared to High-Dose Long-Acting Octreotide (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4)a,b Laboratory abnormalityb LUTATHERA with long-acting Octreotide (30 mg) (N = 111) Long-acting Octreotide (60 mg) (N = 112) All Grades % Grades 3-4 % All Grades % Grades 3-4 % Hematology Lymphopenia 90 44 39 5 Anemia 81 0 55 1 Leukopenia 55 2 20 0 Thrombocytopenia 53 1 17 0 Neutropenia 26 3 11 0 Renal/Metabolic Creatinine increased 85 1 73 0 Hyperglycemia 82 4 67 2 Hyperuricemia 34 6 30 6 Hypocalcemia 32 0 14 0 Hypokalemia 26 4 21 2 Hyperkalemia 19 0 11 0 Hypernatremia 17 0 7 0 Hypoglycemia 15 0 8 0 Hepatic GGT increased 66 20 67 16 Alkaline phosphatase increased 65 5 55 9 AST increased 50 5 35 0 ALT increased 43 4 34 0 Blood bilirubin increased 30 2 28 0 aValues are worst grade observed after randomization. bNational Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Only displays laboratory abnormalities occurring at a higher incidence in LUTATHERA-treated patients [between arm difference of ≥ 5% (all Grades) or ≥ 2% (Grades 3-4)]. ERASMUS Safety data are available from 1214 patients in ERASMUS, an international, single-institution, single-arm, open-label trial of patients with somatostatin receptor-positive tumors (neuroendocrine and other primaries). Patients received LUTATHERA 7.4 GBq (200 mCi) administered every 6 to 13 weeks with or without octreotide. Retrospective medical record review was conducted on a subset of 811 patients to document serious adverse reactions. Eighty-one (81%) percent of patients in the subset received a cumulative dose ≥ 22.2 GBq (≥ 600 mCi). With a median follow-up time of more than 4 years, the following rates of serious adverse reactions were reported: myelodysplastic syndrome (2%), acute leukemia (1%), renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%). Pediatric Population NETTER-P Safety data are available from 9 pediatric patients in NETTER-P (NCT04711135), an international, multi- center, single-arm, open-label trial of patients with somatostatin receptor-positive tumors, including 4 patients with GEP-NETs. Patients received LUTATHERA 7.4 GBq (200 mCi) administered every 8 weeks concurrently with the recommended amino acid solution. Adverse reactions observed in NETTER-P were similar to those observed in adults treated with LUTATHERA. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of LUTATHERA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.  Immune System Disorders: hypersensitivity reactions, including angioedema 7 DRUG INTERACTIONS 7.1 Somatostatin Analogs Somatostatin and its analogs competitively bind to somatostatin receptors and may interfere with the efficacy of LUTATHERA. Discontinue long-acting somatostatin analogs at least 4 weeks and short-acting octreotide at least 24 hours prior to each LUTATHERA dose. Administer short- and long-acting octreotide during LUTATHERA treatment as recommended [see Dosage and Administration (2.3)]. 7.2 Glucocorticoids Glucocorticoids can induce down-regulation of subtype 2 somatostatin receptors (SSTR2). Avoid repeated administration of high doses of glucocorticoids during treatment with LUTATHERA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on LUTATHERA use in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, radioactive emissions, including those from LUTATHERA, can cause fetal harm. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary There are no data on the presence of lutetium Lu 177 dotatate in human milk, or its effects on the breastfed child or milk production. No lactation studies in animals were conducted. Because of the potential risk for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LUTATHERA and for 2.5 months after the last dose. 8.3 Females and Males of Reproductive Potential Based on mechanism of action, LUTATHERA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA [see Use in Specific Populations (8.1)]. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with LUTATHERA and for 7 months after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with LUTATHERA and for 4 months after the last dose [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. Infertility The recommended cumulative dose of 29.6 GBq of LUTATHERA results in a radiation absorbed dose to the testes and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy [see Dosage and Administration (2.6)]. 8.4 Pediatric Use Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors The safety and effectiveness of LUTATHERA have been established in pediatric patients 12 years and older with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Use of LUTATHERA for this indication is supported by evidence from an adequate and well-controlled study of LUTATHERA in adults with additional safety, pharmacokinetic, and dosimetry data in pediatric patients aged 12 years and older with somatostatin receptor-positive tumors, including 4 pediatric patients with GEP-NETs [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14)]. The risks of radiation exposure associated with LUTATHERA are greater in pediatric patients than in adult patients due to longer life expectancy. Continued follow-up is recommended for evaluation of long-term effects. There was no clinically relevant difference in lutetium Lu 177 dotatate exposure in pediatric patients aged 13 to 16 years versus adult patients [see Clinical Pharmacology (12.3)]. The pharmacokinetic profile and safety of LUTATHERA in pediatric patients 12 years and older with baseline renal impairment have not been studied. The safety and effectiveness of LUTATHERA have not been established in pediatric patients younger than 12 years old with somatostatin receptor-positive GEP-NETs. 8.5 Geriatric Use Of the 1325 patients treated with LUTATHERA in clinical trials, 438 patients (33%) were 65 years and older. No overall differences in safety or effectiveness were observed between older and younger patients. 8.6 Renal Impairment No dose adjustment is recommended for patients with baseline mild to moderate (creatinine clearance 30 to 89 mL/min by Cockcroft-Gault formula) renal impairment. However, patients with baseline mild or moderate renal impairment may be at greater risk of toxicity, including renal toxicity, due to increased radiation exposure. Perform more frequent assessments of renal function in patients with baseline mild to moderate impairment. The pharmacokinetic profile and safety of LUTATHERA in patients with baseline severe renal impairment (creatinine clearance < 30 mL/min by Cockcroft-Gault formula) or end-stage renal disease have not been studied [see Warnings and Precautions (5.4)]. 8.7 Hepatic Impairment No dose adjustment is recommended for patients with baseline mild or moderate hepatic impairment. The pharmacokinetic profile and safety of LUTATHERA in patients with baseline severe hepatic impairment (total bilirubin > 3 times upper limit of normal, regardless of AST level) have not been studied. 11 DESCRIPTION Lutetium Lu 177 dotatate is a radiolabeled somatostatin analog. The drug substance lutetium Lu 177 dotatate is a cyclic peptide linked with the covalently bound chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid to a radionuclide. Table 8. Physical Decay Chart: Lutetium-177 Physical Half-Life = 6.647 Days Hours Fraction remaining Hours Fraction remaining 0 1.000 48 (2 days) 0.812 1 0.996 72 (3 days) 0.731 2 0.991 168 (7 days) 0.482 5 0.979 336 (14 days) 0.232 10 0.958 720 (30 days) 0.044 24 (1 day) 0.901 1080 (45 days) 0.009 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lutetium Lu 177 dotatate binds to somatostatin receptors with highest affinity for subtype 2 somatostatin receptors (SSTR2). Upon binding to somatostatin receptor expressing cells, including malignant somatostatin receptor-positive tumors, the compound is internalized. The beta-minus emission from lutetium-177 induces cellular damage by formation of free radicals in somatostatin receptor-positive cells and in neighboring cells. 12.2 Pharmacodynamics Lutetium Lu 177 dotatate exposure-response relationships and the time course of pharmacodynamics response are unknown. Cardiac Electrophysiology The ability of LUTATHERA to prolong the QTc interval at the recommended dose was assessed in an open- label study in 20 patients with somatostatin receptor-positive midgut carcinoid tumors. No large changes in the mean QTc interval (i.e., > 20 ms) were detected. 12.3 Pharmacokinetics The pharmacokinetics (PK) of lutetium Lu 177 dotatate have been characterized in patients with progressive, somatostatin receptor-positive neuroendocrine tumors. The mean blood exposure (area under the curve) of lutetium Lu 177 dotatate at the recommended dose is 41 ng.h/mL [coefficient of variation (CV) 36%]. The mean maximum blood concentration (Cmax) for lutetium Lu 177 dotatate is 10 ng/mL (CV 50%), which generally occurred at the end of the LUTATHERA infusion. Distribution The mean volume of distribution (Vz) for lutetium Lu 177 dotatate is 460 L (CV 54%). The non-radioactive lutetium Lu 175 dotatate is 43% bound to human plasma proteins. Within 4 hours after administration, lutetium Lu 177 dotatate distributes in kidneys, tumor lesions, liver, spleen, and, in some patients, pituitary gland and thyroid. The co-administration of amino acids reduced the median radiation dose to the kidneys by 47% (34% to 59%) and increased the mean beta-phase blood clearance of lutetium Lu 177 dotatate by 36%. Elimination The mean clearance (CL) is 4.5 L/h (CV 31%) and the mean terminal half-life is 71 (±28) hours for lutetium 177 dotatate. Metabolism Lutetium Lu 177 dotatate does not undergo hepatic metabolism. Excretion Lutetium Lu 177 dotatate is primarily eliminated renally with cumulative excretion of 44% within 5 hours, 58% within 24 hours, and 65% within 48 hours following LUTATHERA administration. Prolonged elimination of lutetium Lu 177 dotatate in the urine is expected; however, based on the half-life of lutetium-177 and terminal half-life of lutetium Lu 177 dotatate, greater than 99% of the administered radioactivity will be eliminated within 14 days after administration of LUTATHERA [see Warnings and Precautions (5.1)]. Special Populations Pediatric Patients There were no clinically relevant differences in exposure of lutetium Lu 177 dotatate in pediatric patients 12 years and older compared to that of adult patients. Drug Interaction Studies In Vitro Studies CYP450 enzymes: The non-radioactive lutetium Lu 175 dotatate is not an inhibitor or inducer of cytochrome P450 (CYP) 1A2, 2B6, 2C9, 2C19 or 2D6 in vitro. Transporters: The non-radioactive lutetium Lu 175 dotatate is not an inhibitor of P-glycoprotein, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3 in vitro. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity and mutagenicity studies have not been conducted with lutetium Lu 177 dotatate; however, radiation is a carcinogen and mutagen. No animal studies were conducted to determine the effects of lutetium Lu 177 dotatate on fertility. 13.2 Animal Toxicology and/or Pharmacology The primary target organ in animal studies using the non-radioactive lutetium Lu 175 dotatate was the pancreas, a high SSTR2 expressing organ. Pancreatic acinar apoptosis occurred at lutetium Lu 175 dotatate doses ≥ 5 mg/kg in repeat dose toxicology studies in rats. Pancreatic acinar cell atrophy also occurred in repeat dose toxicology studies in dogs at doses ≥ 500 mcg/kg. These findings were consistent with high uptake of the radiolabeled peptide in the pancreas in animal biodistribution studies. 14 CLINICAL STUDIES 14.1 Progressive, Well-Differentiated Advanced or Metastatic Somatostatin Receptor-Positive Midgut Carcinoid Tumors The efficacy of LUTATHERA in patients with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor-positive midgut carcinoid tumors was established in NETTER-1 (NCT01578239), a randomized, multicenter, open-label, active-controlled trial. Key eligibility criteria included Ki67 index ≤ 20%, Karnofsky performance status ≥ 60, confirmed presence of somatostatin receptors on all lesions (OctreoScan uptake ≥ normal liver), creatinine clearance ≥ 50 mL/min, no prior treatment with peptide receptor radionuclide therapy (PRRT), and no prior external beam radiation therapy to more than 25% of the bone marrow. At the time of the primary analysis, 229 patients were randomized (1:1) to receive either LUTATHERA 7.4 GBq (200 mCi) every 8 weeks (±1 week) for up to 4 administrations (maximum cumulative dose of 29.6 GBq) or high-dose long-acting octreotide (defined as 60 mg by intramuscular injection every 4 weeks). Patients in the LUTATHERA arm also received long-acting octreotide 30 mg as an intramuscular injection 4 to 24 hours after each LUTATHERA dose and every 4 weeks after completion of LUTATHERA treatment until disease progression or until week 76 of the study. Patients in both arms could receive short-acting octreotide for symptom management; however, short-acting octreotide was withheld at least 24 hours before each LUTATHERA dose. Randomization was stratified by OctreoScan tumor uptake score (Grade 2, 3, or 4) and the length of time that patients had been on the most recent constant dose of octreotide prior to randomization (≤ 6 or > 6 months). The major efficacy outcome measure was progression-free survival (PFS) as determined by a blinded independent review committee (IRC) per RECIST v1.1. Additional efficacy outcome measures were overall response rate (ORR) by IRC, duration of response (DoR) by IRC, and overall survival (OS). Demographic and baseline disease characteristics were balanced between the treatment arms. Of the 229 patients, 82% were White, 4% were Black, 3% were Hispanic or Latino, 0.4% were Asian, 0.4% were Other, and 9% were not reported. The median age was 64 years (28 to 87 years); 51% were male, 74% had an ileal primary, and 96% had metastatic disease in the liver. The median Karnofsky performance score was 90 (60 to 100), 74% received a constant dose of octreotide for > 6 months and 12% received prior treatment with everolimus. Sixty-nine percent of patients had Ki67 expression in ≤ 2% of tumor cells, 77% had CgA > 2 times the upper limit of normal (ULN), 65% had 5-HIAA > 2 times ULN, and 65% had alkaline phosphatase ≤ ULN. At the time of the final OS analysis, which occurred 66 months after the primary PFS analysis, 117 patients were randomized to the LUTATHERA arm and 114 patients were randomized to the octreotide arm. In the final OS analysis, there was no statistically significant difference in OS between the two treatment arms. Efficacy results for NETTER-1 are presented in Table 9 and Figure 1. Table 9. Efficacy Results in NETTER-1 LUTATHERA with long- acting Octreotide (30 mg) N = 116 Long-acting Octreotide (60 mg) N = 113 PFS by IRC Events (%) 27 (23%) 78 (69%) Progressive disease, n (%) 15 (13%) 61 (54%) Death, n (%) 12 (10%) 17 (15%) Median in months (95% CI) NR (18.4, NE) 8.5 (6.0, 9.1) Hazard ratioa (95% CI) 0.21 (0.13, 0.32) p-valueb < 0.0001 ORR by IRC ORR, % (95% CI) 13% (7%, 19%) 4% (0.1%, 7%) Complete response rate, n (%) 1 (1%) 0 Partial response rate, n (%) 14 (12%) 4 (4%) p-valuec 0.0148 Duration of response, median in months (95% CI) NR (2.8, NE) 1.9 (1.9, NE) Abbreviations: CI, confidence interval; IRC, independent radiology committee; NE, not evaluable; NR, not reached; ORR, overall response rate; PFS, progression-free survival. aHazard ratio based on the unstratified Cox model. bUnstratified log rank test. cFisher’s exact test. The shelf life is 72 hours from the date and time of calibration. Discard appropriately at 72 hours. Lutetium-177 for LUTATHERA may be prepared using two different sources of stable nuclides (either lutetium-176 or ytterbium-176) resulting in different waste management. Consult the documentation provided before using LUTATHERA to ensure appropriate waste management. 17 PATIENT COUNSELING INFORMATION Risk From Radiation Exposure Advise patients and/or caregivers to minimize radiation exposure to household contacts during and after treatment with LUTATHERA consistent with institutional good radiation safety practices and patient management procedures [see Dosage and Administration (2.1), Warnings and Precautions (5.1)]. Myelosuppression Advise patients and/or caregivers to contact their healthcare provider for any signs or symptoms of myelosuppression or infection [see Warnings and Precautions (5.2)]. Secondary Myelodysplastic Syndrome and Leukemia Advise patients and/or caregivers of the potential for secondary cancers, including myelodysplastic syndrome and acute leukemia [see Warnings and Precautions (5.3)]. Renal Toxicity Advise patients and/or caregivers to hydrate and to urinate frequently before, on the day of, and the day after administration of LUTATHERA [see Warnings and Precautions (5.4)]. Advise patients to contact their healthcare provider for any signs or symptoms of renal toxicity [see Warnings and Precautions (5.4)]. Hepatotoxicity Advise patients and/or caregivers of the need for periodic laboratory tests to monitor for hepatotoxicity [see Warnings and Precautions (5.5)]. Advise patients to contact their healthcare provider for any signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.5)]. Hypersensitivity Advise patients and/or caregivers that LUTATHERA may cause hypersensitivity reactions, including angioedema, and to seek immediate medical attention for signs or symptoms of hypersensitivity [see Warnings and Precautions (5.6)]. Neuroendocrine Hormonal Crises Advise patients and/or caregivers to contact their healthcare provider for signs or symptoms that may occur following tumor-related hormonal release [see Warnings and Precautions (5.7)]. Embryo-Fetal Toxicity Advise pregnant women and males and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive potential to use effective contraception during treatment with LUTATHERA and for 7 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LUTATHERA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. Lactation Advise females not to breastfeed during treatment with LUTATHERA and for 2.5 months after the last dose [see Use in Specific Populations (8.2)]. Infertility Advise female and male patients that LUTATHERA may impair fertility [see Warnings and Precautions (5.9), Use in Specific Populations (8.3)]. Distributed by: Advanced Accelerator Applications USA, Inc., Millburn, NJ 07041 ©202Y Advanced Accelerator Applications USA, Inc. LUTATHERA® is a registered trademark of Novartis AG and/or its affiliates. U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov NDA 208700/S-032 Lead Shielding Label Vial Label Type A Package Ramesh Raghavachari Digitally signed by Ramesh Raghavachari Date: 11/26/2024 10:22:15PM GUID: 502d0913000029f375128b0de8c50020 (
custom-source
2025-02-12T15:47:27.359498
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NDA 212909/S-002 Page 4 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BIORPHEN® safely and effectively. See full prescribing information for BIORPHEN. BIORPHEN (phenylephrine hydrochloride) injection, for intravenous use Initial U.S. Approval: 1954 ----------------------------RECENT MAJOR CHANGES---------------------------- Dosage and Administration. (2) 03/2021 ----------------------------INDICATIONS AND USAGE---------------------------- BIORPHEN injection is an alpha-1 adrenergic receptor agonist indicated for the treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia. (1) -----------------------DOSAGE AND ADMINISTRATION-------------------------- • BIORPHEN 500 mcg/5 mL (100 mcg/mL)/mL injection MUST NOT BE DILUTED before administration as an intravenous bolus. It is supplied as a READY-TO-USE formulation. (2) • BIORPHEN 10 mg/mL injection MUST BE DILUTED before administration as an intravenous bolus or continuous intravenous infusion to achieve the desired concentration. (2) Dosing for treatment of hypotension during anesthesia • Bolus intravenous injection: Initial dose is 40 mcg to 100 mcg. Additional boluses up to 200 mcg may be administered every 1 to 2 minutes as needed. (2) • Adjust the dose according to the pressor response (i.e., titrate to effect). (2) • Biorphen 10 mg/mL Only: Continuous intravenous infusion: 10 mcg/min to 35 mcg/min, titrating to effect, not to exceed 200 mcg/min. (2) ------------------------DOSAGE FORMS AND STRENGTHS----------------------- • Biorphen 500 mcg/5 mL (100 mcg/mL) Injection: Single-dose ampule containing 5 mL of solution for injection corresponding to 0.5 mg of phenylephrine hydrochloride per ampule. (3) • Biorphen 500 mcg/5 mL (100 mcg/mL) Injection: Single-dose vial containing 5 mL of solution for injection corresponding to 0.5 mg of phenylephrine hydrochloride per vial. (3) • Biorphen 10 mg/mL Injection: Single-dose ampule containing 1 mL of solution for injection corresponding to 10 mg of phenylephrine hydrochloride per ampule. (3) --------------------------------CONTRAINDICATIONS-------------------------------- None. (4) -------------------------WARNINGS AND PRECAUTIONS------------------------- Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension: BIORPHEN can precipitate angina in patients with severe arteriosclerosis or history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure. (5.1) Peripheral and Visceral Ischemia: BIORPHEN can cause excessive peripheral and visceral vasoconstriction and ischemia to vital organs. (5.2) Skin and Subcutaneous Necrosis: Extravasation during intravenous administration may cause necrosis or sloughing of tissue. (5.3) Bradycardia: BIORPHEN can cause severe bradycardia and decreased cardiac output. (5.4) ----------------------------------ADVERSE REACTION--------------------------------- Most common adverse reactions during treatment: nausea, vomiting, and headache. (6) To report SUSPECTED ADVERSE REACTIONS, contact Eton Pharmaceuticals, Inc. at 1-855-224-0233 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------------------DRUG INTERACTIONS------------------------------- Agonistic Effects (increase in BIORPHEN blood pressure effect) can occur with monoamine oxidase inhibitors (MAOI), oxytocin and oxytocic drugs, tricyclic antidepressants, angiotensin and aldosterone, atropine, steroids, norepinephrine transporter inhibitors, ergot alkaloids. (7.1) Antagonistic Effects (decrease in BIORPHEN blood pressure effect) can occur with α-adrenergic antagonists, phosphodiesterase Type 5 inhibitors, mixed α- and β-receptor antagonists, calcium channel blockers, benzodiazepines and ACE inhibitors, centrally acting sympatholytic agents. (7.2) See 17 for PATIENT COUNSELING INFORMATION Revised: 04/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 General Dosage and Administration Instructions 2.2 Dosing for Treatment of Hypotension during Anesthesia 2.3 Preparation of a 100 mcg/mL Solution for Bolus Intravenous Administration from BIORPHEN 10 mg/mL Injection 2.4 Preparation of Solution for Continuous Intravenous Administration from BIORPHEN 10 mg/mL Injection 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension 5.2 Peripheral and Visceral Ischemia 5.3 Skin and Subcutaneous Necrosis 5.4 Bradycardia 5.5 Renal Toxicity 5.6 Risk of Augmented Pressor Affect in Patients with Autonomic Dysfunction 5.7 Pressor Effect with Concomitant Oxytocic Drugs 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 Interactions that Augment the Pressor Effect 7.2 Interactions that Antagonize the Pressor Effect 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE BIORPHEN is indicated for the treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia. DOSAGE AND ADMINISTRATION General Dosage and Administration Instructions During BIORPHEN administration: • Correct intravascular volume depletion. • Correct acidosis. Acidosis may reduce the effectiveness of phenylephrine. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if the solution is colored or cloudy, or if it contains particulate matter. Discard any unused portion. BIORPHEN 500 mcg/5 mL (100 mcg/mL) and 10 mg/mL Injection have important differences in administration instructions: Administration Instructions for BIORPHEN 500 mcg/5 mL (100 mcg/mL) Injection: BIORPHEN 500 mcg/5 mL (100 mcg/mL) injection MUST NOT BE DILUTED before administration as an intravenous bolus. It is supplied as READY-TO-USE formulation. Administration Instructions for BIORPHEN 10 mg/mL Injection: BIORPHEN 10 mg/mL injection MUST BE DILUTED before administration as an intravenous bolus or continuous intravenous infusion to achieve the desired concentration: • Bolus: Dilute with normal saline or 5% dextrose in water. • Continuous infusion: Dilute with normal saline or 5% dextrose in water. The diluted solution should not be held for more than 4 hours at room temperature or for more than 24 hours under refrigerated conditions. Dosing for Treatment of Hypotension during Anesthesia The following are the recommended dosages for the treatment of hypotension during anesthesia. BIORPHEN 500 mcg/5 mL (100 mcg/mL) Injection: • The recommended initial dose is 40 mcg to 100 mcg administered by intravenous bolus. Additional boluses up to 200 mcg may be administered every 1 to 2 minutes as needed. • Adjust dosage according to the blood pressure goal. BIORPHEN 10 mg/mL Injection: • The recommended initial dose is 40 mcg to 100 mcg administered by intravenous bolus. Additional boluses up to 200 mcg may be administered every 1 to 2 minutes as needed. • If blood pressure is below the target goal, start a continuous intravenous infusion with an infusion rate of 10 mcg/minute to 35 mcg/minute; not to exceed 200 mcg/minute. • Adjust dosage according to the blood pressure goal. Preparation of a 100 mcg/mL Solution for Bolus Intravenous Administration from BIORPHEN 10 mg/mL Injection For bolus intravenous administration, prepare a solution containing a final concentration of 100 mcg/mL of BIORPHEN 10 mg/mL Injection: • Withdraw 10 mg i.e. 1 mL of BIORPHEN 10 mg/mL Injection and dilute with 99 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. • Withdraw an appropriate dose from the 100 mcg/mL solution prior to bolus intravenous administration. Preparation of Solution for Continuous Intravenous Administration from BIORPHEN 10 mg/mL Injection For continuous intravenous infusion, prepare a solution containing a final concentration of 20 mcg/mL of BIORPHEN 10 mg/mL Injection in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. • Withdraw 10 mg i.e. 1 mL of BIORPHEN 10 mg/mL Injection and dilute with 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP. DOSAGE FORMS AND STRENGTHS BIORPHEN 500 mcg/5 mL (100 mcg/mL) Injection: Ampule BIORPHEN injection, 500 mcg/5 mL (100 mcg/mL), for intravenous use, is a clear and colorless solution available in a type I one point cut clear colorless glass single-dose ampule containing 5 mL of solution for injection, corresponding to 0.5 mg of phenylephrine hydrochloride per ampule (equivalent to 0.41 mg of phenylephrine base). Vial BIORPHEN injection, 500 mcg/5 mL (100 mcg/mL), for intravenous use, is a clear and colorless solution available in a type I clear colorless glass single-dose vial containing 5 mL of solution for injection, corresponding to 0.5 mg of phenylephrine hydrochloride per vial (equivalent to 0.41 mg of phenylephrine base). BIORPHEN 10 mg/mL Injection: BIORPHEN injection, 10 mg/mL, for intravenous use, is a clear and colorless solution available in a type I one point cut clear colorless glass single-dose ampule containing 1 mL of solution for injection, corresponding to 10 mg of phenylephrine hydrochloride per ampule (equivalent to 8.2 mg of phenylephrine base). CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension Because of its increasing blood pressure effects, BIORPHEN can precipitate angina in patients with severe arteriosclerosis or history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure. Peripheral and Visceral Ischemia BIORPHEN can cause excessive peripheral and visceral vasoconstriction and ischemia to vital organs, particularly in patients with extensive peripheral vascular disease. Skin and Subcutaneous Necrosis Extravasation of BIORPHEN can cause necrosis or sloughing of tissue. Avoid extravasation by checking infusion site for free flow. Bradycardia BIORPHEN can cause severe bradycardia and decreased cardiac output. Renal Toxicity BIORPHEN can increase the need for renal replacement therapy in patients with septic shock. Monitor renal function. Risk of Augmented Pressor Affect in Patients with Autonomic Dysfunction The increasing blood pressure response to adrenergic drugs, including BIORPHEN, can be increased in patients with autonomic dysfunction, as may occur with spinal cord injuries. Pressor Effect with Concomitant Oxytocic Drugs Oxytocic drugs potentiate the increasing blood pressure effect of sympathomimetic pressor amines including BIORPHEN [see Drug Interactions (7.1)], with the potential for hemorrhagic stroke. ADVERSE REACTIONS Adverse reactions to BIORPHEN are primarily attributable to excessive pharmacologic activity. Adverse reactions reported in published clinical studies, observational trials, and case reports of BIORPHEN are listed below by body system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Cardiac disorders: Reflex bradycardia, lowered cardiac output, ischemia, hypertension, arrhythmias Gastrointestinal disorders: Epigastric pain, vomiting, nausea Nervous system disorders: Headache, blurred vision, neck pain, tremors Vascular disorders: Hypertensive crisis Respiratory, Thoracic and Mediastinal Disorders: Dyspnea Skin and subcutaneous tissue disorders: Pruritis DRUG INTERACTIONS Interactions that Augment the Pressor Effect The increasing blood pressure effect of BIORPHEN is increased in patients receiving: • Monoamine oxidase inhibitors (MAOI) • Oxytocin and oxytocic drugs • Tricyclic antidepressants • Angiotensin, aldosterone • Atropine • Steroids, such as hydrocortisone • Norepinephrine transporter inhibitors, such as atomoxetine • Ergot alkaloids, such as methylergonovine maleate Interactions that Antagonize the Pressor Effect The increasing blood pressure effect of BIORPHEN is decreased in patients receiving: • α-adrenergic antagonists • Phosphodiesterase Type 5 inhibitors • Mixed α- and β-receptor antagonists • Calcium channel blockers, such as nifedipine • Benzodiazepines • ACE inhibitors • Centrally acting sympatholytic agents, such as reserpine, guanfacine USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Data from randomized controlled trials and meta-analyses with phenylephrine hydrochloride injection use in pregnant women during caesarean section have not established a drug-associated risk of major birth defects and miscarriage. These studies have not identified an adverse effect on maternal outcomes or infant Apgar scores [see Data]. There are no data on the use of phenylephrine during the first or second trimester. In animal reproduction and development studies in normotensive animals, evidence of fetal malformations was noted when phenylephrine was administered during organogenesis via a 1-hour infusion at 1.2 times the human daily dose (HDD) of 10 mg/60 kg/day. Decreased pup weights were noted in offspring of pregnant rats treated with 2.9 times the HDD [See Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk Untreated hypotension associated with spinal anesthesia for cesarean section is associated with an increase in maternal nausea and vomiting. A sustained decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis. Data Human Data Published randomized controlled trials over several decades, which compared the use of phenylephrine injection to other similar agents in pregnant women during cesarean section, have not identified adverse maternal or infant outcomes. At recommended doses, phenylephrine does not appear to affect fetal heart rate or fetal heart variability to a significant degree. There are no studies on the safety of phenylephrine injection exposure during the period of organogenesis, and therefore, it is not possible to draw any conclusions on the risk of birth defects following exposure to phenylephrine injection during pregnancy. In addition, there are no data on the risk of miscarriage following fetal exposure to phenylephrine injection. Animal Data No clear malformations or fetal toxicity were reported when normotensive pregnant rabbits were treated with phenylephrine via continuous intravenous infusion over 1 hour (0.5 mg/kg/day; approximately equivalent to a HDD based on body surface area) from Gestation Day 7 to 19. At this dose, which demonstrated no maternal toxicity, there was evidence of developmental delay (altered ossification of sternebra). In a non-GLP dose range-finding study in normotensive pregnant rabbits, fetal lethality and cranial, paw, and limb malformations were noted following treatment with 1.2 mg/kg/day of phenylephrine via continuous intravenous infusion over 1 hour (2.3-times the HDD). This dose was clearly maternally toxic (increased mortality and significant body weight loss). An increase in the incidence of limb malformation (hyperextension of the forepaw) coincident with high fetal mortality was noted in a single litter at 0.6 mg/kg/day (1.2-times the HDD) in the absence of maternal toxicity. No malformations or embryo-fetal toxicity were reported when normotensive pregnant rats were treated with up to 3 mg/kg/day phenylephrine via continuous intravenous infusion over 1 hour (2.9-times the HDD) from Gestation Day 6 to 17. This dose was associated with some maternal toxicity (decreased food consumption and body weights). Decreased pup weights were reported in a pre- and postnatal development toxicity study in which normotensive pregnant rats were administered phenylephrine via continuous intravenous infusion over 1 hour (0.3, 1.0, or 3.0 mg/kg/day; 0.29, 1, or 2.9 times the HDD) from Gestation Day 6 through Lactation Day 21). No adverse effects on growth and development (learning and memory, sexual development, and fertility) were noted in the offspring of pregnant rats at any dose tested. Maternal toxicities (mortality late in gestation and during lactation period, decreased food consumption and body weight) occurred at 1 and 3 mg/kg/day of phenylephrine (equivalent to and 2.9 times the HDD, respectively). Lactation Risk Summary There are no data on the presence of Phenylephrine Hydrochloride Injection or its metabolite in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for phenylephrine hydrochloride injection and any potential adverse effects on the breastfed infant from phenylephrine hydrochloride injection or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of phenylephrine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment In patients with liver cirrhosis [Child Pugh Class B and Class C], dose-response data indicate decreased responsiveness to phenylephrine. Start dosing in the recommended dose range but more phenylephrine may be needed in this population. Renal Impairment In patients with end stage renal disease (ESRD), dose-response data indicate increased responsiveness to phenylephrine. Consider starting at the lower end of the recommended dose range, and adjusting dose based on the target blood pressure goal. 10 OVERDOSAGE Overdose of BIORPHEN (phenylephrine hydrochloride) can cause a rapid rise in blood pressure. Symptoms of overdose include headache, vomiting, hypertension, reflex bradycardia, a sensation of fullness in the head, tingling of the extremities, and cardiac arrhythmias including ventricular extrasystoles and ventricular tachycardia. 11 DESCRIPTION Phenylephrine is an alpha-1 adrenergic receptor agonist. The chemical name of phenylephrine hydrochloride is (-)-m-hydroxy-α-[(methylamino) methyl] benzyl alcohol hydrochloride, its molecular formula is C9H13NO2·HCl (Molecular Weight: 203.67 g/mol). Its structural formula is depicted below: Phenylephrine hydrochloride is soluble in water and ethanol, and insoluble in chloroform and ethyl ether. BIORPHEN Injection, 500 mcg/5 mL (100 mcg/mL): BIORPHEN (phenylephrine hydrochloride) injection, 500 mcg/5 mL (100 mcg/mL), is a sterile, nonpyrogenic, clear and colorless solution for intravenous use. It MUST NOT BE DILUTED before administration as an intravenous bolus. Each mL contains: phenylephrine hydrochloride 100 mcg (equivalent to 80 mcg of phenylephrine base), sodium chloride 9.0 mg in water for injection. The pH is adjusted with hydrochloric acid if necessary. The pH range is 3.0 to 5.0. BIORPHEN Injection, 10 mg/mL: BIORPHEN (phenylephrine hydrochloride) injection, 10 mg/mL, is a sterile, nonpyrogenic, clear and colorless solution for intravenous use. It MUST BE DILUTED before administration as an intravenous bolus or continuous intravenous infusion. Each mL contains: phenylephrine hydrochloride 10 mg (equivalent to 8.2 mg of phenylephrine base), sodium chloride 6.0 mg in water for injection. The pH is adjusted with hydrochloric acid if necessary. The pH range is 3.0 to 5.0. CLINICAL PHARMACOLOGY Mechanism of Action Phenylephrine hydrochloride is an α-1 adrenergic receptor agonist. Pharmacodynamics Interaction of phenylephrine with α-1 adrenergic receptors on vascular smooth muscle cells causes activation of the cells and results in vasoconstriction. Following phenylephrine hydrochloride intravenous administration, increases in systolic and diastolic blood pressures, mean arterial blood pressure, and total peripheral vascular resistance are observed. The onset of blood pressure increase following an intravenous bolus phenylephrine hydrochloride administration is rapid, typically within minutes. As blood pressure increases following intravenous administration, vagal activity also increases, resulting in reflex bradycardia. Phenylephrine has activity on most vascular beds, including renal, pulmonary, and splanchnic arteries. Pharmacokinetics Following an intravenous infusion of phenylephrine hydrochloride, the observed effective half-life was approximately 5 minutes. The steady-state volume of distribution of approximately 340 L suggests a high distribution into organs and peripheral tissues. The average total serum clearance is approximately 2100 mL/min. The observed phenylephrine plasma terminal elimination half-life was 2.5 hours. Phenylephrine is metabolized primarily by monoamine oxidase and sulfotransferase. After intravenous administration of radiolabeled phenylephrine, approximately 80% of the total dose was eliminated within first 12 h; and approximately 86% of the total dose was recovered in the urine within 48 h. The excreted unchanged parent drug was 16% of the total dose in the urine at 48 h post intravenous administration. There are two major metabolites, with approximately 57 and 8% of the total dose excreted as m-hydroxymandelic acid and sulfate conjugates, respectively. The metabolites are considered not pharmacologically active. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Long-term animal studies that evaluated the carcinogenic potential of orally administered phenylephrine hydrochloride in F344/N rats and B6C3F1 mice were completed by the National Toxicology Program using the dietary route of administration. There was no evidence of carcinogenicity in mice administered approximately 270 mg/kg/day (131 times the human daily dose (HDD) of 10 mg/60 kg/day based on body surface area) or rats administered approximately 50 mg/kg/day (48 times the HDD). Mutagenesis: Phenylephrine hydrochloride tested negative in the in vitro bacterial reverse mutation assay (S. typhimurium strains TA98, TA100, TA1535 and TA1537), the in vitro chromosomal aberrations assay, the in vitro sister chromatid exchange assay, and the in vivo rat micronucleus assay. Positive results were reported in only one of two replicates of the in vitro mouse lymphoma assay. Impairment of Fertility: Phenylephrine did not impair mating, fertility, or reproductive outcome in normotensive male rats treated with 3 mg/kg/day phenylephrine via continuous intravenous infusion over 1 hour (2.9 times the HDD) for 28 days prior to mating and for a minimum of 63 days prior to sacrifice and female rats treated with the same dosing regimen for 14 days prior to mating and through Gestation Day 6. This dose was associated with increased mortality in both male and female rats and decreased body weight gain in treated males. There were decreased caudal sperm density and increased abnormal sperm reported in males treated with 3 mg/kg/day phenylephrine (2.9 times the HDD). 14 CLINICAL STUDIES The evidence for the efficacy of BIORPHEN, is derived from studies of phenylephrine hydrochloride in the published literature. The literature support includes 16 studies evaluating the use of intravenous phenylephrine to treat hypotension during anesthesia. The 16 studies include 9 studies where phenylephrine was used in low-risk (ASA 1 and 2) pregnant women undergoing neuraxial anesthesia during Cesarean delivery, 6 studies in non-obstetric surgery under general anesthesia, and 1 study in non-obstetric surgery under combined general and neuraxial anesthesia. Phenylephrine has been shown to raise systolic and mean blood pressure when administered either as a bolus dose or by continuous infusion following the development of hypotension during anesthesia. 16 HOW SUPPLIED/STORAGE AND HANDLING BIORPHEN (phenylephrine hydrochloride) injection is supplied as follows: Unit of Sale Strength Each NDC No. 71863-208-05 5 mL single-dose vial 500 mcg/5 mL (100 mcg/mL) NDC No. 71863-208-05 5 mL single-dose vial NDC No.71863-202-06 pack of 10 single-dose ampules 500 mcg/5 mL (100 mcg/mL) NDC No. 71863-202-05 5 mL single-dose ampule NDC No. 71863-203-02 Pack of 10 single-dose ampules 10 mg/mL NDC No. 71863-203-01 1 mL single-dose ampule Store BIORPHEN (phenylephrine hydrochloride) injection at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Discard any unused portion. 17 PATIENT COUNSELING INFORMATION If applicable, inform patient, family member, or caregiver that certain medical conditions and medications might influence how BIORPHEN injection works. Manufactured for: Eton Pharmaceuticals, Inc. Deer Park, IL 60010 USA Rev. 04/2024 LB5BIPR2 David Lewis Digitally signed by David Lewis Date: 4/12/2024 09:53:54AM GUID: 508da72000029f287fa31e664741b577 (
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NDA 208845/S-021 Page 4 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZILRETTA safely and effectively. See full prescribing information for ZILRETTA. ZILRETTA® (triamcinolone acetonide extended-release injectable suspension), for intra-articular use Initial U.S. Approval: 1957 __________________ INDICATIONS AND USAGE _________________ ZILRETTA is an extended-release synthetic corticosteroid indicated as an intra-articular injection for the management of osteoarthritis pain of the knee. (1) Limitation of Use The efficacy and safety of repeat administration of ZILRETTA have not been demonstrated. (2.1) _______________ DOSAGE AND ADMINISTRATION ______________ • 32 mg (5 mL) administered as a single intra-articular injection in the knee. (2.1) • See Instructions for Use (IFU) for instructions on reconstitution of ZILRETTA with the supplied diluent. (2.2) • It is normal for some residue to be left behind on the vial walls after withdrawing the suspension. (2.2) • ZILRETTA is NOT substitutable with other formulations of injectable triamcinolone acetonide. (2.3) ______________ DOSAGE FORMS AND STRENGTHS _____________ ZILRETTA is an injectable suspension that delivers 32 mg of triamcinolone acetonide. It is supplied as a single-dose kit containing one vial of ZILRETTA microsphere powder, one vial of 5 mL diluent, and one sterile vial adapter. (3) ___________________ CONTRAINDICATIONS____________________ Patients with hypersensitivity to triamcinolone acetonide or any component of the product. (4) _______________ WARNINGS AND PRECAUTIONS _______________ • Intra-articular Use Only: Do not administer ZILRETTA by epidural, intrathecal, intravenous, intraocular, intramuscular, intradermal, or subcutaneous routes. (5.1) • Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration: Serious neurologic events have been reported following epidural or intrathecal corticosteroid administration. Corticosteroids are not approved for this use. (5.2) • Hypersensitivity Reactions: Serious reactions have been reported with triamcinolone acetonide injection. Institute appropriate care upon occurrence of an anaphylactic reaction. (5.3) • Joint Infection and Damage: May cause joint pain accompanied by joint swelling. If this occurs, conduct appropriate evaluation to exclude septic arthritis and institute appropriate antimicrobial therapy if septic arthritis is confirmed. (5.4) ____________________ ADVERSE REACTIONS ____________________ Most commonly reported adverse reactions (incidence ≥1%) in clinical studies include sinusitis, cough, and contusions. (6) To report SUSPECTED ADVERSE REACTIONS, contact Pacira Pharmaceuticals, Inc. at 1-844-353-9466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information 2.2 Preparation and Administration of Intra-Articular Suspension 2.3 Non-Interchangeability with Other Formulations of Triamcinolone Acetonide for Intra-articular Use 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Warnings and Precautions Specific for ZILRETTA 5.2 Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration 5.3 Hypersensitivity Reactions 5.4 Joint Infection and Damage 5.5 Increased Risk of Infections 5.6 Alterations in Endocrine Function 5.7 Cardiovascular Effects 5.8 Renal Effects 5.9 Increased Intraocular Pressure 5.10 Gastrointestinal Perforation 5.11 Alterations in Bone Density 5.12 Behavioral and Mood Disturbances 6 ADVERSE REACTIONS 6.1 Clinical Trials 6.2 Post-marketing Experience 6.3 Corticosteroid Adverse Reactions 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE ZILRETTA (triamcinolone acetonide extended-release injectable suspension) is indicated as an intra- articular injection for the management of osteoarthritis pain of the knee. Limitation of Use The efficacy and safety of repeat administration of ZILRETTA have not been demonstrated. [see Dosage and Administration (2.1)]. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information • ZILRETTA is administered as a single intra-articular extended-release injection of triamcinolone acetonide, to deliver 32 mg (5 mL). • ZILRETTA is for intra-articular use only. Do NOT administer by the following routes: epidural, intrathecal, intravenous, intraocular, intramuscular, intradermal, subcutaneous. • ZILRETTA is not suitable for use in small joints, such as the hand. • The efficacy and safety of repeat administration of ZILRETTA have not been demonstrated [see Adverse Reactions (6) and Nonclinical Toxicology (13.2)]. • The efficacy and safety of ZILRETTA for management of osteoarthritis pain of shoulder and hip have not been evaluated. 2.2 Preparation and Administration of Intra-Articular Suspension Refer to the Instructions for Use for directions on the preparation and administration of ZILRETTA. ZILRETTA is supplied as a single-dose kit containing a vial of ZILRETTA microsphere powder, a vial of sterile diluent, and a sterile vial adapter. ZILRETTA must be prepared using the diluent supplied in the kit. Preparation of ZILRETTA requires close attention to the Instructions for Use to ensure successful administration. Use proper aseptic technique throughout the dose preparation and administration procedure. ZILRETTA is a suspension product and it is normal for some residue to be left behind on the vial walls after withdrawing the contents. Promptly inject ZILRETTA after preparation to avoid settling of the suspension. If needed, the ZILRETTA suspension can be stored in the vial for up to 4 hours at ambient conditions. Gently swirl the vial to resuspend any of the settled microspheres prior to preparing the syringe for injection. The usual technique for intra-articular injection should be followed. Aspiration of synovial fluid may be performed based on clinical judgment prior to administration of ZILRETTA. 3 2.3 Non-Interchangeability with Other Formulations of Triamcinolone Acetonide for Intra-articular Use ZILRETTA is NOT substitutable with other formulations of injectable triamcinolone acetonide. 3 DOSAGE FORMS AND STRENGTHS ZILRETTA is an injectable suspension that delivers 32 mg of triamcinolone acetonide. ZILRETTA is supplied as a single-dose kit, containing: • One vial of ZILRETTA white to off-white microsphere powder • One vial of 5 mL sterile, colorless to pale yellow, clear diluent • One sterile vial adapter 4 CONTRAINDICATIONS ZILRETTA is contraindicated in patients who are hypersensitive to triamcinolone acetonide, corticosteroids or any components of the product [see Warnings and Precautions (5.3) and How Supplied/Storage and Handling (16)]. 5 WARNINGS AND PRECAUTIONS 5.1 Warnings and Precautions Specific for ZILRETTA ZILRETTA has not been evaluated and should not be administered by the following routes: • Epidural • Intrathecal • Intravenous • Intraocular • Intramuscular • Intradermal • Subcutaneous [see Warnings and Precautions (5.2)]. 5.2 Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke [see Adverse Reactions (6)]. These serious neurologic events have been reported with and without use of fluoroscopy. Reports of serious medical events have been associated with the intrathecal route of corticosteroid administration [see Adverse Reactions (6)]. 4 The safety and effectiveness of epidural and intrathecal administration of corticosteroids have not been established, and corticosteroids are not approved for this use. In particular, the formulation of ZILRETTA should not be considered safe to use for epidural or intrathecal administration. 5.3 Hypersensitivity Reactions Rare instances of anaphylaxis have occurred in patients with hypersensitivity to corticosteroids. Cases of serious anaphylaxis, including death, have been reported in individuals receiving triamcinolone acetonide injection, regardless of the route of administration [see Adverse Reactions (6)]. Institute appropriate care upon occurrence of an anaphylactic reaction. 5.4 Joint Infection and Damage Intra-articular injection of corticosteroid may be complicated by joint infection. A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and a diagnosis of septic arthritis is confirmed, institute appropriate antimicrobial therapy [see Adverse Reactions (6)]. Avoid injection of a corticosteroid into an infected site. Local injection of a corticosteroid into a previously infected joint is not usually recommended. Examine any joint fluid present to exclude a septic process. Corticosteroid injection into unstable joints is generally not recommended. Intra-articular injection may result in damage to joint tissues. 5.5 Increased Risk of Infections Intra-articularly injected corticosteroids are systemically absorbed. Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Advise patients to inform their health care provider if they develop fever or other signs or symptoms of infection. Advise patients who have not been vaccinated to avoid exposure to chicken pox or measles. Instruct patients to contact their health care provider immediately if they are exposed [see Patient Counseling Information (17)]. 5.6 Alterations in Endocrine Function Corticosteroids can produce reversible hypothalamic-pituitary-adrenal axis suppression, with the potential for adrenal insufficiency after withdrawal of treatment, which may persist for months. In situations of stress during that period (as in trauma, surgery, or illness), institute corticosteroid replacement therapy. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. 5 5.7 Cardiovascular Effects Corticosteroids can cause elevations of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic derivatives. Monitor patients with congestive heart failure or hypertension for signs of edema, weight gain, and imbalance in serum electrolytes. Dietary salt restriction and potassium supplementation may be necessary. 5.8 Renal Effects Corticosteroids can cause salt and water retention, and increased excretion of potassium. These effects are less likely to occur with synthetic derivatives. All corticosteroids increase calcium excretion. Monitor patients with renal insufficiency for signs of edema, weight gain, and imbalance in serum electrolytes. Dietary salt restriction and potassium supplementation may be necessary. 5.9 Increased Intraocular Pressure Corticosteroid use may be associated with development or exacerbation of increased intraocular pressure. Monitor patients with elevated intraocular pressure for potential treatment adjustment. 5.10 Gastrointestinal Perforation Corticosteroid administration is associated with increased risk of gastrointestinal perforation in patients with certain GI disorders such as active or latent peptic ulcers, diverticulosis, diverticulitis, ulcerative colitis and in patients with fresh intestinal anastomoses. Avoid corticosteroids in these patients because signs of peritoneal irritation following gastrointestinal perforation may be minimal or absent. 5.11 Alterations in Bone Density Corticosteroids decrease bone formation and increase bone resorption through their effect on calcium regulation and inhibition of osteoblast function. Special consideration should be given to patients with or at increased risk of osteoporosis (e.g., postmenopausal women) before initiating corticosteroid therapy. 5.12 Behavioral and Mood Disturbances Corticosteroid use may be associated with new or aggravated adverse psychiatric reactions ranging from euphoria, insomnia, mood swings, and personality changes to severe depression and frank psychotic manifestations. Special consideration should be given to patients with previous or current emotional instability or psychiatric illness before initiating corticosteroid therapy. Advise patients and/or caregivers to immediately report any new or worsening behavior or mood disturbances to their health care provider. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling. • Serious Neurologic Adverse Reactions with Epidural and Intrathecal Administration [see Warnings and Precautions (5.2)] 6 • Hypersensitivity Reactions [see Warnings and Precautions (5.3)] • Joint Infection and Damage [see Warnings and Precautions (5.4)] • Increased Risk of Infections [see Warnings and Precautions (5.5)] • Alterations in Endocrine Function [see Warnings and Precautions (5.6)] • Cardiovascular Effects [see Warnings and Precautions (5.7)] • Renal Effects [see Warnings and Precautions (5.8)] • Increased Intraocular Pressure [see Warnings and Precautions (5.9)] • Gastrointestinal Perforation [see Warnings and Precautions (5.10)] • Alternations in Bone Density [see Warnings and Precautions (5.11)] • Behavioral and Mood Disturbances [see Warnings and Precautions (5.12)] 6.1 Clinical Trials Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to a single 32 mg intra-articular injection of ZILRETTA in clinical studies in patients with moderate to severe pain due to osteoarthritis of the knee. Clinical studies included randomized, double-blind, parallel-group, placebo and/or active-controlled, and pharmacokinetic/pharmacodynamic studies with follow-up ranging from 6-24 weeks. A total of 424 patients received ZILRETTA and 262 received placebo. Treatment emergent adverse reactions reported by greater than or equal to 1% of patients in the ZILRETTA arms are summarized below (Table 1 and 2). Overall, the incidence and nature of adverse reactions was similar to that observed with placebo. Table 1: Most Commonly Reported Treatment-Emergent Adverse Reactions with ZILRETTA (Incidence ≥1%) in Patients with Osteoarthritis of the Knee Preferred Term (MedDRA) ZILRETTA (N=424) Placebo (N=262) Sinusitis 2% 1% Cough 2% 1% Contusions 2% 1% 7 Table 2: Most Commonly Reported Treatment-Emergent Injected Knee Adverse Reactions with ZILRETTA (Incidence ≥1%) in Patients with Osteoarthritis of the Knee Preferred Term (MedDRA) ZILRETTA (N=424) Placebo (N=262) Joint Swelling 3% 2% Contusions 2% 1% The safety of repeat administration of ZILRETTA was evaluated in a multicenter, open-label, single-arm study in patients with osteoarthritis pain of the knee. A total of 179 patients received a repeat injection on or after Week 12 (median 16.6 weeks) and were followed for 52 weeks from the initial injection. As assessed by adverse event rates for the periods of baseline to second dose and second dose to the comparable period after the second dose, there were higher rates of reported mild to moderate arthralgia after the second dose (16%) than after the first dose (6%). The data from this study are insufficient to fully characterize the safety of repeat administration of ZILRETTA. [See also Nonclinical Toxicology (13.2)]. 6.2 Post-marketing Experience The following adverse reactions, presented alphabetically by body system, have been identified during post-approval use of ZILRETTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Endocrine: Increased blood glucose (in diabetic patients). General and administration site conditions: Pain including injection site pain or discomfort and leg pain. Immune system: Hypersensitivity reactions including pruritus, rash, angioedema, and anaphylaxis [see Contraindications (4), Warnings and Precautions (5.3)]. Infections and Infestations: Septic arthritis [see Warning and Precautions (5.4)]. Musculoskeletal: Arthralgia, joint swelling or effusion, muscle spasms. Nervous system: Headache. Reproductive system: Postmenopausal vaginal bleeding (similar to a menstrual period). Skin and Subcutaneous Tissue: Pruritus. 6.3 Corticosteroid Adverse Reactions The following adverse reactions, presented alphabetically by body system, are from voluntary reports or clinical studies of corticosteroids. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Anaphylactic reactions: Anaphylaxis including death, angioedema [see Warnings and Precautions (5.3)]. Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, hypertension [see Warnings and Precautions (5.7)], fat embolism, 8 hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction, pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic: Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, lupus erythematosus-like lesions, purpura, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria. Endocrine: Decreased carbohydrate and glucose tolerance, development of Cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients. Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients [see Warnings and Precautions (5.7)], fluid retention, sodium retention. Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration) [see Warnings and Precautions (5.2)], elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease) [see Warnings and Precautions (5.10)], ulcerative esophagitis. Metabolic: Negative nitrogen balance due to protein catabolism. Musculoskeletal: Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, post injection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures. Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychiatric disorders [see Warnings and Precautions (5.12)], vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration. Spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke (including brainstem) have been reported after epidural administration of corticosteroids [see Warnings and Precautions (5.2)]. Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure [see Warnings and Precautions (5.9)], posterior subcapsular cataracts, rare instances of blindness associated with periocular injections. Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain. 7 DRUG INTERACTIONS No drug-drug interaction studies have been conducted with ZILRETTA. Table 3 contains drug interactions associated with systemic corticosteroids. 9 Table 3: Drug Interactions Associated with Systemic Corticosteroids Aminoglutethimide Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression. Amphotericin B injection and potassium-depleting agents When corticosteroids are administered concomitantly with potassium- depleting agents (i.e., amphotericin B, diuretics), observe patients closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure. Antibiotics Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance. Anticholinesterases Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, withdraw anticholinesterase agents at least 24 hours before initiating corticosteroid therapy. Anticoagulants, oral Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, monitor coagulation indices frequently to maintain the desired anticoagulant effect. Antidiabetics Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required. Antitubercular drugs Serum concentrations of isoniazid may be decreased. CYP 3A4 inducers (e.g., barbiturates, phenytoin, carbamazepine, and rifampin) Drugs which induce hepatic microsomal drug metabolizing enzyme activity may enhance metabolism of corticosteroids and require that the dosage of corticosteroid be increased. CYP 3A4 inhibitors (e.g., ketoconazole) Ketoconazole, a strong CYP3A4 inhibitor, has been reported to decrease the metabolism of certain corticosteroids by up to 60% leading to an increased risk of corticosteroid side effects. Cholestyramine Cholestyramine may increase the clearance of corticosteroids. Cyclosporine Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use. Digitalis glycosides Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia. Estrogens, including oral contraceptives Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect. Nonsteroidal anti-inflammatory drugs (NSAIDs) Concomitant use of aspirin (or other nonsteroidal anti-inflammatory drugs) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids. Skin tests Corticosteroids may suppress reactions to allergy related skin tests. 10 Vaccines Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. If possible, defer routine administration of vaccines or toxoids until corticosteroid therapy is discontinued. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no data regarding the use of ZILRETTA in pregnant women to inform a drug associated risk of adverse developmental outcomes. Published studies on the association between corticosteroids and fetal outcomes have reported inconsistent findings and have important methodological limitations. The majority of published literature with corticosteroid exposure during pregnancy includes the oral, topical and inhaled dosage formulations; therefore, the applicability of these findings to a single intra-articular injection of triamcinolone acetonide is limited. In animal reproductive studies from the published literature, pregnant mice, rats, rabbits, or primates administered triamcinolone acetonide during the period of organogenesis at doses that produced exposures less than the maximum recommended human dose (MRHD) caused resorptions, decreased fetal body weight, craniofacial and/or other abnormalities such as omphalocele (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data The exposure margins listed below are based on body surface area comparisons (mg/m2) to the highest daily triamcinolone acetonide exposure at the MRHD of 32 mg triamcinolone acetonide via ZILRETTA. Pregnant mice dosed with triamcinolone acetonide via intramuscular or subcutaneous injection at doses equivalent to 0.8 times the MRHD or higher during organogenesis caused cleft palate and a higher rate of resorption. In pregnant rats dosed with triamcinolone acetonide via intramuscular or subcutaneous injection at doses equivalent to 0.3 times the MRHD or higher during organogenesis caused developmental abnormality (cleft palate, omphalocele, late resorption, and growth retardation) and fetal mortality. No notable maternal toxicity was observed in rodents. Pregnant rabbits dosed with triamcinolone acetonide via intramuscular injection for 4 days during organogenesis at doses equivalent to 0.15 times the MRHD or higher caused resorption and cleft palate. No notable maternal toxicity was observed. Pregnant primates dosed with triamcinolone acetonide via intramuscular injection for 4 days during organogenesis at doses equivalent to 3 times the MRHD or higher caused severe craniofacial CNS and skeletal/visceral malformation and higher prenatal death. No notable maternal toxicity was observed. 11 No peri- and post-natal development studies of triamcinolone acetonide in animals have been conducted. 8.2 Lactation Risk Summary There are no available data on the presence of triamcinolone acetonide in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. However, corticosteroids have been detected in human milk and may suppress milk production. It is not known whether intra-articular administration of ZILRETTA could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZILRETTA and any potential adverse effects on the breastfed infant from ZILRETTA or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Corticosteroids may result in menstrual pattern irregularities such as deviations in timing and duration of menses and an increased or decreased loss of blood. 8.4 Pediatric Use The safety and effectiveness of ZILRETTA in pediatric patients have not been established. The adverse effects of corticosteroids in pediatric patients are similar to those in adults. Carefully observe pediatric patients, including weight, height, linear growth, blood pressure, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Weigh potential growth effects of treatment against clinical benefits obtained and the availability of treatment alternatives. 8.5 Geriatric Use Of the total number of patients administered 32 mg ZILRETTA in clinical studies (N=424), 143 patients were 65 years of age or older. No overall differences in safety or effectiveness were observed between elderly and younger subjects, and other reported clinical experience with triamcinolone acetonide has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 11 DESCRIPTION ZILRETTA (triamcinolone acetonide extended-release injectable suspension) is a microsphere formulation of triamcinolone acetonide, a corticosteroid, to be administered by intra-articular injection. ZILRETTA is formulated in 75:25 poly(lactic-co-glycolic acid) (PLGA) microspheres with a nominal drug load of 25% (w/w) and is provided as a sterile white to off-white powder. ZILRETTA is prepared with a supplied diluent containing an isotonic, sterile, aqueous solution of sodium chloride (NaCl; 0.9% w/w), sodium carboxymethylcellulose (CMC; 0.5% w/w), polysorbate-80 (0.1% w/w) and with sodium hydroxide (NaOH) and hydrochloric acid (HCl) as pH adjusters, as required to form a 5 mL sterile suspension intended for intra-articular injection. 12 Active Ingredient The chemical name for triamcinolone acetonide is 9-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene- 3,20-dione cyclic 16,17-acetal with acetone. Its structural formula is: MW 434.50 with a molecular formula of C24H31FO6 Triamcinolone acetonide occurs as a white to almost white, crystalline powder having not more than a slight odor and is practically insoluble in water and very soluble in alcohol. Each vial of ZILRETTA powder contains 40 mg of triamcinolone acetonide in 160 mg of microspheres, resulting in 32 mg of deliverable triamcinolone acetonide when prepared according to the Instructions for Use. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Triamcinolone acetonide is a corticosteroid with anti-inflammatory and immunomodulating properties. It binds to and activates the glucocorticoid receptor, leading to activation of anti-inflammatory transcription factors such as lipocortins and inhibition of inflammatory transduction pathways by blocking the release of arachidonic acid and preventing the synthesis of prostaglandins and leukotrienes. 12.2 Pharmacodynamics Studies indicate that following a single intramuscular dose of 60 to 100 mg of immediate-release triamcinolone acetonide injectable suspension, adrenal suppression occurs within 24 to 48 hours and then gradually returns to normal, usually in 30 to 40 days. To assess potential effects of the systemic levels of triamcinolone acetonide associated with a single intra-articular (IA) administration of ZILRETTA on hypothalamic pituitary adrenal (HPA) axis function, serum and urine cortisol levels were monitored over 6 weeks post injection. Adrenal suppression with ZILRETTA occurred within 12-24 hours and then gradually returned to normal, within 30-42 days. Corticosteroids may increase blood glucose concentrations. 13 In a study where 18 patients with osteoarthritis knee pain and controlled type 2 diabetes mellitus received a single IA injection of ZILRETTA into the knee, the change from baseline in average blood glucose over the 72 hours after injection as measured by a continuous glucose monitoring device was 8.2 mg/dL (95% confidence interval 0.1, 29.2). 12.3 Pharmacokinetics ZILRETTA is an extended-release dosage form consisting of microspheres of poly(lactic-co-glycolic acid) (PLGA) containing triamcinolone acetonide. Plasma pharmacokinetic parameters for triamcinolone acetonide following IA administration of ZILRETTA or 40 mg immediate- release triamcinolone acetonide into the knee are provided in Table 4. Table 4: Summary of Mean (SD) Plasma Pharmacokinetic Parameters for Triamcinolone Acetonide Following IA Administration of ZILRETTA or 40 mg Immediate-Release Triamcinolone Acetonide Triamcinolone Acetonide PK Parameters1 ZILRETTA (N=60) Triamcinolone Acetonide (N=18) Cmax (pg/mL) 1,143.7 (611.06) 21,062.2 (18,466.79) AUC0-24 hour (pg•h/mL) 21,219.2 (11,325.62) 297,545.3 (222,402.77) AUC0-inf (pg•h/mL) 842,149.2 (1,062,004.97)* 1,567,565.0 (1,246,330.95)† tmax (h) 7 (1, 1,008) 6 (2, 24) t1/2 (h) 633.9 (893.0)* 146.9 (213.29)† * 33 patients contributed to the analyses of these parameters † 14 patients contributed to the analyses of these parameters 1 Median (min, max) values for tmax 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term animal studies to evaluate the carcinogenic potential of ZILRETTA have not been conducted. Mutagenesis Adequate mutagenicity studies have not been conducted with ZILRETTA. Impairment of Fertility Studies in animals to evaluate the impairment of fertility of ZILRETTA have not been conducted. 14 13.2 Animal Toxicology and/or Pharmacology Single and repeat administrations (one injection every three months for a total of three injections) of ZILRETTA in non-arthritic knee joints of healthy dogs have been studied at ~1.9 times the maximum recommended human dose (MRHD) of 32 mg (based on estimated drug concentrations within the knee joints). ZILRETTA microspheres were degraded by approximately 4-and 6-months post dosing in single and repeat dose studies, respectively. Single administration resulted in a slightly increased incidence, severity (minimal to slight), and/or duration of microscopic changes (infiltration of macrophages, lymphocytes, plasma cells and fibrosis) and decreased Safranin O staining (decreased proteoglycan content in the cartilage of the knees) compared to administration of an equivalent dose of immediate-release triamcinolone acetonide. These responses were mostly reversed after 6 to 9 months post injection. Repeat administration resulted in an increase in the incidence, severity (minimal to slight) and duration of microscopic changes (infiltration of macrophages, lymphocytes, plasma cells, neutrophils; fibrosis; neovascularization; granulation tissue; and debris) and decreased Safranin O staining (decreased proteoglycan content in the cartilage of the knees) compared to the equivalent dose of immediate-release triamcinolone acetonide. These local responses were still reversing at 6 months post the last injection. No effect on the animals according to observations related to gait/walking, pain/discomfort in the injected knee, local swelling, local redness or local tenderness were noted. The clinical relevance of these findings in the arthritic knee is unknown. 14 CLINICAL STUDIES The efficacy of ZILRETTA was demonstrated in a multi-center, international, randomized, double-blind, parallel-arm, placebo- and active-controlled study in patients with osteoarthritis pain of the knee. A total of 484 patients (ZILRETTA 32 mg, N=161; placebo [saline], N=162; active control [a crystalline suspension, immediate-release formulation of triamcinolone acetonide 40 mg], N=161) were treated and followed for up to 24 weeks. Patients had a mean age of 62 (range 40 to 85 years); baseline demographics and disease characteristics were balanced across treatment arms. Twenty-five percent (25%) of patients had received at least one prior corticosteroid intra-articular injection more than 3 months prior to treatment. A total of 470 patients (97%) completed follow-up to Week 12, the time point for primary efficacy determination, and 443 (91.5%) completed to Week 24. The primary efficacy endpoint comparing ZILRETTA to placebo was change from baseline at Week 12 in the weekly mean of the Average Daily Pain intensity scores (ADP) as assessed by a 0-10 Numeric Rating Scale (NRS). ZILRETTA demonstrated a statistically significant reduction in pain intensity at the primary endpoint vs placebo. ZILRETTA also demonstrated a reduction in pain intensity scores each week from Weeks 1 through 12 (Figure 1). 15 Figure 1: Weekly Change from Baseline to Week 12 in Average Daily Pain 16 HOW SUPPLIED/STORAGE AND HANDLING Description NDC Presentation/How Supplied ZILRETTA NDC 65250-003-01 ZILRETTA (triamcinolone acetonide extended-release injectable suspension) single-dose kit. Kit Contents ZILRETTA microsphere powder NDC 65250-001-01 Single-dose vial to deliver 32 mg of triamcinolone acetonide supplied as a sterile, white to off-white powder in a cerium glass (clear) vial with a rubber stopper and an aluminum seal with a gray plastic cap. Diluent NDC 65250-002-01 5 mL single-dose vial supplied as a sterile, colorless to pale yellow, clear liquid solution of 0.9% w/w sodium chloride (normal saline) containing 0.5% w/w sodium carboxymethylcellulose, and 0.1% w/w polysorbate-80 in a glass vial with a rubber stopper, aluminum seal and white plastic cap. Sterile vial adapter STORAGE To maintain expiry period, refrigerate the ZILRETTA single-dose kit 2-8°C (36-46°F) before use. 16 If refrigeration is unavailable, store the ZILRETTA single-dose kit in the sealed, unopened kit at temperatures not exceeding 25°C (77°F) for up to three weeks and then discard. Do not expose the ZILRETTA single-dose kit to temperatures above 25°C (77°F). Do not freeze. Store vials in carton. 17 PATIENT COUNSELING INFORMATION Increased Risk of Infections Inform patients that they may be more likely to develop infections when taking corticosteroids. Instruct patients to contact their health care provider if they develop fever or other signs or symptoms of infection. Advise patients who have not been vaccinated to avoid exposure to chicken pox or measles. Instruct patients to contact their health care provider immediately if they are exposed [see Warnings and Precautions (5.5)]. Risk of Drug Interactions There are a number of medicines that can interact with corticosteroids such as triamcinolone acetonide. Advise patients to alert their health care provider(s) to assess the need to adjust their medication(s) [see Drug Interactions (7)]. Risk of Adverse Psychiatric Reactions Inform patients that corticosteroid use may be associated with adverse psychiatric reactions. Advise patients and/or caregivers to immediately report any new or worsening behavioral or mood disturbances to their health care provider [see Warnings and Precautions (5.12)]. Manufactured for Pacira Pharmaceuticals, Inc., a wholly owned subsidiary of Pacira BioSciences, Inc. San Diego, CA 92121 USA Trademark of Pacira Therapeutics, Inc., a wholly owned subsidiary of Pacira BioSciences, Inc. ©2022 Pacira Pharmaceuticals, Inc. All rights reserved. For more information, go to ZILRETTA.com or call 1-844-353-9466. Part Number: 60-009-08 Version: 8, 11/2024
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2025-02-12T15:47:27.999558
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IMFINZI safely and effectively. See full prescribing information for IMFINZI. IMFINZI® (durvalumab) injection, for intravenous use Initial U.S. Approval: 2017 -------------------------- RECENT MAJOR CHANGES -------------------------­ Indications and Usage (1.1, 1.2, 1.5) 12/2024 Dosage and Administration (2.1, 2.2, 2.3, 2.4) 12/2024 Warnings and Precautions (5.1) 12/2024 --------------------------- INDICATIONS AND USAGE -------------------------­ IMFINZI is a programmed death-ligand 1 (PD-L1) blocking antibody indicated: • in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as a single agent as adjuvant treatment after surgery, for the treatment of adult patients with resectable (tumors ≥ 4 cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements. (1.1) • as a single agent, for the treatment of adult patients with unresectable, Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. (1.1) • in combination with tremelimumab-actl and platinum-based chemotherapy, for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations. (1.1) • as a single agent, for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. (1.2) • in combination with etoposide and either carboplatin or cisplatin, as first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). (1.2) • in combination with gemcitabine and cisplatin, as treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC). (1.3) • in combination with tremelimumab-actl, for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). (1.4) • in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR). (1.5) ---------------------- DOSAGE AND ADMINISTRATION ---------------------­ • Administer IMFINZI as an intravenous infusion over 60 minutes after dilution. (2.4) • Neoadjuvant and Adjuvant Treatment of Resectable NSCLC: o Weight ≥ 30 kg: Neoadjuvant: IMFINZI 1,500 mg in combination with chemotherapy every 3 weeks for up to 4 cycles prior to surgery. Adjuvant: IMFINZI 1,500 mg as a single agent every 4 weeks for up to 12 cycles after surgery. (2.2) o Weight < 30 kg Neoadjuvant: IMFINZI 20 mg/kg every 3 weeks in combination with chemotherapy for up to 4 cycles prior to surgery. Adjuvant: 20 mg/kg every 4 weeks as a single agent for up to 12 cycles after surgery. (2.2) • Unresectable Stage III NSCLC, following concurrent platinum-based chemotherapy and radiation therapy: o Weight ≥ 30 kg: IMFINZI 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks. (2.2) o Weight < 30 kg: IMFINZI 10 mg/kg every 2 weeks. (2.2) • Metastatic NSCLC: o Weight ≥ 30 kg: IMFINZI 1,500 mg every 3 weeks in combination with tremelimumab-actl 75 mg and platinum-based chemotherapy for 4 cycles, and then administer IMFINZI 1,500 mg every 4 weeks as a single agent with histology-based pemetrexed maintenance therapy every 4 weeks, and a fifth dose of tremelimumab-actl 75 mg in combination with IMFINZI dose 6 at week 16. (2.2) o Weight < 30 kg: IMFINZI 20 mg/kg every 3 weeks in combination with tremelimumab-actl 1 mg/kg and platinum-based chemotherapy, and then administer IMFINZI 20 mg/kg every 4 weeks as a single agent with histology-based pemetrexed therapy every 4 weeks, and a 1 fifth dose of tremelimumab-actl 1 mg/kg in combination with IMFINZI dose 6 at week 16. (2.2) • LS-SCLC, following concurrent platinum-based chemotherapy and radiation therapy: o Weight ≥ 30 kg: 1,500 mg every 4 weeks. (2.2) o Weight < 30 kg: 20 mg/kg every 4 weeks. (2.2) • ES-SCLC: o Weight ≥ 30 kg: With etoposide and either carboplatin or cisplatin, administer IMFINZI 1,500 mg every 3 weeks in combination with chemotherapy, and then 1,500 mg every 4 weeks as a single agent. (2.2) o Weight < 30 kg: With etoposide and either carboplatin or cisplatin, administer IMFINZI 20 mg/kg every 3 weeks in combination with chemotherapy, and then 10 mg/kg every 2 weeks as a single agent. (2.2) • BTC: o Weight ≥ 30 kg: administer IMFINZI 1,500 mg every 3 weeks in combination with chemotherapy, and then 1,500 mg every 4 weeks as a single agent. (2.2) o Weight < 30 kg: administer IMFINZI 20 mg/kg every 3 weeks in combination with chemotherapy, and then 20 mg/kg every 4 weeks as a single agent. (2.2) • uHCC: o Weight ≥ 30 kg: IMFINZI 1,500 mg in combination with tremelimumab-actl 300 mg as a single dose at Cycle 1/Day 1, followed by IMFINZI as a single agent every 4 weeks. (2.2) o Weight < 30 kg: IMFINZI 20 mg/kg in combination with tremelimumab-actl 4 mg/kg as a single dose at Cycle 1/Day 1, followed by IMFINZI as a single agent every 4 weeks. (2.2) • dMMR endometrial cancer: o Weight ≥ 30 kg: IMFINZI 1,120 mg in combination with carboplatin and paclitaxel every 3 weeks for 6 cycles, followed by IMFINZI 1,500 mg every 4 weeks as a single agent. (2.1, 2.2) o Weight < 30 kg: IMFINZI 15 mg/kg in combination with carboplatin and paclitaxel every 3 weeks for 6 cycles, followed by IMFINZI 20 mg/kg every 4 weeks as a single agent. (2.1, 2.2) • See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions. --------------------- DOSAGE FORMS AND STRENGTHS -------------------­ • Injection: 500 mg/10 mL (50 mg/mL) solution in a single-dose vial. (3) • Injection: 120 mg/2.4 mL (50 mg/mL) solution in a single-dose vial. (3) ------------------------------ CONTRAINDICATIONS ----------------------------­ None. (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------------­ • Immune-Mediated Adverse Reactions (5.1) o Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune- mediated nephritis and renal dysfunction, solid organ transplant rejection, and immune-mediated pancreatitis. o Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. o Withhold or permanently discontinue based on severity and type of reaction. • Infusion-Related Reactions: Interrupt, slow the rate of infusion, or permanently discontinue IMFINZI based on the severity of the reaction. (5.2) • Complications of Allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. (5.3) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. (5.4, 8.1, 8.3) ------------------------------ ADVERSE REACTIONS ----------------------------­ IMFINZI in Combination with Chemotherapy • Most common adverse reactions (≥ 20%) of patients with resectable, Stage II/III NSCLC [neoadjuvant /adjuvant]) are anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash. (6.1) IMFINZI as a Single Agent Reference ID: 5489972 _______________________________________________________________________________________________________________________________________ • Most common adverse reactions (≥ 20%) of patients with unresectable, Stage III NSCLC) are cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. (6.1) IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemotherapy • Most common adverse reactions (≥ 20%) of patients with metastatic NSCLC) are nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea. (6.1) IMFINZI as a Single Agent • Most common adverse reactions (≥ 20%) of patients with limited-stage SCLC) are pneumonitis or radiation pneumonitis, and fatigue. (6.1) IMFINZI in Combination with Platinum-Based Chemotherapy • Most common adverse reactions (≥ 20%) of patients with extensive- stage SCLC) are nausea, fatigue/asthenia, and alopecia. (6.1) IMFINZI in Combination with Gemcitabine and Cisplatin • Most common adverse reactions (≥ 20%) of patients with BTC) are fatigue, nausea, constipation, decreased appetite, abdominal pain, rash, and pyrexia. (6.1) IMFINZI in Combination with Tremelimumab-actl • Most common adverse reactions (≥ 20%) of patients with uHCC) are rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. (6.1) IMFINZI in Combination with Carboplatin and Paclitaxel, followed by IMFINZI as a single agent • Most common adverse reactions (≥ 20%) of patients with endometrial cancer) were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, decreased magnesium, increased ALT, increased AST, diarrhea, vomiting, cough, decreased potassium, dyspnea, headache, and increased alkaline phosphatase. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------- USE IN SPECIFIC POPULATIONS ---------------------­ Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 8.2 Lactation 1 INDICATIONS AND USAGE 8.3 Females and Males of Reproductive Potential 1.1 Non-Small Cell Lung Cancer 8.4 Pediatric Use 1.2 Small Cell Lung Cancer 8.5 Geriatric Use 1.3 Biliary Tract Cancers 11 DESCRIPTION 1.4 Hepatocellular Carcinoma 12 CLINICAL PHARMACOLOGY 1.5 Endometrial Cancer 12.1 Mechanism of Action 2 DOSAGE AND ADMINISTRATION 12.2 Pharmacodynamics 2.1 patient Selection 12.3 Pharmacokinetics 2.2 Recommended Dosage 12.6 Immunogenicity 2.3 Dosage Modifications for Adverse Reactions 13 NONCLINICAL TOXICOLOGY 2.4 Preparation and Administration 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 3 DOSAGE FORMS AND STRENGTHS 13.2 Animal Toxicology and/or Pharmacology 4 CONTRAINDICATIONS 14 CLINICAL STUDIES 5 WARNINGS AND PRECAUTIONS 14.1 Non-Small Cell Lung Cancer (NSCLC) 5.1 Immune-Mediated Adverse Reactions 14.2 Small Cell Lung Cancer (SCLC) 5.2 Infusion-Related Reactions 14.3 Biliary Tract Cancer (BTC) 5.3 Complications of Allogeneic HSCT after IMFINZI 14.4 Hepatocellular Carcinoma (HCC) 5.4 Embryo-Fetal Toxicity 14.5 Endometrial cancer 6 ADVERSE REACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING 6.1 Clinical Trials Experience 17 PATIENT COUNSELING INFORMATION 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy *Sections or subsections omitted from the full prescribing information are not listed. 2 Reference ID: 5489972 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Non-Small Cell Lung Cancer • IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by IMFINZI continued as a single agent as adjuvant treatment after surgery, is indicated for the treatment of adult patients with resectable (tumors ≥ 4 cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements. • IMFINZI, as a single agent, is indicated for the treatment of adult patients with unresectable Stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT). • IMFINZI, in combination with tremelimumab-actl and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations. 1.2 Small Cell Lung Cancer • IMFINZI, as a single agent, is indicated for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (cCRT). • IMFINZI, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). 1.3 Biliary Tract Cancers IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC). 1.4 Hepatocellular Carcinoma IMFINZI, in combination with tremelimumab-actl, is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). 1.5 Endometrial Cancer IMFINZI, in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR). 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Advanced or Recurrent dMMR Endometrial Cancer Select patients for treatment based on the presence of dMMR in tumor specimens [see Clinical Studies (14.5)]. 1 Reference ID: 5489972 An FDA-approved test for the detection of dMMR in tumor specimens from patients with primary advanced or recurrent endometrial cancer for treatment with IMFINZI is not available. 2.2 Recommended Dosage The recommended dosages for IMFINZI as a single agent and IMFINZI in combination with other therapeutic agents are presented in Table 1. The recommended dosage schedule and regimens for IMFINZI for the treatment of metastatic NSCLC are provided in Tables 2 and 3 [see Indications and Usage (1.1)]. Administer IMFINZI as an intravenous infusion after dilution as recommended [see Dosage and Administration (2.3)]. Table 1. Recommended Dosages of IMFINZI Indication Recommended IMFINZI Dosage Duration of Therapy Neoadjuvant and Adjuvant Treatment of Resectable NSCLC Patients with a body weight of ≥ 30 kg: Neoadjuvant: IMFINZI 1,500 mg in combination with chemotherapy* every 3 weeks for up to 4 cycles prior to surgery Adjuvant: IMFINZI 1,500 mg as a single agent every 4 weeks for up to 12 cycles after surgery. Patients with a body weight of < 30 kg: Neoadjuvant: IMFINZI 20 mg/kg every 3 weeks in combination with chemotherapy* for up to 4 cycles prior to surgery. Adjuvant: IMFINZI 20 mg/kg every 4 weeks for up to 12 cycles as a single agent after surgery. Until disease progression that precludes definitive surgery, recurrence, unacceptable toxicity, or a maximum of 12 cycles after surgery Unresectable Stage III NSCLC Following concurrent platinum- based chemotherapy and radiation therapy: Patients with a body weight of ≥ 30 kg: 10 mg/kg every 2 weeks or Until disease progression, unacceptable toxicity, or a maximum of 12 months 2 Reference ID: 5489972 Indication Recommended IMFINZI Dosage Duration of Therapy 1,500 mg every 4 weeks Patients with a body weight of < 30 kg: 10 mg/kg every 2 weeks Limited Stage SCLC Following concurrent platinum- based chemotherapy and radiation therapy: Patients with a body weight of ≥ 30 kg: 1,500 mg every 4 weeks Patients with a body weight of < 30 kg: 20 mg/kg every 4 weeks Until disease progression, unacceptable toxicity, or a maximum of 24 months Extensive Stage SCLC Patients with a body weight of ≥ 30 kg: 1,500 mg in combination with chemotherapy* every 3 weeks (21 days) for 4 cycles, followed by 1,500 mg every 4 weeks as a single agent Patients with a body weight of < 30 kg: 20 mg/kg in combination with chemotherapy* every 3 weeks (21 days) for 4 cycles, followed by 10 mg/kg every 2 weeks as a single agent Until disease progression or unacceptable toxicity BTC Patients with a body weight of ≥ 30 kg: 1,500 mg in combination with chemotherapy* every 3 weeks (21 days) up to 8 cycles followed by 1,500 mg every 4 weeks as a single agent Patients with a body weight of < 30 kg: 20 mg/kg in combination with chemotherapy* every 3 weeks (21 days) up to 8 cycles Until disease progression or until unacceptable toxicity 3 Reference ID: 5489972   I Indication Recommended IMFINZI Dosage Duration of Therapy followed by 20 mg/kg every 4 weeks as a single agent uHCC Patients with a body weight of ≥ 30 kg: • IMFINZI 1,500 mg following a single dose of tremelimumab­ actl$ 300 mg at Day 1 of Cycle 1; • Continue IMFINZI 1,500 mg as a single agent every 4 weeks Patients with a body weight of < 30 kg: • IMFINZI 20 mg/kg following a single dose of tremelimumab­ actl$ 4 mg/kg at Day 1 of Cycle 1; • Continue IMFINZI 20 mg/kg as a single agent every 4 weeks After Cycle 1 of combination therapy, administer IMFINZI as a single agent every 4 weeks until disease progression or unacceptable toxicity dMMR endometrial cancer Patients with a body weight of ≥ 30 kg: IMFINZI 1,120 mg in combination with carboplatin and paclitaxel* every 3 weeks (21 days) for 6 cycles, followed by IMFINZI 1,500 mg every 4 weeks as a single agent Patients with a body weight of < 30 kg: IMFINZI 15 mg/kg in combination with carboplatin and paclitaxel* every 3 weeks (21 days) for 6 cycles, followed by IMFINZI 20 mg/kg every 4 weeks as a single agent Until disease progression or unacceptable toxicity * Administer IMFINZI prior to chemotherapy on the same day. Refer to the Prescribing Information for the agent administered in combination with IMFINZI for recommended dosage information, as appropriate. 4 Reference ID: 5489972 $ Administer tremelimumab-actl prior to IMFINZI on the same day. When tremelimumab-actl is administered in combination with IMFINZI, refer to the Prescribing Information for tremelimumab-actl dosing information. IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemotherapy The recommended dosage schedule and regimens for IMFINZI for the treatment of metastatic NSCLC are provided in Tables 2 and 3. Weigh patients prior to each infusion. Calculate the appropriate dose using Table 3 below based on the patient’s weight and tumor histology. Table 2. Recommended Dosage Schedule for Metastatic NSCLC Week *,$ 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Cycle: 1 2 3 4 5 6 7 8 IMFINZI *,¶ X X X X X X X X Tremelimumab­ actl¶,# X X X X X Chemotherapy X X X X XÞ XÞ XÞ XÞ * continue IMFINZI until disease progression or intolerable toxicity. $ note the dosing interval change from every 3 weeks to every 4 weeks starting at cycle 5. ¶ intravenous infusion over 60 minutes [see Dosage and Administration (2.4)]. # if patients receive fewer than 4 cycles of platinum-based chemotherapy, the remaining cycles of tremelimumab­ actl (up to a total of 5) should be given after the platinum-based chemotherapy phase, in combination with IMFINZI, every 4 weeks. Þ optional pemetrexed therapy from week 12 until disease progression or intolerable toxicity for patients with non- squamous disease who received treatment with pemetrexed and carboplatin/cisplatin. Table 3. Recommended Regimen and Dosage for Metastatic NSCLC Tumor Histology Patient Weight IMFINZI Dosage Tremelimumab­ actl Dosage* Platinum-based Chemotherapy Regimen* Non-Squamous ≥ 30 kg 1,500 mg 75 mg • carboplatin & nab­ paclitaxel OR • carboplatin or cisplatin & pemetrexed < 30 kg 20 mg/kg 1 mg/kg Squamous ≥ 30 kg 1,500 mg 75 mg • carboplatin & nab­ paclitaxel OR • carboplatin or cisplatin & gemcitabine < 30 kg 20 mg/kg 1 mg/kg * Refer to the Prescribing Information for dosing information. 5 Reference ID: 5489972 2.3 Dosage Modifications for Adverse Reactions No dose reduction for IMFINZI is recommended. In general, withhold IMFINZI for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue IMFINZI for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. Dosage modifications for IMFINZI or IMFINZI in combination with tremelimumab-actl or chemotherapy for adverse reactions that require management different from these general guidelines are summarized in Table 4. Table 4. Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity* Dosage Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] Pneumonitis Grade 2 Withhold† Grade 3 or 4 Permanently discontinue Colitis Grade 2 Withhold† Grade 3 Withhold† or permanently discontinue‡ Grade 4 Permanently discontinue Intestinal perforation Any grade Permanently discontinue Hepatitis with no tumor involvement of the liver ALT or AST increases to more than 3 and up to 8 times the ULN or total bilirubin increases to more than 1.5 and up to 3 times ULN Withhold† ALT or AST increases to more than 8 times ULN or total bilirubin increases to more than 3 times the ULN Permanently discontinue Hepatitis with tumor involvement of the liver§ AST or ALT is more than 1 and up to 3 times ULN at baseline and increases to more than 5 and up to 10 times ULN or AST or ALT is more than 3 and up to 5 times ULN at baseline and increases to more than 8 and up to 10 times ULN Withhold† 6 Reference ID: 5489972 Adverse Reaction Severity* Dosage Modification AST or ALT increases to more than 10 times ULN or total bilirubin increases to more than 3 times ULN Permanently discontinue Endocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold† Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold† Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grade 2, 3, or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold† Grade 3 or 4 Permanently discontinue Other Adverse Reactions Infusion-related reactions [see Warnings and Precautions (5.2)] Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal. * Based on National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. † Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating corticosteroids or an inability to reduce corticosteroid dose to 10 mg of prednisone or less per day (or equivalent) within 12 weeks of initiating corticosteroids. ‡ Permanently discontinue IMFINZI for Grade 3 colitis when administered as part of a tremelimumab-actl containing regimen. § If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue IMFINZI based on recommendations for hepatitis with no liver involvement. 2.4 Preparation and Administration Preparation • Visually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. • Do not shake the vial. 7 Reference ID: 5489972 • Withdraw the required volume from the vial(s) of IMFINZI and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL. • Discard partially used or empty vials of IMFINZI. Storage of Infusion Solution • IMFINZI does not contain a preservative. • Administer infusion solution immediately once prepared. If the infusion solution is not administered immediately and needs to be stored, the time from preparation until the completion of the infusion should not exceed: o 28 days in a refrigerator at 2°C to 8°C (36°F to 46°F). o 8 hours at room temperature up to 25°C (77°F). • Do not freeze. • Do not shake. Administration • Administer infusion solution intravenously over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter. • Use separate infusion bags and filters for each drug product. IMFINZI in Combination with Other Products • Administer all intravenous drug products as separate infusions. • Do not co-administer other intravenous drugs through the same infusion line. • For platinum-based chemotherapy, refer to Prescribing Information for administration information. • For pemetrexed therapy, refer to Prescribing Information for administration information. Combination Regimens: Order of Infusions IMFINZI in Combination with Tremelimumab-actl • Infuse tremelimumab-actl first, followed by IMFINZI on the same day of dosing. IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemotherapy • Infuse tremelimumab-actl first, followed by IMFINZI and then platinum-based chemotherapy on the day of dosing. 8 Reference ID: 5489972 IMFINZI in Combination with Tremelimumab-actl and Pemetrexed Therapy • Infuse tremelimumab-actl first, followed by IMFINZI and then pemetrexed therapy on the day of dosing. IMFINZI in Combination with Carboplatin and Paclitaxel • Infuse IMFINZI first and then carboplatin and paclitaxel on the same day of dosing. Combination Regimens: Infusion Instructions IMFINZI in Combination with Tremelimumab-actl • Administer tremelimumab-actl over 60 minutes followed by a 60 minute observation period. Then administer IMFINZI as a separate intravenous infusion over 60 minutes. IMFINZI in Combination with Tremelimumab-actl and Platinum-Based Chemotherapy/ Pemetrexed Therapy Cycle 1 • Infuse tremelimumab-actl over 60 minutes. One to two hours after completion of tremelimumab-actl infusion, infuse IMFINZI over 60 minutes. One to two hours after completion of IMFINZI infusion, administer platinum-based chemotherapy. Subsequent Cycles • If there are no infusion reactions during cycle 1, subsequent cycles of IMFINZI can be given immediately after tremelimumab-actl. The time between the end of the IMFINZI infusion and the start of chemotherapy can be reduced to 30 minutes. 3 DOSAGE FORMS AND STRENGTHS Injection: 120 mg/2.4 mL (50 mg/mL) and 500 mg/10 mL (50 mg/mL) clear to opalescent, colorless to slightly yellow solution in a single-dose vial. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Mediated Adverse Reactions IMFINZI is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. 9 Reference ID: 5489972 The incidence and severity of immune-mediated adverse reactions were similar when IMFINZI was administered as a single agent or in combination with chemotherapy or in combination with tremelimumab-actl and platinum-based chemotherapy, unless otherwise noted. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.3)]. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. IMFINZI as a Single Agent In Patients Who Did Not Receive Recent Prior Radiation In patients who received IMFINZI on clinical studies in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (< 0.1%), and Grade 3-4 (0.4%) adverse reactions. Events resolved in 19 of the 34 patients and resulted in permanent discontinuation in 5 patients. Systemic corticosteroids were required in 19 patients (19/34) with pneumonitis who did not receive chemoradiation prior to initiation of IMFINZI. The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar whether IMFINZI was given as a single agent in patients 10 Reference ID: 5489972 with various cancers in a pooled data set or in patients with ES-SCLC or BTC when given in combination with chemotherapy. In Patients Who Received Recent Prior Radiation The incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% had a fatal adverse reaction and 2.7% had Grade 3 adverse reactions. Events resolved in 50 of the 87 (57%) patients and resulted in permanent discontinuation in 27 of the 87 (31%) patients. Systemic corticosteroids were required in 64 patients (64/87) with pneumonitis who had received chemoradiation prior to initiation of IMFINZI, while 2 patients required use of infliximab with high-dose steroids. The incidence of pneumonitis (including radiation pneumonitis) in patients with LS-SCLC following chemoradiation within 42 days prior to initiation of IMFINZI in ADRIATIC was 14% (37/262) in patients receiving IMFINZI and 6% (16/265) in patients receiving placebo. Of the patients who received IMFINZI (262), 0.4% had a fatal adverse reaction and 2.7% had Grade 3 adverse reactions. Events resolved in 19 of the 37 (51%) patients and resulted in permanent discontinuation in 18 of the 37 (49%) patients. Systemic corticosteroids were required in all patients, while 1 patient required use of infliximab with high-dose steroids. IMFINZI with Tremelimumab-actl Immune-mediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including fatal (0.3%) and Grade 3 (0.2%) adverse reactions. Events resolved in 3 of the 5 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in all patients; of these, 4 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient (1/5) required other immunosuppressants. IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated pneumonitis occurred in 3.5% (21/596) of patients receiving IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy, including fatal (0.5%), and Grade 3 (1%) adverse reactions. Events resolved in 11 of the 21 patients and resulted in permanent discontinuation in 7 patients. Systemic corticosteroids were required in all patients with immune-mediated pneumonitis, while 1 patient (1/21) required other immunosuppressants. Immune-Mediated Colitis IMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune- mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. IMFINZI as a Single Agent 11 Reference ID: 5489972 Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (< 0.1%) and Grade 3 (0.4%) adverse reactions. Events resolved in 27 of the 37 patients and resulted in permanent discontinuation in 8 patients. Systemic corticosteroids were required in all patients with immune-mediated colitis, while 2 patients (2/37) required other immunosuppressants (e.g., infliximab, mycophenolate). IMFINZI with Tremelimumab-actl Immune-mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (3.6%) adverse reactions. Events resolved in 22 of the 23 patients and resulted in permanent discontinuation in 5 patients. All patients received systemic corticosteroids, and 20 of the 23 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also received other immunosuppressants. Intestinal perforation has been observed in other studies of IMFINZI in combination with tremelimumab­ actl. IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated colitis occurred in 6.5% (39/596) of patients receiving IMFINZI in combination with tremelimumab-actl including fatal (0.2%) and Grade 3 (2.5%) adverse reactions. Events resolved in 33 of 39 patients and resulted in permanent discontinuation in 11 patients. Systemic corticosteroids were required in all patients with immune-mediated colitis, while 4 patients (4/39) required other corticosteroids. Intestinal perforation and large intestine perforation were reported in 0.1% of patients receiving IMFINZI in combination with tremelimumab-actl. Immune-Mediated Hepatitis IMFINZI can cause immune-mediated hepatitis. IMFINZI as a Single Agent Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions. Events resolved in 21 of the 52 patients and resulted in permanent discontinuation of IMFINZI in 6 patients. Systemic corticosteroids were required in all patients with immune-mediated hepatitis, while 2 patients (2/52) required use of mycophenolate with high-dose steroids. IMFINZI with Tremelimumab-actl Immune-mediated hepatitis occurred in 7.5% (29/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including fatal (0.8%), Grade 4 (0.3%), and Grade 3 (4.1%) adverse reactions. Events resolved in 12 of the 29 patients and resulted in permanent discontinuation in 9 patients. Systemic corticosteroids were required in all 29 patients and all 29 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients (8/29) required other immunosuppressants. 12 Reference ID: 5489972 IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated hepatitis occurred in 3.9% (23/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including fatal (0.3%), Grade 4 (0.5%), and Grade 3 (2.0%) adverse reactions. Events resolved in 12 of the 23 patients and resulted in permanent discontinuation in 10 patients. Systemic corticosteroids were required in all patients with immune-mediated hepatitis, while 2 patients (2/23) required use of other immunosuppressants. Immune-Mediated Endocrinopathies Adrenal Insufficiency IMFINZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.3)]. IMFINZI as a Single Agent Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (< 0.1%) adverse reactions. Events resolved in 1 of the 9 patients and did not lead to permanent discontinuation of IMFINZI in any patients. Systemic corticosteroids were required in all patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids. IMFINZI with Tremelimumab-actl Immune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in all 6 patients, and of these, 1 patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated adrenal insufficiency occurred in 2.2% (13/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.8%) adverse reactions. Events resolved in 2 of the 13 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in all patients with adrenal insufficiency. One patient also required endocrine therapy. Hypophysitis IMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.3)]. IMFINZI as a Single Agent 13 Reference ID: 5489972 Grade 3 hypophysitis/hypopituitarism occurred in < 0.1% (1/1889) of patients who received IMFINZI. Treatment with systemic corticosteroids was administered in this patient. The event did not lead to permanent discontinuation of IMFINZI. IMFINZI with Tremelimumab-actl Immune-mediated hypophysitis/hypopituitarism occurred in 1% (4/388) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in 2 of the 4 patients. Systemic corticosteroids were required in 3 patients, and of these, 1 patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Two patients also required endocrine therapy. IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated hypophysitis occurred in 1.3% (8/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.5%) adverse reactions. Events resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in 6 patients with immune-mediated hypophysitis; of these, 2 of the 8 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also required endocrine therapy. Thyroid Disorders IMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or discontinue IMFINZI based on the severity [see Dosage and Administration (2.3)]. Thyroiditis IMFINZI as a Single Agent Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (< 0.1%) adverse reactions. Events resolved in 4 of the 9 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in 3 patients (3/9) with immune- mediated thyroiditis, while 8 patients (8/9) required endocrine therapy. IMFINZI with Tremelimumab-actl Immune-mediated thyroiditis occurred in 1.5% (6/388) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in 2 patients (2/6) with immune-mediated thyroiditis; of these, 1 patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker. IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated thyroiditis occurred in 1.2% (7/596) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in 2 of the 7 patients and one resulted in permanent 14 Reference ID: 5489972 discontinuation. Systemic corticosteroids were required in 2 patients (2/7) with immune-mediated thyroiditis, while all patients required endocrine therapy. Hyperthyroidism IMFINZI as a Single Agent Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI. Events resolved in 30 of the 39 patients and did not lead to permanent discontinuation of IMFINZI in any patients. Systemic corticosteroids were required in 9 patients (9/39) with immune-mediated hyperthyroidism, while 35 patients (35/39) required endocrine therapy. IMFINZI with Tremelimumab-actl Immune-mediated hyperthyroidism occurred in 4.6% (18/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions. Events resolved in 15 of the 18 patients. Two patients (2/18) required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seventeen patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker). IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated hyperthyroidism occurred in 5% (30/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.2%) adverse reactions. Events resolved in 21 of the 30 patients. Systemic corticosteroids were required in 5 patients (5/30) with immune-mediated hyperthyroidism, while 28 patients (28/30) required endocrine therapy. Hypothyroidism IMFINZI as a Single Agent Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Events resolved in 31 of the 156 patients and did not lead to permanent discontinuation of IMFINZI in any patients. Systemic corticosteroids were required in 11 patients (11/156) and the majority of patients (152/156) required long-term thyroid hormone replacement. IMFINZI with Tremelimumab-actl Immune-mediated hypothyroidism occurred in 11% (42/388) of patients receiving IMFINZI in combination with tremelimumab-actl. Events resolved in 5 of the 42 patients. One patient received high- dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta- blocker). IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy 15 Reference ID: 5489972 Immune-mediated hypothyroidism occurred in 8.6% (51/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.5%) adverse reactions. Systemic corticosteroids were required in 2 patients (2/51) and all patients required endocrine therapy. IMFINZI with Carboplatin and Paclitaxel Immune-mediated hypothyroidism occurred in 14% (34/235) of patients receiving IMFINZI in combination with carboplatin and paclitaxel. Events resolved in 8 of the 34 patients. Endocrine therapy was required in 34 of the 34 patients. Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.3)]. IMFINZI as a Single Agent Grade 3 immune-mediated type 1 diabetes mellitus occurred in < 0.1% (1/1889) of patients receiving IMFINZI. This patient required long-term insulin therapy and IMFINZI was permanently discontinued. Two additional patients (0.1%, 2/1889) had events of hyperglycemia requiring insulin therapy that did not resolve at the time of reporting. IMFINZI with Tremelimumab-actl Two patients (0.5%, 2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up. IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated Type 1 diabetes mellitus occurred in 0.5% (3/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions. All patients required endocrine therapy. Immune-Mediated Nephritis with Renal Dysfunction IMFINZI can cause immune-mediated nephritis. IMFINZI as a Single Agent Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (< 0.1%) adverse reactions. Events resolved in 5 of the 10 patients and resulted in permanent discontinuation in 3 patients. Systemic corticosteroids were required in all patients with immune- mediated nephritis. IMFINZI with Tremelimumab-actl Immune-mediated nephritis occurred in 1% (4/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.5%) adverse reactions. Events resolved in 3 of the 4 patients and 16 Reference ID: 5489972 resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis; of these, 3 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated nephritis occurred in 0.7% (4/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.2%) adverse reactions. Events resolved in 1 of the 4 patients and resulted in permanent discontinuation in 3 patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis. Immune-Mediated Dermatology Reactions IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.3)]. IMFINZI as a Single Agent Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions. Events resolved in 19 of the 34 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis. IMFINZI with Tremelimumab-actl Immune-mediated rash or dermatitis occurred in 4.9% (19/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. Events resolved in 13 of the 19 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis; of these, 12 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient received other immunosuppressants. IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Immune-mediated rash or dermatitis occurred in 7.2% (43/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions. Events resolved in 32 of the 43 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis. Immune-Mediated Pancreatitis IMFINZI in combination with tremelimumab-actl can cause immune-mediated pancreatitis. IMFINZI with Tremelimumab-actl 17 Reference ID: 5489972 Immune-mediated pancreatitis occurred in 2.3% (9/388) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. Events resolved in 6 of the 9 patients. Systemic corticosteroids were required in all 9 patients, and of these 7 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Other Immune-Mediated Adverse Reactions The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or IMFINZI in combination with tremelimumab-actl, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Cardiac/vascular: Myocarditis, pericarditis, vasculitis. Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy. Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada­ like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis. Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic. Endocrine: Hypoparathyroidism. Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection. 5.2 Infusion-Related Reactions IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.3)]. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. IMFINZI as a Single Agent Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions. IMFINZI in Combination with Tremelimumab-actl 18 Reference ID: 5489972 Infusion-related reactions occurred in 2.6% (10/388) of patients receiving IMFINZI in combination with tremelimumab-actl. IMFINZI with Tremelimumab-actl and Platinum-Based Chemotherapy Infusion-related reactions occurred in 2.9% (17/596) of patients receiving IMFINZI in combination with tremelimumab-actl, including Grade 3 (0.3%) adverse reactions. 5.3 Complications of Allogeneic HSCT after IMFINZI Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant- related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT. 5.4 Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of durvalumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased premature delivery, fetal loss and premature neonatal death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for 3 months after the last dose of IMFINZI [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]. • Infusion-Related Reactions [see Warnings and Precautions (5.2)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to IMFINZI as a single agent in a total of 1,889 patients enrolled in the PACIFIC study (a randomized, placebo-controlled study that enrolled 475 patients with unresectable Stage III NSCLC), Study 1108 (an open-label, single- arm, multicohort study that enrolled 970 patients with advanced solid tumors), and an additional open- label, single-arm study (ATLANTIC Study) that enrolled 444 patients with advanced solid tumors, 19 Reference ID: 5489972 including NSCLC. In these studies, IMFINZI was administered at a dose of 10 mg/kg every 2 weeks. Among the 1889 patients, 38% were exposed for 6 months or more and 18% were exposed for 12 months or more. The data also reflect exposure to IMFINZI 1,500 mg every 4 weeks as a single agent in 262 patients from the ADRIATIC study (a randomized, double-blind study in patients with LS-SCLC) and to IMFINZI in combination with chemotherapy in 265 patients from the CASPIAN study (a randomized, open-label study in patients with ES-SCLC) and in 338 patients from the TOPAZ-1 study (a randomized, double-blind study in patients with BTC). In the CASPIAN and TOPAZ-1 studies, IMFINZI was administered at a dose of 1,500 mg every 3 or 4 weeks. The data also reflect exposure to IMFINZI 1,120 mg in combination with carboplatin and paclitaxel (every 3 weeks for up to 6 cycles) followed by IMFINZI 1,500 mg (every 4 weeks) as a single agent in 235 patients in DUO-E (a randomized, placebo-controlled trial in endometrial cancer). Among the 235 patients, 77% (181 patients) were exposed to IMFINZI for 6 months or more and 41% (96 patients) for 12 months or more. The data also reflect exposure to IMFINZI 1,500 mg in combination with tremelimumab-actl 300 mg in 388 patients in HIMALAYA. In the HIMALAYA study patients received IMFINZI 1,500 mg in combination with tremelimumab-actl as a single intravenous infusion of 300 mg, followed by IMFINZI 1,500 mg every 4 weeks. The pooled safety population (N = 596) described in the WARNINGS AND PRECAUTIONS section reflect exposure to IMFINZI 1,500 mg in combination with tremelimumab-actl 75 mg and histology-based platinum chemotherapy regimens in 330 patients in POSEIDON [see Clinical Studies (14.1)], and 266 patients with ES-SCLC in CASPIAN who received up to four cycles of platinum-etoposide plus IMFINZI 1,500 mg with tremelimumab-actl 75 mg every 3 weeks, followed by IMFINZI 1,500 mg every 4 weeks (an unapproved regimen for extensive stage small cell lung cancer). Among the 596 patients, 55% were exposed to IMFINZI for 6 months or more and 24% were exposed for 12 months or more. The data described in this section reflect exposure to IMFINZI in patients with unresectable Stage III NSCLC enrolled in the PACIFIC study, in patients with metastatic NSCLC enrolled in the POSEIDON study, in patients with LS-SCLC enrolled in the ADRIATIC study, in patients with ES-SCLC enrolled in the CASPIAN study, in patients with BTC enrolled in the TOPAZ-1 study, in patients with uHCC included in the HIMALAYA study, in patients with dMMR endometrial cancer enrolled in the DUO-E study, and in patients with resectable NSCLC enrolled in the AEGEAN study. Non-Small Cell Lung Cancer Neoadjuvant and Adjuvant Treatment of Resectable NSCLC – AEGEAN The safety of IMFINZI in combination with neoadjuvant platinum-containing chemotherapy followed by surgery, and continued adjuvant treatment with IMFINZI as a single agent after surgery, was investigated in AEGEAN, a randomized, double-blind, placebo-controlled, multicenter study for patients with resectable NSCLC (Stage IIA to select Stage IIIB [AJCC, 8th edition]); squamous or non-squamous) [see Clinical Studies (14.1)]. Safety data are available for the 799 patients who received IMFINZI in combination with chemotherapy (n=401) or placebo in combination with chemotherapy (n=398). 20 Reference ID: 5489972 The median duration of exposure to IMFINZI 1,500 mg every 3 weeks in the neoadjuvant phase was 12 weeks (range: 0 to 19 weeks). The median duration of exposure to IMFINZI 1,500 mg every 4 weeks in the adjuvant phase was 37 weeks (range: 4 to 67 weeks). The median age of patients who received IMFINZI was 65 years (range: 30 to 88), 52% age 65 or older, 12% age 75 or older; 65% male; 54% White, 41% Asian, 1% Black, 3% Other races; and 17% Hispanic or Latino. The most common adverse reactions (occurring in ≥ 20% of patients) were anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash. Table 5 summarizes the adverse reactions that occurred in (≥ 10%) patients treated with IMFINZI in combination with chemotherapy. Table 5. Adverse Reactions Occurring in ≥ 10% of Patients in the AEGEAN Study Adverse Reaction IMFINZI with Chemotherapy N=401 Placebo with Chemotherapy N=398 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Nausea 25 0.2 29 0.3 Constipation 25 0.2 21 0 Diarrhea* 14 1.0 13 1.3 Vomiting 11 0.7 11 1.0 General disorders and administration site conditions Fatigue† 25 0 25 1.5 Skin and subcutaneous tissue disorders RashÞ 22 0.5 14 0.3 Pruritus 12 0.2 6 0 Musculoskeletal and connective tissue disorders Musculoskeletal painß 24 1.0 29 0.5 Metabolism and nutrition disorders Decreased appetite 18 0.2 18 0.3 Nervous system disorders 21 Reference ID: 5489972 Adverse Reaction IMFINZI with Chemotherapy N=401 Placebo with Chemotherapy N=398 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Peripheral neuropathyà 16 0.5 22 0.8 Endocrine disorders Hypothyroidism¶ 11 0 3.8 0 Respiratory, thoracic and mediastinal disorders Cough / Productive cough 11 0 13 0 Pneumonia#,‡ 11 3.5 10 3.0 COVID-19§ 11 0.2 9 0.8 Psychiatric Disorders Insomnia 10 0 12 0 * includes colitis, diarrhea, enteritis, and proctitis. † includes fatigue and asthenia. Þ includes dermatitis, dermatitis acneiform, drug eruption, eczema, eczema asteatotic, erythema, palmar-erythrodysaesthesia syndrome, pemphigoid, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular, skin exfoliation, and urticarial dermatitis. ß includes arthralgia, arthritis, back pain, bone pain, chest pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, musculoskeletal stiffness,myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain. à includes dysaesthesia, hypoaesthesia, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, and polyneuropathy. ¶ includes blood thyroid stimulating hormone increased and hypothyroidism. # includes lower respiratory tract infection, lung abscess, paracancerous pneumonia, pneumonia, pneumonia aspiration, pneumonia bacterial, pneumonia chlamydial, pneumonia cryptococcal, pneumonia fungal, pneumonia pseudomonal, pneumonia streptococcal, pneumonia viral, and post-procedural pneumonia. ‡ Five Grade 5 events in the IMFINZI arm and four Grade 5 events in the Placebo arm. § Includes COVID-19 and COVID-19 Pneumonia. Five Grade 5 events in the IMFINZI arm and One Grade 5 event in the placebo arm. Table 6 summarizes the laboratory abnormalities in patients treated with IMFINZI in combination with chemotherapy. 22 Reference ID: 5489972 Table 6. Select Laboratory Abnormalities (> 20%) That Worsened from Baseline in Patients with Disease Who Received IMFINZI with Chemotherapy in AEGEAN Laboratory Abnormality* IMFINZI with Chemotherapy† Placebo with ChemotherapyÞ All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Hemoglobin decreased 78 10 75 9 Leukocytes decreased 63 12 64 11 Neutrophils decreased 52 24 56 27 Platelets decreased 46 7 44 8 Lymphocytes decreased 41 11 37 9 Chemistry Calcium corrected, decreased 51 3.3 52 4.5 Alanine aminotransferase increased 49 6 42 2 Aspartate aminotransferase increased 47 3.5 37 1.8 Potassium increased 33 1.5 29 2 Sodium decreased 35 5 33 6 Gamma glutamyl transferase increased 36 4.7 35 2.1 Creatinine increased 32 2.3 27 3.3 Amylase increased 25 4.7 24 3.6 Magnesium decreased 22 2.8 20 3.6 Lipase increased 23 4.9 24 7 * Graded per NCI CTCAE V5. † The denominator used to calculate the rate varied from 349 to 399 based on the number of patients with a baseline value and at least one post-treatment value. Þ The denominator used to calculate the rate varied from 333 to 398 based on the number of patients with a baseline value and at least one post-treatment value. Neoadjuvant Phase of AEGEAN A total of 401 patients received at least 1 dose of IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment and 398 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment. Serious adverse reactions occurred in 21% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥1%) serious adverse reactions were pneumonia (2.7%), anemia (1.5%), myelosuppression (1.5%), vomiting (1.2%), neutropenia (1%), and acute kidney injury (1%). Fatal adverse reactions occurred in 2% of patients, including death due to COVID-19 pneumonia (0.5%), sepsis (0.5%), myocarditis (0.2%), decreased appetite (0.2%), hemoptysis (0.2%), and death not otherwise specified (0.2%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 14% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (>0.5%) adverse reactions that led to permanent discontinuation of any study drug were anemia (1.5%), neutropenia (0.7%), myelosuppression (0.7%), and periphery sensory neuropathy (0.7%). 23 Reference ID: 5489972 Permanent discontinuation of IMFINZI due to an adverse reaction occurred in 6.7% of patients who received IMFINZI in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥0.5%) adverse reactions that led to permanent discontinuation of IMFINZI were peripheral sensory neuropathy (0.7%) and pneumonitis (0.5%). Of the 401 IMFINZI-treated patients and 398 placebo-treated patients who received neoadjuvant treatment, 1.7% (n=7) and 1% (n=4), respectively, did not receive surgery due to adverse reactions. Adverse reactions that led to cancellation of surgery in the IMFINZI arm were COVID-19 pneumonia, HIV infection, pneumonitis, prostate cancer, colon cancer, pruritus, and colitis. Of the 325 IMFINZI-treated patients who received surgery, 4% (n=15) experienced delay of surgery (a surgical delay is defined as on-study surgery occurring more than 40 days after the last dose of study treatment in the neoadjuvant period) due to adverse reactions. Of the 326 placebo-treated patients who received surgery, 4% (n=16) experienced delay of surgery due to adverse reactions. Of the 325 IMFINZI-treated patients who received surgery, 6.5% (n=21) did not receive adjuvant treatment due to adverse reactions. Of the 326 placebo-treated patients who received surgery, 5.8% (n=19) did not receive adjuvant treatment due to adverse reactions. Adjuvant Phase of AEGEAN A total of 265 patients in the IMFINZI arm and 254 patients in the placebo arm received at least 1 dose of adjuvant treatment. Of the patients who received single agent IMFINZI as adjuvant treatment, 13% experienced serious adverse reactions. The most frequent serious adverse reactions reported in >1% of patients were pneumonia (1.9%), pneumonitis (1.1%), and COVID-19 (1.1%). Four fatal adverse reactions occurred during the adjuvant phase of the study, including COVID-19 pneumonia, pneumonia aspiration, interstitial lung disease and aortic aneurysm. Permanent discontinuation of adjuvant IMFINZI due to an adverse reaction occurred in 8% of patients. The most frequent (≥0.5%) adverse reaction that led to permanent discontinuation of adjuvant IMFINZI was pneumonitis (1.1%) and rash (0.8%). Unresectable Stage III NSCLC - PACIFIC The safety of IMFINZI in patients with Stage III NSCLC who completed concurrent platinum-based chemoradiotherapy within 42 days prior to initiation of study drug was evaluated in the PACIFIC study, a multicenter, randomized, double-blind, placebo-controlled study. A total of 475 patients received IMFINZI 10 mg/kg intravenously every 2 weeks. The study excluded patients who had disease progression following chemoradiation, with active or prior autoimmune disease within 2 years of initiation of the study or with medical conditions that required systemic immunosuppression [see Clinical Studies (14.1)]. The study population characteristics were: median age of 64 years (range: 23 to 90), 45% age 65 years or older, 70% male, 69% White, 27% Asian, 75% former smoker, 16% current smoker, and 51% had WHO performance status of 1. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy. The median duration of exposure to IMFINZI was 10 months (range: 0.2 to 12.6). 24 Reference ID: 5489972 IMFINZI was discontinued due to adverse reactions in 15% of patients. The most common adverse reactions leading to IMFINZI discontinuation were pneumonitis or radiation pneumonitis in 6% of patients. Serious adverse reactions occurred in 29% of patients receiving IMFINZI. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in < 2% of patients and were similar across arms. The most common adverse reactions (occurring in ≥ 20% of patients) were cough, fatigue, pneumonitis or radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. Table 7 summarizes the adverse reactions that occurred in at least 10% of patients treated with IMFINZI. Table 7. Adverse Reactions Occurring in ≥ 10% of Patients in the PACIFIC Study IMFINZI N = 475 Placebo N = 234 Adverse Reaction All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Respiratory, Thoracic, and Mediastinal Disorders Cough/Productive Cough 40 0.6 30 0.4 Pneumonitis*/Radiation Pneumonitis 34 3.4 25 3 Dyspnea† 25 1.5 25 2.6 General Disorders FatigueÞ 34 0.8 32 1.3 Pyrexia 15 0.2 9 0 Infections Upper respiratory tract infectionsß 26 0.4 19 0 Pneumoniaà 17 7 12 6 Skin and Subcutaneous Tissue Disorders Rash¶ 23 0.6 12 0 Pruritus# 12 0 6 0 Gastrointestinal Disorders Diarrhea 18 0.6 19 1.3 Abdominal pain‡ 10 0.4 6 0.4 Endocrine Disorders Hypothyroidism§ 12 0.2 1.7 0 * Includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, pulmonary fibrosis. † Includes dyspnea, and exertional dyspnea. Þ Includes asthenia and fatigue. ß Includes laryngitis, nasopharyngitis, peritonsillar abscess, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis, and upper respiratory tract infection. à Includes lung infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia adenoviral, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia haemophilus, pneumonia klebsiella, pneumonia necrotizing, pneumonia pneumococcal, and pneumonia streptococcal. 25 Reference ID: 5489972 ¶ Includes rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema, rash, and dermatitis. # Includes pruritus generalized and pruritus. ‡ Includes abdominal pain, abdominal pain lower, abdominal pain upper, and flank pain. § Includes autoimmune hypothyroidism and hypothyroidism. Other adverse reactions occurring in less than 10% of patients treated with IMFINZI were dysphonia, dysuria, night sweats, peripheral edema, and increased susceptibility to infections. Table 8 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI. Table 8. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the PACIFIC Study IMFINZI Placebo Laboratory Abnormality All Grades* (%)† Grade 3 or 4 (%) All Grades* (%)† Grade 3 or 4 (%) Chemistry Hyperglycemia 52 8 51 8 Hypocalcemia 46 0.2 41 0 Increased ALT 39 2.3 22 0.4 Increased AST 36 2.8 21 0.4 Hyponatremia 33 3.6 30 3.1 Hyperkalemia 32 1.1 29 1.8 Increased GGT 24 3.4 22 1.7 Hematology Lymphopenia 43 17 39 18 * Graded according to NCI CTCAE version 4.0. † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI (range: 464 to 470) and placebo (range: 224 to 228). Metastatic NSCLC - POSEIDON The safety of IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy in patients with metastatic NSCLC was evaluated in POSEIDON (NCT03164616), a randomized, open- label, multicenter, active-controlled study. A total of 330 patients received IMFINZI 1,500 mg in combination with tremelimumab-actl (≥ 30 kg body weight received 75 mg and < 30 kg body weight received 1 mg/kg) and histology-based platinum chemotherapy regimens [see Clinical Studies (14.1)]. Of these patients, 66% received the maximum 5 doses of tremelimumab-actl and 79% received at least 4 doses. Treatment was continued with IMFINZI as a single agent (or with IMFINZI and histologically­ based pemetrexed for non-squamous patients based on the investigator’s decision) until disease progression or unacceptable toxicity. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants [see Clinical Studies (14.1)]. 26 Reference ID: 5489972 The median age of patients who received IMFINZI in combination with tremelimumab-actl and platinum- based chemotherapy was 63 years (range: 27 to 87); 80% male; 61% White, 29% Asian, 58% former smoker, 25% current smoker, and 68% ECOG performance of 1. Serious adverse reactions occurred in 44% of patients receiving IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (11%), anemia (5%), diarrhea (2.4%), thrombocytopenia (2.4%), pyrexia (2.4%), and febrile neutropenia (2.1%). Fatal adverse reactions occurred in a total of 4.2% of patients receiving IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy. These include hepatitis, nephritis, myocarditis, pancreatitis (all in the same patient), death (2 patients), sepsis (2 patients), pneumonitis (2 patients), acute kidney injury (2 patients), febrile neutropenia (1 patient), chronic obstructive pulmonary disease (COPD) (1 patient), dyspnea (1 patient), sudden death (1 patient), and ischemic stroke (1 patient). Permanent discontinuation of IMFINZI or tremelimumab-actl due to an adverse reaction occurred in 17% of the patients. Adverse reactions which resulted in permanent discontinuation of IMFINZI or tremelimumab-actl in > 2% of patients included pneumonia. Dosage interruption or delay of IMFINZI and tremelimumab-actl due to an adverse reaction occurred in 41% of patients. Adverse reactions which required dosage interruption or delay of IMFINZI and tremelimumab-actl in > 1% of patients included anemia, leukopenia/white blood cell count decreased, pneumonia, pneumonitis, colitis, diarrhea, hepatitis, rash, asthenia, amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, neutropenia/ neutrophil count decreased, and thrombocytopenia/platelet count decreased. The most common adverse reactions (occurring in ≥ 20% of patients) were nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea. Grade 3 or 4 laboratory abnormalities (≥ 10%) were neutropenia, anemia, leukopenia, lymphocytopenia, lipase increased, hyponatremia and thrombocytopenia. Table 9 summarizes the adverse reactions in POSEIDON. Table 9. Adverse Reactions (≥ 10%) in Patients with NSCLC Who Received IMFINZI in the POSEIDON Study IMFINZI with tremelimumab­ actl and platinum-based chemotherapy N = 330 Platinum-based chemotherapy N = 333 Adverse Reaction All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Nausea 42 1.8 37 2.1 Diarrhea 22 1.5 15 1.5 Constipation 19 0 24 0.6 Vomiting 18 1.2 14 1.5 Stomatitis† 10 0 6 0.3 27 Reference ID: 5489972 IMFINZI with tremelimumab­ actl and platinum-based chemotherapy N = 330 Platinum-based chemotherapy N = 333 Adverse Reaction All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) General disorders and administration site conditions Fatigue/Asthenia¶ 36 5 32 4.5 Pyrexia# 19 0 8 0 EdemaÞ 10 0 10 0.6 Musculoskeletal and connective tissue disorders Musculoskeletal Painß 29 0.6 22 1.5 Metabolism and nutrition disorders Decreased appetite 28 1.5 25 1.2 Skin and subcutaneous tissue disorders Rash§ 27 2.4 10 0.6 Pruritus 11 0 4.5 0 Alopecia 10 0 6 0 Infections and Infestations Pneumoniaà 17 8 12 4.2 Upper respiratory tract infectionsè 15 0.6 9 0.9 Endocrine disorders Hypothyroidism‡ 13 0 2.1 0 Respiratory, thoracic and mediastinal disorders Cough/Productive Cough* 12 0 8 0.3 Nervous system disorders Headacheð 11 0 8 0.6 † Includes mucosal inflammation and stomatitis. ¶ Includes asthenia and fatigue. # Includes body temperature increased, hyperpyrexia, hyperthermia, and pyrexia. Þ Includes face edema, localized edema, and edema peripheral. ß Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, and spinal pain. § Includes eczema, erythema, dermatitis, drug eruption, erythema multiforme, pemphigoid, rash, rash maculo­ papular, rash papular, rash pruritic, and rash pustular. à Includes lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia aspiration, and pneumonia bacterial. è Includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis and upper respiratory tract infection. ‡ Includes blood thyroid stimulating hormone increased and hypothyroidism. * Includes cough and productive cough. ð Includes headache and migraine. Table 10 summarizes the laboratory abnormalities in POSEIDON. 28 Reference ID: 5489972 Table 10. Select Laboratory Abnormalities (≥ 10%) That Worsened from Baseline in Patients with NSCLC Who Received IMFINZI in the POSEIDON Study Laboratory Abnormality* IMFINZI with tremelimumab-actl and platinum-based chemotherapy† Platinum-based chemotherapy§ All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Blood creatinine increased 89 4 83 1.9 Increased ALT 64 6 56 4.7 Increased AST 63 5 55 2.2 Hypocalcemia 58 0.9 49 0.9 Hyponatremia 55 13 50 11 Hyperkalemia 49 2.2 35 2.8 Hyperglycemia 42 6 37 3.1 Amylase increased 41 9 25 6 Gamma Glutamyl Transferase increased 38 2.2 35 4.7 Lipase increased 35 14 25 5 Increased Alkaline Phosphatase 33 3.4 26 1.2 Albumin decreased 27 1.9 18 0.9 Hypokalemia 21 7 17 2.8 Bilirubinemia 16 0.9 8 0.3 Hypernatremia 15 0 14 0 Hypomagnesemia 12 4 23 0 Hematology Anemia 84 24 84 25 Leukopenia 77 21 81 18 Neutropenia 71 37 69 32 Lymphocytopenia 67 20 60 19 Thrombocytopenia 53 11 54 12 * Graded according to NCI CTCAE version 4.03. † The denominator used to calculate the rate varied from 45 to 326 based on the number of patients with a baseline value and at least one post-treatment value. § The denominator used to calculate the rate varied from 43 to 323 based on the number of patients with a baseline value and at least one post-treatment value. Small Cell Lung Cancer Limited Stage Small Cell Lung Cancer – ADRIATIC The safety of IMFINZI as a single agent in patients with LS-SCLC without disease progression following completion of concurrent platinum-based chemoradiotherapy (60-66 Gy once daily over 6 weeks or 45 Gy twice daily over 3 weeks) within 42 days prior to initiation of study drug, was evaluated in the ADRIATIC study, a multicenter, randomized, double-blind, placebo-controlled study [see Clinical 29 Reference ID: 5489972 Studies (14.2)]. A total of 262 patients received IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity or a maximum of 24 months. The study excluded patients with Stage I or II LS-SCLC who were considered medically operable and patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants. The study population characteristics were: median age of 62 years (range: 28 to 84); 39% age 65 years or older, 6% age 75 years or older; 69% male; 50% white, 48% Asian, 1.3% other races; 4.2% Hispanic or Latino; 68% former smoker, 22% current smoker; and 51% had WHO performance status of 1. Sixty- seven percent of patients received a total radiation dose of 60 Gy to 66 Gy once daily and 27% of patients received a total radiation dose of 45 Gy twice daily. The median duration of exposure to IMFINZI was 9.2 months (range: 0.92 to 25) in the IMFINZI arm. Serious adverse reactions occurred in 30% of patients receiving IMFINZI. The most frequent serious adverse reactions reported in ≥ 1% of patients receiving IMFINZI were pneumonitis or radiation pneumonitis (12%), and pneumonia (5%). Fatal adverse reactions occurred in 2.7% of patients who received IMFINZI including pneumonia (1.5%), cardiac failure, encephalopathy and pneumonitis (0.4% each). Permanent discontinuation of IMFINZI due to adverse reactions occurred in 16% of the patients.. Adverse reactions which resulted in permanent discontinuation of IMFINZI in ≥ 1% of patients included pneumonitis or radiation pneumonitis (9%) and pneumonia (1.5%). Dosage interruptions of IMFINZI due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included pneumonitis or radiation pneumonitis (17%). The most common adverse reactions occurring in ≥ 20% of patients receiving IMFINZI were pneumonitis or radiation pneumonitis (38%), and fatigue (21%). Table 11 summarizes the adverse reactions that occurred in patients treated with IMFINZI in the ADRIATIC study. Table 11. Adverse Reactions (≥ 10%) in Patients with LS-SCLC Who Received IMFINZI in the ADRIATIC Study IMFINZI (n=262) Placebo (n=265) Adverse Reaction All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Respiratory, thoracic and mediastinal disorders Pneumonitis or Radiation pneumonitis* 38 3.1 30 2.6 Cough/Productive cough 17 0 14 0 Dyspnea† 11 0.4 7 0 General disorders Fatigueè 21 0.4 20 2.3 Skin and subcutaneous tissue disorders Rash‡ 18 0.4 11 0 Pruritus 13 0 7 0 Endocrine disorders Hypothyroidism¶ 17 0 4.9 0 30 Reference ID: 5489972 IMFINZI (n=262) Placebo (n=265) Adverse Reaction All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hyperthyroidism# 12 0 1.9 0 Metabolism and nutrition disorders Decreased appetite 17 0 13 0 Nervous system disorders Dizzinessß 14 0 9 0 Infections and infestations Pneumonia§ 13 3.1 9 4.2 Gastrointestinal disorders Nausea 13 0 11 0 Diarrhea 11 1.9 8 0 Constipation 10 0 10 0 * Includes pneumonitis, immune-mediated lung disease, interstitial lung disease, radiation pneumonitis, and lung radiation fibrosis. † Includes dyspnea and exertional dyspnea. è Includes fatigue and asthenia. ‡ Includes dermatitis, acneiform dermatitis, eczema, rash, maculo-papular rash, papular rash, pruritic rash, and skin exfoliation. ¶ Includes hypothyroidism, increased blood thyroid stimulating hormone, and decreased thyroxine free. # Includes hyperthyroidism, decreased blood thyroid stimulating hormone, increased thyroxine free, increased thyroxine, increased tri-iodothyronine free, and increased tri-iodothyronine. § Includes pneumonia, atypical pneumonia, lower respiratory tract infection, bacterial pneumonia, pneumocystis jirovecii pneumonia, legionella pneumonia, and viral pneumonia. ß Includes dizziness, postural dizziness, vertigo, and positional vertigo. Table 12 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI. Table 12. Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with LS-SCLC Who Received IMFINZI in the ADRIATIC Study Laboratory Abnormality* IMFINZI† Placebo‡ All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Hypocalcemia 43 0 43 0.8 Hyperglycemia 38 3.2 45 1.5 ALT increased 36 2.3 29 2.3 AST increased 33 2.3 28 1.5 Gamma Glutamyl Transferase increased 32 7 27 2.9 Hyponatremia 32 5 29 6.2 Hyperkalemia 23 1.2 17 0.8 Creatinine increased* 21 0 17 0.8 31 Reference ID: 5489972 Laboratory Abnormality* IMFINZI† Placebo‡ All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Lymphocytes decreased 34 10 33 10 Leukocytes decreased 26 0.4 33 1.1 * Graded according to NCI CTCAE version 4.03, except creatinine increased which is graded according to NCI CTCAE version 5.0. † The denominator used to calculate the rate varied from 63 to 259 based on the number of patients with a baseline value and at least one post-treatment value. ‡ The denominator used to calculate the rate varied from 65 to 262 based on the number of patients with a baseline value and at least one post-treatment value. Extensive Stage Small Cell Lung Cancer – CASPIAN The safety of IMFINZI in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was evaluated in CASPIAN, a randomized, open-label, multicenter, active-controlled study. A total of 265 patients received IMFINZI 1,500 mg in combination with chemotherapy every 3 weeks for 4 cycles followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity. The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids or immunosuppressants [see Clinical Studies (14.2)]. Among 265 patients receiving IMFINZI, 49% were exposed for 6 months or longer and 19% were exposed for 12 months or longer. Among 266 patients receiving chemotherapy alone, 57% of the patients received 6 cycles of chemotherapy and 8% of the patients received prophylactic cranial irradiation (PCI) after chemotherapy. IMFINZI was discontinued due to adverse reactions in 7% of the patients receiving IMFINZI plus chemotherapy. These include pneumonitis, hepatotoxicity, neurotoxicity, sepsis, diabetic ketoacidosis and pancytopenia (1 patient each). Serious adverse reactions occurred in 31% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 1% of patients were febrile neutropenia (4.5%), pneumonia (2.3%), anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%) and COPD (1.1%). Fatal adverse reactions occurred in 4.9% of patients receiving IMFINZI plus chemotherapy. These include pancytopenia, sepsis, septic shock, pulmonary artery thrombosis, pulmonary embolism, and hepatitis (1 patient each) and sudden death (2 patients). The most common adverse reactions (occurring in ≥ 20% of patients) were nausea, fatigue/asthenia and alopecia. Table 13 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. 32 Reference ID: 5489972 Table 13. Adverse Reactions Occurring in ≥ 10% of Patients in the CASPIAN Study IMFINZI with etoposide and either carboplatin or cisplatin N = 265 Etoposide and either carboplatin or cisplatin N = 266 Adverse Reaction All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Gastrointestinal disorders Nausea 34 0.4 34 1.9 Constipation 17 0.8 19 0 Vomiting 15 0 17 1.1 Diarrhea 10 1.1 11 1.1 General disorders and administration site conditions Fatigue/Asthenia 32 3.4 32 2.3 Skin and subcutaneous tissue disorders Alopecia 31 1.1 34 0.8 Rash† 11 0 6 0 Metabolism and nutrition disorders Decreased appetite 18 0.8 17 0.8 Respiratory, thoracic and mediastinal disorders Cough/Productive Cough 15 0.8 9 0 Endocrine disorders Hyperthyroidism* 10 0 0.4 0 † Includes rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema, rash and dermatitis. * Includes hyperthyroidism and Basedow's disease. Table 14 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with IMFINZI plus chemotherapy. Table 14. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20%* of Patients in the CASPIAN Study IMFINZI with Etoposide and either Carboplatin or Cisplatin Etoposide and either Carboplatin or Cisplatin Laboratory Abnormality Grade† 3 or 4 (%)‡ Grade† 3 or 4 (%)‡ Chemistry Hyponatremia 11 13 Hypomagnesemia 11 6 Hyperglycemia 5 5 Increased Alkaline Phosphatase 4.9 3.5 Increased ALT 4.9 2.7 Increased AST 4.6 1.2 33 Reference ID: 5489972 IMFINZI with Etoposide and either Carboplatin or Cisplatin Etoposide and either Carboplatin or Cisplatin Laboratory Abnormality Grade† 3 or 4 (%)‡ Grade† 3 or 4 (%)‡ Hypocalcemia 3.5 2.4 Blood creatinine increased 3.4 1.1 Hyperkalemia 1.5 3.1 TSH decreased < LLN§ and ≥ LLN at baseline NA NA Hematology Neutropenia 41 48 Lymphopenia 14 13 Anemia 13 22 Thrombocytopenia 12 15 * The frequency cut off is based on any grade change from baseline. † Graded according to NCI CTCAE version 4.03. ‡ Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI (range: 258 to 263) and chemotherapy (range: 253 to 262) except magnesium IMFINZI with chemotherapy (18) and chemotherapy (16). § LLN = lower limit of normal. Biliary Tract Cancer Locally Advanced or Metastatic BTC - TOPAZ-1 The safety of IMFINZI in combination with gemcitabine and cisplatin in locally advanced or metastatic BTC was evaluated in TOPAZ-1, a randomized, double-blind, placebo-controlled, multicenter study. A total of 338 patients received IMFINZI 1,500 mg in combination with gemcitabine and cisplatin every 3 weeks up to 8 cycles followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity.Patients with active or prior documented autoimmune or inflammatory disorders, HIV infection or other active infections, including tuberculosis or hepatitis C were ineligible [see Clinical Studies (14.3)]. IMFINZI was discontinued due to adverse reactions in 6% of the patients receiving IMFINZI plus chemotherapy. The most frequently reported events resulting in discontinuation were sepsis (3 patients) and ischemic stroke (2 patients). The remaining events were dispersed across system organ classes and reported in 1 patient each. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients) and upper gastrointestinal hemorrhage (2 patients). The most common adverse reactions (occurring in ≥ 20% of patients) were fatigue, nausea, constipation, decreased appetite, abdominal pain, rash and pyrexia. Table 15 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy. 34 Reference ID: 5489972 Table 15. Adverse Reactions Occurring in ≥ 10% of Patients in the TOPAZ-1 Study IMFINZI with Gemcitabine and Cisplatin N = 338 Placebo with Gemcitabine and Cisplatin N = 342 Adverse Reaction All Grades * (%) Grade* 3-4 (%) All Grades * (%) Grade* 3-4 (%) General disorders and administration site conditions Fatigue† 42 6 43 6 Pyrexia 20 1.5 16 0.6 Gastrointestinal disorders Nausea 40 1.5 34 1.8 Constipation 32 0.6 29 0.3 Abdominal pain‡ 24 0.6 23 2.9 Vomiting 18 1.5 18 2.0 Diarrhea 17 1.2 15 1.8 Metabolism and nutrition disorders Decreased appetite 26 2.1 23 0.9 Skin and subcutaneous tissue disorders Rash§ 23 0.9 14 0 Pruritus 11 0 8 0 Psychiatric disorders Insomnia 10 0 11 0 * Graded according to NCI CTCAE version 5.0. † Includes fatigue, malaise, cancer fatigue and asthenia. ‡ Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain. § Includes rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash erythematous, dermatitis acneiform, dermatitis bullous, drug eruption, eczema, erythema, dermatitis and rash. Table 16 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy. Table 16. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20%* of Patients in the TOPAZ-1 Study IMFINZI with Gemcitabine and Cisplatin Placebo with Gemcitabine and Cisplatin Laboratory Abnormality Grade† 3 or 4 (%) Grade† 3 or 4 (%) Chemistry Hyponatremia 18 13 Gamma-glutamyltransferase increased 12 13 Increased bilirubin 10 14 Hypokalemia 8 4.4 Increased AST 8 8 Increased ALT 7 6 Blood creatinine increased 5 2.1 35 Reference ID: 5489972 IMFINZI with Gemcitabine and Cisplatin Placebo with Gemcitabine and Cisplatin Laboratory Abnormality Grade† 3 or 4 (%) Grade† 3 or 4 (%) Hypomagnesemia 4.5 2.2 Hypoalbuminemia 3.6 2.9 Hyperkalemia 2.1 2.1 Increased Alkaline Phosphatase 1.8 3.8 Hypocalcemia 1.8 2.4 Hematology Neutropenia 48 49 Anemia 31 28 Leukopenia 28 28 Lymphopenia 23 15 Thrombocytopenia 18 18 * The frequency cut off is based on any grade change from baseline. † Graded according to NCI CTCAE version 5.0. Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with gemcitabine/cisplatin (range: 312 to 335) and Placebo with gemcitabine/cisplatin (range: 319 to 341). Hepatocellular Carcinoma Unresectable HCC - HIMALAYA The safety of IMFINZI in combination with tremelimumab-actl was evaluated in a total of 388 patients with uHCC in HIMALAYA, a randomized, open-label, multicenter study [see Clinical Studies (14.1)]. Patients received IMFINZI 1,500 mg administered as a single intravenous infusion in combination with tremelimumab-actl 300 mg on the same day, followed by IMFINZI every 4 weeks or sorafenib 400 mg given orally twice daily. Serious adverse reactions occurred in 41% of patients who received IMFINZI in combination with tremelimumab-actl. Serious adverse reactions in > 1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8% of patients who received IMFINZI in combination with tremelimumab-actl, including death (1%), hemorrhage intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%). The most common adverse reactions (occurring in ≥ 20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. Permanent discontinuation of treatment regimen due to an adverse reaction occurred in 14% of patients; the most common adverse reactions leading to treatment discontinuation (≥ 1%) were hemorrhage (1.8%), diarrhea (1.5%), AST increased (1%), and hepatitis (1%). Dosage interruptions or delay of the treatment regimen due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dosage interruption or delay in ≥ 1% of patients included ALT 36 Reference ID: 5489972 increased (3.6%), diarrhea (3.6%), rash (3.6%), amylase increased (3.4%), AST increased (3.1%), lipase increased (2.8%), pneumonia (1.5%), hepatitis (1.5%), pyrexia (1.5%), anemia (1.3%), thrombocytopenia (1%), hyperthyroidism (1%), pneumonitis (1%), and blood creatinine increased (1%). Table 17 summarizes the adverse reactions that occurred in patients treated with IMFINZI in combination with tremelimumab-actl in the HIMALAYA study. Table 17. Adverse Reactions Occurring in ≥ 10% of Patients in the HIMALAYA Study IMFINZI and Tremelimumab-actl (N = 388) Sorafenib (N = 374) Adverse Reaction All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Skin and subcutaneous tissue disorders Rash* 32 2.8 57 12 Pruritus 23 0 6 0.3 Gastrointestinal disorders Diarrhea* 27 6 45 4.3 Abdominal pain* 20 1.8 24 4 Nausea 12 0 14 0 General disorders and administration site conditions Fatigue* 26 3.9 30 6 Pyrexia* 13 0.3 9 0.3 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain* 22 2.6 17 0.8 Metabolism and nutrition disorders Decreased appetite 17 1.3 18 0.8 Endocrine disorders Hypothyroidism* 14 0 6 0 Psychiatric disorders Insomnia 10 0.3 4.3 0 * Represents a composite of multiple related terms. Table 18 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI in combination with tremelimumab-actl in the HIMALAYA study. Table 18. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients in the HIMALAYA Study IMFINZI and Tremelimumab-actl Sorafenib Laboratory Abnormality Any grade† (%)‡ Grade 3† or 4 (%)‡ Any grade† (%)‡ Grade 3† or 4 (%)‡ Chemistry 37 Reference ID: 5489972 IMFINZI and Tremelimumab-actl Sorafenib Laboratory Abnormality Any grade† (%)‡ Grade 3† or 4 (%)‡ Any grade† (%)‡ Grade 3† or 4 (%)‡ Aspartate Aminotransferase increased 63 27 55 21 Alanine Aminotransferase increased 56 18 53 12 Sodium decreased 46 15 40 11 Bilirubin increased 41 8 47 11 Alkaline Phosphatase increased 41 8 44 5 Glucose increased 39 14 29 4 Calcium decreased 34 0 43 0.3 Albumin decreased 31 0.5 37 1.7 Potassium increased 28 3.8 21 2.6 Creatinine increased 21 1.3 15 0.9 Hematology Hemoglobin decreased 52 4.8 40 6 Lymphocytes decreased 41 11 39 10 Platelets decreased 29 1.6 35 3.1 Leukocytes decreased 20 0.8 30 1.1 † Graded according to NCI CTCAE version 4.03. ‡ Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with tremelimumab-actl (range: 367-378) and sorafenib (range:344-352). Endometrial Cancer Advanced or Recurrent dMMR Endometrial Cancer – DUO-E The safety of IMFINZI in combination with carboplatin and paclitaxel followed by IMFINZI as a single agent was evaluated in 44 patients with dMMR advanced or recurrent endometrial cancer in DUO-E, a randomized, double-blind, placebo-controlled trial [See Clinical Studies (14.5)]. Patients received IMFINZI 1,120 mg with carboplatin and paclitaxel every 3 weeks for up to six 21-day cycles followed by IMFINZI 1,500 mg every 4 weeks or carboplatin and paclitaxel every 3 weeks for up to six 21-day cycles alone. Treatment was continued until disease progression or unacceptable toxicity. The median duration of exposure to IMFINZI with carboplatin and paclitaxel was 14.8 months (range: 0.7 to 31.7). Serious adverse reactions occurred in 30% of patients who received IMFINZI with carboplatin and paclitaxel. The most common serious adverse reactions (≥4%) were constipation (4.5%) and rash (4.5%). Permanent discontinuation of IMFINZI due to adverse reactions occurred in 11% of patients. The adverse reaction which resulted in permanent discontinuation of IMFINZI (≥4%) was rash (4.5%). 38 Reference ID: 5489972 Dosage interruptions of IMFINZI due to adverse reactions occurred in 52% of patients. Adverse reactions which required dosage interruptions of IMFINZI (≥4%) were anemia (11%), thrombocytopenia (9%), neutropenia (9%), COVID-19 (9%), increased ALT (4.5%), and pneumonitis (4.5%). The most common adverse reactions (>20%), including laboratory abnormalities, were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, decreased magnesium, increased ALT, increased AST, diarrhea, vomiting, cough, decreased potassium, dyspnea, headache, increased alkaline phosphatase, and decreased appetite. Tables 19 and 20 summarize adverse reactions and laboratory abnormalities in DUO-E, respectively. Table 19. Adverse Reactions Occurring in ≥ 10% of Patients with dMMR tumors in DUO-E Adverse Reactions IMFINZI with Carboplatin and Paclitaxel (N=44) Carboplatin and Paclitaxel (N=46) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Nervous system disorders Peripheral neuropathya 61 2.3 61 4.3 Headache 23 0 17 0 Musculoskeletal and connective tissue disorders Musculoskeletal painb 59 2.3 52 2.2 Gastrointestinal disorders Nausea 59 0 48 2.2 Abdominal painc 39 0 24 2.2 Constipationd 39 4.5 35 2.2 Diarrhea 27 2.3 24 2.2 Vomiting 27 0 22 4.3 Skin and subcutaneous tissue disorders Alopecia 52 0 41 0 Rashe 39 2.3 17 2.2 Pruritus 16 0 11 0 General disorders and administration site conditions Fatiguef 41 4.5 57 11 Peripheral edemag 16 0 13 2.2 Respiratory, thoracic and mediastinal disorders Cough / productive cough 27 0 20 0 Dyspneah 25 2.3 9 0 Metabolism and nutrition disorders Decreased appetite 18 0 18 0 Infections and infestations Upper respiratory tract infectioni 14 0 4.3 0 Endocrine disorders Hypothyroidismj 11 0 4.3 0 a Includes neuropathy peripheral, peripheral sensory neuropathy, hypoasthesia, peripheral motor neuropathy, and parasthesia. 39 Reference ID: 5489972 I b Includes arthralgia, pain in extremity, back pain, non-cardiac chest pain, myalgia, musculoskeletal pain, musculoskeletal chest pain, arthritis, bone pain, musculoskeletal stiffness, neck pain, musculoskeletal discomfort, and spinal pain. c Includes abdominal pain, abdominal pain lower, flank pain, abdominal discomfort, and abdominal pain upper. d Includes constipation and fecaloma. e Includes eczema, rash, rash erythematous, rash maculo-papular, dermatitis, rash pustular, skin exfoliation, and symmetrical drug-related intertriginous, and flexural exanthema. f Includes asthenia and fatigue. g Includes peripheral edema, peripheral swelling, and edema. h Includes dyspnea and exertional dyspnea. i Includes nasopharyngitis, pharyngitis, rhinitis, sinusitis, tracheobronchitis, and upper respiratory tract infection. j Includes blood thyroid stimulating hormone increased, and hypothyroidism. Clinically relevant adverse reactions in < 10% of patients who received IMFINZI with carboplatin and paclitaxel included autoimmune hemolytic anemia, colitis, immune-mediated thyroiditis, infusion related reaction, interstitial lung disease, myositis, pneumonitis, pulmonary embolism, and sepsis. Table 20 summarizes the laboratory abnormalities that occurred in patients treated with IMFINZI with carboplatin and paclitaxel followed by IMFINZI as a single agent. Table 20. Select Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with dMMR tumors in DUO-E Laboratory Abnormality IMFINZI with Carboplatin and Paclitaxel‡ Carboplatin and Paclitaxel ‡ All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Chemistry Magnesium decreased 36 0 30 2.5 ALT increased 32 2.3 22 2.2 AST increased 30 2.3 22 0 Potassium decreased 25 0 24 2.2 Alkaline phosphatase increased 20 0 16 0 ‡ Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI with carboplatin and paclitaxel (range: 40 to 44), and carboplatin and paclitaxel (range: 37 to 46). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, IMFINZI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of IMFINZI in pregnant women. In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg based on area under the curve (AUC), resulted in an increase in premature delivery, fetal loss, and premature neonatal death (see Data). Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the 40 Reference ID: 5489972 potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at a clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth), and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. 8.2 Lactation Risk Summary There are no data on the presence of durvalumab in human milk, its effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to IMFINZI are unknown. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death (see Data). Because of the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with IMFINZI and for 3 months after the last dose. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended duration to not breastfeed, as appropriate. Data In lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature neonatal death. 8.3 Females and Males of Reproductive Potential Pregnancy testing Verify pregnancy status of females of reproductive potential prior to initiating treatment with IMFINZI. Contraception 41 Reference ID: 5489972 Females IMFINZI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for 3 months following the last dose of IMFINZI. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended contraception duration, as appropriate. 8.4 Pediatric Use The safety and effectiveness of IMFINZI have not been established in pediatric patients. Safety and efficacy were assessed but not established in a multi-center, open-label study (NCT03837899) in 45 pediatric patients aged 1 to < 17 years with advanced solid tumors. All 45 patients received at least a single dose of IMFINZI, and 41 patients received IMFINZI in combination with tremelimumab-actl. No new safety signals were observed in pediatric patients in this study. Durvalumab systemic exposure in pediatric patients weighing ≥ 35 kg was within the range of values previously observed in adults given the same weight-based dose, whereas the systemic exposure in pediatric patients weighing < 35 kg was lower than that observed in adults. 8.5 Geriatric Use Of the 401 patients with resectable NSCLC treated with IMFINZI in combination with chemotherapy in the AEGEAN study, 209 (52%) patients were 65 years or older and 49 (12%) patients were 75 years or older. There were no overall clinically meaningful differences in safety or efficacy between patients ≥ 65 years of age and younger patients. Of the 476 patients with unresectable, Stage III NSCLC treated with IMFINZI in the PACIFIC study, 45% were 65 years or older, while 7.6% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients. Of the 330 patients with metastatic NSCLC treated with IMFINZI in combination with tremelimumab­ actl and platinum-based chemotherapy, 143 (43%) patients were 65 years or older and 35 (11%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients. Of the 262 patients with LS-SCLC treated with IMFINZI, 103 (39%) patients were 65 years or older and 15 (6%) patients were 75 years or older. There were no clinically meaningful differences in safety and efficacy between patients 65 years or older and younger patients. Of the 265 patients with ES-SCLC treated with IMFINZI in combination with chemotherapy 101 (38%) patients were 65 years or older and 19 (7.2%) patients were 75 years or older. There were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients. Of the 338 patients with BTC treated with IMFINZI in combination with chemotherapy in the TOPAZ-1 study, 158 (47%) patients were 65 years or older and 38 (11%) patients were 75 years or older. No overall 42 Reference ID: 5489972 differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients. Of the 393 patients with uHCC treated with IMFINZI in combination with tremelimumab-actl, 50% of patients were 65 years of age or older and 13% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients. Of the 235 patients with endometrial cancer treated with IMFINZI with carboplatin and paclitaxel, 49% of patients were 65 years of age or older and 12% of patients were 75 years of age or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients. 11 DESCRIPTION Durvalumab is a programmed cell death ligand 1 (PD-L1) blocking antibody. Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture. IMFINZI (durvalumab) Injection for intravenous use is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution, free from visible particles. Each 500 mg vial of IMFINZI contains 500 mg of durvalumab in 10 mL solution. Each mL contains durvalumab, 50 mg, L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), α,α-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection, USP. Each 120 mg vial of IMFINZI contains 120 mg of durvalumab in 2.4 mL solution. Each mL contains durvalumab, 50 mg, L-histidine (2 mg), L-histidine hydrochloride monohydrate (2.7 mg), α,α-trehalose dihydrate (104 mg), Polysorbate 80 (0.2 mg), and Water for Injection, USP. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production. Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC). PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models. 43 Reference ID: 5489972 12.2 Pharmacodynamics The steady state AUC, Ctrough, and Cmax in patients administered with 1,500 mg every 4 weeks are 6% higher, 19% lower, and 55% higher than those administered with 10 mg/kg every 2 weeks, respectively. Based on the modeling of pharmacokinetic data and exposure relationships for safety, there are no anticipated clinically meaningful differences in efficacy and safety for the doses of 1,500 mg every 4 weeks compared to 10 mg/kg every 2 weeks in patients weighing > 30 kg with NSCLC. 12.3 Pharmacokinetics The pharmacokinetics of durvalumab as a single agent was studied in patients with doses ranging from 0.1 mg/kg (0.01 times the approved recommended dosage) to 20 mg/kg (2 times the approved recommended dosage) administered once every two, three, or four weeks. PK exposure increased more than dose-proportionally at doses < 3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses ≥ 3 mg/kg every 2 weeks. Steady state was achieved at approximately 16 weeks. The pharmacokinetics of durvalumab is similar when assessed as a single agent, when in combination with chemotherapy, when in combination with tremelimumab-actl and when in combination with tremelimumab-actl and platinum-based chemotherapy. Distribution The geometric mean (% coefficient of variation [CV%]) steady state volume of distribution (Vss) was 5.4 (13.1%) L. Elimination Durvalumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline values of approximately 23% (57%) resulting in a geometric mean (CV%) steady state clearance (CLss) of 8 mL/h (39%) at day 365; the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life, based on baseline CL was approximately 21 (26%) days. Specific Populations There were no clinically significant differences in the pharmacokinetics of durvalumab based on body weight (31 to 175 kg), age (18 to 96 years), sex, race (White, Black, Asian, Native Hawaiian, Pacific Islander, or Native American), albumin levels (4 to 57 g/L), lactate dehydrogenase levels (18 to 15,800 U/L), soluble PD-L1 (67 to 3,470 pg/mL), tumor type (NSCLC, SCLC, BTC and HCC), mild or moderate renal impairment (CLcr 30 to 89 mL/min), and mild or moderate hepatic impairment (bilirubin ≤ 3x ULN and any AST). The effect of severe renal impairment (CLcr 15 to 29 mL/min) or severe hepatic impairment (bilirubin > 3x ULN and any AST) on the pharmacokinetics of durvalumab is unknown. 12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparison of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies including those of IMFINZI. 44 Reference ID: 5489972 During the 10 to 48 week treatment period across PACIFIC, CASPIAN, TOPAZ-1, HIMALAYA, POSEIDON, DUO-E, AEGEAN and other clinical trials, in patients who received IMFINZI at dosages of 1,500 mg every 4 weeks, 10 mg/kg every 2 weeks, 20 mg/kg every 4 weeks as a single agent or 1,120 mg every 3 weeks, or 1,500 mg every 3 weeks in the combination therapies, 3.2% (151/4668) of evaluable patients tested positive for anti-durvalumab antibodies, and 19.2% (29/151) of ADA positive patients had neutralizing antibodies against durvalumab. There were no identified clinically significant effects of ADAs on durvalumab pharmacokinetics or safety; however, the effect of these ADAs on the effectiveness of IMFINZI is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic and genotoxic potential of durvalumab have not been evaluated. Animal fertility studies have not been conducted with durvalumab. In repeat-dose toxicology studies with durvalumab in sexually mature cynomolgus monkeys of up to 3 months duration, there were no notable effects on the male and female reproductive organs. 13.2 Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade using a primate anti-PD-1 antibody was also shown to exacerbate M. tuberculosis infection in rhesus macaques. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus. 14 CLINICAL STUDIES 14.1 Non-Small Cell Lung Cancer (NSCLC) Neoadjuvant and Adjuvant Treatment of Resectable NSCLC – AEGEAN Study The efficacy of IMFINZI in combination with neoadjuvant chemotherapy, followed by surgery and continued adjuvant treatment with IMFINZI as a single agent was investigated in AEGEAN (NCT03800134), a randomized, double-blind, placebo-controlled, multicenter trial conducted in 802 patients with previously untreated and resectable squamous or non-squamous NSCLC (Stage IIA to select Stage IIIB [AJCC, 8th edition]). Patients were enrolled regardless of tumor PD-L1 expression. Eligible patients had no prior exposure to immune-mediated therapy, a WHO/ECOG Performance status of 0 or 1, and at least one RECIST 1.1 target lesion. Patients with active or prior documented autoimmune disease, or use of any immunosuppressive medication within 14 days of the first dose of IMFINZI were ineligible. The population for efficacy analyses was a modified intent-to-treat [mITT] which excluded patients with known EGFR mutations or ALK rearrangements. 45 Reference ID: 5489972 Crossover between the study arms was not permitted. Randomization was stratified by disease stage (Stage II vs. Stage III) and by PD-L1 expression (TC < 1% vs. TC ≥ 1%) status. Patients were randomized 1:1 to one of the following treatment arms: • Arm 1: Neoadjuvant IMFINZI 1,500 mg once every 3 weeks for up to 4 cycles in combination with: Squamous tumor histology: carboplatin AUC 6 and paclitaxel 200 mg/m2 on Day1 of each 3­ week cycle, OR cisplatin 75 mg/m2 on Day 1 and gemcitabine 1250 mg/m2 on Day 1 and Day 8 of each 3-week cycle, for 4 cycles Non-squamous tumor histology: pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on Day 1 of each 3-week cycle, for 4 cycles OR pemetrexed 500 mg/m2 and carboplatin AUC 5 on Day 1 of each 3-week cycle, for 4 cycles. Followed by adjuvant IMFINZI 1,500 mg as a single agent for up to 12 cycles post-surgery. • Arm 2: Neoadjuvant placebo in combination with 4 cycles of chemotherapy (see above) prior to surgery. Followed by placebo for up to 12 cycles post-surgery. All study medications were administered via intravenous infusion. In the event of unfavorable tolerability, patients who met the eligibility criteria were switched from cisplatin to carboplatin therapy at any point during the study. In patients with comorbidities or unable to tolerate cisplatin as per Investigators judgment, carboplatin AUC 5 could be administered from cycle 1. Treatment with IMFINZI or placebo continued until completion of the treatment, disease progression that precluded definitive surgery, inability to complete definitive surgery, disease recurrence in the adjuvant phase, or unacceptable toxicity. A RECIST 1.1 tumor assessment was performed at baseline, and upon completion of the neoadjuvant period (prior to surgery). Tumor assessments were conducted at 5 weeks postoperatively, prior to the start of adjuvant therapy and every 12 weeks until week 48, every 24 weeks for approximately 4 years, and then every 48 weeks thereafter until disease progression, consent withdrawal, or death. The trial was not designed to isolate the effect of IMFINZI in each phase (neoadjuvant or adjuvant) of treatment. The major efficacy outcome measures of the study were pathological complete response (pCR) by blinded central pathology review and event-free survival (EFS) by blinded independent central review (BICR) assessment. Additional efficacy outcome measures were major pathological response (MPR) by blinded central pathology review, DFS by BICR, and OS. The demographics and baseline disease characteristics were as follows: male (72%); median age 65 years (range: 30 to 88); age ≥ 65 years (52%); WHO/ECOG PS 0 (68%), WHO/ECOG PS 1 (32); White (54%), Asian (41%), Black or African American (0.9%), American Indian or Alaska Native (1.4%), Other Race (2.6%); Not Hispanic or Latino (84%); current or past smokers (86%); squamous histology (49%) and non-squamous histology (51%); Stage II (28%), Stage III (71%); PD-L1 expression status TC ≥ 1% (67%), PD-L1 expression status TC < 1% (33%). In the mITT population, 78% of patients in Arm 1 completed definitive surgery compared to 77% of patients in Arm 2. 46 Reference ID: 5489972 The trial demonstrated statistically significant improvements in EFS and pCR rate (see Table 21 and Figure 1) in the IMFINZI in combination with chemotherapy arm compared to the placebo in combination with chemotherapy arm. Table 21. Efficacy Results for the AEGEAN Study (mITT) IMFINZI 1,500 mg every 3 weeks with chemotherapy/ IMFINZI (N = 366) Placebo with Chemotherapy/Placebo (N = 374) EFS* Number of events, n (%) 98 (27) 138 (37) Median EFS (95% CI) (months) NR (31.9, NR) 25.9 (18.9, NR) Hazard ratio (95% CI) 0.68 (0.53, 0.88) 2-sided p-value†,§ 0.0039 pCR*,‡,§ Number of patients with response 63 16 pCR rate, % (95% CI) 17.2 (13.5, 21.5) 4.3 (2.5, 6.8) p-value < 0.0001 Difference in proportions, % (95% CI) ¥ 13.0 (8.7, 17.6) * Results are based on planned EFS interim analysis and pCR final analysis (DCO: 10 November 2022) which occurred 46.3 months after study initiation. † Compared to a two-sided p-value boundary of 0.00989. ‡ Based on a pre-specified pCR interim analysis (DCO: 14 January 2022) in n = 402, the pCR rate was statistically significant (p = 0.000036) compared to significance level of 0.0082%. § The 2-sided p-value for pCR was calculated based on a stratified CMH test. The 2-sided p-value for EFS was calculated based on based on a stratified log-rank test. Stratification factors include PD-L1 and disease stage. ¥ Confidence interval for the difference in proportions was calculated based on stratified Miettinen and Nurminen method. 47 Reference ID: 5489972 1.0 ~. o. 9 ~ m 0 . 8 -~ > "'""- ~ ~ o. 7 ' ' ' • ~ " '!Ht-,,~ ~ o. 6 " ,t-,...._____._ C " o. 5 > " .... 0 0 . 4 >, ~ rl 0 . 3 "' m .0 0 o. 2 ~ 0 . 1 0 . 0 1--- Durvalumab + soc I --- Placebo + soc 12 15 18 21 24 27 30 33 36 39 42 45 48 Time fr:irn randomi za t ion (months } Number of pat i ents at risk Durvalumab + Soc 366 336 271 194 140 90 78 50 19 31 30 14 11 Placebo + soc 374 339 257 184 136 82 74 53 50 30 25 16 13 Figure 1. Kaplan-Meier Curves of EFS in the AEGEAN Study At the interim analysis, the trial demonstrated a statistically significant difference in MPR rate (34% vs. 14%; p < 0.0001). At the time of the prespecified interim analyses, overall survival (OS) was not formally tested for statistical significance. Unresectable Stage III NSCLC - PACIFIC The efficacy of IMFINZI was evaluated in the PACIFIC study (NCT02125461), a multicenter, randomized, double-blind, placebo-controlled study in patients with unresectable Stage III NSCLC who completed at least 2 cycles of concurrent platinum-based chemotherapy and definitive radiation within 42 days prior to initiation of the study drug and had a WHO performance status of 0 or 1. The study excluded patients who had progressed following concurrent chemoradiation, patients with active or prior documented autoimmune disease within 2 years of initiation of the study or patients with medical conditions that required systemic immunosuppression. Randomization was stratified by sex, age (< 65 years vs. ≥ 65 years), and smoking history (smoker vs. non-smoker). Patients were randomized 2:1 to receive IMFINZI 10 mg/kg or placebo intravenously every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed RECIST v1.1-defined progression. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were progression-free survival (PFS) as assessed by a BICR RECIST v1.1, and overall survival (OS). Additional efficacy outcome measures included ORR and DoR assessed by BICR. A total of 713 patients were randomized: 476 patients to the IMFINZI arm and 237 to the placebo arm. The study population characteristics were: median age of 64 years (range: 23 to 90); 70% male; 69% White and 27% Asian; 16% current smokers, 75% former smokers, and 9% never smokers; 51% WHO performance status of 1; 53% with Stage IIIA and 45% were Stage IIIB; 46% with squamous and 54% with non-squamous histology. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy; 99% of patients received concomitant platinum-based 48 Reference ID: 5489972 chemotherapy (55% cisplatin-based, 42% carboplatin-based chemotherapy, and 2% switched between cisplatin and carboplatin). At a pre-specified interim analysis for OS based on 299 events (61% of total planned events), the study demonstrated a statistically significant improvement in OS in patients randomized to IMFINZI compared to placebo. The pre-specified interim analysis of PFS based on 371 events (81% of total planned events) demonstrated a statistically significant improvement in PFS in patients randomized to IMFINZI compared to placebo. Table 22 and Figure 2 summarizes the efficacy results for PACIFIC. Table 22. Efficacy Results for the PACIFIC Study Endpoint IMFINZI (N = 476)* Placebo (N = 237)* Overall Survival (OS)† Number of deaths 183 (38%) 116 (49%) Median in months (95% CI) NR (34.7, NR) 28.7 (22.9, NR) Hazard Ratio (95% CI)‡ 0.68 (0.53, 0.87) p-value‡,§ 0.0025 Progression-Free Survival (PFS)¶,# Number (%) of patients with event 214 (45%) 157 (66%) Median in months (95% CI) 16.8 (13.0, 18.1) 5.6 (4.6, 7.8) Hazard Ratio (95% CI)‡,Þ 0.52 (0.42, 0.65) p-value‡,ß < 0.0001 * Among the ITT population, 7% in the IMFINZI arm and 10% in the placebo arm had non-measurable disease as assessed by BICR according to RECIST v1.1. † OS results are based on the interim OS analysis conducted at 299 OS events which occurred 46 months after study initiation. ‡ Two-sided p-value based on a log-rank test stratified by sex, age, and smoking history. § Compared with allocated α of 0.00274 (Lan-DeMets spending function approximating O’Brien Fleming boundary) for interim analysis. ¶ As assessed by BICR RECIST v1.1. # PFS results are based on the interim PFS analysis conducted at 371 PFS events which occurred 33 months after study initiation. Þ Pike estimator. ß Compared with allocated α of 0.011035 (Lan-DeMets spending function approximating O’Brien Fleming boundary) for interim analysis. 49 Reference ID: 5489972 1.0 0.9 0.8 0.7 0.6 0.5 ~■■111■1111 11 0.4 0.3 0.2 - IMFINZI 0.1 - Placebo 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 -··-··-··-··-············-·······--··-··--··········-··-··-··-·------ --· ··-·-···-··-··-·-·- Figure 2. Kaplan-Meier Curves of OS in the PACIFIC Study Probability of OS Time from randomization (months) Number of patients at risk Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 IMFINZI 476 464 431 415 385 364 343 319 274 210 115 57 23 2 0 0 Placebo 237 220 198 178 170 155 141 130 117 78 42 21 9 3 1 0 Metastatic NSCLC - POSEIDON The efficacy of IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy in previously untreated metastatic NSCLC patients with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations was investigated in POSEIDON, a randomized, multicenter, active-controlled, open-label study (NCT03164616). Eligible patients had Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 and must have had no prior chemotherapy or any other systemic therapy for metastatic NSCLC. Choice of platinum- based chemotherapy was at the investigator’s discretion, taking into consideration the calculated creatinine clearance. Patients with active and/or untreated brain metastases; a history of active primary immunodeficiency; autoimmune disorders including active or prior documented autoimmune or inflammatory disorders; use of systemic immunosuppressants within 14 days before the first dose of the treatment except physiological dose of systemic corticosteroids were ineligible. Randomization was stratified by tumor cells (TC) PD-L1 expression (TC ≥ 50% vs. TC < 50%), disease stage (Stage IVA vs. Stage IVB), and histology (non-squamous vs. squamous). Patients were randomized 1:1:1 to receive IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy according to the regimens listed below, IMFINZI and platinum-based chemotherapy (an unapproved regimen for metastatic NSCLC), or platinum-based chemotherapy. The evaluation of efficacy for metastatic NSCLC relied on comparison between: 50 Reference ID: 5489972 • IMFINZI 1,500 mg with tremelimumab-actl 75 mg (or 1 mg/kg for patients < 30 kg) and platinum-based chemotherapy every 3 weeks for 4 cycles, followed by IMFINZI 1,500 mg every 4 weeks as a single agent. A fifth dose of tremelimumab-actl 75 mg (or 1 mg/kg for patients < 30 kg) was given at Week 16 in combination with IMFINZI dose 6. • Platinum-based chemotherapy every 3 weeks as monotherapy for 4 cycles. Patients could receive an additional 2 cycles (a total of 6 cycles post-randomization), as clinically indicated, at investigator’s discretion. Patients received IMFINZI in combination with tremelimumab-actl with one of the following platinum- based chemotherapy regimens: • Non-squamous NSCLC • Pemetrexed 500 mg/m2 with carboplatin AUC 5-6 or cisplatin 75 mg/m2 every 3 weeks for 4 cycles. • Squamous NSCLC • Gemcitabine 1,000 or 1,250 mg/m2 on Days 1 and 8 with cisplatin 75 mg/m2 or carboplatin AUC 5-6 on Day 1 every 3 weeks for 4 cycles. • Non-squamous and Squamous NSCLC • Nab-paclitaxel 100 mg/m2 on Days 1, 8, and 15 with carboplatin AUC 5-6 on Day 1 every 3 weeks for 4 cycles. Tremelimumab-actl was given up to a maximum of 5 doses. IMFINZI and histology-based pemetrexed continued every 4 weeks until disease progression or unacceptable toxicity. Administration of IMFINZI monotherapy was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Patients with disease progression during IMFINZI monotherapy were given the option to be retreated with 4 additional cycles of tremelimumab-actl in combination with IMFINZI. Tumor assessments were performed at Week 6, Week 12, and then every 8 weeks thereafter. The major efficacy outcome measures were progression free survival (PFS) and overall survival (OS) of IMFINZI and tremelimumab-actl in combination with platinum-based chemotherapy compared to platinum-based chemotherapy alone. Additional efficacy outcome measures were overall response rate (ORR) and duration of response (DoR). PFS, ORR, and DoR were assessed using Blinded Independent Central Review (BICR) according to RECIST v1.1. A total of 675 patients were randomized to receive either IMFINZI with tremelimumab-actl and platinum­ based-chemotherapy (n = 338) or platinum-based chemotherapy (n = 337). The median age was 63 years (range: 27 to 87), 46% of patients age ≥ 65 years, 77% male, 57% White, 34% Asian, 0.3% Native Hawaiian or Other Pacific Islander, 3% American Indian or Alaska Native, 2% Black or African American, 4% Other Race, 79% former or current smoker, 34% ECOG PS 0, and 66% ECOG PS 1. Thirty-six percent had squamous histology, 63% non-squamous histology, 29% PD-L1 expression TC ≥ 50%, 71% PD-L1 expression TC < 50%. Efficacy results are summarized in Table 23 and Figure 3. 51 Reference ID: 5489972 1.0 0.8 1/l 0 0.6 0 g :.0 ro ..c 0.4 e 0.. 0.2 0.0 --+- IMFINZI + tremelimumab-actl + platinum-based chemotherapy .... , .... Platinum-based chemotherapy 0 3 6 9 12 15 18 21 24 27 30 Time from randomization (months) 33 36 39 42 45 48 Table 23. Efficacy Results for the POSEIDON Study IMFINZI with tremelimumab-actl and platinum-based chemotherapy (n = 338) Platinum-based chemotherapy (n = 337) OS1 Number of deaths (%) 251 (74) 285 (85) Median OS (months) (95% CI) 14.0 (11.7, 16.1) 11.7 (10.5, 13.1) HR (95% CI) 0.77 (0.65, 0.92) p-value2 0.00304 PFS2 Number of events (%) 238 (70) 258 (77) Median PFS (months) (95% CI) 6.2 (5.0, 6.5) 4.8 (4.6, 5.8) HR (95% CI) 0.72 (0.60, 0.86) p-value2 0.00031 ORR % (95% CI)3 39 (34, 44) 24 (20, 29) Median DoR (months) (95% CI) 9.5 (7.2, NR) 5.1 (4.4, 6.0) 1 PFS/OS results are based on planned analyses which occurred 25/45 months respectively after study initiation. 2 2-sided p-values based on log-rank tests stratified by PD-L1, histology and disease stage and compared to a boundary value of 0.00735 for PFS and 0.00797 for OS. 3 Confirmed responses with 95% Clopper-Pearson confidence interval. NR=Not Reached, CI=Confidence Interval. Figure 3. Kaplan-Meier Curves of OS in the POSEIDON Study Number of patients at risk Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 IMFINZI + tremelimumab-actl + platinum-based chemotherapy 52 Reference ID: 5489972 338 298 256 217 183 159 137 120 109 95 88 64 41 20 9 0 Platinum-based chemotherapy 337 284 236 204 160 132 111 91 72 62 52 38 21 13 6 0 14.2 Small Cell Lung Cancer (SCLC) Limited-stage SCLC - ADRIATIC The efficacy of IMFINZI was evaluated in the ADRIATIC Study (NCT03703297), a randomized, double- blind, placebo-controlled, multicenter study in 730 patients with histologically or cytologically confirmed LS-SCLC (Stage I to III according to AJCC, 8th edition) whose disease had not progressed following concurrent chemoradiation therapy (cCRT). Patients who had Stage I or II disease had to be medically inoperable as determined by the investigator. Eligible patients completed cCRT consisting of 4 cycles of platinum-based chemotherapy and either 60-66 Gy once daily over 6 weeks or 45 Gy twice daily over 3 weeks radiation therapy within 42 days prior to the first dose of IMFINZI or placebo. Prophylactic cranial irradiation (PCI) could be delivered at the discretion of the investigator after cCRT and had to be completed within 42 days prior to the first dose of IMFINZI or placebo. Patients with active or prior documented autoimmune disease within 5 years of initiation into the study; a history of active primary immunodeficiency; a history of Grade ≥ 2 pneumonitis or active tuberculosis or hepatitis B or C or HIV infection; active interstitial lung disease were ineligible. Patients with mixed SCLC and NSCLC histology were also ineligible. Randomization was stratified by stage (I/II versus III) and receipt of PCI (yes versus no). Patients were randomized 1:1:1 to receive IMFINZI as a single agent, IMFINZI in combination with another agent, or placebo. All study medications were administered intravenously. The evaluation of efficacy for LS-SCLC relied on comparison between: • Arm 1: IMFINZI 1,500 mg in combination with placebo every 4 weeks for 4 cycles, followed by IMFINZI 1,500 mg every 4 weeks. • Arm 2: Placebo in combination with a second placebo every 4 weeks for 4 cycles, followed by a single placebo every 4 weeks. A total of 530 patients were randomized between Arms 1 and 2, 264 patients to the IMFINZI arm and 266 patients to the placebo arm. Treatment continued until disease progression, until unacceptable toxicity, or for a maximum of 24 months. Tumor assessments were conducted every 8 weeks for the first 72 weeks, then every 12 weeks up to 96 weeks and then every 24 weeks thereafter. The major efficacy outcome measures were OS and PFS assessed by BICR according to RECIST v1.1. The baseline demographics and disease characteristics for patients in the IMFINZI and placebo arms were as follows: male (69%); age ≥ 65 years (39%); White (50%), Black or African-American (0.8%), Asian (48%), other race (1.3%); Hispanic or Latino (4.2%); current smoker (22%), past-smoker (68%), never smoker (9%); WHO/ECOG PS 0 (49%), WHO/ECOG PS 1 (51%); and Stage I (3.6%), Stage II (9%), Stage III (87%). Prior to randomization, all patients received platinum-based chemotherapy (66% cisplatin-etoposide, 34% carboplatin-etoposide) with 88% of patients receiving 4 cycles; 72% of patients received once daily 53 Reference ID: 5489972 radiation (of which 92% received ≥ 60 - ≤ 66 Gy QD); 28% received twice daily radiation (of which 97% received 45 Gy twice daily) and 54% of patients received PCI. Efficacy results are presented in Table 24 and Figure 4. Table 24. Efficacy Results for the ADRIATIC Study IMFINZI (n=264) Placebo (n=266) OS Number of deaths (%) 115 (44) 146 (55) Median OS (months) (95% CI)† 55.9 (37.3, NR) 33.4 (25.5, 39.9) HR (95% CI)‡ 0.73 (0.57, 0.93) p-value§ 0.0104 PFS¶ Number of events (%) 139 (53) 169 (64) Median PFS (months) (95% CI)† 16.6 (10.2, 28.2) 9.2 (7.4, 12.9) HR (95% CI)# 0.76 (0.61, 0.95) p-value§ 0.0161 † Calculated using the Kaplan Meier technique. CI for median derived based on Brookmeyer-Crowley method. ‡ Based on Cox proportional hazards model stratified by receipt of PCI. § Compared with allocated alpha of 0.0168 for OS and 0.0280 for PFS (Lan‑DeMets spending function approximating O’Brien Fleming boundary) for interim analysis. ¶ Assessed by BICR according to RECIST v1.1. # Based on Cox proportional hazards model stratified by TNM stage and receipt of PCI. 54 Reference ID: 5489972 U) 0 "' o 0. 6 >, +-' .... ,.... .... ,., "' '3 0. 4 .., "' () ,) 18 21 2, 33 36 42 4 :) 'l'.'...me fro_":'J. rc.ndorr.lzaLion {.11onLhs } Numbe r oI s ubj ecLs a l r.isk IMFINZI 2 64 26:.. 2 48 236 223 207 189 ! EU 172 1 62 :_41 11 0 9:: Sl Pl a cebo 266 26G 24 l 231 2 ll: 19!; l "/~- 164 1~:.. 1 43 :..23 C:ii 62 44 31 --- r M:,rnz1 --- Pl a.ce.oc 60 63 L / l s 11 2.3 19 Figure 4. Kaplan-Meier Curves of OS in the ADRIATIC Study Extensive-stage SCLC – CASPIAN The efficacy of IMFINZI in combination with etoposide and either carboplatin or cisplatin in previously untreated ES-SCLC was investigated in CASPIAN, a randomized, multicenter, active-controlled, open- label study (NCT03043872). Eligible patients had WHO Performance Status of 0 or 1 and were suitable to receive a platinum-based chemotherapy regimen as first-line treatment for SCLC. Patients with asymptomatic or treated brain metastases were eligible. Choice of platinum agent was at the investigator’s discretion, taking into consideration the calculated creatinine clearance. Patients with history of chest radiation therapy; a history of active primary immunodeficiency; autoimmune disorders including paraneoplastic syndrome; active or prior documented autoimmune or inflammatory disorders; use of systemic immunosuppressants within 14 days before the first dose of the treatment except physiological dose of systemic corticosteroids were ineligible. Randomization was stratified by the planned platinum-based therapy in cycle 1 (carboplatin or cisplatin). The evaluation of efficacy for ES-SCLC relied on comparison between: IMFINZI 1,500 mg, and investigator’s choice of carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75­ 80 mg/m2) on Day 1 and etoposide (80-100 mg/m2) intravenously on Days 1, 2, and 3 of each 21-day cycle for 4 cycles, followed by IMFINZI 1,500 mg every 4 weeks until disease progression or unacceptable toxicity, or 55 Reference ID: 5489972 Investigator’s choice of carboplatin (AUC 5 or 6 mg/mL/min) or cisplatin (75-80 mg/m2) on Day 1 and etoposide (80-100 mg/m2) intravenously on Days 1, 2, and 3 of each 21-day cycle, up to 6 cycles. After completion of chemotherapy, PCI as administered per investigator discretion. Administration of IMFINZI as a single agent was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. The major efficacy outcome measure was overall survival (OS) of IMFINZI plus chemotherapy vs. chemotherapy alone. Additional efficacy outcome measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR), per RECIST v1.1. The study population characteristics were: median age of 63 years (range: 28 to 82); 40% age 65 or older; 70% male; 84% White, 15% Asian, and 0.9% Black; 65% WHO/ECOG PS of 1; and 93% were former/current smokers. Ninety percent of patients had Stage IV disease and 10% had brain metastasis at baseline. A total of 25% of the patients received cisplatin and 74% of the patients received carboplatin. In the chemotherapy alone arm, 57% of the patients received 6 cycles of chemotherapy, and 8% of the patients received PCI. The OS results are summarized in Table 25 and Figure 5. Table 25. OS Results for the CASPIAN Study Endpoint IMFINZI with Etoposide and either Carboplatin or Cisplatin (n = 268) Etoposide and either Carboplatin or Cisplatin (n = 269) Overall Survival (OS) Number of deaths (%)* 155 (58) 181 (67) Median OS (months) (95% CI) 13.0 (11.5, 14.8) 10.3 (9.3, 11.2) Hazard Ratio (95% CI)† 0.73 (0.59, 0.91) p-value1 0.0047 * At a pre-specified interim analysis, 336 OS events (79% of total planned events) were observed, and the boundary for declaring efficacy (0.0178) was determined by a Lan-DeMets alpha spending function with O’Brien Fleming type boundary. † The analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in Cycle 1 (carboplatin or cisplatin) and using the rank tests of association approach. 56 Reference ID: 5489972 1.0 ---+-- IMFINZI + chemotherapy 0.9 - - - chemotherapy • Censored 0.8 0.7 0.6 ,.., 'It. 0.5 -'-' 0.4 \..._ 0.3 0.2 '-'----,_ '\........., --, 0.1 I_ .... 0.0 0 3 6 12 15 18 21 24 Figure 5. Kaplan-Meier Curves of OS in the CASPIAN Study Probability of OS Time from randomization (months) Number of patients at risk 0 3 6 9 12 15 18 21 24 IMFINZI + chemotherapy 268 244 214 177 116 57 25 5 0 chemotherapy 269 242 209 153 82 44 17 1 0 Investigator-assessed PFS (96% of total planned events) showed a HR of 0.78 (95% CI: 0.65, 0.94), with median PFS of 5.1 months (95% CI: 4.7, 6.2) in the IMFINZI plus chemotherapy arm and 5.4 months (95% CI: 4.8, 6.2) in the chemotherapy alone arm. The investigator-assessed confirmed ORR was 68% (95% CI: 62%, 73%) in the IMFINZI plus chemotherapy arm and 58% (95% CI: 52%, 63%) in the chemotherapy alone arm. In the exploratory subgroup analyses of OS based on the planned platinum chemotherapy received at cycle 1, the HR was 0.70 (95% CI 0.55, 0.89) in patients who received carboplatin, and the HR was 0.88 (95% CI 0.55, 1.41) in patients who received cisplatin. 14.3 Biliary Tract Cancer (BTC) Locally Advanced or Metastatic BTC - TOPAZ-1 The efficacy of IMFINZI in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic BTC was investigated in TOPAZ-1 (NCT03875235), a randomized, double-blind, placebo- controlled, multicenter study that enrolled 685 patients with histologically confirmed locally advanced unresectable or metastatic BTC who have not previously received systemic therapy. Patients with recurrent disease > 6 months after surgery and/or completion of adjuvant therapy were eligible. Patients had an ECOG Performance status of 0 and 1 and at least one target lesion by RECIST v1.1. Patients with ampullary carcinoma; active or prior documented autoimmune or inflammatory disorders; HIV infection 57 Reference ID: 5489972 or active infections, including tuberculosis or hepatitis C; current or prior use of immunosuppressive medication within 14 days before the first dose of IMFINZI were ineligible. Randomization was stratified by disease status (recurrent vs. initially unresectable) and primary tumor location (intrahepatic cholangiocarcinoma [ICCA] vs. extrahepatic cholangiocarcinoma [ECCA] vs. gallbladder cancer [GBC]). Patients were randomized 1:1 to receive: • IMFINZI 1,500 mg on Day 1+ gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on Days 1 and 8 of each 21-day cycle up to 8 cycles, followed by IMFINZI 1,500 mg every 4 weeks, or • Placebo on Day 1+ gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on Days 1 and 8 of each 21-day cycle up to 8 cycles, followed by placebo every 4 weeks. Treatment with IMFINZI or placebo continued until disease progression, or unacceptable toxicity. Treatment beyond disease progression was permitted if the patient was clinically stable and deriving clinical benefit as determined by the investigator. The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were investigator-assessed progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR). Tumor assessments were conducted every 6 weeks for the first 24 weeks after the date of randomization, and then every 8 weeks until confirmed objective disease progression. The study population characteristics were: 50% male, median age of 64 years (range 20-85), 47% age 65 or older; 56% Asian, 37% White, 2% Black or African American, 0.1% American Indian or Alaskan Native, and 4% other; 51% had an ECOG PS of 1; primary tumor location was ICCA 56%, ECCA 18% and GBC 25%; 20% of patients had recurrent disease; 86% of patients had metastatic and 14% had locally advanced disease. At a pre-specified interim analysis, the study demonstrated a statistically significant improvement in OS and PFS in patients randomized to IMFINZI in combination with chemotherapy compared to placebo in combination with chemotherapy. Table 26 summarizes the efficacy results for TOPAZ-1. Table 26. Efficacy Results for the TOPAZ-1 Study Endpoint IMFINZI with Gemcitabine and Cisplatin (n = 341) Placebo with Gemcitabine and Cisplatin (n = 344) Overall Survival (OS) Number of deaths (%) 198 (58) 226 (66) Median OS (months) (95% CI)* 12.8 (11.1, 14) 11.5 (10.1, 12.5) Hazard Ratio (95% CI)† 0.80 (0.66, 0.97) p-value‡ 0.021 Progression-Free Survival (PFS) Number of patients with event (%) 276 (81) 297 (86) 58 Reference ID: 5489972 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 --- IMFINZI + Oiemotherapy (N• 341) 0.0 - Chemotherapy (N• 344) 0 3 6 9 12 15 18 Time from randomization (montl1s) Number of patients at risk IMFINZI + Chemotherapy 341 331 324 309 294 278 268 252 238 208 174 151 135 118 93 79 74 57 49 39 Chemotherapy 344 337 329 317 299 283 261 242 220 183 159143 125 97 78 65 52 40 29 21 21 24 27 30 29 24 15 12 9 8 4 I 0 15 JO 8 4 4 3 0 0 0 Endpoint IMFINZI with Gemcitabine and Cisplatin (n = 341) Placebo with Gemcitabine and Cisplatin (n = 344) Median in months (95% CI)* 7.2 (6.7, 7.4) 5.7 (5.6, 6.7) Hazard Ratio (95% CI)† 0.75 (0.63, 0.89) p-value§ 0.001 * Kaplan-Meier estimated median with 95% CI derived using Brookmeyer-Crowley method. † Based on Cox proportional hazards model stratified by disease status and primary tumor location. ‡ 2-sided p-value based on a stratified log-rank test compared with alpha boundary of 0.030. § 2-sided p-value based on a stratified log-rank test compared with alpha boundary of 0.048. The investigator-assessed ORR was 27% (95% CI: 22% - 32%) in the IMFINZI plus chemotherapy arm and 19% (95% CI: 15% - 23%) in the chemotherapy alone arm. Figure 6. Kaplan-Meier Curves of OS in the TOPAZ-1 Study 14.4 Hepatocellular Carcinoma (HCC) Unresectable HCC - HIMALAYA The efficacy of IMFINZI in combination with tremelimumab-actl was evaluated in the HIMALAYA study (NCT03298451), a randomized (1:1:1), open-label, multicenter study in patients with confirmed uHCC who had not received prior systemic treatment for HCC. Patients were randomized to one of two investigational arms (IMFINZI plus tremelimumab-actl or IMFINZI) or sorafenib. Study treatment consisted of IMFINZI 1,500 mg in combination with tremelimumab-actl as a one-time single intravenous infusion of 300 mg on the same day, followed by IMFINZI every 4 weeks; IMFINZI 1,500 mg every 59 Reference ID: 5489972 4 weeks; or sorafenib 400 mg given orally twice daily, until disease progression or unacceptable toxicity. The efficacy assessment of IMFINZI is based on patients randomized to the IMFINZI plus tremelimumab-actl arm versus the sorafenib arm. Randomization was stratified by macrovascular invasion (MVI) (yes or no), etiology of liver disease (hepatitis B virus vs. hepatitis C virus vs. others) and ECOG performance status (0 vs. 1). The study enrolled patients with BCLC Stage C or B (not eligible for locoregional therapy). The study excluded patients with co-infection of viral hepatitis B and hepatitis C; active or prior documented gastrointestinal (GI) bleeding within 12 months; ascites requiring non-pharmacologic intervention within 6 months; hepatic encephalopathy within 12 months before the start of treatment; active or prior documented autoimmune or inflammatory disorders. Esophagogastroduodenoscopy was not mandated prior to enrollment but adequate endoscopic therapy, according to institutional standards, was required for patients with history of esophageal variceal bleeding or those assessed as high risk for esophageal variceal bleeding by the treating physician. Study treatment was permitted beyond disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. The major efficacy outcome measure was overall survival (OS) between the IMFINZI plus tremelimumab-actl arm versus the sorafenib arm. Additional efficacy outcomes were investigator- assessed progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR) according to RECIST v1.1. Tumor assessments were conducted every 8 weeks for the first 12 months and then every 12 weeks thereafter. The baseline demographics of the IMFINZI plus tremelimumab-actl and sorafenib arms were as follows: male (85%), age < 65 years (50%), median age of 65 years (range: 18 to 88 years), White (46%), Asian (49%), Black or African American (2%), Native Hawaiian or other Pacific Islander (0.1%), race Unknown (2%), Hispanic or Latino (5%), Not Hispanic or Latino (94%), ethnicity Unknown (1%), ECOG PS 0 (62%); Child-Pugh Class score A (99%), macrovascular invasion (26%), extrahepatic spread (53%), viral etiology; hepatitis B (31%), hepatitis C (27%), and uninfected (42%). Efficacy results are presented in Table 27 and Figure 7. Table 27. Efficacy Results for the HIMALAYA Study Endpoint IMFINZI and Tremelimumab-actl (N = 393) Sorafenib (N = 389) OS Number of deaths (%) 262 (66.7) 293 (75.3) Median OS (months) (95% CI) 16.4 (14.2, 19.6) 13.8 (12.3, 16.1) HR (95% CI)* 0.78 (0.66, 0.92) p-value†, ‡ 0.0035 PFS 60 Reference ID: 5489972 1.0 --- IMFINZI + Tremelimumab - Sorafenib o Censored 0.8 l <f) 0.6 ~ ~ > 0 0 0 -~ 0.4 'l:i .ll e o._ 0.2 .... . .• <Db ~ w oo~ 00 -0 ro - o 0.0 0 4 6 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 Time from randomization (months) IMFINZI + Tremelimumab 393 365 333 308 2ss 262 235 211 197 190 176 168 1ss 1so 119 98 75 ss 32 19 12 11 Sorafenib 389 356 319 283 2ss 231 211 1a3 110 1ss 142 131 121 106 79 62 44 32 21 Endpoint IMFINZI and Tremelimumab-actl (N = 393) Sorafenib (N = 389) Number of events (%) 335 (85.2) 327 (84.1) Median PFS (months) (95% CI) 3.8 (3.7, 5.3) 4.1 (3.7, 5.5) HR (95% CI)* 0.90 (0.77, 1.05) ORR ORR % (95% CI)§, ¶ 20.1 (16.3, 24.4) 5.1 (3.2, 7.8) Complete Response n (%) 12 (3.1) 0 Partial Response n (%) 67 (17.0) 20 (5.1) DoR Median DoR (months) (95% CI) 22.3 (13.7, NR) 18.4 (6.5, 26.0) % with duration ≥ 6 months 82.3 78.9 % with duration ≥ 12 months 65.8 63.2 * HR (IMFINZI and tremelimumab-actl vs. sorafenib) based on the stratified Cox proportional hazard model. † Based on a stratified log-rank test. ‡ Based on a Lan-DeMets alpha spending function with O'Brien Fleming type boundary and the actual number of events observed, the boundary for declaring statistical significance for IMFINZI and tremelimumab-actl vs. sorafenib was 0.0398 (Lan and DeMets 1983). § Confirmed complete response or partial response. ¶ Based on Clopper-Pearson method. CI=Confidence Interval, HR=Hazard Ratio, NR=Not Reached Figure 7. Kaplan-Meier Curves of OS in the Himalaya Study 61 Reference ID: 5489972 14.5 Endometrial cancer Advanced or Recurrent dMMR Endometrial Cancer - DUO-E IMFINZI was evaluated in combination with carboplatin and paclitaxel in DUO-E (NCT04269200), a randomized, multicenter, double-blind, placebo-controlled study in patients with advanced or recurrent endometrial cancer. The trial enrolled patients with newly diagnosed Stage III disease (with measurable disease per RECIST v1.1), or newly diagnosed Stage IV disease. The trial also enrolled patients with recurrent disease with a low potential for cure by radiation therapy or surgery. For patients with recurrent disease, prior chemotherapy was allowed only if it was administered in the adjuvant setting and at least 12 months had elapsed from the date of last dose of chemotherapy to the date of relapse. The trial included patients with epithelial endometrial carcinomas of all histologies, including carcinosarcomas. Patients with endometrial sarcoma were excluded, and patients who had active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified by tumor mismatch repair (MMR) status (proficient or deficient), disease status (recurrent or newly diagnosed), and geographic region (Asia or rest of the world). MMR status was assessed using an immunohistochemistry tumor tissue test. Patients were randomized (1:1:1) to one of the following treatment arms: • IMFINZI 1,120 mg in combination with carboplatin and paclitaxel every 3 weeks for a maximum of 6 cycles. Following completion of chemotherapy treatment, patients received IMFINZI 1,500 mg every 4 weeks as maintenance treatment until disease progression. • Placebo in combination with carboplatin and paclitaxel every 3 weeks for a maximum of 6 cycles. Following completion of chemotherapy treatment, patients received placebo every 4 weeks as maintenance treatment until disease progression. • An additional investigational combination regimen. Treatment was continued until Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression of disease or unacceptable toxicity. Assessment of tumor status was performed every 9 weeks for the first 18 weeks and every 12 weeks thereafter. The major efficacy outcome measure was progression-free survival (PFS), determined by investigator assessment using RECIST 1.1. Additional efficacy outcome measures included overall response rate (ORR), duration of response (DOR) and overall survival (OS). Among 95 patients with dMMR tumor, the baseline characteristics were median age of 63 years (range: 34 to 85); 47% age 65 or older; 62% White, 31% Asian, 2% Black or African American; 7% Hispanic or Latino, 1% American Indian or Alaska Native, and 4% other or not reported; ECOG PS of 0 (55%) or 1 (45%); 48% newly diagnosed (11% Stage III and 38% Stage IV) and 52% recurrent disease. The histologic subtypes were endometrioid (78%), mixed epithelial (6%), carcinosarcoma (5%), serous (4%), undifferentiated (1%), and other (5%). While a statistically significant improvement in PFS was observed in the overall population for IMFINZI with carboplatin and paclitaxel compared to carboplatin and paclitaxel alone, based on an exploratory analysis by MMR status, the PFS improvement in the overall population was primarily attributed to patients with dMMR tumors. 62 Reference ID: 5489972 Efficacy results for DUO-E are summarized in Table 28 and Figure 8 for patients with dMMR tumors. OS data in this subpopulation at the time of PFS analysis were immature with 26% of patients who died. Table 28. Efficacy Results for Patients with dMMR Tumors in the DUO-E Study Endpoint IMFINZI with Carboplatin and Paclitaxel N=46 Carboplatin and Paclitaxel N=49 PFS* Number of events (%) 15 (32.6) 25 (51.0) Median in months (95% CI)‡ NR (NR, NR) 7.0 (6.7, 14.8) HR (95% CI) 0.42 (0.22, 0.80) ORR N=42 N=42 ORR % (95% CI) 71.4 (55.4, 84.3) 40.5 (25.6, 56.7) Complete response % 12 (28.6) 4 (9.5) Partial response % 18 (42.9) 13 (31.0) DOR Median in months (range) NR (2.4+, 26.9+) 10.5 (2.1+, 25.2+) * Investigator assessed. ‡ Calculated using the Kaplan-Meier technique. CI=Confidence Interval, HR=Hazard Ratio, NR=Not Reached, + = response ongoing at last assessment. 63 Reference ID: 5489972 1.0 0.9 0.8 Q) ~ 0.7 ..... C Q) > Q) 0.6 ~ Q) :p 0.5 "' 0.. 0 C 0.4 :8 0 §- 0.3 a: 0.2 0.1 0.0 • t I ., --, I ~ , IMFINZI + Carboplatin and Paclitaxel Carboplatin and Paclitaxel I ___ ..,. .... _., 0 3 6 9 Number of patients at risk: IMFINZI + Carboplatin and Paclitaxel 46 37 36 31 Carboplatin and Paclitaxel 49 41 28 17 -~-1 L .,_ - - ---- - - ..... + - - - - - - - • 12 15 18 Time from randomisation (months) 26 13 19 8 14 5 21 9 2 24 5 2 27 2 0 30 0 0 Figure 8. Kaplan-Meier curves of PFS for Patients with dMMR Tumors in the DUO-E Study 16 HOW SUPPLIED/STORAGE AND HANDLING IMFINZI (durvalumab) Injection is a clear to opalescent, colorless to slightly yellow solution supplied in a carton containing one single-dose vial either as: • 500 mg/10 mL (50 mg/mL) (NDC 0310-4611-50). • 120 mg/2.4 mL (50 mg/mL) (NDC 0310-4500-12). Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Immune-Mediated Adverse Reactions Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of IMFINZI [see Warnings and Precautions (5.1)], including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath. 64 Reference ID: 5489972 • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain. • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus, or hypophysitis. • Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis. • Dermatological Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of severe dermatological reactions. • Pancreatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis. • Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis, aseptic meningitis, encephalitis, immune thrombocytopenia, myocarditis, hemolytic anemia, myositis, uveitis, keratitis, and myasthenia gravis. Infusion-Related Reactions: • Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)]. Complications of Allogeneic HSCT: • Advise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.3)]. Embryo-Fetal Toxicity: • Advise females of reproductive potential that IMFINZI can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)]. • Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of IMFINZI [see Use in Specific Populations (8.3)]. Lactation: • Advise female patients not to breastfeed while taking IMFINZI and for 3 months after the last dose [see Warnings and Precautions (5.4) and Use in Specific Populations (8.2)]. Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 65 Reference ID: 5489972 MEDICATION GUIDE IMFINZI® (im-FIN-zee) (durvalumab) injection What is the most important information I should know about IMFINZI? IMFINZI is a medicine that may treat certain cancers by working with your immune system. IMFINZI can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended. Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including: • Lung problems. o cough o shortness of breath o chest pain • Intestinal problems. o diarrhea (loose stools) or more frequent o severe stomach-area (abdomen) pain or bowel movements than usual tenderness o stools that are black, tarry, sticky, or have blood or mucus • Liver problems. o yellowing of your skin or the whites of o dark urine (tea colored) your eyes o bleeding or bruising more easily than o severe nausea or vomiting normal o pain on the right side of your stomach- area (abdomen) • Hormone gland problems. o headaches that will not go away or o urinating more often than usual unusual headaches o hair loss o eye sensitivity to light o feeling cold o eye problems o constipation o rapid heartbeat o your voice gets deeper o increase sweating o dizziness or fainting o extreme tiredness o changes in mood or behavior, such as o weight gain or weight loss decreased sex drive, irritability, or o feeling more hungry or thirsty than usual forgetfulness • Kidney problems. o decrease in your amount of urine o swelling of your ankles o blood in your urine o loss of appetite • Skin problems. o rash o painful sores or ulcers in mouth or nose, o itching throat, or genital area o skin blistering or peeling o fever or flu-like symptoms o swollen lymph nodes • Pancreas problems o pain in your upper stomach area o loss of appetite (abdomen) o severe nausea or vomiting • Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with IMFINZI. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include: o chest pain, irregular heartbeats, shortness of breath or swelling of ankles 66 Reference ID: 5489972 o confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems o tingling, numbness or weakness of the arms or legs o double vision, blurry vision, sensitivity to light, eye pain, changes in eye-sight o persistent or severe muscle pain or weakness, muscle cramps, joint pain, joint stiffness or swelling o low red blood cells, bruising • Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include: o chills or shaking o dizziness o itching or rash o feel like passing out o flushing o fever o shortness of breath or wheezing o back or neck pain • Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with IMFINZI. Your healthcare provider will monitor you for these complications. Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with IMFINZI. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with IMFINZI, if you have severe side effects. What is IMFINZI? IMFINZI is a prescription medicine used to treat adults with: • a type of lung cancer called non-small cell lung cancer (NSCLC). o IMFINZI may be used in combination with chemotherapy that contains platinum prior to surgery and alone after surgery when your NSCLC: • can be removed by surgery, and • is not known to have an abnormal “EGFR” or “ALK” gene. o IMFINZI may be used alone when your NSCLC: • has not spread outside your chest • cannot be removed by surgery, and • has responded or stabilized with initial treatment with chemotherapy that contains platinum, given at the same time as radiation therapy. o IMFINZI may be used in combination with tremelimumab-actl and chemotherapy that contains platinum when your NSCLC: • has spread to other parts of your body (metastatic), and • does not have an abnormal “EGFR” or “ALK” gene. • a type of lung cancer called small cell lung cancer (SCLC). o for limited-stage small cell lung cancer (LS-SCLC), IMFINZI may be used alone when your LS­ SCLC cannot be removed by surgery, and o has responded or stabilized after initial treatment with chemotherapy that contains platinum, given at the same time as radiation therapy. o for extensive-stage small cell lung cancer (ES-SCLC), IMFINZI may be used with the chemotherapy medicines etoposide and either carboplatin or cisplatin as your first treatment when your ES-SCLC has spread within your lungs or to other parts of the body. • a type of cancer called biliary tract cancer (BTC), including cancer of the bile ducts (cholangiocarcinoma) and gallbladder cancer. IMFINZI may be used in combination with chemotherapy medicines gemcitabine and cisplatin when your BTC: 67 Reference ID: 5489972 o has spread to nearby tissues (locally advanced), or o has spread to other parts of the body (metastatic). • a type of liver cancer that cannot be removed by surgery (unresectable hepatocellular carcinoma or uHCC). IMFINZI is used in combination with tremelimumab-actl to treat uHCC. • a type of uterine cancer called endometrial cancer. IMFINZI may be used in combination with chemotherapy medicines carboplatin and paclitaxel followed by IMFINZI alone when your endometrial cancer: o has spread (advanced) or has come back (recurrent), and o a laboratory test shows that your tumor is mismatch repair deficient (dMMR). It is not known if IMFINZI is safe and effective in children. Before you receive IMFINZI, tell your healthcare provider about all of your medical conditions, including if you: • have immune system problems such as Crohn's disease, ulcerative colitis, or lupus • have received an organ transplant • have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic) • have received radiation treatment to your chest area • have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome • are pregnant or plan to become pregnant. IMFINZI can harm your unborn baby Females who are able to become pregnant: o Your healthcare provider will give you a pregnancy test before you start treatment with IMFINZI. o You should use an effective method of birth control during your treatment and for 3 months after the last dose of IMFINZI. Talk to your healthcare provider about birth control methods that you can use during this time. o Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with IMFINZI. • are breastfeeding or plan to breastfeed. It is not known if IMFINZI passes into your breast milk. Do not breastfeed during treatment and for 3 months after the last dose of IMFINZI. Tell your healthcare provider about all the medicines you take, including prescription and over-the­ counter medicines, vitamins, and herbal supplements. How will I receive IMFINZI? • Your healthcare provider will give you IMFINZI into your vein through an intravenous (IV) line over 60 minutes. • IMFINZI is usually given every 2, 3 or 4 weeks. • Your healthcare provider will decide how many treatments you need. • Your healthcare provider will test your blood to check you for certain side effects. • If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment. What are the possible side effects of IMFINZI? IMFINZI can cause serious side effects, including: See “What is the most important information I should know about IMFINZI?” The most common side effects of IMFINZI when used with platinum-containing chemotherapy in adults with NSCLC that can be removed by surgery include: • low red blood cells (anemia) • feeling tired • nausea • muscle or bone pain • constipation • rash The most common side effects of IMFINZI when used alone in adults with NSCLC that cannot be removed by surgery include: 68 Reference ID: 5489972 • cough • upper respiratory tract infections • feeling tired • shortness of breath • inflammation in the lungs • rash The most common side effects of IMFINZI when used with tremelimumab-actl and platinum-containing chemotherapy in adults with metastatic NSCLC include: • nausea • decreased appetite • feeling tired or weak • rash • muscle or bone pain • diarrhea The most common side effects of IMFINZI when used alone in adults with LS-SCLC include: • inflammation in the lungs • feeling tired or weak The most common side effects of IMFINZI when used with other anticancer medicines in adults with ES-SCLC include: • nausea • feeling tired or weak • hair loss The most common side effects of IMFINZI when used with other anticancer medicines in adults with BTC include: • feeling tired • stomach (abdominal) pain • nausea • rash • constipation • fever • decreased appetite The most common side effects of IMFINZI when used with tremelimumab-actl in adults with uHCC include: • rash • itchiness • diarrhea • muscle or bone pain • feeling tired • stomach (abdominal) pain The most common side effects of IMFINZI when used with carboplatin and paclitaxel in adults with endometrial cancer include: • inflammation of the nerves causing • decreased level of magnesium in the blood numbness, weakness, tingling or • increased liver function tests burning pain of the arms and legs • diarrhea • muscle or bone pain • vomiting • nausea • cough • hair loss • decreased level of potassium in the blood • feeling tired • shortness of breath • stomach (abdominal) pain • headache • constipation • increased level of alkaline phosphatase in the blood • rash Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of IMFINZI. Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800­ FDA-1088. General information about the safe and effective use of IMFINZI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about IMFINZI, talk with your healthcare provider. You can ask your healthcare provider for information about IMFINZI that is written for health professionals. 69 Reference ID: 5489972 What are the ingredients in IMFINZI? Active ingredient: durvalumab Inactive ingredients: L-histidine, L-histidine hydrochloride monohydrate, α,α-trehalose dihydrate, polysorbate 80, Water for Injection, USP. Manufactured for: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 By: AstraZeneca UK Limited, 1 Francis Crick Ave. Cambridge, England CB2 0AA US License No. 2043 IMFINZI is a registered trademark of AstraZeneca group of companies. For more information, call 1-800-236-9933 or go to www.IMFINZI.com © AstraZeneca 2024 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2024 70 Reference ID: 5489972
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Piperacillin and Tazobactam safely and effectively. See full prescribing information for Piperacillin and Tazobactam. ------------------------------ CONTRAINDICATIONS -----------------------------­ Patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. (4) ---------------------------WARNINGS AND PRECAUTIONS -------------------- Piperacillin and Tazobactam for injection, for intravenous use Initial U.S. approval: 1993 -------------------------- RECENT MAJOR CHANGES --------------------------­ Warnings and Precautions, Rhabdomyolysis (5.4) 12/2024 -------------------------- INDICATIONS AND USAGE----------------------------- Piperacillin and Tazobactam for injection, for intravenous use is a combination of piperacillin, a penicillin-class antibacterial and tazobactam, a beta-lactamase inhibitor, indicated for the treatment of: • Intra-abdominal infections in adult and pediatric patients 2 months of age and older (1.1) • Nosocomial pneumonia in adult and pediatric patients 2 months of age and older (1.2) • Skin and skin structure infections in adults (1.3) • Female pelvic infections in adults (1.4) • Community-acquired pneumonia in adults (1.5) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Piperacillin and tazobactam and other antibacterial drugs, Piperacillin and tazobactam should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.6) -------------------------- DOSAGE AND ADMINISTRATION ------------------­ • Adult Patients With Indications Other Than Nosocomial Pneumonia; The usual daily dosage of Piperacillin and tazobactam for injection, for intravenous use for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin and 1.5 g tazobactam). (2.1) • Adult Patients with Nosocomial Pneumonia: Initial presumptive treatment of patients with nosocomial pneumonia should start with Piperacillin and tazobactam for injection, for intravenous use at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin and 2.0 g tazobactam). (2.2) • Adult Patients with Renal Impairment: Dosage in patients with renal impairment (creatinine clearance ≤40 mL/min) and dialysis patients should be reduced, based on the degree of renal impairment. (2.3) • Pediatric Patients by Indication and Age: See Table below (2.4) Recommended Dosage of Piperacillin and tazobactam for injection, for intravenous use for Pediatric Patients 2 months of Age and Older, Weighing up to 40 Kg and With Normal Renal Function Age Appendicitis and /or Peritonitis Nosocomial Pneumonia 2 months to 9 months 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 8 (eight) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 6 (six) hours Older than 9 months 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 8 (eight) hours 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 6 (six) hours • Administer Piperacillin and tazobactam by intravenous infusion over 30 minutes to both adult and pediatric patients. (2.1, 2.2, 2.3, 2.4) • Piperacillin and tazobactam and aminoglycosides should be reconstituted, diluted, and administered separately. Co-administration via Y-site can be done under certain conditions. (2.6) • See the full prescribing information for the preparation and administration instructions for Piperacillin and tazobactam for injection single-dose vials and pharmacy bulk vials. -------------------------- DOSAGE FORMS AND STRENGTHS----------------- Piperacillin and tazobactam for injection, for intravenous use: 2.25 g, 3.375 g, and 4.5 g lyophilized powder for reconstitution in single-dose vials and 40.5 g lyophilized powder for reconstitution in pharmacy bulk vials. [all strengths of Piperacillin and tazobactam for injection, for intravenous use are not currently being marketed] (3, 16) • Serious hypersensitivity reactions (anaphylactic/anaphylactoid) reactions have been reported in patients receiving Piperacillin and tazobactam. Discontinue Piperacillin and tazobactam if a reaction occurs. (5.1) • Piperacillin and tazobactam may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. Discontinue Piperacillin and tazobactam for progressive rashes. (5.2) • Hemophagocytic lymphohistiocytosis (HLH) has been reported with the use of Piperacillin and tazobactam. If HLH is suspected, discontinue Piperacillin and tazobactam immediately. (5.3) • Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue Piperacillin and Tazobactam for injection and initiate appropriate therapy. (5.4) • Hematological effects (including bleeding, leukopenia and neutropenia) have occurred. Monitor hematologic tests during prolonged therapy. (5.5) • As with other penicillins, Piperacillin and tazobactam may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially in the presence of renal impairment may be at greater risk. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures. (5.6) • Nephrotoxicity in critically ill patients has been observed; the use of Piperacillin and tazobactam was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with Piperacillin and tazobactam. (5.7) • Clostridioides difficile-associated diarrhea: evaluate patients if diarrhea occurs. (5.9) -------------------------------- ADVERSE REACTIONS----------------------------­ The most common adverse reactions (incidence >5%) are diarrhea, constipation, nausea, headache, and insomnia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------- DRUG INTERACTIONS ----------------------------­ • Piperacillin and tazobactam administration can significantly reduce tobramycin concentrations in hemodialysis patients. Monitor tobramycin concentrations in these patients. (7.1) • Probenecid prolongs the half-lives of piperacillin and tazobactam and should not be co-administered with Piperacillin and tazobactam unless the benefit outweighs the risk. (7.2) • Co-administration of Piperacillin and tazobactam with vancomycin may increase the incidence of acute kidney injury. Monitor kidney function in patients receiving Piperacillin and tazobactam and vancomycin. (7.3) • Monitor coagulation parameters in patients receiving Piperacillin and tazobactam and heparin or oral anticoagulants. (7.4) • Piperacillin and tazobactam may prolong the neuromuscular blockade of vecuronium and other non-depolarizing neuromuscular blockers. Monitor for adverse reactions related to neuromuscular blockade. (7.5) ---------------------------USE IN SPECIFIC POPULATIONS -------------------­ Dosage in patients with renal impairment (creatinine clearance ≤40 mL/min) should be reduced based on the degree of renal impairment. (2.3, 8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2024 1 Reference ID: 5488042 FULL PRESCRIBING INFORMATION: CONTENTS* 6.2 Postmarketing Experience 6.3 Additional Experience with Piperacillin 1 INDICATIONS AND USAGE 7 DRUG INTERACTIONS 1.1 Intra-abdominal Infections 7.1 Aminoglycosides 1.2 Nosocomial Pneumonia 7.2 Probenecid 1.3 Skin and Skin Structure Infections 7.3 Vancomycin 1.4 Female Pelvic Infections 7.4 Anticoagulants 1.5 Community-acquired Pneumonia 7.5 Vecuronium 1.6 Usage 7.6 Methotrexate 2 DOSAGE AND ADMINISTRATION 7.7 Effects on Laboratory Tests 2.1 Dosage in Adult Patients With Indications Other Than Nosocomial 8 USE IN SPECIFIC POPULATIONS Pneumonia 8.1 Pregnancy 2.2 Dosage in Adult Patients With Nosocomial Pneumonia 8.2 Lactation 2.3 Dosage in Adult Patients With Renal Impairment 8.4 Pediatric Use 2.4 Dosage in Pediatric Patients With Appendicitis/Peritonitis or 8.5 Geriatric Use Nosocomial Pneumonia 8.6 Renal Impairment 2.5 Reconstitution and Dilution of Piperacillin and tazobactam for 8.7 Hepatic Impairment injection 8.8 Patients with Cystic Fibrosis 2.6 Compatibility With Aminoglycosides 10 OVERDOSAGE 3 DOSAGE FORMS AND STRENGTHS 11 DESCRIPTION 4 CONTRAINDICATIONS 12 CLINICAL PHARMACOLOGY 5 WARNINGS AND PRECAUTIONS 12.1 Mechanism of Action 5.1 Hypersensitivity Adverse Reactions 12.2 Pharmacodynamics 5.2 Severe Cutaneous Adverse Reactions 12.3 Pharmacokinetics 5.3 Hemophagocytic Lymphohistiocytosis 12.4 Microbiology 5.4 Rhabdomyolysis 13 NONCLINICAL TOXICOLOGY 5.5 Hematologic Adverse Reactions 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.6 Central Nervous System Adverse Reactions 15 REFERENCES 5.7 Nephrotoxicity in Critically Ill Patients 16 HOW SUPPLIED/STORAGE AND HANDLING 5.8 Electrolyte Effects 17 PATIENT COUNSELING INFORMATION 5.9 Clostridioides difficile-Associated Diarrhea 5.10 Development of Drug-Resistant Bacteria *Sections or subsections omitted from the full prescribing information are not 6 ADVERSE REACTIONS listed. 6.1 Clinical Trials Experience 2 Reference ID: 5488042 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Intra-abdominal Infections Piperacillin and tazobactam is indicated in adults and pediatric patients (2 months of age and older) for the treatment of appendicitis (complicated by rupture or abscess) and peritonitis caused by beta-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron, or B. vulgatus. 1.2 Nosocomial Pneumonia Piperacillin and tazobactam is indicated in adults and pediatric patients (2 months of age and older) for the treatment of nosocomial pneumonia (moderate to severe) caused by beta-lactamase producing isolates of Staphylococcus aureus and by piperacillin and tazobactam-susceptible Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa (Nosocomial pneumonia caused by P. aeruginosa should be treated in combination with an aminoglycoside) [see Dosage and Administration (2)]. 1.3 Skin and Skin Structure Infections Piperacillin and tazobactam is indicated in adults for the treatment of uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by beta-lactamase producing isolates of Staphylococcus aureus. 1.4 Female Pelvic Infections Piperacillin and tazobactam is indicated in adults for the treatment of postpartum endometritis or pelvic inflammatory disease caused by beta-lactamase producing isolates of Escherichia coli. 1.5 Community-acquired Pneumonia Piperacillin and tazobactam is indicated in adults for the treatment of community-acquired pneumonia (moderate severity only) caused by beta-lactamase producing isolates of Haemophilus influenzae. 1.6 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Piperacillin and tazobactam and other antibacterial drugs, Piperacillin and tazobactam should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 3 Reference ID: 5488042 2 DOSAGE AND ADMINISTRATION 2.1 Dosage in Adult Patients With Indications Other Than Nosocomial Pneumonia The usual total daily dosage of Piperacillin and tazobactam for adult patients with indications other than nosocomial pneumonia is 3.375 g every six hours [totaling 13.5 g (12.0 g piperacillin and 1.5 g tazobactam)], to be administered by intravenous infusion over 30 minutes. The usual duration of Piperacillin and tazobactam treatment is from 7 to 10 days. 2.2 Dosage in Adult Patients With Nosocomial Pneumonia Initial presumptive treatment of adult patients with nosocomial pneumonia should start with Piperacillin and tazobactam at a dosage of 4.5 g every six hours plus an aminoglycoside, [totaling 18.0 g (16.0 g piperacillin and 2.0 g tazobactam)], administered by intravenous infusion over 30 minutes. The recommended duration of Piperacillin and tazobactam treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated. 2.3 Dosage in Adult Patients With Renal Impairment In adult patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of Piperacillin and tazobactam should be reduced based on the degree of renal impairment. The recommended daily dosage of Piperacillin and tazobactam for patients with renal impairment administered by intravenous infusion over 30 minutes is described in Table 1. Table 1: Recommended Dosage of Piperacillin and tazobactam in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin and tazobactam)# Creatinine clearance, mL/min All Indications (except nosocomial pneumonia) Nosocomial Pneumonia Greater than 40 mL/min 3.375 every 6 hours 4.5 every 6 hours 20 to 40 mL/min* 2.25 every 6 hours 3.375 every 6 hours Less than 20 mL/min* 2.25 every 8 hours 2.25 every 6 hours Hemodialysis** 2.25 every 12 hours 2.25 every 8 hours CAPD 2.25 every 12 hours 2.25 every 8 hours # Administer Piperacillin and tazobactam by intravenous infusion over 30 minutes. * Creatinine clearance for patients not receiving hemodialysis ** 0.75 g (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days 4 Reference ID: 5488042 For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia. Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g Piperacillin and tazobactam (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of Piperacillin and tazobactam is necessary for CAPD patients. 2.4 Dosage in Pediatric Patients With Appendicitis/Peritonitis or Nosocomial Pneumonia The recommended dosage for pediatric patients with appendicitis and/or peritonitis or nosocomial pneumonia aged 2 months of age and older, weighing up to 40 kg, and with normal renal function, is described in Table 2 [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. Table 2: Recommended Dosage of Piperacillin and tazobactam in Pediatric Patients 2 Months of Age and Older, Weighing Up to 40 kg, and With Normal Renal Function# Age Appendicitis and/or Peritonitis Nosocomial Pneumonia 2 months to 9 months 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 8 (eight) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 6 (six) hours Older than 9 months of age 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 8 (eight) hours 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 6 (six) hours # Administer Piperacillin and tazobactam by intravenous infusion over 30 minutes Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose [see Dosage and Administration (2.1, 2.2)]. Dosage of Piperacillin and tazobactam in pediatric patients with renal impairment has not been determined. 5 Reference ID: 5488042 2.5 Reconstitution and Dilution of Piperacillin and tazobactam for Injection Piperacillin and tazobactam for injection is not currently being marketed. Reconstitution of Piperacillin and tazobactam for Injection for Adult Patients and Pediatric Patients Weighing Over 40 kg Pharmacy Bulk Vials Reconstituted pharmacy bulk vial solution must be transferred and further diluted for intravenous infusion. The pharmacy bulk vial is for use in a hospital pharmacy admixture service only under a laminar flow hood. After reconstitution, entry into the vial must be made with a sterile transfer set or other sterile dispensing device, and contents should be dispensed as aliquots into intravenous solution using aseptic technique. Use entire contents of pharmacy bulk vial promptly. Discard unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Reconstitute the pharmacy bulk vial with exactly 152 mL of a compatible reconstitution diluent, listed below, to a concentration of 200 mg/mL of piperacillin and 25 mg/mL of tazobactam. Shake well until dissolved. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to and during administration whenever solution and container permit. Single-Dose Vials Reconstitute Piperacillin and tazobactam single-dose vials with a compatible reconstitution diluent from the list provided below. 2.25 g, 3.375 g, and 4.5 g Piperacillin and tazobactam should be reconstituted with 10 mL, 15 mL, and 20 mL, respectively. Swirl until dissolved. After reconstitution, the single-dose vials will have a concentration of 202.5 mg/mL (180 mg/mL of piperacillin and 22.5 mg/mL of tazobactam). Compatible Reconstitution Diluents for Pharmacy Bulk Vials and Single-Dose Vials 0.9% sodium chloride for injection Sterile water for injection Dextrose 5% Bacteriostatic saline/parabens Bacteriostatic water/parabens Bacteriostatic saline/benzyl alcohol Bacteriostatic water/benzyl alcohol 6 Reference ID: 5488042 Dilution of the Reconstituted Piperacillin and tazobactam Solution for Adult Patients and Pediatric Patients Weighing Over 40 kg Reconstituted Piperacillin and tazobactam solutions for both pharmacy bulk vials and single- dose vials should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below. Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution. Compatible Intravenous Solutions for Pharmacy Bulk Vials and Single-Dose Vials 0.9% sodium chloride for injection Sterile water for injection (Maximum recommended volume per dose of sterile water for injection is 50 mL) Dextran 6% in saline Dextrose 5% Lactated Ringer's Solution (compatible only with reformulated Piperacillin and tazobactam containing EDTA and is compatible for co-administration via a Y-site) Piperacillin and tazobactam should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established. Piperacillin and tazobactam is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH. Piperacillin and tazobactam should not be added to blood products or albumin hydrolysates. Parenteral drug products should be inspected visually for particulate matter or discoloration prior to administration, whenever solution and container permit. Dilution of the Reconstituted Piperacillin and tazobactam Solution for Pediatric Patients Weighing up to 40 kg The volume of reconstituted solution required to deliver the dose of Piperacillin and tazobactam is dependent on the weight of the child [see Dosage and Administration (2.4)]. Reconstituted Piperacillin and tazobactam solutions for both bulk and single-dose vials should be further diluted in a compatible intravenous solution listed above. 1. Calculate patient dose as described in Table 2 above [see Dosage and Administration (2.4)]. 2. Reconstitute vial with a compatible reconstitution diluent, as listed above under the subheading “Compatible Reconstitution Diluents for Pharmacy Bulk Vials and Single-Dose Vials,” using the appropriate volume of diluent, as listed in tables 3 and 4 below. Following the addition of the diluent, swirl the single-dose vial or shake the pharmacy bulk vial until the powder is completely dissolved. 7 Reference ID: 5488042 Table 3: Reconstitution of Single-Dose Vials and Resulting Concentration Strength per Single-Dose Vial Volume of Diluent to be Added to the Vial Concentration of the Reconstituted Product 2.25 g (2 g piperacillin and 0.25 g tazobactam) 10 mL 202.5 mg/mL (180 mg/mL piperacillin and 22.5 mg/mL tazobactam) 3.375 g (3 g piperacillin and 0.375 g tazobactam) 15 mL 4.5 g (4 g piperacillin and 0.5 g tazobactam) 20 mL Table 4: Reconstitution of Pharmacy Bulk Vial and Resulting Concentration Strength per Pharmacy Bulk Vial Volume of Diluent to be Added to the Vial Concentration of the Reconstituted Product 40.5 g (36 g piperacillin and 4.5 g tazobactam) 152 mL 225 mg/mL (200 mg/mL piperacillin and 25 mg/mL tazobactam) 3. Calculate the required volume (mL) of reconstituted Piperacillin and tazobactam solution based on the required dose. 4. Aseptically withdraw the required volume of reconstituted Piperacillin and tazobactam solution from either the pharmacy bulk vial or single-dose vial. It should be further diluted to a final piperacillin concentration of between 20 mg/mL to 80 mg/mL (tazobactam between 2.5 mg/mL to 10 mg/mL) in a compatible intravenous solution (as listed above) in an appropriately sized syringe or IV bag. 5. Administer the diluted Piperacillin and tazobactam solution by infusion over a period of at least 30 minutes (a programmable syringe or infusion pump is recommended). During the infusion it is desirable to discontinue the primary infusion solution. Stability of Piperacillin and Tazobactam for Injection Following Reconstitution and Dilution Piperacillin and tazobactam for injection reconstituted from pharmacy bulk vials and single-dose vials is stable in glass and plastic containers (plastic syringes, IV bags and tubing) when used with compatible diluents. The pharmacy bulk vials and single-dose vials should NOT be frozen after reconstitution. Single-dose or pharmacy bulk vials should be used immediately after reconstitution. Discard any unused portion after storage for 24 hours at room temperature (20°C to 25°C [68°F to 77°F]), or after storage for 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Stability studies in the IV bags have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature. Piperacillin and tazobactam for injection contains no preservatives. Appropriate consideration of aseptic technique should be used. 8 Reference ID: 5488042 Piperacillin and tazobactam for injection reconstituted from bulk and single-dose vials can be used in ambulatory intravenous infusion pumps. Stability of Piperacillin and tazobactam for injection in an ambulatory intravenous infusion pump has been demonstrated for a period of 12 hours at room temperature. Each dose was reconstituted and diluted to a volume of 37.5 mL or 25 mL. One-day supply of dosing solution were aseptically transferred into the medication reservoir (IV bags or cartridge). The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer's instructions. Stability of Piperacillin and tazobactam for injection is not affected when administered using an ambulatory intravenous infusion pump. 2.6 Compatibility With Aminoglycosides Due to the in vitro inactivation of aminoglycosides by piperacillin, Piperacillin and tazobactam and aminoglycosides are recommended for separate administration. Piperacillin and tazobactam and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated [see Drug Interactions (7.1)]. In circumstances where co-administration via Y-site is necessary, Piperacillin and tazobactam formulations containing EDTA are compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions: Table 5: Compatibility with Aminoglycosides Aminoglyco side Piperacillin and tazobactam Dose (grams) Piperacillin and tazobactam Diluent Volume a (mL) Aminoglycoside Concentration Range b (mg/mL) Acceptable Diluents Amikacin 2.25 3.375 4.5 50 100 150 1.75 - 7.5 0.9% sodium chloride or 5% dextrose Gentamicin 2.25 3.375 4.5 50 100 150 0.7 - 3.32 0.9% sodium chloride or 5% dextrose a Diluent volumes apply only to single vials and bulk pharmacy containers b The concentration ranges in Table 5 are based on administration of the aminoglycoside in divided doses (10­ 15 mg/kg/day in two daily doses for amikacin and 3-5 mg/kg/day in three daily doses for gentamicin). Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y- site with Piperacillin and tazobactam containing EDTA has not been evaluated. See package insert for each aminoglycoside for complete Dosage and Administration instructions. Only the concentration and diluents for amikacin or gentamicin with the dosages of Piperacillin and tazobactam listed above have been established as compatible for co-administration via Y-site infusion. Simultaneous co-administration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by Piperacillin and tazobactam. 9 Reference ID: 5488042 Piperacillin and tazobactam is not compatible with tobramycin for simultaneous co- administration via Y-site infusion. Compatibility of Piperacillin and tazobactam with other aminoglycosides has not been established. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 3 DOSAGE FORMS AND STRENGTHS Piperacillin and tazobactam for injection is a white to off-white powder in vials [all strengths of Piperacillin and tazobactam for injection are not currently being marketed]: • 2.25 g single-dose vial (piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 0.25 g of tazobactam). • 3.375 g single-dose vial (piperacillin sodium equivalent to 3 grams of piperacillin and tazobactam sodium equivalent to 0.375 g of tazobactam). • 4.5 g single-dose vial (piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 0.5 g of tazobactam). • 40.5 g pharmacy bulk vial (piperacillin sodium equivalent to 36 grams of piperacillin and tazobactam sodium equivalent to 4.5 grams tazobactam). 4 CONTRAINDICATIONS Piperacillin and tazobactam is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Adverse Reactions Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with Piperacillin and tazobactam. These reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity or a history of sensitivity to multiple allergens. Before initiating therapy with Piperacillin and tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, Piperacillin and tazobactam should be discontinued and appropriate therapy instituted. 5.2 Severe Cutaneous Adverse Reactions Piperacillin and tazobactam may cause severe cutaneous adverse reactions, such as Stevens- Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic 10 Reference ID: 5488042 symptoms, and acute generalized exanthematous pustulosis. If patients develop a skin rash they should be monitored closely and Piperacillin and tazobactam discontinued if lesions progress. 5.3 Hemophagocytic Lymphohistiocytosis Cases of hemophagocytic lymphohistiocytosis (HLH) have been reported in pediatric and adult patients treated with Piperacillin and tazobactam. Signs and symptoms of HLH may include fever, rash, lymphadenopathy, hepatosplenomegaly and cytopenia. If HLH is suspected, discontinue Piperacillin and tazobactam immediately and institute appropriate management. 5.4 Rhabdomyolysis Rhabdomyolysis has been reported with the use of piperacillin and tazobactam [see Adverse reactions (6.2)]. If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine, or elevated creatine phosphokinase are observed, discontinue Piperacillin and tazobactam for injection and initiate appropriate therapy. 5.5 Hematologic Adverse Reactions Bleeding manifestations have occurred in some patients receiving beta-lactam drugs, including piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, Piperacillin and tazobactam should be discontinued and appropriate therapy instituted. The leukopenia/neutropenia associated with Piperacillin and tazobactam administration appears to be reversible and most frequently associated with prolonged administration. Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, i.e., ≥ 21 days [see Adverse Reactions (6.1)]. 5.6 Central Nervous System Adverse Reactions As with other penicillins, Piperacillin and tazobactam may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially patients with renal impairment may be at greater risk for central nervous system adverse reactions. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures [see Adverse Reactions (6.2)]. 5.7 Nephrotoxicity in Critically Ill Patients The use of Piperacillin and tazobactam was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta­ lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients [see Adverse Reactions (6.1)]. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or 11 Reference ID: 5488042 unavailable, monitor renal function during treatment with Piperacillin and tazobactam [see Dosage and Administration (2.3)]. Combined use of piperacillin and tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury [see Drug Interactions (7.3)]. 5.8 Electrolyte Effects Piperacillin and tazobactam contains a total of 2.84 mEq (65 mg) of Na+ (sodium) per gram of piperacillin in the combination product. This should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics. 5.9 Clostridioides difficile-Associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Piperacillin and tazobactam, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.10 Development of Drug-Resistant Bacteria Prescribing Piperacillin and tazobactam in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypersensitivity Adverse Reactions [see Warnings and Precautions (5.1)] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] 12 Reference ID: 5488042 • Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.3)] • Rhabdomyolysis [see Warnings and Precautions (5.4)] • Hematologic Adverse Reactions [see Warnings and Precautions (5.5)] • Central Nervous System Adverse Reactions [see Warnings and Precautions (5.6)] • Nephrotoxicity in Critically Ill Patients [see Warnings and Precautions (5.7)] • Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adult Patients During the initial clinical investigations, 2621 patients worldwide were treated with Piperacillin and tazobactam in phase 3 trials. In the key North American monotherapy clinical trials (n=830 patients), 90% of the adverse events reported were mild to moderate in severity and transient in nature. However, in 3.2% of the patients treated worldwide, Piperacillin and tazobactam was discontinued because of adverse events primarily involving the skin (1.3%), including rash and pruritus; the gastrointestinal system (0.9%), including diarrhea, nausea, and vomiting; and allergic reactions (0.5%). Table 6: Adverse Reactions from Piperacillin and Tazobactam Monotherapy Clinical Trials System Organ Class Adverse Reaction Gastrointestinal disorders Diarrhea (11.3%) Constipation (7.7%) Nausea (6.9%) Vomiting (3.3%) Dyspepsia (3.3%) Abdominal pain (1.3%) General disorders and administration site conditions Fever (2.4%) Injection site reaction (≤1%) Rigors (≤1%) Immune system disorders Anaphylaxis (≤1%) 13 Reference ID: 5488042 Table 6: Adverse Reactions from Piperacillin and Tazobactam Monotherapy Clinical Trials System Organ Class Adverse Reaction Infections and infestations Candidiasis (1.6%) Pseudomembranous colitis (≤1%) Metabolism and nutrition disorders Hypoglycemia (≤1%) Musculoskeletal and connective tissue disorders Myalgia (≤1%) Arthralgia (≤1%) Nervous system disorders Headache (7.7%) Psychiatric disorders Insomnia (6.6%) Skin and subcutaneous tissue disorders Rash (4.2%, including maculopapular, bullous, and urticarial) Pruritus (3.1%) Purpura (≤1%) Vascular disorders Phlebitis (1.3%) Thrombophlebitis (≤1%) Hypotension (≤1%) Flushing (≤1%) Respiratory, thoracic and mediastinal disorders Epistaxis (≤1%) Nosocomial Pneumonia Trials Two trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with Piperacillin and tazobactam in a dosing regimen of 4.5 g every 6 hours in combination with an aminoglycoside and 215 patients were treated with imipenem/cilastatin (500 mg/500 mg every 6 hours) in combination with an aminoglycoside. In this trial, treatment- emergent adverse events were reported by 402 patients, 204 (91.9%) in the piperacillin and tazobactam group and 198 (92.1%) in the imipenem/cilastatin group. Twenty-five (11.0%) 14 Reference ID: 5488042 patients in the piperacillin and tazobactam group and 14 (6.5%) in the imipenem/cilastatin group (p > 0.05) discontinued treatment due to an adverse event. The second trial used a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside. Table 7: Adverse Reactions from Piperacillin and Tazobactam Plus Aminoglycoside Clinical Trialsa System Organ Class Adverse Reaction Blood and lymphatic system disorders Thrombocythemia (1.4%) Anemia (≤1%) Thrombocytopenia (≤1%) Eosinophilia (≤1%) Gastrointestinal disorders Diarrhea (20%) Constipation (8.4%) Nausea (5.8%) Vomiting (2.7%) Dyspepsia (1.9%) Abdominal pain (1.8%) Stomatitis (≤1%) General disorders and administration site conditions Fever (3.2%) Injection site reaction (≤1%) Infections and infestations Oral candidiasis (3.9%) Candidiasis (1.8%) Investigations BUN increased (1.8%) Blood creatinine increased (1.8%) Liver function test abnormal (1.4%) Alkaline phosphatase increased (≤1%) Aspartate aminotransferase increased (≤1%) Alanine aminotransferase increased (≤1%) Metabolism and nutrition disorders Hypoglycemia (≤1%) Hypokalemia (≤1%) Nervous system disorders 15 Reference ID: 5488042 Table 7: Adverse Reactions from Piperacillin and Tazobactam Plus Aminoglycoside Clinical Trialsa System Organ Class Adverse Reaction Headache (4.5%) Psychiatric disorders Insomnia (4.5%) Renal and urinary disorders Renal failure (≤1%) Skin and subcutaneous tissue disorders Rash (3.9%) Pruritus (3.2%) Vascular disorders Thrombophlebitis (1.3%) Hypotension (1.3%) a For adverse drug reactions that appeared in both studies the higher frequency is presented. Other Trials: Nephrotoxicity In a randomized, multicenter, controlled trial in 1200 adult critically ill patients, piperacillin and tazobactam was found to be a risk factor for renal failure (odds ratio 1.7, 95% CI 1.18 to 2.43), and associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs1 [see Warnings and Precautions (5.7)]. Adverse Laboratory Changes (Seen During Clinical Trials) Of the trials reported, including that of nosocomial lower respiratory tract infections in which a higher dose of Piperacillin and tazobactam was used in combination with an aminoglycoside, changes in laboratory parameters include: Hematologic—decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. These patients were withdrawn from therapy; some had accompanying systemic symptoms (e.g., fever, rigors, chills) Coagulation—positive direct Coombs' test, prolonged prothrombin time, prolonged partial thromboplastin time Hepatic—transient elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin Renal—increases in serum creatinine, blood urea nitrogen 16 Reference ID: 5488042 Additional laboratory events include abnormalities in electrolytes (i.e., increases and decreases in sodium, potassium, and calcium), hyperglycemia, decreases in total protein or albumin, blood glucose decreased, gamma-glutamyltransferase increased, hypokalemia, and bleeding time prolonged. Clinical Trials in Pediatric Patients Clinical studies of Piperacillin and tazobactam in pediatric patients suggest a similar safety profile to that seen in adults. In a prospective, randomized, comparative, open-label clinical trial of pediatric patients, 2 to 12 years of age, with intra-abdominal infections (including appendicitis and/or peritonitis), 273 patients were treated with Piperacillin and tazobactam 112.5 mg/kg given IV every 8 hours and 269 patients were treated with cefotaxime (50 mg/kg) plus metronidazole (7.5 mg/kg) every 8 hours. In this trial, treatment-emergent adverse events were reported by 146 patients, 73 (26.7%) in the Piperacillin and tazobactam group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the Piperacillin and tazobactam group and 5 patients (1.9%) in the cefotaxime/metronidazole group discontinued due to an adverse event. In a retrospective, cohort study, 140 pediatric patients 2 months to less than 18 years of age with nosocomial pneumonia were treated with Piperacillin and tazobactam and 267 patients were treated with comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or ciprofloxacin). The rates of serious adverse reactions were generally similar between the Piperacillin and tazobactam and comparator groups, including patients aged 2 months to 9 months treated with Piperacillin and tazobactam 90 mg/kg IV every 6 hours and patients older than 9 months and less than 18 years of age treated with Piperacillin and tazobactam 112.5 mg/kg IV every 6 hours. 6.2 Postmarketing Experience In addition to the adverse drug reactions identified in clinical trials in Table 6 and Table 7, the following adverse reactions have been identified during post-approval use of Piperacillin and tazobactam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary—hepatitis, jaundice Hematologic—hemolytic anemia, agranulocytosis, pancytopenia Immune—hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock), hemophagocytic lymphohistiocytosis (HLH), acute myocardial ischemia with or without myocardial infarction may occur as part of an allergic reaction Renal—interstitial nephritis 17 Reference ID: 5488042 Nervous system disorders—seizures Psychiatric disorders—delirium Respiratory—eosinophilic pneumonia Skin and Appendages—erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, (DRESS), acute generalized exanthematous pustulosis (AGEP), dermatitis exfoliative, and linear IgA bullous dermatosis Musculoskeletal—rhabdomyolysis Postmarketing experience with Piperacillin and tazobactam in pediatric patients suggests a similar safety profile to that seen in adults. 6.3 Additional Experience with Piperacillin The following adverse reaction has also been reported for piperacillin for injection: Skeletal—prolonged neuromuscular blockade [see Drug Interactions (7.5)]. 7 DRUG INTERACTIONS 7.1 Aminoglycosides Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides. In vivo inactivation: When aminoglycosides are administered in conjunction with piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored. Sequential administration of Piperacillin and tazobactam and tobramycin to patients with either normal renal function or mild to moderate renal impairment has been shown to modestly decrease serum concentrations of tobramycin but no dosage adjustment is considered necessary. In vitro inactivation: Due to the in vitro inactivation of aminoglycosides by piperacillin, Piperacillin and tazobactam and aminoglycosides are recommended for separate administration. Piperacillin and tazobactam and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated. Piperacillin and tazobactam, which contains EDTA, is compatible with amikacin and gentamicin for simultaneous Y-site infusion in 18 Reference ID: 5488042 certain diluents and at specific concentrations. Piperacillin and tazobactam is not compatible with tobramycin for simultaneous Y-site infusion [see Dosage and Administration (2.6)]. 7.2 Probenecid Probenecid administered concomitantly with Piperacillin and tazobactam prolongs the half-life of piperacillin by 21% and that of tazobactam by 71% because probenecid inhibits tubular renal secretion of both piperacillin and tazobactam. Probenecid should not be co-administered with Piperacillin and tazobactam unless the benefit outweighs the risk. 7.3 Vancomycin Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin and tazobactam and vancomycin as compared to vancomycin alone [see Warnings and Precautions (5.7)]. Monitor kidney function in patients concomitantly administered with piperacillin and tazobactam and vancomycin. No pharmacokinetic interactions have been noted between piperacillin and tazobactam and vancomycin. 7.4 Anticoagulants Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function [see Warnings and Precautions (5.5)]. 7.5 Vecuronium Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Piperacillin and tazobactam could produce the same phenomenon if given along with vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing neuromuscular blockers could be prolonged in the presence of piperacillin. Monitor for adverse reactions related to neuromuscular blockade (see package insert for vecuronium bromide). 7.6 Methotrexate Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion. The impact of tazobactam on the elimination of methotrexate has not been evaluated. If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored. 19 Reference ID: 5488042 7.7 Effects on Laboratory Tests There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin and tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with the Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving piperacillin and tazobactam should be interpreted cautiously and confirmed by other diagnostic methods. As with other penicillins, the administration of Piperacillin and tazobactam may result in a false- positive reaction for glucose in the urine using a copper-reduction method (CLINITEST®). It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Piperacillin and tazobactam cross the placenta in humans. However, there are insufficient data with piperacillin and/or tazobactam in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. No fetal structural abnormalities were observed in rats or mice when piperacillin and tazobactam was administered intravenously during organogenesis at doses 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m2). However, fetotoxicity in the presence of maternal toxicity was observed in developmental toxicity and peri/postnatal studies conducted in rats (intraperitoneal administration prior to mating and throughout gestation or from gestation day 17 through lactation day 21) at doses less than the maximum recommended human daily dose based on body-surface area (mg/m2) (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In embryo-fetal development studies in mice and rats, pregnant animals received intravenous doses of piperacillin and tazobactam up to 3000/750 mg/kg/day during the period of organogenesis. There was no evidence of teratogenicity up to the highest dose evaluated, which is 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, in mice and rats respectively, based on body-surface area (mg/m2). Fetal body weights were reduced in rats at maternally toxic doses at or above 500/62.5 mg/kg/day, minimally representing 0.4 times the human dose of both piperacillin and tazobactam based on body-surface area (mg/m2). 20 Reference ID: 5488042 A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin and tazobactam prior to mating and through the end of gestation, reported a decrease in litter size in the presence of maternal toxicity at 640 mg/kg/day tazobactam (4 times the human dose of tazobactam based on body-surface area), and decreased litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity at ≥640/160 mg/kg/day piperacillin and tazobactam (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area). Peri/postnatal development in rats was impaired with reduced pup weights, increased stillbirths, and increased pup mortality concurrent with maternal toxicity after intraperitoneal administration of tazobactam alone at doses ≥320 mg/kg/day (2 times the human dose based on body surface area) or of the combination piperacillin and tazobactam at doses ≥640/160 mg/kg/day (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area) from gestation day 17 through lactation day 21. 8.2 Lactation Risk Summary Piperacillin is excreted in human milk; tazobactam concentrations in human milk have not been studied. No information is available on the effects of piperacillin and tazobactam on the breast­ fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Piperacillin and tazobactam and any potential adverse effects on the breastfed child from Piperacillin and tazobactam or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Piperacillin and tazobactam for intra-abdominal infections, and nosocomial pneumonia have been established in pediatric patients 2 months of age and older. Use of Piperacillin and tazobactam in pediatric patients 2 months of age and older with intra- abdominal infections including appendicitis and/or peritonitis is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and in pediatric patients. This includes a prospective, randomized, comparative, open-label clinical trial with 542 pediatric patients 2 to 12 years of age with intra-abdominal infections (including appendicitis and/or peritonitis), in which 273 pediatric patients received piperacillin and tazobactam [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Use of Piperacillin and tazobactam in pediatric patients 2 months of age and older with nosocomial pneumonia is supported by evidence from well-controlled studies in adults with nosocomial pneumonia, a simulation study performed with a population pharmacokinetic model, and a retrospective, cohort study of pediatric patients with nosocomial pneumonia in which 140 pediatric patients were treated with Piperacillin and tazobactam and 267 patients treated with 21 Reference ID: 5488042 comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or ciprofloxacin) [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. The safety and effectiveness of Piperacillin and tazobactam have not been established in pediatric patients less than 2 months of age [see Clinical Pharmacology (12) and Dosage and Administration (2)]. Dosage of Piperacillin and tazobactam in pediatric patients with renal impairment has not been determined. 8.5 Geriatric Use Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal impairment [see Dosage and Administration (2)]. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Piperacillin and tazobactam contains 65 mg (2.84 mEq) of sodium per gram of piperacillin in the combination product. At the usual recommended doses, patients would receive between 780 and 1040 mg/day (34.1 and 45.5 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Renal Impairment In patients with creatinine clearance ≤ 40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose of Piperacillin and tazobactam should be reduced to the degree of renal function impairment [see Dosage and Administration (2)]. 8.7 Hepatic Impairment Dosage adjustment of Piperacillin and tazobactam is not warranted in patients with hepatic cirrhosis [see Clinical Pharmacology (12.3)]. 8.8 Patients with Cystic Fibrosis As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients. 22 Reference ID: 5488042 10 OVERDOSAGE There have been postmarketing reports of overdose with piperacillin and tazobactam. The majority of those events experienced, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or seizures if higher than recommended doses are given intravenously (particularly in the presence of renal failure) [see Warnings and Precautions (5.6)]. Treatment should be supportive and symptomatic according to the patient's clinical presentation. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of piperacillin and tazobactam, the percentage of the piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively [see Clinical Pharmacology (12)]. 11 DESCRIPTION Piperacillin and tazobactam for injection is an injectable antibacterial combination product consisting of the semisynthetic antibacterial piperacillin sodium and the beta-lactamase inhibitor tazobactam sodium for intravenous administration. Piperacillin sodium is derived from D(-)-α-aminobenzyl-penicillin. The chemical name of piperacillin sodium is sodium (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazine­ carboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2­ carboxylate. The chemical formula is C23H26N5NaO7S and the molecular weight is 539.5. The chemical structure of piperacillin sodium is: Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Its chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1­ azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide. The chemical formula is C10H11N4NaO5S and the molecular weight is 322.3. The chemical structure of tazobactam sodium is: Piperacillin and tazobactam contains a total of 2.84 mEq (65 mg) of sodium (Na+) per gram of piperacillin in the combination product. 23 Reference ID: 5488042 Piperacillin and tazobactam for injection, is a white to off-white sterile, cryodesiccated powder consisting of piperacillin and tazobactam as their sodium salts packaged in glass vials [all strengths of Piperacillin and tazobactam for injection are not currently being marketed]. The formulation contains edetate disodium dihydrate (EDTA) and sodium citrate. • Each Piperacillin and tazobactam 2.25 g single-dose vial contains an amount of drug sufficient for withdrawal of piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 0.25 g of tazobactam. The product also contains 0.5 mg of EDTA per vial. • Each Piperacillin and tazobactam 3.375 g single-dose vial contains an amount of drug sufficient for withdrawal of piperacillin sodium equivalent to 3 grams of piperacillin and tazobactam sodium equivalent to 0.375 g of tazobactam. The product also contains 0.75 mg of EDTA per vial. • Each Piperacillin and tazobactam 4.5 g single-dose vial contains an amount of drug sufficient for withdrawal of piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 0.5 g of tazobactam. The product also contains 1 mg of EDTA per vial. • Each Piperacillin and tazobactam 40.5 g pharmacy bulk vial contains piperacillin sodium equivalent to 36 grams of piperacillin and tazobactam sodium equivalent to 4.5 g of tazobactam sufficient for delivery of multiple doses. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Piperacillin and tazobactam is an antibacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics The pharmacodynamic parameter for piperacillin and tazobactam that is most predictive of clinical and microbiological efficacy is time above MIC. 12.3 Pharmacokinetics The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of piperacillin and tazobactam after multiple intravenous doses are summarized in Table 8. 24 Reference ID: 5488042 Table 8: Mean (CV%) Piperacillin and Tazobactam PK Parameters Piperacillin Piperacillin and Tazobactam Cmax AUCb CL V T1/2 CLR Dosea (mcg/mL) (mcg•h/mL) (mL/min) (L) (h) (mL/min) 2.25 g 134 131 [14] 257 17.4 0.79 -­ 3.375 g 242 242 [10] 207 15.1 0.84 140 4.5 g 298 322 [16] 210 15.4 0.84 -- Tazobactam Piperacillin and Tazobactam Cmax AUCb CL V T1/2 CLR Dosea (mcg/mL) (mcg•h/mL) (mL/min) (L) (h) (mL/min) 2.25 g 15 16.0 [21] 258 17.0 0.77 -­ 3.375 g 24 25.0 [8] 251 14.8 0.68 166 4.5 g 34 39.8 [15] 206 14.7 0.82 -­ a Piperacillin and tazobactam were given in combination, infused over 30 minutes. b Numbers in []parentheses are coefficients of variation [CV%]. Cmax : maximum observed concentration, AUC: Area under the curve, CL=clearance, CLR= Renal clearance V=volume of distribution, T1/2 = elimination half-life Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of Piperacillin and tazobactam. Piperacillin plasma concentrations, following a 30-minute infusion of Piperacillin and tazobactam, were similar to those attained when equivalent doses of piperacillin were administered alone. Steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose due to the short half-lives of piperacillin and tazobactam. Distribution Both piperacillin and tazobactam are approximately 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible. Piperacillin and tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those in plasma. Distribution of piperacillin and tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins (see Table 9). 25 Reference ID: 5488042 Table 9: Piperacillin and Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min IV Infusion of Piperacillin and tazobactam Tissue or Fluid Na Sampling periodb (h) Mean PIP Concentration Range (mg/L) Tissue:Plasma Range Tazo Concentration Range (mg/L) Tazo Tissue:Plasma Range Skin 35 0.5 – 4.5 34.8 – 94.2 0.60 – 1.1 4.0 – 7.7 0.49 – 0.93 Fatty Tissue 37 0.5 – 4.5 4.0 – 10.1 0.097 – 0.115 0.7 – 1.5 0.10 – 0.13 Muscle 36 0.5 – 4.5 9.4 – 23.3 0.29 – 0.18 1.4 – 2.7 0.18 – 0.30 Proximal Intestinal Mucosa 7 1.5 – 2.5 31.4 0.55 10.3 1.15 Distal Intestinal Mucosa 7 1.5 – 2.5 31.2 0.59 14.5 2.1 Appendix 22 0.5 – 2.5 26.5 – 64.1 0.43 – 0.53 9.1 – 18.6 0.80 – 1.35 a Each subject provided a single sample. b Time from the start of the infusion Metabolism Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities. Excretion Following single or multiple Piperacillin and tazobactam doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion. Both piperacillin and tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also secreted into the bile. Specific Populations Renal Impairment After the administration of single doses of piperacillin and tazobactam to subjects with renal impairment, the half-life of piperacillin and of tazobactam increases with decreasing creatinine 26 Reference ID: 5488042 clearance. At creatinine clearance below 20 mL/min, the increase in half-life is twofold for piperacillin and fourfold for tazobactam compared to subjects with normal renal function. Dosage adjustments for Piperacillin and tazobactam are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of Piperacillin and tazobactam. See Dosage and Administration (2) for specific recommendations for the treatment of patients with renal-impairment. Hemodialysis removes 30% to 40% of a piperacillin and tazobactam dose with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the piperacillin and tazobactam doses, respectively, with up to 16% of the tazobactam dose removed as the tazobactam metabolite. For dosage recommendations for patients undergoing hemodialysis [see Dosage and Administration (2)]. Hepatic Impairment The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, this difference does not warrant dosage adjustment of Piperacillin and tazobactam due to hepatic cirrhosis. Pediatrics Piperacillin and tazobactam pharmacokinetics were studied in pediatric patients 2 months of age and older. The clearance of both compounds is slower in the younger patients compared to older children and adults. In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) mL/min/kg. The piperacillin clearance estimate is 80% of this value for pediatric patients 2 - 9 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older children; however, it is not adequately characterized for dosing recommendations. The population mean (SE) for piperacillin volume of distribution is 0.243 (0.011) L/kg and is independent of age. Geriatrics The impact of age on the pharmacokinetics of piperacillin and tazobactam was evaluated in healthy male subjects, aged 18 - 35 years (n=6) and aged 65 to 80 years (n=12). Mean half-life for piperacillin and tazobactam was 32% and 55% higher, respectively, in the elderly compared to the younger subjects. This difference may be due to age-related changes in creatinine clearance. 27 Reference ID: 5488042 Race The effect of race on piperacillin and tazobactam was evaluated in healthy male volunteers. No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4/0.5 g doses. Drug Interactions The potential for pharmacokinetic drug interactions between Piperacillin and tazobactam and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated [see Drug Interactions (7)]. 12.4 Microbiology Mechanism of Action Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is, however, a beta-lactamase inhibitor of the Molecular class A enzymes, including Richmond-Sykes class III (Bush class 2b & 2b') penicillinases and cephalosporinases. It varies in its ability to inhibit class II and IV (2a & 4) penicillinases. Tazobactam does not induce chromosomally-mediated beta-lactamases at tazobactam concentrations achieved with the recommended dosage regimen. Antimicrobial Activity Piperacillin and tazobactam has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]: Aerobic bacteria Gram-positive bacteria Staphylococcus aureus (methicillin susceptible isolates only) Gram-negative bacteria Acinetobacter baumannii Escherichia coli Haemophilus influenzae (excluding beta-lactamase negative, ampicillin-resistant isolates) Klebsiella pneumoniae Pseudomonas aeruginosa (given in combination with an aminoglycoside to which the isolate is susceptible) Anaerobic bacteria Bacteroides fragilis group (B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus) The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) 28 Reference ID: 5488042 less than or equal to the susceptible breakpoint for piperacillin and tazobactam against isolates of similar genus or organism group. However, the efficacy of Piperacillin and tazobactam in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Aerobic bacteria Gram-positive bacteria Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only) Staphylococcus epidermidis (methicillin susceptible isolates only) Streptococcus agalactiae† Streptococcus pneumoniae† (penicillin-susceptible isolates only) Streptococcus pyogenes† Viridans group streptococci† Gram-negative bacteria Citrobacter koseri Moraxella catarrhalis Morganella morganii Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Serratia marcescens Providencia stuartii Providencia rettgeri Salmonella enterica Anaerobic bacteria Clostridium perfringens Bacteroides distasonis Prevotella melaninogenica † These are not beta-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone. Susceptibility Testing For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in animals have not been conducted with piperacillin and tazobactam, piperacillin, or tazobactam. 29 Reference ID: 5488042 Mutagenesis Piperacillin and tazobactam was negative in microbial mutagenicity assays, the unscheduled DNA synthesis (UDS) test, a mammalian point mutation (Chinese hamster ovary cell HPRT) assay, and a mammalian cell (BALB/c-3T3) transformation assay. In vivo, piperacillin and tazobactam did not induce chromosomal aberrations in rats. Fertility Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility when piperacillin and tazobactam is administered intravenously up to a dose of 1280/320 mg/kg piperacillin and tazobactam, which is similar to the maximum recommended human daily dose based on body-surface area (mg/m2). 15 REFERENCES 1. Jensen J-US, Hein L, Lundgren B, et al. BMJ Open 2012; 2:e000635. doi:10.1136. 16 HOW SUPPLIED/STORAGE AND HANDLING Piperacillin and tazobactam for injection was supplied as single-dose vials and pharmacy bulk vials in the following sizes; however all strengths of Piperacillin and tazobactam for injection are not currently being marketed: • Each Piperacillin and tazobactam 2.25 g vial provides piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 0.25 g of tazobactam. Each vial contains 5.68 mEq (130 mg) of sodium. Supplied 10 per box—NDC 0206-0022-10 • Each Piperacillin and tazobactam 3.375 g vial provides piperacillin sodium equivalent to 3 grams of piperacillin and tazobactam sodium equivalent to 0.375 g of tazobactam. Each vial contains 8.52 mEq (195 mg) of sodium. Supplied 10 per box—NDC 0206-0577-10 • Each Piperacillin and tazobactam 4.5 g vial provides piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 0.5 g of tazobactam. Each vial contains 11.36 mEq (260 mg) of sodium. Supplied 10 per box—NDC 0206-1714-10 • Each Piperacillin and tazobactam 40.5 g pharmacy bulk vial provides piperacillin sodium equivalent to 36 grams of piperacillin and tazobactam sodium equivalent to 4.5 grams of tazobactam. Each pharmacy bulk vial contains 100.4 mEq (2,304 mg) of sodium. NDC 0206­ 0112-01 Store Piperacillin and tazobactam for injection vials at controlled room temperature (20°C to 25°C [68°F to 77°F]) prior to reconstitution. 17 PATIENT COUNSELING INFORMATION Serious Hypersensitivity Reactions Advise patients, their families, or caregivers that serious hypersensitivity reactions, including serious allergic cutaneous reactions, could occur with use of Piperacillin and tazobactam that 30 Reference ID: 5488042 require immediate treatment. Ask them about any previous hypersensitivity reactions to Piperacillin and tazobactam, other beta-lactams (including cephalosporins), or other allergens [see Warnings and Precautions (5.2)]. Hemophagocytic Lymphohistiocytosis Prior to initiation of treatment with Piperacillin and tazobactam, inform patients that excessive immune activation may occur with Piperacillin and tazobactam and that they should report signs or symptoms such as fever, rash, or lymphadenopathy to a healthcare provider immediately [see Warnings and Precautions (5.3)]. Diarrhea Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including Piperacillin and tazobactam, which usually ends when the drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.9)]. Antibacterial Resistance Patients should be counseled that antibacterial drugs including Piperacillin and tazobactam should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Piperacillin and tazobactam is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Piperacillin and tazobactam or other antibacterial drugs in the future. Pregnancy and Lactation Patients should be counseled that Piperacillin and tazobactam can cross the placenta in humans and is excreted in human milk [see Use in Specific Populations (8.1, 8.2)]. 31 Reference ID: 5488042 ii] - t ' ~Pfizer Distributed by Wyeth Pharmaceuticals LLC A subsidiary of Pfizer Inc. Philadelphia, PA 19101 This product's labeling may have been updated. For the most recent prescribing information, please visit http://www.pfizer.com. CLINITEST® is a registered trademark of Siemens Healthcare Diagnostics Inc. LAB-0690-20.2 32 Reference ID: 5488042
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2025-02-12T15:47:28.624619
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use MERREM IV safely and effectively. See full prescribing information for MERREM IV MERREM® IV (meropenem for injection), for intravenous use Initial U.S. Approval: 1996 -------------------------- RECENT MAJOR CHANGES --------------------------­ Warnings and Precautions, Rhabdomyolysis (5.3) 12/2024 --------------------------- INDICATIONS AND USAGE -------------------------­ MERREM IV is a penem antibacterial indicated for the treatment of: • Complicated skin and skin structure infections (adult patients and pediatric patients 3 months of age and older only). (1.1) • Complicated intra-abdominal infections (adult and pediatric patients). (1.2) • Bacterial meningitis (pediatric patients 3 months of age and older only). (1.3) To reduce the development of drug-resistant bacteria and maintain the effectiveness of MERREM IV and other antibacterial drugs, MERREM IV should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. ---------------------- DOSAGE AND ADMINISTRATION ---------------------­ • 500 mg every 8 hours by intravenous infusion over 15 to 30 minutes for complicated skin and skin structure infections (cSSSI) for adult patients. When treating infections caused by Pseudomonas aeruginosa, a dose of 1 gram every 8 hours is recommended. (2.1) • 1 gram every 8 hours by intravenous infusion over 15 minutes to 30 minutes for intra-abdominal infections for adult patients. (2.1) • 1 gram every 8 hours by intravenous bolus injection (5 mL to 20 mL) over 3 minutes to 5 minutes for adult patients. (2.1) • Dosage should be reduced in adult patients with renal impairment. (2.2) Recommended MERREM IV Dosage Schedule for Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Dose (dependent on type of infection) Dosing Interval Greater than 50 Recommended dose (500 mg cSSSI and 1 gram Intra-abdominal) Every 8 hours 26-50 Recommended dose Every 12 hours 10-25 One-half recommended dose Every 12 hours Less than 10 One-half recommended dose Every 24 hours Pediatric patients 3 months of age and older Recommended MERREM IV Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function (2.3) Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Complicated skin and skin structure* 10 500 mg Every 8 hours Intra-abdominal 20 1 gram Every 8 hours Meningitis 40 2 gram Every 8 hours - Intravenous infusion is to be given over approximately 15 minutes to 30 minutes. - Intravenous bolus injection (5 mL to 20 mL) is to be given over approximately 3 minutes-5 minutes. - There is no experience in pediatric patients with renal impairment. *20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended when treating complicated skin and skin structure infections caused by P. aeruginosa. (2.3) Pediatric patients less than 3 months of age Recommended MERREM IV Dosage Schedule for Pediatric Patients Less than 3 Months of Age with Complicated Intra-Abdominal Infections and Normal Renal Function (2.3) Age Group Dose (mg/kg) Dose Interval Infants less than 32 weeks GA and PNA less than 2 weeks 20 Every 12 hours Infants less than 32 weeks GA and PNA 2 weeks and older 20 Every 8 hours Infants 32 weeks and older GA and PNA less than 2 weeks 20 Every 8 hours Infants 32 weeks and older GA and PNA 2 weeks and older 30 Every 8 hours - Intravenous infusion is to be given over 30 minutes. - There is no experience in pediatric patients with renal impairment. GA: gestational age and PNA: postnatal age --------------------- DOSAGE FORMS AND STRENGTHS -------------------­ 500 mg meropenem for Injection Vial (3) 1 gram meropenem for Injection Vial (3) ------------------------------ CONTRAINDICATIONS ----------------------------­ Known hypersensitivity to product components or anaphylactic reactions to β-lactams. (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------------­ • Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactams. (5.1) • Severe cutaneous adverse reactions have been reported in patients receiving MERREM IV. (5.2) • Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue MERREM IV and initiate appropriate therapy. (5.3) • Seizures and other adverse CNS experiences have been reported during treatment. (5.4) • Co-administration of MERREM IV with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. (5.5, 7.2) • Clostridioides difficile-associated diarrhea (ranging from mild diarrhea to fatal colitis) has been reported. Evaluate if diarrhea occurs. (5.6) • In patients with renal dysfunction, thrombocytopenia has been observed. (5.9) ------------------------------ ADVERSE REACTIONS ----------------------------­ Most common adverse reactions (2% or less) are: headache, nausea, constipation, diarrhea, anemia, vomiting, and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS ----------------------------­ • Co-administration of MERREM IV with probenecid inhibits renal excretion of meropenem and is therefore not recommended. (7.1) • The concomitant use of MERREM IV and valproic acid or divalproex sodium is generally not recommended. Antibacterial drugs other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. (5.5, 7.2) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------­ • Renal Impairment: Dose adjustment is necessary, if creatinine clearance is 50 mL/min or less. (2.2, 8.6) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/2024 Reference ID: 5488062 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Complicated Skin and Skin Structure Infections (Adult Patients and Pediatric Patients 3 Months of Age and Older Only) 1.2 Complicated Intra-abdominal Infections (Adult and Pediatric Patients) 1.3 Bacterial Meningitis (Pediatric Patients 3 Months of Age and Older Only) 1.4 Usage 2 DOSAGE AND ADMINISTRATION 2.1 Adult Patients 2.2 Use in Adult Patients with Renal Impairment 2.3 Use in Pediatric Patients 2.4 Preparation and Administration of MERREM IV 2.5 Compatibility 2.6 Stability and Storage 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Severe Cutaneous Adverse Reactions 5.3 Rhabdomyolysis 5.4 Seizure Potential 5.5 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid 5.6 Clostridioides difficile–associated Diarrhea 5.7 Development of Drug-Resistant Bacteria 5.8 Overgrowth of Nonsusceptible Organisms 5.9 Thrombocytopenia 5.10 Potential for Neuromotor Impairment 6 ADVERSE REACTIONS 6.1 Adverse Reactions from Clinical Trials 6.2 Post marketing Experience 7 DRUG INTERACTIONS 7.1 Probenecid 7.2 Valproic Acid 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Patients with Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Complicated Skin and Skin Structure Infections 14.2 Complicated Intra-Abdominal Infections 14.3 Bacterial Meningitis 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed Reference ID: 5488062 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Complicated Skin and Skin Structure Infections (Adult Patients and Pediatric Patients 3 Months of Age and Older Only) MERREM IV is indicated for the treatment of complicated skin and skin structure infections (cSSSI) due to Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis (vancomycin-susceptible isolates only), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species. 1.2 Complicated Intra-abdominal Infections (Adult and Pediatric Patients) MERREM IV is indicated for the treatment of complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species. 1.3 Bacterial Meningitis (Pediatric Patients 3 Months of Age and Older Only) MERREM IV is indicated for the treatment of bacterial meningitis caused by Haemophilus influenzae, Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae. MERREM IV has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis. 1.4 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of MERREM IV and other antibacterial drugs, MERREM IV should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Adult Patients The recommended dose of MERREM IV is 500 mg given every 8 hours for skin and skin structure infections and 1 gram given every 8 hours for intra-abdominal infections. When treating complicated skin and skin structure infections caused by P. aeruginosa, a dose of 1 gram every 8 hours is recommended. MERREM IV should be administered by intravenous infusion over approximately 15 minutes to 30 minutes. Doses of 1 gram may also be administered as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes. 2.2 Use in Adult Patients with Renal Impairment Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less. (See dosing table below.) When only serum creatinine is available, the following formula (Cockcroft and Gault equation)1 may be used to estimate creatinine clearance. Males: Creatinine Clearance (mL/min) = Weight (kg) x (140 - age) 72 x serum creatinine (mg/dL) Reference ID: 5488062 Females: 0.85 x above value Table 1: Recommended MERREM IV Dosage Schedule for Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Dose (dependent on type of infection) Dosing Interval Greater than 50 Recommended dose (500 mg cSSSI and 1 gram Intra-abdominal) Every 8 hours 26-50 Recommended dose Every 12 hours 10-25 One-half recommended dose Every 12 hours Less than 10 One-half recommended dose Every 24 hours There is inadequate information regarding the use of MERREM IV in patients on hemodialysis or peritoneal dialysis. 2.3 Use in Pediatric Patients Pediatric Patients 3 Months of Age and Older • For pediatric patients 3 months of age and older, the MERREM IV dose is 10 mg/kg, 20 mg/kg or 40 mg/kg every 8 hours (maximum dose is 2 grams every 8 hours), depending on the type of infection (cSSSI, cIAI, intra-abdominal infection or meningitis). See dosing table 2 below. • For pediatric patients weighing over 50 kg administer MERREM IV at a dose of 500 mg every 8 hours for cSSSI, 1 gram every 8 hours for cIAI and 2 grams every 8 hours for meningitis. • Administer MERREM IV as an intravenous infusion over approximately 15 minutes to 30 minutes or as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes. • There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 grams) bolus dose. Table 2: Recommended MERREM IV Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Complicated skin and skin structure infections 10 500 mg Every 8 hours Complicated intra-abdominal infections 20 1 gram Every 8 hours Meningitis 40 2 grams Every 8 hours There is no experience in pediatric patients with renal impairment. When treating cSSSI caused by P. aeruginosa, a dose of 20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended. Pediatric Patients Less Than 3 Months of Age For pediatric patients (with normal renal function) less than 3 months of age, with complicated intra-abdominal infections, the MERREM IV dose is based on gestational age (GA) and postnatal age (PNA). See dosing table 3 below. MERREM IV should be given as intravenous infusion over 30 minutes. Reference ID: 5488062 Table 3: Recommended MERREM IV Dosage Schedule for Pediatric Patients Less than 3 Months of Age with Complicated Intra-abdominal Infections and Normal Renal Function Age Group Dose (mg/kg) Dose Interval Infants less than 32 weeks GA and PNA less than 2 weeks 20 Every 12 hours Infants less than 32 weeks GA and PNA 2 weeks and older 20 Every 8 hours Infants 32 weeks and older GA and PNA less than 2 weeks 20 Every 8 hours Infants 32 weeks and older GA and PNA 2 weeks and older 30 Every 8 hours There is no experience in pediatric patients with renal impairment. 2.4 Preparation and Administration of MERREM IV Important Administration Instructions: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. For Intravenous Bolus Administration Re-constitute injection vials (500 mg and 1 gram) with sterile Water for Injection (see table 4 below). Shake to dissolve and let stand until clear. Table 4: Volume of Sterile Water for Injection for Reconstitution of Injection Vials Vial Size Amount of Diluent Added (mL) Approximate Withdrawable Volume (mL) Approximate Average Concentration (mg/mL) 500 mg 10 10 50 1 gram 20 20 50 For Infusion • Injection vials (500 mg and 1 gram) may be directly re-constituted with a compatible infusion fluid. • Alternatively, an injection vial may be re-constituted, then the resulting solution added to an intravenous container and further diluted with an appropriate infusion fluid [see Dosage and Administration (2.5) and (2.6)]. • Do not use flexible container in series connections. 2.5 Compatibility Compatibility of MERREM IV with other drugs has not been established. MERREM IV should not be mixed with or physically added to solutions containing other drugs. 2.6 Stability and Storage Freshly prepared solutions of MERREM IV should be used. However, re-constituted solutions of MERREM IV maintain satisfactory potency under the conditions described below. Solutions of intravenous MERREM IV should not be frozen. Intravenous Bolus Administration Reference ID: 5488062 MERREM IV injection vials re-constituted with sterile Water for Injection for bolus administration (up to 50 mg/mL of MERREM IV) may be stored for up to 3 hours at up to 25oC (77oF) or for 13 hours at up to 5oC (41oF). Intravenous Infusion Administration Solutions prepared for infusion (MERREM IV concentrations ranging from 1 mg/mL to 20 mg/mL) re-constituted with Sodium Chloride Injection 0.9% may be stored for 1 hour at up to 25oC (77oF) or 15 hours at up to 5oC (41oF). Solutions prepared for infusion (MERREM IV concentrations ranging from 1 mg/mL to 20 mg/mL) re-constituted with Dextrose Injection 5% should be used immediately. 3 DOSAGE FORMS AND STRENGTHS Single dose clear glass vials of MERREM IV containing 500 mg or 1 gram (as the trihydrate blended with anhydrous sodium carbonate for re-constitution) of sterile meropenem powder. 4 CONTRAINDICATIONS MERREM IV is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta (β)-lactams. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another β-lactam. Before initiating therapy with MERREM IV, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to MERREM IV occurs, discontinue the drug immediately. 5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving MERREM IV [see Adverse Reactions (6.2)]. If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered. 5.3 Rhabdomyolysis Rhabdomyolysis has been reported with the use of meropenem [see Adverse Reactions (6.2)]. If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine or elevated creatine phosphokinase are observed, discontinue MERREM IV and initiate appropriate therapy. 5.4 Seizure Potential Seizures and other adverse CNS experiences have been reported during treatment with MERREM IV These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function [see Adverse Reactions (6.1) and Drug Interactions (7.2)]. During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (based on 20 patients with this adverse event). All meropenem-treated patients with seizures had Reference ID: 5488062 pre-existing contributing factors. Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential. Dosage adjustment is recommended in patients with advanced age and/or adult patients with creatinine clearance of 50 mL/min or less [see Dosage and Administration (2.2)]. Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Continue anti-convulsant therapy in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate neurologically, placed on anti-convulsant therapy if not already instituted, and re-examine the dosage of MERREM IV to determine whether it should be decreased or discontinued. 5.5 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of MERREM IV is necessary, consider supplemental anti-convulsant therapy [see Drug Interactions (7.2)]. 5.6 Clostridioides difficile–associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MERREM IV, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.7 Development of Drug-Resistant Bacteria Prescribing MERREM IV in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 5.8 Overgrowth of Nonsusceptible Organisms As with other broad-spectrum antibacterial drugs, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken. 5.9 Thrombocytopenia In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported [see Dosage and Administration (2.2), Adverse Reactions (6.1), Use in Specific Populations (8.5) and (8.6), and Clinical Pharmacology (12.3)]. Reference ID: 5488062 5.10 Potential for Neuromotor Impairment Alert patients receiving MERREM IV on an outpatient basis regarding adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that MERREM IV is well tolerated, advise patients not to operate machinery or motorized vehicles [see Adverse Reactions (6.1)]. 6 ADVERSE REACTIONS The following are discussed in greater detail in other sections of labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.1)] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] • Rhabdomyolysis [see Warnings and Precautions (5.3)] • Seizure Potential [see Warnings and Precautions (5.4)] • Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid [see Warnings and Precautions (5.5)] • Clostridioides difficile – associated Diarrhea [see Warnings and Precautions (5.6)] • Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.7)] • Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.8)] • Thrombocytopenia [see Warnings and Precautions (5.9)] • Potential for Neuromotor Impairment [see Warnings and Precautions (5.10)] 6.1 Adverse Reactions from Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Patients: During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with MERREM IV (500 mg or 1 gram every 8 hours). Deaths in 5 patients were assessed as possibly related to meropenem; 36 (1.2%) patients had meropenem discontinued because of adverse events. Many patients in these trials were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with MERREM IV. The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with MERREM IV. Local Adverse Reactions Local adverse events that were reported with MERREM IV were as follows: Inflammation at the injection site 2.4% Injection site reaction 0.9% Phlebitis/thrombophlebitis 0.8% Pain at the injection site 0.4% Edema at the injection site 0.2% Systemic Adverse Reactions Reference ID: 5488062 Systemic adverse events that were reported with MERREM IV occurring in greater than 1.0% of the patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%), and pruritus (1.2%). Additional systemic adverse events that were reported with MERREM IV and occurring in less than or equal to 1.0% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency: Bleeding events were seen as follows: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%). Body as a Whole: pain, abdominal pain, chest pain, fever, back pain, abdominal enlargement, chills, pelvic pain Cardiovascular: heart failure, heart arrest, tachycardia, hypertension, myocardial infarction, pulmonary embolus, bradycardia, hypotension, syncope Digestive System: oral moniliasis, anorexia, cholestatic jaundice/jaundice, flatulence, ileus, hepatic failure, dyspepsia, intestinal obstruction Hemic/Lymphatic: anemia, hypochromic anemia, hypervolemia Metabolic/Nutritional: peripheral edema, hypoxia Nervous System: insomnia, agitation, delirium, confusion, dizziness, seizure, nervousness, paresthesia, hallucinations, somnolence, anxiety, depression, asthenia [see Warnings and Precautions (5.4) and (5.10)] Respiratory: respiratory disorder, dyspnea, pleural effusion, asthma, cough increased, lung edema Skin and Appendages: urticaria, sweating, skin ulcer Urogenital System: dysuria, kidney failure, vaginal moniliasis, urinary incontinence Adverse Laboratory Changes Adverse laboratory changes that were reported and occurring in greater than 0.2% of the patients were as follows: Hepatic: increased alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), and bilirubin Hematologic: increased platelets, increased eosinophils, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased white blood cell (WBC), shortened prothrombin time and shortened partial thromboplastin time, leukocytosis, hypokalemia Renal: increased creatinine and increased blood urea nitrogen (BUN) Urinalysis: presence of red blood cells Complicated Skin and Skin Structure Infections In a study of complicated skin and skin structure infections, the adverse reactions were similar to those listed above. The most common adverse events occurring in greater than 5% of the patients were: headache (7.8%), nausea (7.8%), constipation (7.0%), diarrhea (7.0%), anemia (5.5%), and pain (5.1%). Adverse events with an incidence of greater than 1%, and not listed above, include: pharyngitis, accidental injury, gastrointestinal disorder, hypoglycemia, peripheral vascular disorder, and pneumonia. Reference ID: 5488062 Patients with Renal Impairment: For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported with MERREM IV, increased in patients with moderately severe renal impairment (creatinine clearance 10 to 26 mL/min) [see Dosage and Administration (2.2), Warnings and Precautions (5.10), Use in Specific Populations (8.5) and (8.6) and Clinical Pharmacology (12.3)]. Pediatric Patients: Systemic and Local Adverse Reactions Pediatric Patients with Serious Bacterial Infections (excluding Bacterial Meningitis): MERREM IV was studied in 515 pediatric patients (3 months to less than 13 years of age) with serious bacterial infections (excluding meningitis, see next section) at dosages of 10 mg/kg to 20 mg/kg every 8 hours. The types of systemic and local adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to MERREM IV and their rates of occurrence as follows: Diarrhea 3.5% Rash 1.6% Nausea and Vomiting 0.8% Pediatric Patients with Bacterial Meningitis: MERREM IV was studied in 321 pediatric patients (3 months to less than 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of systemic and local adverse events seen in these patients are similar to the adults, with the most common adverse reactions reported as possibly, probably, or definitely related to MERREM IV and their rates of occurrence as follows: Diarrhea 4.7% Rash (mostly diaper area moniliasis) 3.1% Oral Moniliasis 1.9% Glossitis 1.0% In the meningitis studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents (either cefotaxime or ceftriaxone). In the MERREM IV treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm. The meropenem group had a statistically higher number of patients with transient elevation of liver enzymes. Pediatric Patients (Neonates and Infants less than 3 months of Age): MERREM IV was studied in 200 neonates and infants less than 3 months of age. The study was open-label, uncontrolled, 98% of the infants received concomitant medications, and the majority of adverse events were reported in neonates less than 32 weeks gestational age and critically ill at baseline, making it difficult to assess the relationship of the adverse events to MERREM IV. The adverse reactions seen in these patients that were reported and their rates of occurrence are as follows: Convulsion 5.0% Hyperbilirubinemia (conjugated) 4.5% Vomiting 2.5% Reference ID: 5488062 Adverse Laboratory Changes in Pediatric Patients: Laboratory changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies. 6.2 Post marketing Experience The following adverse reactions have been identified during post-approval use of meropenem, including MERREM IV. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Worldwide post-marketing adverse reactions not otherwise listed in the Adverse Reactions from Clinical Trials section of this prescribing information and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity. Blood and Lymphatic System Disorders: agranulocytosis, neutropenia, and leukopenia; a positive direct or indirect Coombs test, and hemolytic anemia. Immune System Disorders: angioedema. Skin and Subcutaneous Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme and acute generalized exanthematous pustulosis. Musculoskeletal Disorders: rhabdomyolysis. 7 DRUG INTERACTIONS 7.1 Probenecid Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. Co-administration of probenecid with meropenem is not recommended. 7.2 Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. If administration of MERREM IV is necessary, then supplemental anti-convulsant therapy should be considered [see Warnings and Precautions (5.5)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem in pregnant women. No fetal toxicity or malformations were observed in pregnant rats and Cynomolgus monkeys administered intravenous meropenem during organogenesis at doses up to 2.4 and 2.3 times the maximum recommended human dose (MRHD) based on body surface area comparison, respectively. In rats administered intravenous meropenem in late pregnancy and Reference ID: 5488062 during the lactation period, there were no adverse effects on offspring at doses equivalent to approximately 3.2 times the MRHD based on body surface area comparison (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Meropenem administered to pregnant rats during organogenesis (Gestation Day 6 to Gestation Day 17) in intravenous doses of 240, 500, and 750 mg/kg/day was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity. The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 2.4 times the MRHD of 1 gram every 8 hours based on body surface area comparison). Meropenem administered intravenously to pregnant Cynomolgus monkeys during organogenesis from Day 20 to 50 after mating at doses of 120, 240, and 360 mg/kg/day did not produce maternal or fetal toxicity at the NOAEL dose of 360 mg/kg/day (approximately 2.3 times the MRHD based on body surface area comparison). In a peri-postnatal study in rats described in the published literature2, intravenous meropenem was administered to dams from Gestation Day 17 until Lactation Day 21 at doses of 240, 500, and 1000 mg/kg/day. There were no adverse effects in the dams and no adverse effects in the first-generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second-generation offspring. Second-generation offspring showed no meropenem-related effects. The NOAEL value was considered to be 1000 mg/kg/day (approximately 3.2 times the MRHD based on body surface area comparisons). 8.2 Lactation Risk Summary Meropenem has been reported to be excreted in human milk. No information is available on the effects of meropenem on the breast-fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MERREM IV and any potential adverse effects on the breast-fed child from MERREM IV or from the underlying maternal conditions. 8.4 Pediatric Use The safety and effectiveness of MERREM IV have been established for pediatric patients 3 months of age and older with complicated skin and skin structure infections and bacterial meningitis, and for pediatric patients of all ages with complicated intra-abdominal infections. Skin and Skin Structure Infections Use of MERREM IV in pediatric patients 3 months of age and older with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study in adults and additional data from pediatric pharmacokinetics studies [see Indications and Usage (1.3), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. Intra-abdominal Infections Use of MERREM IV in pediatric patients 3 months of age and older with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. Use of MERREM IV in pediatric patients less than 3 months of age with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional Reference ID: 5488062 data from a pediatric pharmacokinetic and safety study [see Indications and Usage (1.2), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. Bacterial Meningitis Use of MERREM IV in pediatric patients 3 months of age and older with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population [see Indications and Usage (1.3), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. 8.5 Geriatric Use Of the total number of subjects in clinical studies of MERREM IV, approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older. Additionally, in a study of 511 patients with complicated skin and skin structure infections, 93 (18%) were 65 years of age and older, while 38 (7%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; spontaneous reports and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Meropenem is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. A pharmacokinetic study with MERREM IV in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance [see Clinical Pharmacology (12.3)]. 8.6 Patients with Renal Impairment Dosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less [see Dosage and Administration (2.2), Warnings and Precautions (5.9), and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In mice and rats, large intravenous doses of meropenem (2200 mg/kg to 4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities. Intentional overdosing of MERREM IV is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function. The largest dose of meropenem administered in clinical trials has been 2 grams given intravenously every 8 hours. At this dosage, no adverse pharmacological effects or increased safety risks have been observed. Limited postmarketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction. Consider symptomatic treatments. In individuals with normal renal function, rapid renal elimination takes place. Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage. 11 DESCRIPTION MERREM IV (meropenem for injection) is a sterile, pyrogen-free, synthetic, carbapenem antibacterial for intravenous administration. It is (4R,5S,6S)-3- [[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6- [(1R)-1-hydroxyethyl]-4­ methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate. Its empirical formula is C17H25N3O5S•3H2O with a molecular weight of 437.52. Its structural formula is: Reference ID: 5488062 0 COOH I N CON(CH3)2 ~ .,,, H ■ NH - H3C - ·,; - ·3H20 H '/ H H CH3 MERREM IV is a white to pale yellow crystalline powder. The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether. When re-constituted as instructed, each 1 gram MERREM IV vial will deliver 1 gram of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq). Each 500 mg MERREM IV vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq) [see Dosage and Administration (2.4)]. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Meropenem is an antibacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics The percentage of time of a dosing interval that unbound plasma concentration of meropenem exceeds the meropenem minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection. 12.3 Pharmacokinetics Plasma Concentrations At the end of a 30-minute intravenous infusion of a single dose of MERREM IV in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 mcg/mL (range 14-26) for the 500 mg dose and 49 mcg/mL (range 39-58) for the 1 gram dose. A 5-minute intravenous bolus injection of MERREM IV in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18-65) for the 500 mg dose and 112 mcg/mL (range 83-140) for the 1 gram dose. Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 mcg/mL at 6 hours after administration. No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 gram administered every 6 hours in healthy volunteers with normal renal function. Distribution The plasma protein binding of meropenem is approximately 2%. Reference ID: 5488062 After a single intravenous dose of MERREM IV, the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour (0.5 hours to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in Table 5 below. Table 5: Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported) Tissue Intravenous. Dose (gram) Number of Samples Mean [μg/mL or mcg/(gram)]1 Range [μg/mL or mcg/(gram)] Endometrium 0.5 7 4.2 1.7–10.2 Myometrium 0.5 15 3.8 0.4–8.1 Ovary 0.5 8 2.8 0.8–4.8 Cervix 0.5 2 7 5.4–8.5 Fallopian tube 0.5 9 1.7 0.3-3.4 Skin 0.5 22 3.3 0.5–12.6 Interstitial fluid2 0.5 9 5.5 3.2-8.6 Skin 1 10 5.3 1.3–16.7 Interstitial fluid2 1 5 26.3 20.9–37.4 Colon 1 2 2.6 2.5–2.7 Bile 1 7 14.6 (3 hours) 4–25.7 Gall bladder 1 1 — 3.9 Peritoneal fluid 1 9 30.2 7.4–54.6 Lung 1 2 4.8 (2 hours) 1.4–8.2 Bronchial mucosa 1 7 4.5 1.3–11.1 Muscle 1 2 6.1 (2 hours) 5.3–6.9 Fascia 1 9 8.8 1.5–20 Heart valves 1 7 9.7 6.4–12.1 Myocardium 1 10 15.5 5.2–25.5 CSF (inflamed) 20 mg/kg3 40 mg/kg4 8 5 1.1 (2 hours) 3.3 (3 hours) 0.2-2.8 0.9-6.5 CSF (uninflamed) 1 4 0.2 (2 hours) 0.1–0.3 1. at 1 hour unless otherwise noted 2. obtained from blister fluid 3. in pediatric patients of age 5 months to 8 years 4. in pediatric patients of age 1 month to 15 years Elimination In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour. Metabolism There is one metabolite of meropenem that is microbiologically inactive. Excretion Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50% – 75%) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Fecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion. Urinary concentrations of meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose. Reference ID: 5488062 Specific Populations Patients with Renal Impairment Pharmacokinetic studies with MERREM IV in patients with renal impairment have shown that the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment (creatinine clearance 50 mL/min or less) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)]. Meropenem IV is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage [see Overdosage (10)]. Patients with Hepatic Impairment A pharmacokinetic study with MERREM IV in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem. Geriatric Patients A pharmacokinetic study with MERREM IV in elderly patients with renal impairment showed a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance. Pediatric Patients The pharmacokinetics of meropenem for injection IV, in pediatric patients 2 years of age or older, are similar to those in adults. The elimination half-life for meropenem was approximately 1.5 hours in pediatric patients of age 3 months to 2 years. The pharmacokinetics of meropenem in patients less than 3 months of age receiving combination antibacterial drug therapy are given below. Table 6: Meropenem Pharmacokinetic Parameters in Patients Less Than 3 Months of Age* GA less than 32 weeks PNA less than 2 weeks (20mg/kg every 12 hours) GA less than 32 weeks PNA 2 weeks or older (20mg/kg every 8 hours) GA 32 weeks or older PNA less than 2 weeks (20mg/kg every 8 hours) GA 32 weeks or older PNA 2 weeks or older (30mg/kg every 8 hours) Overall CL (L/h/kg) 0.089 0.122 0.135 0.202 0.119 V (L/kg) 0.489 0.467 0.463 0.451 0.468 AUC0-24 (mcg-h/mL) 448 491 445 444 467 Cmax (mcg/mL) 44.3 46.5 44.9 61 46.9 Cmin (mcg/mL) 5.36 6.65 4.84 2.1 5.65 T1/2 (h) 3.82 2.68 2.33 1.58 2.68 *Values are derived from a population pharmacokinetic analysis of sparse data Drug Interactions Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38% [see Drug Interactions (7.1)]. Reference ID: 5488062 12.4 Microbiology Mechanism of Action The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding-protein (PBP) targets. Meropenem binds to PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus. Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 hours to 24 hours) are typically 1-2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed. Meropenem does not have in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE). Resistance There are several mechanisms of resistance to carbapenems: 1) decreased permeability of the outer membrane of gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake, 2) reduced affinity of the target PBPs, 3) increased expression of efflux pump components, and 4) production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases). Cross-resistance is sometimes observed with isolates resistant to other carbapenems. Interaction with Other Antimicrobials In vitro tests show meropenem to act synergistically with aminoglycoside antibacterial drugs against some isolates of Pseudomonas aeruginosa. Antimicrobial Activity Meropenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]. Gram-positive bacteria Enterococcus faecalis (vancomycin-susceptible isolates only) Staphylococcus aureus (methicillin-susceptible isolates only) Streptococcus agalactiae Streptococcus pneumoniae (penicillin-susceptible isolates only) Streptococcus pyogenes Viridans group streptococci Gram-negative bacteria Escherichia coli Haemophilus influenzae Klebsiella pneumoniae Neisseria meningitidis Proteus mirabilis Pseudomonas aeruginosa Anaerobic bacteria Bacteroides fragilis Bacteroides thetaiotaomicron Peptostreptococcus species The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for Reference ID: 5488062 meropenem against isolates of similar genus or organism group. However, the efficacy of meropenem in treating clinical infections caused by these bacteria have not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Staphylococcus epidermidis (methicillin-susceptible isolates only) Gram-negative bacteria Aeromonas hydrophila Campylobacter jejuni Citrobacter freundii Citrobacter koseri Enterobacter cloacae Hafnia alvei Klebsiella oxytoca Moraxella catarrhalis Morganella morganii Pasteurella multocida Proteus vulgaris Serratia marcescens Anaerobic bacteria Bacteroides ovatus Bacteroides uniformis Bacteroides ureolyticus Bacteroides vulgatus Clostridium difficile Clostridium perfringens Eggerthella lenta Fusobacterium species Parabacteroides distasonis Porphyromonas asaccharolytica Prevotella bivia Prevotella intermedia Prevotella melaninogenica Propionibacterium acnes Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Carcinogenesis studies have not been performed. Mutagenesis: Genetic toxicity studies were performed with meropenem using the bacterial reverse mutation test, the Chinese hamster ovary HGPRT assay, cultured human lymphocytes cytogenic assay, and the mouse micronucleus test. There was no evidence of mutagenic potential found in any of these tests. Reference ID: 5488062 Impairment of Fertility: In fertility studies, intravenous meropenem was administered to male rats beginning 11 weeks before mating and throughout mating and to female rats from 2 weeks before mating through Gestation Day 7 at doses of 240, 500, and 1000 mg/kg/day. There was no evidence of impaired fertility at doses up to 1000 mg/kg/day (on the basis of body surface area comparison, approximately 3.2 times to the MRHD of 1 gram every 8 hours). 14 CLINICAL STUDIES 14.1 Complicated Skin and Skin Structure Infections Adult patients with complicated skin and skin structure infections including complicated cellulitis, complex abscesses, perirectal abscesses, and skin infections requiring intravenous antimicrobials, hospitalization, and surgical intervention were enrolled in a randomized, multi-center, international, double-blind trial. The study evaluated meropenem at doses of 500 mg administered intravenously every 8 hours and imipenem-cilastatin at doses of 500 mg administered intravenously every 8 hours. The study compared the clinical response between treatment groups in the clinically evaluable population at the follow-up visit (test-of-cure). The trial was conducted in the United States, South Africa, Canada, and Brazil. At enrollment, approximately 37% of the patients had underlying diabetes, 12% had underlying peripheral vascular disease and 67% had a surgical intervention. The study included 510 patients randomized to meropenem and 527 patients randomized to imipenem-cilastatin. Two hundred and sixty one (261) patients randomized to meropenem and 287 patients randomized to imipenem-cilastatin were clinically evaluable. The success rates in the clinically evaluable patients at the follow-up visit were 86% (225/261) in the meropenem arm and 83% (238/287) in imipenem-cilastatin arm. The success rates for the clinically evaluable population are provided in Table 7. Table 7: Success Rates at Test-of-Cure Visit for Clinically Evaluable Population with Complicated Skin and Skin Structure Infections Population MERREM IV n1/N2 (%) Imipenem-cilastatin n1/N2 (%) Total 225/261 (86) 238/287 (83) Diabetes mellitus 83/97 (86) 76/105 (72) No diabetes mellitus 142/164 (87) 162/182 (89) Less than 65 years of age 190/218 (87) 205/241 (85) 65 years of age or older 35/43 (81) 33/46 (72) Men 130/148 (88) 137/172 (80) Women 95/113 (84) 101/115 (88) 1. n=number of patients with satisfactory response. 2. N=number of patients in the clinically evaluable population or respective subgroup within treatment groups. The clinical efficacy rates by pathogen are provided in Table 8. The values represent the number of patients clinically cured/number of clinically evaluable patients at the post-treatment follow-up visit, with the percent cure in parentheses (Fully Evaluable analysis set). Reference ID: 5488062 Table 8: Clinical Efficacy Rates by Pathogen for Clinically Evaluable Population MICROORGANISMS1 MERREM IV n2/N3 (%)4 Imipenem-cilastatin n2/N3 (%)4 Gram-positive aerobes Staphylococcus aureus, methicillin susceptible 82/88 (93) 84/100 (84) Streptococcus pyogenes (Group A) 26/29 (90) 28/32 (88) Streptococcus agalactiae (Group B) 12/17 (71) 16/19 (84) Enterococcus faecalis 9/12 (75) 14/20 (70) Viridans group streptococci 11/12 (92) 5/6 (83) Gram-negative aerobes Escherichia coli 12/15 (80) 15/21 (71) Pseudomonas aeruginosa 11/15 (73) 13/15 (87) Proteus mirabilis 11/13 (85) 6/7 (86) Anaerobes Bacteroides fragilis 10/11 (91) 9/10 (90) Peptostreptococcus Species 10/13 (77) 14/16 (88) 1. Patients may have more than one pretreatment pathogen. 2. n=number of patients with satisfactory response. 3. N=number of patients in the clinically evaluable population or subgroup within treatment groups. 4. %= Percent of satisfactory clinical response at follow-up evaluation. The proportion of patients who discontinued study treatment due to an adverse event was similar for both treatment groups (meropenem, 2.5% and imipenem-cilastatin, 2.7%). 14.2 Complicated Intra-Abdominal Infections One controlled clinical study of complicated intra-abdominal infection was performed in the United States where meropenem was compared with clindamycin/tobramycin. Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; meropenem was compared with imipenem (two trials) and cefotaxime/metronidazole (one trial). Using strict evaluability criteria and microbiologic eradication and clinical cures at follow-up which occurred 7 or more days after completion of therapy, the presumptive microbiologic eradication/clinical cure rates and statistical findings are provided in Table 9: Table 9: Presumptive Microbiologic Eradication and Clinical Cure Rates at Test-of-Cure Visit in the Evaluable Population with Complicated Intra-Abdominal Infection Treatment Arm No. evaluable/ No. enrolled (%) Microbiologic Eradication Rate Clinical Cure Rate Outcome meropenem 146/516 (28%) 98/146 (67%) 101/146 (69%) imipenem 65/220 (30%) 40/65 (62%) 42/65 (65%) meropenem equivalent to control cefotaxime/ metronidazole 26/85 (30%) 22/26 (85%) 22/26 (85%) meropenem not equivalent to control clindamycin/ tobramycin 50/212 (24%) 38/50 (76%) 38/50 (76%) meropenem equivalent to control Reference ID: 5488062 The finding that meropenem was not statistically equivalent to cefotaxime/metronidazole may have been due to uneven assignment of more seriously ill patients to the meropenem arm. Currently there is no additional information available to further interpret this observation. 14.3 Bacterial Meningitis Four hundred forty-six patients (397 pediatric patients 3 months to less than 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with meropenem (n=225) at a dose of 40 mg/kg every 8 hours or a comparator drug, i.e., cefotaxime (n=187) or ceftriaxone (n=34), at the approved dosing regimens. A comparable number of patients were found to be clinically evaluable (ranging from 61-68%) and with a similar distribution of pathogens isolated on initial CSF culture. Patients were defined as clinically not cured if any one of the following three criteria were met: 1. At the 5-7 week post-completion of therapy visit, the patient had any one of the following: moderate to severe motor, behavior or development deficits, hearing loss of greater than 60 decibels in one or both ears, or blindness. 2. During therapy the patient’s clinical status necessitated the addition of other antibacterial drugs. 3. Either during or post-therapy, the patient developed a large subdural effusion needing surgical drainage, or a cerebral abscess, or a bacteriologic relapse. Using the definition, the following efficacy rates were obtained, per organism (noted in Table 10). The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses. Table 10: Efficacy rates by Pathogen in the Clinically Evaluable Population with Bacterial Meningitis MICROORGANISMS MERREM IV COMPARATOR S. pneumoniae 17/24 (71) 19/30 (63) H. influenzae (+)1 8/10 (80) 6/6 (100) H. influenzae (-/NT)2 44/59 (75) 44/60 (73) N. meningitidis 30/35 (86) 35/39 (90) Total (including others) 102/131 (78) 108/140 (77) 1. (+) β-lactamase-producing 2. (-/NT) non-β-lactamase-producing or not tested Sequelae were the most common reason patients were assessed as clinically not cured. Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the meropenem group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa). With respect to hearing loss, 263 of the 271 evaluable patients had at least one hearing test performed post-therapy. The following table shows the degree of hearing loss between the meropenem-treated patients and the comparator-treated patients. Table 11: Hearing Loss at Post-Therapy in the Evaluable Population Treated with Meropenem Degree of Hearing Loss (in one or both ears) Meropenem n = 128 Comparator n = 135 No loss 61% 56% 20-40 decibels 20% 24% Greater than 40-60 decibels 8% 7% Greater than 60 decibels 9% 10% Reference ID: 5488062 ~Pfizer Hospital Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 15 REFERENCES 1. Cockcroft DW, MH Gault, 1976, Prediction of creatinine clearance from serum creatinine, Nephron, 16:31-41. 2. Kawamura S, AW Russell, SJ Freeman, and RA Siddall, 1992, Reproductive and Developmental Toxicity of Meropenem in Rats, Chemotherapy, 40:S238-250. 16 HOW SUPPLIED/STORAGE AND HANDLING MERREM IV is supplied in 20 mL and 30 mL injection vials containing sufficient meropenem to deliver 500 mg or 1 gram for intravenous administration, respectively. The dry powder should be stored at controlled room temperature 20º-25ºC (68º-77ºF) [see USP]. 500 mg Injection Vial (NDC 0069-0313-01) in a pack of 10 x 500 mg Injection Vials (NDC 0069-0313-10) 1 gram Injection Vial (NDC 0069-0314-01) in a pack of 10 x 1 g Injection Vials (NDC 0069-0314-10) 17 PATIENT COUNSELING INFORMATION • Counsel patients that antibacterial drugs including MERREM IV should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When MERREM IV is prescribed to treat a bacterial infection, tell patients that although it is common to feel better early in the course of therapy, take the medication exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by MERREM IV or other antibacterial drugs in the future. • Counsel patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.6)]. • Counsel patients to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with MERREM IV. If treatment with MERREM IV is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed [see Warnings and Precautions (5.5)]. • Patients receiving MERREM IV on an outpatient basis must be alerted of adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that MERREM IV is well tolerated, patients should not operate machinery or motorized vehicles [see Warnings and Precautions (5.10)]. LAB-1020-5.2 Reference ID: 5488062
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2025-02-12T15:47:28.928048
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use MEROPENEM FOR INJECTION AND SODIUM CHLORIDE INJECTION safely and effectively. See full prescribing information for MEROPENEM FOR INJECTION AND SODIUM CHLORIDE INJECTION. MEROPENEM for injection AND SODIUM CHLORIDE injection, for intravenous use Initial U.S. Approval: 1996 -------------------------- RECENT MAJOR CHANGES ------------------------­ Warnings and Precautions, Rhabdomyolysis (5.3) 12/2024 -------------------------- INDICATIONS AND USAGE -------------------------- Meropenem for Injection and Sodium Chloride Injection is a penem antibacterial indicated for the treatment of: • Complicated skin and skin structure infections (adult patients and pediatric patients 3 months of age and older requiring the full adult dose only). (1.1) • Complicated intra-abdominal infections (adult patients and pediatric patients 3 months of age and older requiring the full adult dose only). (1.2) • Bacterial meningitis (pediatric patients 3 months of age and older requiring the full adult dose only). (1.3) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for Injection and Sodium Chloride Injection and other antibacterial drugs, Meropenem for Injection and Sodium Chloride Injection should only be used to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ---------------------- DOSAGE AND ADMINISTRATION ---------------------­ Use this formulation of meropenem only in patients who require the entire 500 mg or 1 gram dose and not any fraction thereof. (2.1) • 500 mg every 8 hours by intravenous infusion over 15 to 30 minutes for complicated skin and skin structure infections (cSSSI) for adult patients. When treating infections caused by Pseudomonas aeruginosa, a dose of 1 gram every 8 hours is recommended (2.1). • 1 gram every 8 hours by intravenous infusion over 15 to 30 minutes for intra-abdominal infections for adult patients. (2.1) • Dosage should be reduced in adult patients with renal impairment. If less than a full dose (1 gram or 500 mg) is required, an alternative formulation should be used to avoid risk of overdose. (2.2) Recommended Meropenem for Injection Dosage Schedule for Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Dose (dependent on type of infection) Dosing Interval greater than 50 Recommended dose (500 mg cSSSI and 1 gram Intra-abdominal infection) Every 8 hours 26-50 Recommended dose Every 12 hours 10-25 One-half recommended dose Every 12 hours less than 10 One-half recommended dose Every 24 hours Meropenem for Injection and Sodium Chloride Injection in the DUPLEX® Container is designed to deliver a 500 mg or 1 gram dose of Meropenem. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of Meropenem. Meropenem is not to be used in pediatric patients aged less than three months. There is no experience in pediatric patients with renal impairment. • Pediatric patients 3 months of age and older. (2.3) Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients with Normal Renal Function Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Complicated skin and skin structure* 10 500 mg Every 8 hours Intra-abdominal 20 1 gram Every 8 hours Meningitis 40 2 grams Every 8 hours - Intravenous infusion is to be given over approximately 15 to 30 minutes. - There is no experience in pediatric patients with renal impairment. *20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended when treating complicated skin and skin structure infections caused by P. aeruginosa (2.3). --------------------- DOSAGE FORMS AND STRENGTHS -------------------­ Single-dose DUPLEX® Container consisting of: • 500 mg Meropenem for Injection and 50 mL Sodium Chloride Injection 0.9% (3) • 1 gram Meropenem for Injection and 50 mL Sodium Chloride Injection 0.9% (3) ------------------------------ CONTRAINDICATIONS -----------------------------­ • Known hypersensitivity to product components or anaphylactic reactions to beta-lactams. (4) • Contraindicated where the administration of sodium or chloride could be clinically detrimental. (4) ------------------------ WARNINGS AND PRECAUTIONS ---------------------­ • Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactams. (5.1) • Severe cutaneous adverse reactions have been reported in patients receiving meropenem intravenous. Discontinue meropenem immediately if patients experience these signs and symptoms and consider alternative treatment. (5.2) • Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue Meropenem for Injection and Sodium Chloride Injection and initiate appropriate therapy. (5.3) • Seizures and other adverse CNS experiences have been reported during treatment. (5.4) • Co-administration of Meropenem for Injection with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. (5.5, 7.2) • Clostridioides difficile-associated diarrhea (ranging from mild diarrhea to fatal colitis) has been reported. Evaluate if diarrhea occurs. (5.6) • In patients with renal dysfunction, thrombocytopenia has been observed. (5.9) • Solutions containing sodium ions should be used with great care, if at all, in patients where the administration of sodium could be detrimental. (5.11) ------------------------------ ADVERSE REACTIONS ----------------------------­ Most common adverse reactions (greater than or equal to 2%) are: headache, nausea, constipation, diarrhea, anemia, vomiting, and rash (6.1) To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-800-854-6851 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS -----------------------------­ • Co-administration of Meropenem for Injection with probenecid inhibits renal excretion of meropenem and is therefore not recommended. (7.1) • The concomitant use of Meropenem and valproic acid or divalproex sodium is generally not recommended. Antibacterial drugs other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. (5.5, 7.2) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------­ • Pediatric use: Meropenem for Injection and Sodium Chloride Injection should not be used in pediatric patients who require less than the full adult dose of meropenem. (8.4) • Renal Impairment: Dose adjustment is necessary, if creatinine clearance is 50 mL/min or less. (2.2, 8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2024 Reference ID: 5488100 FULL PRESCRIBING INFORMATION: CONTENTS * 1 INDICATIONS AND USAGE 1.1 Complicated Skin and Skin Structure Infections (Adult Patients and Pediatric Patients 3 Months of age and older requiring the full adult dose only) 1.2 Complicated Intra-abdominal Infections (Adult Patients and Pediatric Patients 3 Months of age and older requiring the full adult dose only) 1.3 Bacterial Meningitis (Pediatric Patients 3 Months of age and older requiring the full adult dose only) 1.4 Usage 2 DOSAGE AND ADMINISTRATION 2.1 Adult Patients 2.2 Use in Adult Patients with Renal Impairment 2.3 Use in Pediatric Patients (3 Months of age and older only) 2.4 Preparation and Administration of Meropenem for Injection and Sodium Chloride Injection in DUPLEX® Container 2.5 Compatibility 2.6 Stability and Storage 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Severe Cutaneous Adverse Reactions 5.3 Rhabdomyolysis 5.4 Seizure Potential 5.5 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid 5.6 Clostridioides difficile–Associated Diarrhea 5.7 Development of Drug-Resistant Bacteria 5.8 Overgrowth of Nonsusceptible Organisms 5.9 Thrombocytopenia 5.10 Potential for Neuromotor Impairment 5.11 High Sodium Load 6 ADVERSE REACTIONS 6.1 Adverse Reactions from Clinical Trials 6.2 Post-Marketing Experience 7 DRUG INTERACTIONS 7.1 Probenecid 7.2 Valproic Acid 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Patients with Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Complicated Skin and Skin Structure Infections 14.2 Complicated Intra-Abdominal Infections 14.3 Bacterial Meningitis 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5488100 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Complicated Skin and Skin Structure Infections (Adult Patients and Pediatric Patients 3 Months of age and older requiring the full adult dose only) Meropenem for Injection and Sodium Chloride Injection is indicated for the treatment of complicated skin and skin structure infections (cSSSI) due to Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis (vancomycin-susceptible isolates only), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species. 1.2 Complicated Intra-abdominal Infections (Adult Patients and Pediatric Patients 3 Months of age and older requiring the full adult dose only) Meropenem for Injection and Sodium Chloride Injection is indicated for the treatment of complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species. 1.3 Bacterial Meningitis (Pediatric Patients 3 Months of age and older requiring the full adult dose only) Meropenem for Injection and Sodium Chloride Injection is indicated for the treatment of bacterial meningitis caused by Haemophilus influenzae, Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae. Meropenem has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis. For information regarding use in pediatric patients (3 months of age and older) [see Indications and Usage (1.1), (1.2) or (1.3); Dosage and Administration (2.3), and Adverse Reactions (6.1)]. 1.4 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for Injection and Sodium Chloride Injection and other antibacterial drugs, Meropenem for Injection and Sodium Chloride Injection should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Reference ID: 5488100 2 DOSAGE AND ADMINISTRATION 2.1 Adult Patients Meropenem for Injection and Sodium Chloride Injection in the DUPLEX® Container should be used only in patients who require the entire 500 mg or 1 gram dose and not any fraction thereof. The recommended dose of Meropenem for Injection and Sodium Chloride Injection is 500 mg given every 8 hours for skin and skin structure infections and 1 gram given every 8 hours for intra-abdominal infections. When treating complicated skin and skin structure infections caused by P. aeruginosa, a dose of 1 gram every 8 hours is recommended. Meropenem for Injection and Sodium Chloride Injection should be administered by intravenous infusion over approximately 15 to 30 minutes. 2.2 Use in Adult Patients with Renal Impairment Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less. (See dosing table below.) Dosage should be reduced in renal failure if less than a full dose (1 gram or 500 mg) is required and an alternative formulation should be used to avoid risk of overdose. When only serum creatinine is available, the following formula (Cockcroft and Gault equation)1 may be used to estimate creatinine clearance. Males: Creatinine Clearance (mL/min) = Weight (kg) x (140 - age) 72 x serum creatinine (mg/dL) Females: 0.85 x above value Table 1: Recommended Meropenem for Injection Dosage Schedule for Adult Patients With Renal Impairment Creatinine Clearance (mL/min) Dose (dependent on type of infection) Dosing Interval greater than 50 Recommended dose (500 mg cSSSI and 1 gram Intra-abdominal infection) Every 8 hours 26-50 Recommended dose Every 12 hours 10-25 One-half recommended dose Every 12 hours less than 10 One-half recommended dose Every 24 hours There is inadequate information regarding the use of meropenem for injection in patients on hemodialysis or peritoneal dialysis. Reference ID: 5488100 2.3 Use in Pediatric Patients (3 Months of age and older only) • Meropenem for Injection and Sodium Chloride Injection in the DUPLEX® Container is designed to deliver a 500 mg or 1 gram dose of meropenem. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of meropenem. Meropenem is not to be used in pediatric patients aged less than three months. For pediatric patients 3 months of age and older, the Meropenem for Injection and Sodium Chloride Injection dose is 10 mg/kg, 20 mg/kg or 40 mg/kg every 8 hours (maximum dose is 2 grams every 8 hours), depending on the type of infection (cSSSI, cIAI, intra-abdominal infection or meningitis). See dosing table 2 below. [see Use in Specific Populations (8.4)]. • For pediatric patients weighing over 50 kg administer Meropenem for Injection and Sodium Chloride Injection at a dose of 500 mg every 8 hours for cSSSI, 1 gram every 8 hours for cIAI and 2 grams every 8 hours for meningitis. • Administer Meropenem for Injection and Sodium Chloride Injection as an intravenous infusion over approximately 15 minutes to 30 minutes. Table 2: Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients With Normal Renal Function Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Complicated Skin and Skin Structure Infections 10 500 mg Every 8 hours Complicated Intra-abdominal Infections 20 1 gram Every 8 hours Meningitis 40 2 grams Every 8 hours There is no experience in pediatric patients with renal impairment. When treating cSSSI caused by P. aeruginosa, a dose of 20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended. 2.4 Preparation and Administration of Meropenem for Injection and Sodium Chloride Injection in DUPLEX® Container Important Administration Instructions • Do not use in series connections. Such use would result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. • Do not introduce additives into the DUPLEX® Container. • Administer Meropenem for Injection and Sodium Chloride Injection intravenously over approximately 15 to 30 minutes. Reference ID: 5488100 Diagram 1 = Diluent Chamber Hanger Tab h ..._________ setPort with Foil Diagram 2 Cover This reconstituted solution is for intravenous use only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Use only if solution is clear and container and seals are intact. DUPLEX® Container Storage • To avoid inadvertent activation, the DUPLEX® Container should remain in the folded position until activation is intended. Patient Labeling and Drug Powder/Diluent Inspection • Apply patient-specific label on foil side of container. Use care to avoid activation. Do not cover any portion of foil strip with patient label. • Unlatch side tab and unfold DUPLEX® Container (see Diagram 1). • Visually inspect diluent chamber for particulate matter. • Use only if container and seals are intact. • To inspect the drug powder for foreign matter or discoloration, peel foil strip from drug chamber (see Diagram 2). • Protect from light after removal of foil strip. Note: If foil strip is removed, the container should be re-folded and the side tab latched until ready to activate. The product must then be used within 7 days at room temperature, but not beyond the labeled expiration date. Reference ID: 5488100 0iagram3 Reconstitution (Activation) • Do not use directly after storage by refrigeration, allow the product to equilibrate to room temperature before patient use. • Unfold the DUPLEX® Container and point the set port in a downward direction. Starting at the hanger tab end, fold the DUPLEX® Container just below the diluent meniscus trapping all air above the fold. To activate, squeeze the folded diluent chamber until the seal between the diluent and powder opens, releasing diluent into the drug powder chamber (see Diagram 3). • Agitate the liquid-powder mixture until the drug powder is completely dissolved. Note: Following reconstitution (activation), product must be used within 1 hour if stored at room temperature or within 15 hours if stored under refrigeration. Administration • Visually inspect the reconstituted solution for particulate matter. • Point the set port in a downwards direction. Starting at the hanger tab end, fold the DUPLEX® Container just below the solution meniscus trapping all air above the fold. Squeeze the folded DUPLEX® Container until the seal between reconstituted drug solution and set port opens, releasing liquid to set port (see Diagram 4). • Prior to attaching the IV set, check for minute leaks by squeezing container firmly. If leaks are found, discard container and solution as sterility may be compromised. Reference ID: 5488100 Set Port_) J! --Foil Cover Diagrams ) • Using aseptic technique, peel foil cover from the set port and attach sterile administration set (see Diagram 5). • Refer to directions for use accompanying the administration set. • Discard unused portion. 2.5 Compatibility Compatibility of Meropenem for Injection and Sodium Chloride Injection with other drugs has not been established. Meropenem for Injection and Sodium Chloride Injection should not be mixed with or physically added to solutions containing other drugs. 2.6 Stability and Storage Freshly prepared solutions of Meropenem for Injection and Sodium Chloride Injection should be used. Following reconstitution (activation) in the DUPLEX® Container, the product maintains satisfactory potency for 1 hour at up to 25ºC (77ºF) or for 15 hours at up to 5ºC (41ºF). Solutions of intravenous Meropenem for Injection and Sodium Chloride Injection should not be frozen. 3 DOSAGE FORMS AND STRENGTHS Single-dose DUPLEX® (Dual-chamber) container: • 500 mg meropenem for injection USP (as a blend of sterile meropenem trihydrate USP and sterile sodium carbonate USP/NF) and 50 mL of sodium chloride injection USP • 1 gram meropenem for injection USP (as a blend of sterile meropenem trihydrate USP and sterile sodium carbonate USP/NF) and 50 mL of sodium chloride injection USP 4 CONTRAINDICATIONS Meropenem for Injection and Sodium Chloride Injection is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams. Reference ID: 5488100 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another beta-lactam. Before initiating therapy with Meropenem for Injection and Sodium Chloride Injection, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams, and other allergens. If an allergic reaction to Meropenem for Injection and Sodium Chloride Injection occurs, discontinue the drug immediately. 5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving meropenem [see Adverse Reactions (6.2)]. If signs and symptoms suggestive of these reactions appear, Meropenem for Injection and Sodium Chloride Injection should be withdrawn immediately and an alternative treatment should be considered. 5.3 Rhabdomyolysis Rhabdomyolysis has been reported with the use of meropenem [see Adverse Reactions (6.2)]. If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine, or elevated creatine phosphokinase are observed, discontinue Meropenem for Injection and Sodium Chloride Injection and initiate appropriate therapy. 5.4 Seizure Potential Seizures and other adverse CNS experiences have been reported during treatment with meropenem for injection. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function [see Adverse Reactions (6.1) and Drug Interactions (7.2)]. During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (based on 20 patients with this adverse event). All meropenem-treated patients with seizures had pre-existing contributing factors. Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential. Dosage adjustment is recommended in patients with advanced age and/or adult patients with creatinine clearance of 50 mL/min or less [see Dosage and Administration (2.2)]. Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Anti-convulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate neurologically, place on anti-convulsant therapy if not already instituted, and re-examine the dosage of Meropenem for Injection and Sodium Chloride Injection to determine whether it should be decreased or discontinued. Reference ID: 5488100 5.5 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of Meropenem for Injection and Sodium Chloride Injection is necessary, consider supplemental anti-convulsant therapy [see Drug Interactions (7.2)]. 5.6 Clostridioides difficile–Associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including meropenem for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.7 Development of Drug-Resistant Bacteria Prescribing Meropenem for Injection and Sodium Chloride Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 5.8 Overgrowth of Nonsusceptible Organisms As with other broad-spectrum antibacterial drugs, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken. 5.9 Thrombocytopenia In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported [see Dosage and Administration (2.2), Adverse Reactions (6.1), Use In Specific Populations (8.5) and (8.6), and Clinical Pharmacology (12.3)]. Reference ID: 5488100 5.10 Potential for Neuromotor Impairment Alert patients receiving meropenem for injection on an outpatient basis regarding adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that meropenem for injection is well tolerated, advise patients not to operate machinery or motorized vehicles [see Adverse Reactions (6.1)]. 5.11 High Sodium Load Each 500 mg of Meropenem for Injection and Sodium Chloride Injection delivers 245.1 mg (10.7 mEq) of sodium and each 1 gram of Meropenem for Injection and Sodium Chloride Injection delivers 290.2 mg (12.6 mEq) of sodium. Avoid use of Meropenem for Injection and Sodium Chloride Injection in patients with congestive heart failure, elderly patients and patients requiring restricted sodium intake. 6 ADVERSE REACTIONS The following are discussed in greater detail in other sections of labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.1)] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] • Rhabdomyolysis [see Warnings and Precautions (5.3)] • Seizure Potential [see Warnings and Precautions (5.4)] • Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid [see Warnings and Precautions (5.5)] • Clostridioides difficile – Associated Diarrhea [see Warnings and Precautions (5.6)] • Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.7)] • Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.8)] • Thrombocytopenia [see Warnings and Precautions (5.9)] • Potential for Neuromotor Impairment [see Warnings and Precautions (5.10)] • High Sodium Load [see Warnings and Precautions (5.11)] 6.1 Adverse Reactions from Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Patients: During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with meropenem for injection (500 mg or 1000 mg every 8 hours). Deaths in 5 patients were assessed as possibly related to meropenem; 36 (1.2%) patients had meropenem discontinued because of adverse events. Many patients in these trials were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with meropenem for injection. The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with meropenem for injection. Reference ID: 5488100 Local Adverse Reactions Local adverse reactions that were reported with meropenem for injection were as follows: Inflammation at the injection site 2.4% Injection site reaction 0.9% Phlebitis/thrombophlebitis 0.8% Pain at the injection site 0.4% Edema at the injection site 0.2% Systemic Adverse Reactions Systemic adverse events that were reported with meropenem for injection occurring in greater than 1.0% of the patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%), and pruritus (1.2%). Additional systemic adverse reactions that were reported with meropenem for injection and occurring in less than or equal to 1.0% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency: Bleeding events were seen as follows: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%). Body as a Whole: pain, abdominal pain, chest pain, fever, back pain, abdominal enlargement, chills, pelvic pain Cardiovascular: heart failure, heart arrest, tachycardia, hypertension, myocardial infarction, pulmonary embolus, bradycardia, hypotension, syncope Digestive System: oral moniliasis, anorexia, cholestatic jaundice/jaundice, flatulence, ileus, hepatic failure, dyspepsia, intestinal obstruction Hemic/Lymphatic: anemia, hypochromic anemia, hypervolemia Metabolic/Nutritional: peripheral edema, hypoxia Nervous System: insomnia, agitation, delirium, confusion, dizziness, seizure, nervousness, paresthesia, hallucinations, somnolence, anxiety, depression, asthenia [see Warnings and Precautions (5.4) and (5.10)] Respiratory: respiratory disorder, dyspnea, pleural effusion, asthma, cough increased, lung edema Skin and Appendages: urticaria, sweating, skin ulcer Urogenital System: dysuria, kidney failure, vaginal moniliasis, urinary incontinence Adverse Laboratory Changes Adverse laboratory changes that were reported and occurring in greater than 0.2% of the patients were as follows: Reference ID: 5488100 Hepatic: increased alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), and bilirubin Hematologic: increased platelets, increased eosinophils, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased white blood cell (WBC), shortened prothrombin time and shortened partial thromboplastin time, leukocytosis, hypokalemia Renal: increased creatinine and increased blood urea nitrogen (BUN) Urinalysis: presence of red blood cells Complicated Skin and Skin Structure Infections In a study of complicated skin and skin structure infections, the adverse reactions were similar to those listed above. The most common adverse events occurring in greater than 5% of the patients were: headache (7.8%), nausea (7.8%), constipation (7.0%), diarrhea (7.0%), anemia (5.5%), and pain (5.1%). Adverse events with an incidence of greater than 1%, and not listed above, include: pharyngitis, accidental injury, gastrointestinal disorder, hypoglycemia, peripheral vascular disorder, and pneumonia. Patients with Renal Impairment: For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported irrespective of relationship to meropenem for injection, increased in patients with moderately severe renal impairment (creatinine clearance greater than 10 to 26 mL/min) [see Dosage and Administration (2.2), Warnings and Precautions (5.9), Use in Specific Populations (8.5) and (8.6) and Clinical Pharmacology (12.3)]. Pediatric Patients Systemic and Local Adverse Reactions Pediatric Patients with Serious Bacterial Infections (excluding Bacterial Meningitis): Meropenem for injection was studied in 515 pediatric patients (3 months of age and older to below 13 years of age) with serious bacterial infections (excluding meningitis, see next section) at dosages of 10 to 20 mg/kg every 8 hours. The types of systemic and local adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to meropenem for injection and their rates of occurrence as follows: Diarrhea 3.5% Rash 1.6% Nausea and Vomiting 0.8% Pediatric Patients with Bacterial Meningitis: Reference ID: 5488100 Meropenem for injection was studied in 321 pediatric patients (3 months of age and older to below 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of systemic and local adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to meropenem for injection and their rates of occurrence as follows: Diarrhea 4.7% Rash (mostly diaper area moniliasis) 3.1% Oral Moniliasis 1.9% Glossitis 1.0% In the meningitis studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents (either cefotaxime or ceftriaxone). In the meropenem for injection treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm. The meropenem group had a statistically higher number of patients with transient elevation of liver enzymes. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of meropenem, including meropenem for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Worldwide post-marketing adverse reactions not otherwise listed in the Adverse Reactions from Clinical Trials section of this prescribing information and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity. Blood and Lymphatic System Disorders: agranulocytosis, neutropenia, and leukopenia; a positive direct or indirect Coombs test, and hemolytic anemia. Immune System Disorders: angioedema. Skin and Subcutaneous Disorders: toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalized exanthematous pustulosis (AGEP). Musculoskeletal Disorders: rhabdomyolysis 7 DRUG INTERACTIONS 7.1 Probenecid Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. Coadministration of probenecid with meropenem is not recommended. Reference ID: 5488100 7.2 Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. If administration of meropenem for injection is necessary, then supplemental anti-convulsant therapy should be considered [see Warnings and Precautions (5.5)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem in pregnant women. No fetal toxicity or malformations were observed in pregnant rats and cynomolgus macaques administered intravenous meropenem during organogenesis at doses up to 3.2 and 2.3 times the maximum recommended human dose based on body surface area comparison, respectively. In rats administered intravenous meropenem in late pregnancy and during the lactation period, there were no adverse effects on offspring at doses equivalent to approximately 3.2 times the maximum recommended human dose based on body surface area comparison [see Data]. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Reproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day and in cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of body surface area comparisons, approximately 3.2 times and 2.3 times higher, respectively, than the maximum recommended human dose of 1 gram every 8 hours). These studies revealed no evidence of harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (equivalent to approximately 0.8 times the maximum recommended human dose of 1 gram every 8 hours based on body surface area comparison) and above in rats. In a published study2, meropenem administered to pregnant rats from Gestation Day 6 to Gestation Day 17, was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity. The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 2.4 times the highest recommended human dose based on body surface area comparison). Reference ID: 5488100 In a peri-postnatal study in rats described in the published literature1, intravenous meropenem was administered to dams from Gestation Day 17 until Postpartum Day 21. There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring. Second generation offspring showed no meropenem-related effects. The NOAEL value was considered to be 1000 mg/kg/day (approximately 3.2 times the highest recommended clinical dose based on body surface area comparisons). 8.2 Lactation Risk Summary Meropenem has been reported to be excreted in human milk. No information is available on the effects of meropenem on the breastfed –child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Meropenem for Injection and Sodium Chloride Injection in the DUPLEX® Container and any potential adverse effects on the breastfed-child from Meropenem for Injection and Sodium Chloride Injection in the DUPLEX® Container or from the underlying maternal conditions. 8.4 Pediatric Use Meropenem for Injection and Sodium Chloride Injection in the DUPLEX® Container is designed to deliver a 500 mg or 1 gram dose of meropenem. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of meropenem. Meropenem is not to be used in pediatric patients aged less than three months. [see Dosage and Administration (2.3)]. Use of meropenem for injection in pediatric patients with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population. Use of meropenem for injection in pediatric patients with intra-abdominal infections is supported by evidence from adequate and well-controlled studies with adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. Use of meropenem for injection in pediatric patients with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study with adults and additional data from pediatric pharmacokinetics studies [see Indications and Usage (1), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)]. 8.5 Geriatric Use Of the total number of subjects in clinical studies of meropenem for injection, approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older. Additionally, in a study of 511 patients with complicated skin and skin structure infections, 93 (18%) were 65 years of age and older, while 38 (7%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; spontaneous reports and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Reference ID: 5488100 Meropenem is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. A pharmacokinetic study with meropenem for injection in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance [see Clinical Pharmacology (12.3)]. Each 500 mg of Meropenem for Injection and Sodium Chloride Injection delivers 245.1 mg (10.7 mEq) of sodium and each 1 gram of Meropenem for Injection and Sodium Chloride Injection delivers 290.2 mg (12.6 mEq) of sodium. At the usual recommended doses of 500 mg or 1000 mg every 8 hours, patients would receive between 735 mg/day and 870 mg/day (32 mEq and 38 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure [see Contraindications (4) and Warnings and Precautions (5.11)]. 8.6 Patients with Renal Impairment Dosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less [see Dosage and Administration (2.2), Warnings and Precautions (5.9), and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In mice and rats, large intravenous doses of meropenem (2200-4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities. Intentional overdosing of Meropenem for Injection and Sodium Chloride Injection is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function. The largest dose of meropenem administered in clinical trials has been 2 grams given intravenously every 8 hours. At this dosage, no adverse pharmacological effects or increased safety risks have been observed. Limited post-marketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction. Symptomatic treatments should be considered. In individuals with normal renal function, rapid renal elimination takes place. Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage. 11 DESCRIPTION Meropenem for injection is a sterile, pyrogen-free, synthetic, carbapenem antibacterial drug for intravenous administration. Meropenem is (4R,5S,6S)-3- [[(3S,5S)-5-(Dimethylcarbamoyl)-3­ pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate. Its empirical formula is C17H25N3O5S•3H2O with a molecular weight of 437.52. Reference ID: 5488100 Its structural formula is: Meropenem for injection is a white to pale yellow crystalline powder containing meropenem trihydrate and sodium carbonate. The constituted solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether. Meropenem for Injection USP and Sodium Chloride Injection USP is supplied as a sterile, nonpyrogenic, single-dose packaged combination of meropenem (drug chamber) and 50 mL of sodium chloride (diluent) in the DUPLEX® sterile container. When reconstituted as instructed, each 1 gram Meropenem for injection in the DUPLEX® Container will deliver 1 gram of meropenem and a total sodium content of 290.2 mg (12.6 mEq). Each 500 mg Meropenem for injection in the DUPLEX® Container will deliver 500 mg of meropenem and a total sodium content of 245.1 mg (10.7 mEq) [see Dosage and Administration (2.4)]. The osmolality of the reconstituted solution of Meropenem for Injection USP and Sodium Chloride Injection USP is approximately 356 mOsmol/kg for the 500 mg dose and approximately 417 mOsmol/kg for the 1 gram dose. The DUPLEX® Container is a flexible dual chamber container. After removing the peelable foil strip, activating the seals, and thoroughly mixing, the reconstituted drug product is hyperosmotic and is intended for single intravenous use. The product (diluent and drug) contact layer is a mixture of thermoplastic rubber and a polypropylene ethylene copolymer that contains no plasticizers. Not made with natural rubber latex, PVC or Di(2-ethylhexyl)phthalate (DEHP). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Meropenem is an antibacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics The percentage of time of a dosing interval that unbound plasma concentration of meropenem exceeds the meropenem minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection. Reference ID: 5488100 12.3 Pharmacokinetics Plasma Concentrations At the end of a 30-minute intravenous infusion of a single dose of meropenem for injection in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 mcg/mL (range 14-26) for the 500 mg dose and 49 mcg/mL (range 39-58) for the 1 gram dose. A 5-minute intravenous bolus injection of meropenem in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18-65) for the 500 mg dose and 112 mcg/mL (range 83-140) for the 1 gram dose. Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 mcg/mL at 6 hours after administration. No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 gram administered every 6 hours in healthy volunteers with normal renal function. Distribution The plasma protein binding of meropenem is approximately 2%. After a single intravenous dose of meropenem for injection, the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour (0.5 to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in table 3 below. Table 3: Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported) Tissue Intravenous Dose (gram) Number of Samples Mean [mcg/mL or mcg/(g)]1 Range [mcg/mL or mcg/(g)] Endometrium 0.5 7 4.2 1.7-10.2 Myometrium 0.5 15 3.8 0.4-8.1 Ovary 0.5 8 2.8 0.8-4.8 Cervix 0.5 2 7 5.4-8.5 Fallopian tube 0.5 9 1.7 0.3-3.4 Skin 0.5 22 3.3 0.5-12.6 Interstitial fluid2 0.5 9 5.5 3.2-8.6 Skin 1 10 5.3 1.3-16.7 Interstitial fluid2 1 5 26.3 20.9-37.4 Colon 1 2 2.6 2.5-2.7 Bile 1 7 14.6 (3 hours) 4.0-25.7 Gall bladder 1 1 - 3.9 Peritoneal fluid 1 9 30.2 7.4-54.6 Lung 1 2 4.8 (2 hours) 1.4-8.2 Bronchial mucosa 1 7 4.5 1.3-11.1 Reference ID: 5488100 Muscle 1 2 6.1 (2 hours) 5.3-6.9 Fascia 1 9 8.8 1.5-20 Heart valves 1 7 9.7 6.4-12.1 Myocardium 1 10 15.5 5.2-25.5 CSF (inflamed) 20 mg/kg3 8 1.1 (2 hours) 0.2-2.8 40 mg/kg4 5 3.3 (3 hours) 0.9-6.5 CSF (uninflamed) 1 4 0.2 (2 hours) 0.1-0.3 1 at 1 hour unless otherwise noted 2 obtained from blister fluid 3 in pediatric patients of age 5 months to 8 years 4 in pediatric patients of age 1 month to 15 years Elimination In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour. Metabolism There is one metabolite of meropenem that is microbiologically inactive. Excretion Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50 – 75%) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Fecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion. Urinary concentrations of meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose. Specific Populations Patients with Renal Impairment Pharmacokinetic studies with meropenem for injection in patients with renal impairment have shown that the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment (creatinine clearance 50 mL/min or less) [see Dosage and Administration (2.2) and Use In Specific Populations (8.6)]. Meropenem is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage [see Overdosage (10)]. Reference ID: 5488100 Patients with Hepatic Impairment A pharmacokinetic study with meropenem for injection in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem. Geriatric Patients A pharmacokinetic study with meropenem for injection in elderly patients with renal impairment showed a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance. Pediatric Patients The pharmacokinetics of meropenem in pediatric patients 2 years of age or older are similar to those in adults. The elimination half-life for meropenem was approximately 1.5 hours in pediatric patients of age 3 months to 2 years. The pharmacokinetics of meropenem in patients less than 3 months of age receiving combination antibacterial drug therapy are given below. Table 4: Meropenem Pharmacokinetic Parameters in Patients Less Than 3 Months of Age* GA GA less than GA GA less than 32 weeks 32 weeks or 32 weeks 32 weeks PNA older or older PNA 2 weeks or PNA less than PNA less than older 2 weeks 2 weeks or Overall 2 weeks (20mg/kg (20mg/kg older (20mg/kg every every (30mg/kg every 8 hours) 8 hours) every 12 hours) 8 hours) CL (L/h/kg) 0.089 0.122 0.135 0.202 0.119 V (L/kg) 0.489 0.467 0.463 0.451 0.468 AUC0-24 (mcg-h/mL) 448 491 445 444 467 Cmax (mcg/mL) 44.3 46.5 44.9 61 46.9 Cmin (mcg/mL) 5.36 6.65 4.84 2.1 5.65 T1/2 (h) 3.82 2.68 2.33 1.58 2.68 *Values are derived from a population pharmacokinetic analysis of sparse data Reference ID: 5488100 Drug Interactions Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38%. Co-administration of probenecid with meropenem is not recommended. 12.4 Microbiology Mechanism of Action The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. Meropenem binds to PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus. Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 to 24 hours) are typically 1-2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed. Meropenem has significant stability to hydrolysis by beta-lactamases, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria. Meropenem does not have in-vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE). Resistance There are several mechanisms of resistance to carbapenems: 1) decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake, 2) reduced affinity of the target PBPs, 3) increased expression of efflux pump components, and 4) production of antibacterial drug-destroying enzymes (carbapenemases, metallo-beta-lactamases). Cross-Resistance Cross-resistance is sometimes observed with isolates resistant to other carbapenems. Interaction with Other Antimicrobials In vitro tests show meropenem to act synergistically with aminoglycoside antibacterial drugs against some isolates of Pseudomonas aeruginosa. Antimicrobial Activity Meropenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]. Reference ID: 5488100 Gram-positive bacteria Enterococcus faecalis (vancomycin-susceptible isolates only) Staphylococcus aureus (methicillin-susceptible isolates only) Streptococcus agalactiae Streptococcus pneumoniae (penicillin-susceptible isolates only) Streptococcus pyogenes Viridans group streptococci Gram-negative bacteria Escherichia coli Haemophilus influenzae Klebsiella pneumoniae Neisseria meningitidis Proteus mirabilis Pseudomonas aeruginosa Anaerobic bacteria Bacteroides fragilis Bacteroides thetaiotaomicron Peptostreptococcus species The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for meropenem against isolates of similar genus or organism group. However, the efficacy of meropenem in treating clinical infections caused by these microorganisms has not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Staphylococcus epidermidis (methicillin-susceptible isolates only) Gram-negative bacteria Aeromonas hydrophila Campylobacter jejuni Citrobacter freundii Citrobacter koseri Reference ID: 5488100 Enterobacter cloacae Hafnia alvei Klebsiella oxytoca Moraxella catarrhalis Morganella morganii Pasteurella multocida Proteus vulgaris Serratia marcescens Anaerobic bacteria Bacteroides ovatus Bacteroides uniformis Bacteroides ureolyticus Bacteroides vulgatus Clostridioides difficile Clostridium perfringens Eggerthella lenta Fusobacterium species Parabacteroides distasonis Porphyromonas asaccharolytica Prevotella bivia Prevotella intermedia Prevotella melaninogenica Propionibacterium acnes Susceptibility Test Methods For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC. Reference ID: 5488100 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Carcinogenesis studies have not been performed. Mutagenesis: Genetic toxicity studies were performed with meropenem using the bacterial reverse mutation test, the Chinese hamster ovary HGPRT assay, cultured human lymphocytes cytogenic assay, and the mouse micronucleus test. There was no evidence of mutagenic potential found in any of these tests. Impairment of Fertility: Reproductive studies performed with meropenem in rats at doses up to 1000 mg/kg/day, (approximately 1.8 times the human exposure at a dose of 1 gram every 8 hours based on AUC) showed no evidence of fertility impairment. 14 CLINICAL STUDIES 14.1 Complicated Skin and Skin Structure Infections Adult patients with complicated skin and skin structure infections including complicated cellulitis, complex abscesses, perirectal abscesses, and skin infections requiring intravenous antimicrobials, hospitalization, and surgical intervention were enrolled in a randomized, multi-center, international, double-blind trial. The study evaluated meropenem at doses of 500 mg administered intravenously every 8 hours and imipenem-cilastatin at doses of 500 mg administered intravenously every 8 hours. The study compared the clinical response between treatment groups in the clinically evaluable population at the follow-up visit (test-of-cure). The trial was conducted in the United States, South Africa, Canada, and Brazil. At enrollment, approximately 37% of the patients had underlying diabetes, 12% had underlying peripheral vascular disease and 67% had a surgical intervention. The study included 510 patients randomized to meropenem and 527 patients randomized to imipenem-cilastatin. Two hundred and sixty one (261) patients randomized to meropenem and 287 patients randomized to imipenem-cilastatin were clinically evaluable. The success rates in the clinically evaluable patients at the follow-up visit were 86% (225/261) in the meropenem arm and 83% (238/287) in imipenem-cilastatin arm. Reference ID: 5488100 The success rates for clinically evaluable population are provided in Table 5. Table 5: Success Rates at Test-of-Cure Visit for Clinically Evaluable Population with Complicated Skin and Skin Structure Infections Population Meropenem for Injection n1/N2 (%) Imipenem-cilastatin n1/N2 (%) Total 225/261 (86) 238/287 (83) Diabetes mellitus 83/97 (86) 76/105 (72) No diabetes mellitus 142/164 (87) 162/182 (89) Less than 65 years of age 190/218 (87) 205/241 (85) 65 years of age and older 35/43 (81) 33/46 (72) Men 130/148 (88) 137/172 (80) Women 95/113 (84) 101/115 (88) 1 n=number of patients with satisfactory response. 2 N=number of patients in the clinically evaluable population or respective subgroup within treatment groups. The clinical efficacy rates by pathogen are provided in Table 6. The values represent the number of patients clinically cured/number of clinically evaluable patients at the post-treatment follow-up visit, with the percent cure in parentheses (Fully Evaluable analysis set). Table 6: Clinical Efficacy Rates by Pathogen for Clinically Evaluable Population MICROORGANISMS1 Meropenem for Injection n2/N3 (%)4 Imipenem-cilastatin n2/N3 (%)4 Gram-positive aerobes Staphylococcus aureus, methicillin susceptible 82/88 (93) 84/100 (84) Streptococcus pyogenes (Group A) 26/29 (90) 28/32 (88) Streptococcus agalactiae (Group B) 12/17 (71) 16/19 (84) Enterococcus faecalis 9/12 (75) 14/20 (70) Viridans group streptococci 11/12 (92) 5/6 (83) Gram-negative aerobes Escherichia coli 12/15 (80) 15/21 (71) Pseudomonas aeruginosa 11/15 (73) 13/15 (87) Proteus mirabilis 11/13 (85) 6/7 (86) Anaerobes Bacteroides fragilis 10/11 (91) 9/10 (90) Peptostreptococcus spp. 10/13 (77) 14/16 (88) Reference ID: 5488100 1 Patients may have more than one pretreatment pathogen. 2 n=number of patients with satisfactory response. 3 N=number of patients in the clinically evaluable population or subgroup within treatment groups. 4 %= Percent of satisfactory clinical response at follow-up evaluation. The proportion of patients who discontinued study treatment due to an adverse event was similar for both treatment groups (meropenem, 2.5% and imipenem-cilastatin, 2.7%). 14.2 Complicated Intra-Abdominal Infections One controlled clinical study of complicated intra-abdominal infection was performed in the United States where meropenem was compared with clindamycin/tobramycin. Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; meropenem was compared with imipenem (two trials) and cefotaxime/metronidazole (one trial). Using strict evaluability criteria and microbiologic eradication and clinical cures at follow-up which occurred 7 or more days after completion of therapy, the presumptive microbiologic eradication/clinical cure rates and statistical findings are provided in Table 7. Table 7: Presumptive Microbiologic Eradication and Clinical Cure Rates at Test-of-Cure Visit in the Evaluable population with Complicated intra-abdominal infections Treatment Arm No. evaluable/ No. enrolled (%) Microbiologic Eradication Rate Clinical Cure Rate Outcome meropenem 146/516 (28%) 98/146 (67%) 101/146 (69%) imipenem 65/220 (30%) 40/65 (62%) 42/65 (65%) Meropenem equivalent to control cefotaxime/ metronidazole 26/85 (30%) 22/26 (85%) 22/26 (85%) Meropenem not equivalent to control clindamycin/ tobramycin 50/212 (24%) 38/50 (76%) 38/50 (76%) Meropenem equivalent to control The finding that meropenem was not statistically equivalent to cefotaxime/metronidazole may have been due to uneven assignment of more seriously ill patients to the meropenem arm. Currently there is no additional information available to further interpret this observation. Reference ID: 5488100 14.3 Bacterial Meningitis Four hundred forty-six patients (397 pediatric patients 3 months of age and older to below 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with meropenem (n=225) at a dose of 40 mg/kg every 8 hours or a comparator drug, i.e., cefotaxime (n=187) or ceftriaxone (n=34), at the approved dosing regimens. A comparable number of patients were found to be clinically evaluable (ranging from 61-68%) and with a similar distribution of pathogens isolated on initial CSF culture. Patients were defined as clinically not cured if any one of the following three criteria were met: 1. At the 5-7 week post-completion of therapy visit, the patient had any one of the following: moderate to severe motor, behavior or development deficits, hearing loss of greater than 60 decibels in one or both ears, or blindness. 2. During therapy the patient’s clinical status necessitated the addition of other antibacterial drugs. 3. Either during or post-therapy, the patient developed a large subdural effusion needing surgical drainage, or a cerebral abscess, or a bacteriologic relapse. Using the definition, the following efficacy rates were obtained, per organism (noted in Table 8). The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses. Table 8: Efficacy Rates by Pathogen in the Clinically Evaluable Population with Bacterial Meningitis MICROORGANISMS MEROPENEM FOR INJECTION COMPARATOR S. pneumoniae 17/24 (71) 19/30 (63) H. influenzae (+)1 8/10 (80) 6/6 (100) H. influenzae (-/NT)2 44/59 (75) 44/60 (73) N. meningitidis 30/35 (86) 35/39 (90) Total (including others) 102/131 (78) 108/140 (77) 1 (+) beta-lactamase-producing 2 (-/NT) non-beta-lactamase-producing or not tested Sequelae were the most common reason patients were assessed as clinically not cured. Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the meropenem group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa). With respect to hearing loss, 263 of the 271 evaluable patients had at least one hearing test performed post-therapy. The following table shows the degree of hearing loss between the meropenem-treated patients and the comparator-treated patients. Reference ID: 5488100 Table 9: Hearing Loss at Post-Therapy in the Evaluable Population treated with Meropenem Degree of Hearing Loss (in one or both ears) Meropenem n = 128 Comparator n = 135 No loss 61% 56% 20-40 decibels 20% 24% greater than 40-60 decibels 8% 7% greater than 60 decibels 9% 10% 15 REFERENCES 1. Cockcroft DW, MH Gault, 1976, Prediction of creatinine clearance from serum creatinine, Nephron, 16:31-41. 2. Kawamura S, AW Russell, SJ Freeman, and RA Siddall, 1992, Reproductive and Developmental Toxicity of Meropenem in Rats, Chemotherapy, 40:S238-250. 16 HOW SUPPLIED/STORAGE AND HANDLING Meropenem for Injection USP and Sodium Chloride Injection USP in the DUPLEX® Container is a flexible dual chamber single-dose container supplied in two concentrations. The diluent chamber contains approximately 50 mL of 0.9% Sodium Chloride Injection USP. After reconstitution, the delivered doses are equivalent to 500* mg and 1* gram meropenem. Meropenem for Injection USP and Sodium Chloride Injection USP is supplied sterile and nonpyrogenic in the DUPLEX® Container packaged 24 units per case. NDC REF Dose Volume 0264-3183-11 0264-3185-11 *Anhydrous basis. 3183-11 3185-11 500 mg 1 gram 50 mL 50 mL Store the unactivated unit at 20°C–25°C (68°F–77°F). Excursion permitted to 15°C-30°C. [See USP Controlled Room Temperature.] Protect from freezing. Use only if prepared solution is clear and free from particulate matter. Reference ID: 5488100 17 PATIENT COUNSELING INFORMATION • Patients should be counseled that antibacterial drugs including Meropenem for Injection and Sodium Chloride Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Meropenem for Injection and Sodium Chloride Injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Meropenem for Injection and Sodium Chloride Injection or other antibacterial drugs in the future. • Counsel patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.6)]. • Counsel patients to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with Meropenem for Injection and Sodium Chloride Injection. If treatment with Meropenem for Injection and Sodium Chloride Injection is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed [see Warnings and Precautions (5.5)]. • Patients receiving Meropenem for Injection and Sodium Chloride Injection on an outpatient basis must be alerted of adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that Meropenem for Injection and Sodium Chloride Injection is well tolerated, patients should not operate machinery or motorized vehicles [see Warnings and Precautions (5.10)]. • Meropenem for Injection and Sodium Chloride Injection contains a high sodium load. Instruct patients to inform or report symptoms of difficulty breathing, swelling, or increased weight [see Warnings and Precautions (5.11)]. DUPLEX is a registered trademark of B. Braun Medical Inc. ATCC is a registered trademark of the American Type Culture Collection Manufactured for: B. Braun Medical Inc. Bethlehem, PA 18018-3524 USA 1-800-227-2862 Manufactured by: ACS Dobfar S.p.A. Prepared in Italy. API from Italy and Austria. Y36-003-091 LD-244-5 Reference ID: 5488100
custom-source
2025-02-12T15:47:29.459920
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZOSYN ---------------------------WARNINGS AND PRECAUTIONS -------------------­ safely and effectively. See full prescribing information for ZOSYN. ZOSYN® (piperacillin and tazobactam) injection, for intravenous use Initial U.S. approval: 1993 ---------------------------RECENT MAJOR CHANGES--------------------------­ Warnings and Precautions, Rhabdomyolysis (5.4) 12/2024 -------------------------- INDICATIONS AND USAGE----------------------------­ ZOSYN is a combination of piperacillin, a penicillin-class antibacterial and tazobactam, a beta-lactamase inhibitor, indicated for the treatment of: • Intra-abdominal infections in adult and pediatric patients 2 months of age and older (1.1) • Nosocomial pneumonia in adult and pediatric patients 2 months of age and older (1.2) • Skin and skin structure infections in adults (1.3) • Female pelvic infections in adults (1.4) • Community-acquired pneumonia in adults (1.5) To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZOSYN and other antibacterial drugs, ZOSYN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.6) -------------------------- DOSAGE AND ADMINISTRATION ------------------­ • If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered. (2.1) • Adult Patients With Indications Other Than Nosocomial Pneumonia; The usual daily dosage of ZOSYN for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin and 1.5 g tazobactam). (2.2) • Adult Patients with Nosocomial Pneumonia: Initial presumptive treatment of patients with nosocomial pneumonia should start with ZOSYN at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin and 2.0 g tazobactam). (2.3) • Adult Patients with Renal Impairment: Dosage in patients with renal impairment (creatinine clearance ≤40 mL/min) and dialysis patients should be reduced, based on the degree of renal impairment. (2.4) • Pediatric Patients by Indication and Age: See Table below (2.5) Recommended Dosage of ZOSYN for Pediatric Patients 2 months of Age and Older, Weighing up to 40 Kg and With Normal Renal Function Age Appendicitis and /or Peritonitis Nosocomial Pneumonia 2 months to 9 months 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 8 (eight) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 6 (six) hours Older than 9 months 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 8 (eight) hours 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 6 (six) hours • Administer ZOSYN by intravenous infusion over 30 minutes to both adult and pediatric patients (2.2, 2.3, 2.4, 2.5). • ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately. Co-administration via Y-site can be done under certain conditions. (2.7) • See the full prescribing information for the preparation and administration instructions for ZOSYN Injection in GALAXY Containers. -------------------------- DOSAGE FORMS AND STRENGTHS----------------­ ZOSYN® Injection: 2.25 g in 50 mL, 3.375 g in 50 mL, and 4.5 g in 100 mL frozen solution in single-dose GALAXY Containers. (3, 16) -------------------------- CONTRAINDICATIONS ---------------------------------­ Patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. (4) • Serious hypersensitivity reactions (anaphylactic/anaphylactoid) reactions have been reported in patients receiving ZOSYN. Discontinue ZOSYN if a reaction occurs. (5.1) • ZOSYN may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. Discontinue ZOSYN for progressive rashes. (5.2) • Hemophagocytic lymphohistiocytosis (HLH) has been reported with the use of ZOSYN. If HLH is suspected, discontinue ZOSYN immediately. (5.3) • Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue ZOSYN and initiate appropriate therapy. (5.4) • Hematological effects (including bleeding, leukopenia and neutropenia) have occurred. Monitor hematologic tests during prolonged therapy. (5.5) • As with other penicillins, ZOSYN may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially in the presence of renal impairment may be at greater risk. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures. (5.6) • Nephrotoxicity in critically ill patients has been observed; the use of ZOSYN was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with ZOSYN. (5.7) • Clostridioides difficile-associated diarrhea: evaluate patients if diarrhea occurs. (5.9) -------------------------------- ADVERSE REACTIONS----------------------------­ The most common adverse reactions (incidence >5%) are diarrhea, constipation, nausea, headache, and insomnia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------- DRUG INTERACTIONS ----------------------------­ • ZOSYN administration can significantly reduce tobramycin concentrations in hemodialysis patients. Monitor tobramycin concentrations in these patients. (7.1) • Probenecid prolongs the half-lives of piperacillin and tazobactam and should not be co-administered with ZOSYN unless the benefit outweighs the risk. (7.2) • Co-administration of ZOSYN with vancomycin may increase the incidence of acute kidney injury. Monitor kidney function in patients receiving ZOSYN and vancomycin. (7.3) • Monitor coagulation parameters in patients receiving ZOSYN and heparin or oral anticoagulants. (7.4) • ZOSYN may prolong the neuromuscular blockade of vecuronium and other non-depolarizing neuromuscular blockers. Monitor for adverse reactions related to neuromuscular blockade. (7.5) ---------------------------USE IN SPECIFIC POPULATIONS -------------------­ Dosage in patients with renal impairment (creatinine clearance ≤40 mL/min) should be reduced based on the degree of renal impairment. (2.4, 8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2024 1 Reference ID: 5488091 FULL PRESCRIBING INFORMATION: CONTENTS* 6.2 Postmarketing Experience 6.3 Additional Experience with Piperacillin 1 INDICATIONS AND USAGE 7 DRUG INTERACTIONS 1.1 Intra-abdominal Infections 7.1 Aminoglycosides 1.2 Nosocomial Pneumonia 7.2 Probenecid 1.3 Skin and Skin Structure Infections 7.3 Vancomycin 1.4 Female Pelvic Infections 7.4 Anticoagulants 1.5 Community-acquired Pneumonia 7.5 Vecuronium 1.6 Usage 7.6 Methotrexate 2 DOSAGE AND ADMINISTRATION 7.7 Effects on Laboratory Tests 2.1 Important Administration Instructions 8 USE IN SPECIFIC POPULATIONS 2.2 Dosage in Adult Patients With Indications Other Than Nosocomial 8.1 Pregnancy Pneumonia 8.2 Lactation 2.3 Dosage in Adult Patients With Nosocomial Pneumonia 8.4 Pediatric Use 2.4 Dosage in Adult Patients With Renal Impairment 8.5 Geriatric Use 2.5 Dosage in Pediatric Patients With Appendicitis/Peritonitis or 8.6 Renal Impairment Nosocomial Pneumonia 8.7 Hepatic Impairment 2.6 Directions for Use of ZOSYN Injection 8.8 Patients with Cystic Fibrosis 2.7 Compatibility With Aminoglycosides 10 OVERDOSAGE 3 DOSAGE FORMS AND STRENGTHS 11 DESCRIPTION 4 CONTRAINDICATIONS 12 CLINICAL PHARMACOLOGY 5 WARNINGS AND PRECAUTIONS 12.1 Mechanism of Action 5.1 Hypersensitivity Adverse Reactions 12.2 Pharmacodynamics 5.2 Severe Cutaneous Adverse Reactions 12.3 Pharmacokinetics 5.3 Hemophagocytic Lymphohistiocytosis 12.4 Microbiology 5.4 Rhabdomyolysis 13 NONCLINICAL TOXICOLOGY 5.5 Hematologic Adverse Reactions 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.6 Central Nervous System Adverse Reactions 15 REFERENCES 5.7 Nephrotoxicity in Critically Ill Patients 16 HOW SUPPLIED/STORAGE AND HANDLING 5.8 Electrolyte Effects 17 PATIENT COUNSELING INFORMATION 5.9 Clostridioides difficile-Associated Diarrhea 5.10 Development of Drug-Resistant Bacteria *Sections or subsections omitted from the full prescribing information are not 6 ADVERSE REACTIONS listed. 6.1 Clinical Trials Experience 2 Reference ID: 5488091 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Intra-abdominal Infections ZOSYN is indicated in adults and pediatric patients (2 months of age and older) for the treatment of appendicitis (complicated by rupture or abscess) and peritonitis caused by beta-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron, or B. vulgatus. 1.2 Nosocomial Pneumonia ZOSYN is indicated in adults and pediatric patients (2 months of age and older) for the treatment of nosocomial pneumonia (moderate to severe) caused by beta-lactamase producing isolates of Staphylococcus aureus and by piperacillin and tazobactam-susceptible Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa (Nosocomial pneumonia caused by P. aeruginosa should be treated in combination with an aminoglycoside) [see Dosage and Administration (2)]. 1.3 Skin and Skin Structure Infections ZOSYN is indicated in adults for the treatment of uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by beta-lactamase producing isolates of Staphylococcus aureus. 1.4 Female Pelvic Infections ZOSYN is indicated in adults for the treatment of postpartum endometritis or pelvic inflammatory disease caused by beta-lactamase producing isolates of Escherichia coli. 1.5 Community-acquired Pneumonia ZOSYN is indicated in adults for the treatment of community-acquired pneumonia (moderate severity only) caused by beta-lactamase producing isolates of Haemophilus influenzae. 1.6 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZOSYN and other antibacterial drugs, ZOSYN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 3 Reference ID: 5488091 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered. 2.2 Dosage in Adult Patients With Indications Other Than Nosocomial Pneumonia The usual total daily dosage of ZOSYN for adult patients with indications other than nosocomial pneumonia is 3.375 g every six hours [totaling 13.5 g (12.0 g piperacillin and 1.5 g tazobactam)], to be administered by intravenous infusion over 30 minutes. The usual duration of ZOSYN treatment is from 7 to 10 days. 2.3 Dosage in Adult Patients With Nosocomial Pneumonia Initial presumptive treatment of adult patients with nosocomial pneumonia should start with ZOSYN at a dosage of 4.5 g every six hours plus an aminoglycoside, [totaling 18.0 g (16.0 g piperacillin and 2.0 g tazobactam)], administered by intravenous infusion over 30 minutes. The recommended duration of ZOSYN treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated. 2.4 Dosage in Adult Patients With Renal Impairment In adult patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of ZOSYN should be reduced based on the degree of renal impairment. The recommended daily dosage of ZOSYN for patients with renal impairment administered by intravenous infusion over 30 minutes is described in Table 1. 4 Reference ID: 5488091 Table 1: Recommended Dosage of ZOSYN in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin and tazobactam)# Creatinine clearance, mL/min All Indications (except nosocomial pneumonia) Nosocomial Pneumonia Greater than 40 mL/min 3.375 every 6 hours 4.5 every 6 hours 20 to 40 mL/min* 2.25 every 6 hours 3.375 every 6 hours Less than 20 mL/min* 2.25 every 8 hours 2.25 every 6 hours Hemodialysis** 2.25 every 12 hours 2.25 every 8 hours CAPD 2.25 every 12 hours 2.25 every 8 hours # Administer ZOSYN by intravenous infusion over 30 minutes. * Creatinine clearance for patients not receiving hemodialysis ** 0.75 g (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia. Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g ZOSYN (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of ZOSYN is necessary for CAPD patients. 2.5 Dosage in Pediatric Patients With Appendicitis/Peritonitis or Nosocomial Pneumonia The recommended dosage for pediatric patients with appendicitis and/or peritonitis or nosocomial pneumonia aged 2 months of age and older, weighing up to 40 kg, and with normal renal function, is described in Table 2 [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. 5 Reference ID: 5488091 Table 2: Recommended Dosage of ZOSYN in Pediatric Patients 2 Months of Age and Older, Weighing Up to 40 kg, and With Normal Renal Function#, ## Age Appendicitis and/or Peritonitis Nosocomial Pneumonia 2 months to 9 months 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 8 (eight) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 6 (six) hours Older than 9 months of age 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 8 (eight) hours 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 6 (six) hours # Administer ZOSYN by intravenous infusion over 30 minutes ## If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered [see Use in Specific Populations (8.4)]. Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose [see Dosage and Administration (2.2, 2.3)]. Dosage of ZOSYN in pediatric patients with renal impairment has not been determined. 2.6 Directions for Use of ZOSYN Injection Important Administration Instructions for ZOSYN Injection in GALAXY Containers Administer ZOSYN Injection in GALAXY Containers using sterile equipment, after thawing to room temperature. ZOSYN containing EDTA is compatible for co-administration via a Y-site intravenous tube with Lactated Ringer’s injection, USP. Do NOT add supplementary medication. Unused portions of ZOSYN Injection should be discarded. Do NOT use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. Handle frozen product containers with care. Product containers may be fragile in the frozen state. 6 Reference ID: 5488091 Thawing of Plastic Container Thaw frozen container at room temperature 20°C to 25°C [68°F to 77°F] or under refrigeration (2°C to 8°C [36°F to 46°F]). Do not force thaw by immersion in water baths or by microwave irradiation. Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired. The container should be visually inspected. Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. Potency is not affected. Agitate after solution has reached room temperature. If after visual inspection, the solution remains cloudy or if an insoluble precipitate is noted or if any seals or outlet ports are not intact, the container should be discarded. Administration Instructions for ZOSYN Injection in GALAXY Containers to Adult Patients Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution. Administration Instruction for ZOSYN Injection in GALAXY Containers to Pediatric Patients Weighing up to 40 kg If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered. Storage of ZOSYN Injection Store in a freezer capable of maintaining a temperature of -20°C (-4°F). For GALAXY Containers, the thawed solution is stable for 14 days under refrigeration (2°C to 8°C [36°F to 46°F]) or 24 hours at room temperature 20°C to 25°C [68°F to 77°F]. Do not refreeze thawed ZOSYN Injection. 2.7 Compatibility With Aminoglycosides Due to the in vitro inactivation of aminoglycosides by piperacillin, ZOSYN and aminoglycosides are recommended for separate administration. ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated [see Drug Interactions (7.1)]. In circumstances where co-administration via Y-site is necessary, ZOSYN formulations containing EDTA are compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions: 7 Reference ID: 5488091 Table 3: Compatibility with Aminoglycosides Aminoglycoside ZOSYN Dose (grams) Aminoglycoside Concentration Range a (mg/mL) Acceptable Diluents Amikacin 2.25 3.375 4.5 1.75 - 7.5 0.9% sodium chloride or 5% dextrose Gentamicin 2.25 3.375b 4.5 0.7 - 3.32 0.9% sodium chloride or 5% dextrose a The concentration ranges in Table 3 are based on administration of the aminoglycoside in divided doses (10­ 15 mg/kg/day in two daily doses for amikacin and 3-5 mg/kg/day in three daily doses for gentamicin). Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y-site with ZOSYN containing EDTA has not been evaluated. See package insert for each aminoglycoside for complete Dosage and Administration instructions. b ZOSYN 3.375 g per 50 mL GALAXY Containers are NOT compatible with gentamicin for co-administration via a Y-site due to the higher concentrations of piperacillin and tazobactam. Only the concentration and diluents for amikacin or gentamicin with the dosages of ZOSYN listed above have been established as compatible for co-administration via Y-site infusion. Simultaneous co-administration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by ZOSYN. ZOSYN is not compatible with tobramycin for simultaneous co-administration via Y-site infusion. Compatibility of ZOSYN with other aminoglycosides has not been established. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 3 DOSAGE FORMS AND STRENGTHS ZOSYN® (piperacillin and tazobactam) Injection is supplied in GALAXY Containers as a frozen, iso-osmotic, sterile, non-pyrogenic solution in single-dose plastic containers: 2.25 g (piperacillin sodium equivalent to 2 g piperacillin and tazobactam sodium equivalent to 0.25 g tazobactam) in 50 mL. 3.375 g (piperacillin sodium equivalent to 3 g piperacillin and tazobactam sodium equivalent to 0.375 g tazobactam) in 50 mL. 8 Reference ID: 5488091 4.5 g (piperacillin sodium equivalent to 4 g piperacillin and tazobactam sodium equivalent to 0.5 g tazobactam) in 100 mL. 4 CONTRAINDICATIONS ZOSYN is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Adverse Reactions Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with ZOSYN. These reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity or a history of sensitivity to multiple allergens. Before initiating therapy with ZOSYN, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, ZOSYN should be discontinued and appropriate therapy instituted. 5.2 Severe Cutaneous Adverse Reactions ZOSYN may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. If patients develop a skin rash they should be monitored closely and ZOSYN discontinued if lesions progress. 5.3 Hemophagocytic Lymphohistiocytosis Cases of hemophagocytic lymphohistiocytosis (HLH) have been reported in pediatric and adult patients treated with ZOSYN. Signs and symptoms of HLH may include fever, rash, lymphadenopathy, hepatosplenomegaly and cytopenia. If HLH is suspected, discontinue ZOSYN immediately and institute appropriate management. 5.4 Rhabdomyolysis Rhabdomyolysis has been reported with the use of piperacillin and tazobactam [see Adverse Reactions (6.2)]. If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine, or elevated creatine phosphokinase are observed, discontinue ZOSYN and initiate appropriate therapy. 5.5 Hematologic Adverse Reactions Bleeding manifestations have occurred in some patients receiving beta-lactam drugs, including piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to 9 Reference ID: 5488091 occur in patients with renal failure. If bleeding manifestations occur, ZOSYN should be discontinued and appropriate therapy instituted. The leukopenia/neutropenia associated with ZOSYN administration appears to be reversible and most frequently associated with prolonged administration. Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, i.e., ≥ 21 days [see Adverse Reactions (6.1)]. 5.6 Central Nervous System Adverse Reactions As with other penicillins, ZOSYN may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially patients with renal impairment may be at greater risk for central nervous system adverse reactions. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures [see Adverse Reactions (6.2)]. 5.7 Nephrotoxicity in Critically Ill Patients The use of ZOSYN was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients [see Adverse Reactions (6.1)]. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with ZOSYN [see Dosage and Administration (2.4)]. Combined use of piperacillin and tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury [see Drug Interactions (7.3)]. 5.8 Electrolyte Effects ZOSYN contains a total of 2.84 mEq (65 mg) of Na+ (sodium) per gram of piperacillin in the combination product. This should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics. 5.9 Clostridioides difficile-Associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ZOSYN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can 10 Reference ID: 5488091 be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.10 Development of Drug-Resistant Bacteria Prescribing ZOSYN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypersensitivity Adverse Reactions [see Warnings and Precautions (5.1)] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] • Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.3)] • Rhabdomyolysis [see Warnings and Precautions (5.4)] • Hematologic Adverse Reactions [see Warnings and Precautions (5.5)] • Central Nervous System Adverse Reactions [see Warnings and Precautions (5.6)] • Nephrotoxicity in Critically Ill Patients [see Warnings and Precautions (5.7)] • Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adult Patients During the initial clinical investigations, 2621 patients worldwide were treated with ZOSYN in phase 3 trials. In the key North American monotherapy clinical trials (n=830 patients), 90% of the adverse events reported were mild to moderate in severity and transient in nature. However, in 3.2% of the patients treated worldwide, ZOSYN was discontinued because of adverse events primarily involving the skin (1.3%), including rash and pruritus; the gastrointestinal system (0.9%), including diarrhea, nausea, and vomiting; and allergic reactions (0.5%). Table 4: Adverse Reactions from ZOSYN Monotherapy Clinical Trials 11 Reference ID: 5488091 System Organ Class Adverse Reaction Gastrointestinal disorders Diarrhea (11.3%) Constipation (7.7%) Nausea (6.9%) Vomiting (3.3%) Dyspepsia (3.3%) Abdominal pain (1.3%) General disorders and administration site conditions Fever (2.4%) Injection site reaction (≤1%) Rigors (≤1%) Immune system disorders Anaphylaxis (≤1%) Infections and infestations Candidiasis (1.6%) Pseudomembranous colitis (≤1%) Metabolism and nutrition disorders Hypoglycemia (≤1%) Musculoskeletal and connective tissue disorders Myalgia (≤1%) Arthralgia (≤1%) Nervous system disorders Headache (7.7%) Psychiatric disorders Insomnia (6.6%) Skin and subcutaneous tissue disorders Rash (4.2%, including maculopapular, bullous, and urticarial) Pruritus (3.1%) Purpura (≤1%) 12 Reference ID: 5488091 Table 4: Adverse Reactions from ZOSYN Monotherapy Clinical Trials System Organ Class Adverse Reaction Vascular disorders Phlebitis (1.3%) Thrombophlebitis (≤1%) Hypotension (≤1%) Flushing (≤1%) Respiratory, thoracic and mediastinal disorders Epistaxis (≤1%) Nosocomial Pneumonia Trials Two trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with ZOSYN in a dosing regimen of 4.5 g every 6 hours in combination with an aminoglycoside and 215 patients were treated with imipenem/cilastatin (500 mg/500 mg every 6 hours) in combination with an aminoglycoside. In this trial, treatment-emergent adverse events were reported by 402 patients, 204 (91.9%) in the piperacillin and tazobactam group and 198 (92.1%) in the imipenem/cilastatin group. Twenty-five (11.0%) patients in the piperacillin and tazobactam group and 14 (6.5%) in the imipenem/cilastatin group (p > 0.05) discontinued treatment due to an adverse event. The second trial used a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside. Table 5: Adverse Reactions from ZOSYN Plus Aminoglycoside Clinical Trialsa System Organ Class Adverse Reaction Blood and lymphatic system disorders Thrombocythemia (1.4%) Anemia (≤1%) Thrombocytopenia (≤1%) Eosinophilia (≤1%) Gastrointestinal disorders Diarrhea (20%) Constipation (8.4%) Nausea (5.8%) Vomiting (2.7%) Dyspepsia (1.9%) Abdominal pain (1.8%) 13 Reference ID: 5488091 Table 5: Adverse Reactions from ZOSYN Plus Aminoglycoside Clinical Trialsa System Organ Class Adverse Reaction Stomatitis (≤1%) General disorders and administration site conditions Fever (3.2%) Injection site reaction (≤1%) Infections and infestations Oral candidiasis (3.9%) Candidiasis (1.8%) Investigations BUN increased (1.8%) Blood creatinine increased (1.8%) Liver function test abnormal (1.4%) Alkaline phosphatase increased (≤1%) Aspartate aminotransferase increased (≤1%) Alanine aminotransferase increased (≤1%) Metabolism and nutrition disorders Hypoglycemia (≤1%) Hypokalemia (≤1%) Nervous system disorders Headache (4.5%) Psychiatric disorders Insomnia (4.5%) Renal and urinary disorders Renal failure (≤1%) Skin and subcutaneous tissue disorders Rash (3.9%) Pruritus (3.2%) Vascular disorders Thrombophlebitis (1.3%) Hypotension (1.3%) a For adverse drug reactions that appeared in both studies the higher frequency is presented. 14 Reference ID: 5488091 Other Trials: Nephrotoxicity In a randomized, multicenter, controlled trial in 1200 adult critically ill patients, piperacillin and tazobactam was found to be a risk factor for renal failure (odds ratio 1.7, 95% CI 1.18 to 2.43), and associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs1 [see Warnings and Precautions (5.7)]. Adverse Laboratory Changes (Seen During Clinical Trials) Of the trials reported, including that of nosocomial lower respiratory tract infections in which a higher dose of ZOSYN was used in combination with an aminoglycoside, changes in laboratory parameters include: Hematologic—decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. These patients were withdrawn from therapy; some had accompanying systemic symptoms (e.g., fever, rigors, chills) Coagulation—positive direct Coombs' test, prolonged prothrombin time, prolonged partial thromboplastin time Hepatic—transient elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin Renal—increases in serum creatinine, blood urea nitrogen Additional laboratory events include abnormalities in electrolytes (i.e., increases and decreases in sodium, potassium, and calcium), hyperglycemia, decreases in total protein or albumin, blood glucose decreased, gamma-glutamyltransferase increased, hypokalemia, and bleeding time prolonged. Clinical Trials in Pediatric Patients Clinical studies of ZOSYN in pediatric patients suggest a similar safety profile to that seen in adults. In a prospective, randomized, comparative, open-label clinical trial of pediatric patients, 2 to 12 years of age, with intra-abdominal infections (including appendicitis and/or peritonitis), 273 patients were treated with ZOSYN 112.5 mg/kg given IV every 8 hours and 269 patients were treated with cefotaxime (50 mg/kg) plus metronidazole (7.5 mg/kg) every 8 hours. In this trial, treatment-emergent adverse events were reported by 146 patients, 73 (26.7%) in the ZOSYN group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the ZOSYN group and 5 patients (1.9%) in the cefotaxime/metronidazole group discontinued due to an adverse event. In a retrospective, cohort study, 140 pediatric patients 2 months to less than 18 years of age with nosocomial pneumonia were treated with ZOSYN and 267 patients were treated with comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or 15 Reference ID: 5488091 ciprofloxacin). The rates of serious adverse reactions were generally similar between the ZOSYN and comparator groups, including patients aged 2 months to 9 months treated with ZOSYN 90 mg/kg IV every 6 hours and patients older than 9 months and less than 18 years of age treated with ZOSYN 112.5 mg/kg IV every 6 hours. 6.2 Postmarketing Experience In addition to the adverse drug reactions identified in clinical trials in Table 4 and Table 5, the following adverse reactions have been identified during post-approval use of ZOSYN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary—hepatitis, jaundice Hematologic—hemolytic anemia, agranulocytosis, pancytopenia Immune—hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock), hemophagocytic lymphohistiocytosis (HLH), acute myocardial ischemia with or without myocardial infarction may occur as part of an allergic reaction. Renal—interstitial nephritis Nervous system disorders—seizures Psychiatric disorders—delirium Respiratory—eosinophilic pneumonia Skin and Appendages—erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, (DRESS), acute generalized exanthematous pustulosis (AGEP), dermatitis exfoliative, and linear IgA bullous dermatosis. Musculoskeletal Disorders—rhabdomyolysis Postmarketing experience with ZOSYN in pediatric patients suggests a similar safety profile to that seen in adults. 6.3 Additional Experience with Piperacillin The following adverse reaction has also been reported for piperacillin for injection: Skeletal—prolonged neuromuscular blockade [see Drug Interactions (7.5)]. 16 Reference ID: 5488091 7 DRUG INTERACTIONS 7.1 Aminoglycosides Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides. In vivo inactivation: When aminoglycosides are administered in conjunction with piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored. Sequential administration of ZOSYN and tobramycin to patients with either normal renal function or mild to moderate renal impairment has been shown to modestly decrease serum concentrations of tobramycin but no dosage adjustment is considered necessary. In vitro inactivation: Due to the in vitro inactivation of aminoglycosides by piperacillin, ZOSYN and aminoglycosides are recommended for separate administration. ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated. ZOSYN, which contains EDTA, is compatible with amikacin and gentamicin for simultaneous Y-site infusion in certain diluents and at specific concentrations. ZOSYN is not compatible with tobramycin for simultaneous Y-site infusion [see Dosage and Administration (2.7)]. 7.2 Probenecid Probenecid administered concomitantly with ZOSYN prolongs the half-life of piperacillin by 21% and that of tazobactam by 71% because probenecid inhibits tubular renal secretion of both piperacillin and tazobactam. Probenecid should not be co-administered with ZOSYN unless the benefit outweighs the risk. 7.3 Vancomycin Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin and tazobactam and vancomycin as compared to vancomycin alone [see Warnings and Precautions (5.7)]. Monitor kidney function in patients concomitantly administered with piperacillin and tazobactam and vancomycin. No pharmacokinetic interactions have been noted between piperacillin and tazobactam and vancomycin. 17 Reference ID: 5488091 7.4 Anticoagulants Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function [see Warnings and Precautions (5.5)]. 7.5 Vecuronium Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. ZOSYN could produce the same phenomenon if given along with vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing neuromuscular blockers could be prolonged in the presence of piperacillin. Monitor for adverse reactions related to neuromuscular blockade (see package insert for vecuronium bromide). 7.6 Methotrexate Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion. The impact of tazobactam on the elimination of methotrexate has not been evaluated. If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored. 7.7 Effects on Laboratory Tests There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin and tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with the Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving piperacillin and tazobactam should be interpreted cautiously and confirmed by other diagnostic methods. As with other penicillins, the administration of ZOSYN may result in a false-positive reaction for glucose in the urine using a copper-reduction method (CLINITEST®). It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Piperacillin and tazobactam cross the placenta in humans. However, there are insufficient data with piperacillin and/or tazobactam in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. No fetal structural abnormalities were observed in rats or 18 Reference ID: 5488091 mice when piperacillin and tazobactam was administered intravenously during organogenesis at doses 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m2). However, fetotoxicity in the presence of maternal toxicity was observed in developmental toxicity and peri/postnatal studies conducted in rats (intraperitoneal administration prior to mating and throughout gestation or from gestation day 17 through lactation day 21) at doses less than the maximum recommended human daily dose based on body-surface area (mg/m2) (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In embryo-fetal development studies in mice and rats, pregnant animals received intravenous doses of piperacillin and tazobactam up to 3000/750 mg/kg/day during the period of organogenesis. There was no evidence of teratogenicity up to the highest dose evaluated, which is 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, in mice and rats respectively, based on body-surface area (mg/m2). Fetal body weights were reduced in rats at maternally toxic doses at or above 500/62.5 mg/kg/day, minimally representing 0.4 times the human dose of both piperacillin and tazobactam based on body-surface area (mg/m2). A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin and tazobactam prior to mating and through the end of gestation, reported a decrease in litter size in the presence of maternal toxicity at 640 mg/kg/day tazobactam (4 times the human dose of tazobactam based on body-surface area), and decreased litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity at ≥640/160 mg/kg/day piperacillin and tazobactam (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area). Peri/postnatal development in rats was impaired with reduced pup weights, increased stillbirths, and increased pup mortality concurrent with maternal toxicity after intraperitoneal administration of tazobactam alone at doses ≥320 mg/kg/day (2 times the human dose based on body surface area) or of the combination piperacillin and tazobactam at doses ≥640/160 mg/kg/day (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area) from gestation day 17 through lactation day 21. 8.2 Lactation Risk Summary Piperacillin is excreted in human milk; tazobactam concentrations in human milk have not been studied. No information is available on the effects of piperacillin and tazobactam on the breast­ 19 Reference ID: 5488091 fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOSYN and any potential adverse effects on the breastfed child from ZOSYN or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ZOSYN for intra-abdominal infections, and nosocomial pneumonia have been established in pediatric patients 2 months of age and older. Use of ZOSYN in pediatric patients 2 months of age and older with intra-abdominal infections including appendicitis and/or peritonitis is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and in pediatric patients. This includes a prospective, randomized, comparative, open-label clinical trial with 542 pediatric patients 2 to 12 years of age with intra-abdominal infections (including appendicitis and/or peritonitis), in which 273 pediatric patients received piperacillin and tazobactam [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Use of ZOSYN in pediatric patients 2 months of age and older with nosocomial pneumonia is supported by evidence from well-controlled studies in adults with nosocomial pneumonia, a simulation study performed with a population pharmacokinetic model, and a retrospective, cohort study of pediatric patients with nosocomial pneumonia in which 140 pediatric patients were treated with ZOSYN and 267 patients treated with comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or ciprofloxacin) [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Because of the limitations of the available strengths and administration requirements (i.e., administration of fractional doses is not recommended) of ZOSYN Injection supplied in GALAXY Containers, and to avoid unintentional overdose, this product is not recommended for use if a dose of ZOSYN Injection in GALAXY Containers that does not equal 2.25 g, 3.375 g, or 4.5 g is required and an alternative formulation of ZOSYN should be considered [see Dosage and Administration (2.1, 2.5, and 2.6)]. The safety and effectiveness of ZOSYN have not been established in pediatric patients less than 2 months of age [see Clinical Pharmacology (12) and Dosage and Administration (2)]. Dosage of ZOSYN in pediatric patients with renal impairment has not been determined. 8.5 Geriatric Use Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal impairment [see Dosage and Administration (2)]. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 20 Reference ID: 5488091 ZOSYN contains 65 mg (2.84 mEq) of sodium per gram of piperacillin in the combination product. At the usual recommended doses, patients would receive between 780 and 1040 mg/day (34.1 and 45.5 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Renal Impairment In patients with creatinine clearance ≤ 40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose of ZOSYN should be reduced to the degree of renal function impairment [see Dosage and Administration (2)]. 8.7 Hepatic Impairment Dosage adjustment of ZOSYN is not warranted in patients with hepatic cirrhosis [see Clinical Pharmacology (12.3)]. 8.8 Patients with Cystic Fibrosis As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients. 10 OVERDOSAGE There have been postmarketing reports of overdose with piperacillin and tazobactam. The majority of those events experienced, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or seizures if higher than recommended doses are given intravenously (particularly in the presence of renal failure) [see Warnings and Precautions (5.6)]. Treatment should be supportive and symptomatic according to the patient's clinical presentation. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of piperacillin and tazobactam, the percentage of the piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively [see Clinical Pharmacology (12)]. 11 DESCRIPTION 21 Reference ID: 5488091 ZOSYN (piperacillin and tazobactam) Injection is an injectable antibacterial combination product consisting of the semisynthetic antibacterial piperacillin sodium and the beta-lactamase inhibitor tazobactam sodium for intravenous administration. Piperacillin sodium is derived from D(-)-α-aminobenzyl-penicillin. The chemical name of piperacillin sodium is sodium (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazine­ carboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2­ carboxylate. The chemical formula is C23H26N5NaO7S and the molecular weight is 539.5. The chemical structure of piperacillin sodium is: Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Its chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1­ azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide. The chemical formula is C10H11N4NaO5S and the molecular weight is 322.3. The chemical structure of tazobactam sodium is: ZOSYN Injection in the GALAXY Container is a frozen iso-osmotic sterile non-pyrogenic premixed solution. The components and dosage formulations are given in the table below: Table 6: ZOSYN In GALAXY Containers Premixed Frozen Solution Component* Function Dosage Formulations 2.25 g/50 mL 3.375 g/50 mL 4.5 g/100 mL Piperacillin active ingredient 2 g 3 g 4 g Tazobactam beta-lactamase inhibitor 250 mg 375 mg 500 mg Dextrose Hydrous osmolality adjusting agent 1 g 350 mg 2 g Sodium Citrate Dihydrate buffering agent 100 mg 150 mg 200 mg 22 Reference ID: 5488091 Component* Function Dosage Formulations 2.25 g/50 mL 3.375 g/50 mL 4.5 g/100 mL Edetate Disodium Dihydrate metal chelator 0.5 mg 0.75 mg 1 mg Water for Injection solvent q.s. 50 mL q.s. 50 mL q.s. 100 mL *Piperacillin and tazobactam are present in the formulation as sodium salts. Dextrose hydrous, sodium citrate dihydrate, and edetate disodium dihydrate amounts are approximate. ZOSYN contains a total of 2.84 mEq (65 mg) of sodium (Na+) per gram of piperacillin in the combination product. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ZOSYN is an antibacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics The pharmacodynamic parameter for piperacillin and tazobactam that is most predictive of clinical and microbiological efficacy is time above MIC. 12.3 Pharmacokinetics The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of piperacillin and tazobactam after multiple intravenous doses are summarized in Table 7. 23 Reference ID: 5488091 Table 7: Mean (CV%) Piperacillin and Tazobactam PK Parameters Piperacillin Piperacillin and Tazobactam Cmax AUCb CL V T1/2 CLR Dosea (mcg/mL) (mcg•h/mL) (mL/min) (L) (h) (mL/min) 2.25 g 134 131 [14] 257 17.4 0.79 -­ 3.375 g 242 242 [10] 207 15.1 0.84 140 4.5 g 298 322 [16] 210 15.4 0.84 -- Tazobactam Piperacillin and Tazobactam Cmax AUCb CL V T1/2 CLR Dosea (mcg/mL) (mcg•h/mL) (mL/min) (L) (h) (mL/min) 2.25 g 15 16.0 [21] 258 17.0 0.77 -­ 3.375 g 24 25.0 [8] 251 14.8 0.68 166 4.5 g 34 39.8 [15] 206 14.7 0.82 -­ a Piperacillin and tazobactam were given in combination, infused over 30 minutes. b Numbers in []parentheses are coefficients of variation [CV%]. Cmax : maximum observed concentration, AUC: Area under the curve, CL=clearance, CLR= Renal clearance V=volume of distribution, T1/2 = elimination half-life Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of ZOSYN. Piperacillin plasma concentrations, following a 30-minute infusion of ZOSYN, were similar to those attained when equivalent doses of piperacillin were administered alone. Steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose due to the short half-lives of piperacillin and tazobactam. Distribution Both piperacillin and tazobactam are approximately 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible. Piperacillin and tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those 24 Reference ID: 5488091 in plasma. Distribution of piperacillin and tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins (see Table 8). Table 8: Piperacillin and Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min IV Infusion of ZOSYN Tissue or Fluid Na Sampling periodb (h) Mean PIP Concentration Range (mg/L) Tissue:Plasma Range Tazo Concentration Range (mg/L) Tazo Tissue:Plasma Range Skin 35 0.5 – 4.5 34.8 – 94.2 0.60 – 1.1 4.0 – 7.7 0.49 – 0.93 Fatty Tissue 37 0.5 – 4.5 4.0 – 10.1 0.097 – 0.115 0.7 – 1.5 0.10 – 0.13 Muscle 36 0.5 – 4.5 9.4 – 23.3 0.29 – 0.18 1.4 – 2.7 0.18 – 0.30 Proximal Intestinal Mucosa 7 1.5 – 2.5 31.4 0.55 10.3 1.15 Distal Intestinal Mucosa 7 1.5 – 2.5 31.2 0.59 14.5 2.1 Appendix 22 0.5 – 2.5 26.5 – 64.1 0.43 – 0.53 9.1 – 18.6 0.80 – 1.35 a Each subject provided a single sample. b Time from the start of the infusion Metabolism Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities. Excretion Following single or multiple ZOSYN doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion. Both piperacillin and tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also secreted into the bile. 25 Reference ID: 5488091 Specific Populations Renal Impairment After the administration of single doses of piperacillin and tazobactam to subjects with renal impairment, the half-life of piperacillin and of tazobactam increases with decreasing creatinine clearance. At creatinine clearance below 20 mL/min, the increase in half-life is twofold for piperacillin and fourfold for tazobactam compared to subjects with normal renal function. Dosage adjustments for ZOSYN are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of ZOSYN. See Dosage and Administration (2) for specific recommendations for the treatment of patients with renal-impairment. Hemodialysis removes 30% to 40% of a piperacillin and tazobactam dose with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the piperacillin and tazobactam doses, respectively, with up to 16% of the tazobactam dose removed as the tazobactam metabolite. For dosage recommendations for patients undergoing hemodialysis [see Dosage and Administration (2)]. Hepatic Impairment The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, this difference does not warrant dosage adjustment of ZOSYN due to hepatic cirrhosis. Pediatrics Piperacillin and tazobactam pharmacokinetics were studied in pediatric patients 2 months of age and older. The clearance of both compounds is slower in the younger patients compared to older children and adults. In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) mL/min/kg. The piperacillin clearance estimate is 80% of this value for pediatric patients 2 - 9 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older children; however, it is not adequately characterized for dosing recommendations. The population mean (SE) for piperacillin volume of distribution is 0.243 (0.011) L/kg and is independent of age. Geriatrics The impact of age on the pharmacokinetics of piperacillin and tazobactam was evaluated in healthy male subjects, aged 18 - 35 years (n=6) and aged 65 to 80 years (n=12). Mean half-life for piperacillin and tazobactam was 32% and 55% higher, respectively, in the elderly compared to the younger subjects. This difference may be due to age-related changes in creatinine clearance. 26 Reference ID: 5488091 Race The effect of race on piperacillin and tazobactam was evaluated in healthy male volunteers. No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4/0.5 g doses. Drug Interactions The potential for pharmacokinetic drug interactions between ZOSYN and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated [see Drug Interactions (7)]. 12.4 Microbiology Mechanism of Action Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is, however, a beta-lactamase inhibitor of the Molecular class A enzymes, including Richmond-Sykes class III (Bush class 2b & 2b') penicillinases and cephalosporinases. It varies in its ability to inhibit class II and IV (2a & 4) penicillinases. Tazobactam does not induce chromosomally-mediated beta-lactamases at tazobactam concentrations achieved with the recommended dosage regimen. Antimicrobial Activity ZOSYN has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]: Aerobic bacteria Gram-positive bacteria Staphylococcus aureus (methicillin susceptible isolates only) Gram-negative bacteria Acinetobacter baumannii Escherichia coli Haemophilus influenzae (excluding beta-lactamase negative, ampicillin-resistant isolates) Klebsiella pneumoniae Pseudomonas aeruginosa (given in combination with an aminoglycoside to which the isolate is susceptible) Anaerobic bacteria Bacteroides fragilis group (B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus) 27 Reference ID: 5488091 The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin and tazobactam against isolates of similar genus or organism group. However, the efficacy of ZOSYN in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Aerobic bacteria Gram-positive bacteria Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only) Staphylococcus epidermidis (methicillin susceptible isolates only) Streptococcus agalactiae† Streptococcus pneumoniae† (penicillin-susceptible isolates only) Streptococcus pyogenes† Viridans group streptococci† Gram-negative bacteria Citrobacter koseri Moraxella catarrhalis Morganella morganii Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Serratia marcescens Providencia stuartii Providencia rettgeri Salmonella enterica Anaerobic bacteria Clostridium perfringens Bacteroides distasonis Prevotella melaninogenica † These are not beta-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone. Susceptibility Testing For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC. 28 Reference ID: 5488091 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in animals have not been conducted with piperacillin and tazobactam, piperacillin, or tazobactam. Mutagenesis Piperacillin and tazobactam was negative in microbial mutagenicity assays, the unscheduled DNA synthesis (UDS) test, a mammalian point mutation (Chinese hamster ovary cell HPRT) assay, and a mammalian cell (BALB/c-3T3) transformation assay. In vivo, piperacillin and tazobactam did not induce chromosomal aberrations in rats. Fertility Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility when piperacillin and tazobactam is administered intravenously up to a dose of 1280/320 mg/kg piperacillin and tazobactam, which is similar to the maximum recommended human daily dose based on body-surface area (mg/m2). 15 REFERENCES 1. Jensen J-US, Hein L, Lundgren B, et al. BMJ Open 2012; 2:e000635. doi:10.1136. 16 HOW SUPPLIED/STORAGE AND HANDLING ZOSYN® (piperacillin and tazobactam) Injection in GALAXY Containers are supplied as a frozen, iso-osmotic, sterile, nonpyrogenic solution in single-dose plastic containers as follows: • 2.25 g (piperacillin sodium equivalent to 2 g piperacillin and tazobactam sodium equivalent to 0.25 g tazobactam) in 50 mL. Each container has 5.58 mEq (128 mg) of sodium. Supplied 24/box—NDC 0338-9632-24 • 3.375 g (piperacillin sodium equivalent to 3 g piperacillin and tazobactam sodium equivalent to 0.375 g tazobactam) in 50 mL. Each container has 8.38 mEq (192 mg) of sodium. Supplied 24/box—NDC 0338-9636-24 • 4.5 g (piperacillin sodium equivalent to 4 g piperacillin and tazobactam sodium equivalent to 0.5 g tazobactam) in 100 mL. Each container has 11.17 mEq (256 mg) of sodium. Supplied 12/box—NDC 0338-9638-12 ZOSYN® Injection in GALAXY Containers should be stored at or below -20°C (-4°F) [see Dosage and Administration (2.6)]. Handle frozen product containers with care. Product containers may be fragile in the frozen state. 29 Reference ID: 5488091 17 PATIENT COUNSELING INFORMATION Serious Hypersensitivity Reactions Advise patients, their families, or caregivers that serious hypersensitivity reactions, including serious allergic cutaneous reactions, could occur with use of ZOSYN that require immediate treatment. Ask them about any previous hypersensitivity reactions to ZOSYN, other beta-lactams (including cephalosporins), or other allergens [see Warnings and Precautions (5.2)]. Hemophagocytic Lymphohistiocytosis Prior to initiation of treatment with ZOSYN, inform patients that excessive immune activation may occur with ZOSYN and that they should report signs or symptoms such as fever, rash, or lymphadenopathy to a healthcare provider immediately [see Warnings and Precautions (5.3)]. Diarrhea Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including ZOSYN, which usually ends when the drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.9)]. Antibacterial Resistance Patients should be counseled that antibacterial drugs including ZOSYN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ZOSYN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ZOSYN or other antibacterial drugs in the future. Pregnancy and Lactation Patients should be counseled that ZOSYN can cross the placenta in humans and is excreted in human milk [see Use in Specific Populations (8.1, 8.2)]. Baxter Healthcare Corporation Deerfield, IL 60015 USA Made in USA 30 Reference ID: 5488091 Baxter, Galaxy and Zosyn are trademarks of Baxter International Inc. or its subsidiaries. Clinitest is a registered trademark of Siemens Healthcare Diagnostics Inc. 07-19-08-744 31 Reference ID: 5488091
custom-source
2025-02-12T15:47:29.480396
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_______________________________________________________________________________________________________________________________________ _________________________________________________________________________________________ 2IGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use MEROPENEM FOR INJECTION safely and effectively. See full prescribing information for MEROPENEM FOR INJECTION. MEROPENEM for injection, for intravenous use Initial U.S. Approval: 1996 ----------------------------RECENT MAJOR CHANGES------------------------­ Warnings and Precautions, Rhabdomyolysis (5.3) 12/2024 -----------------------------INDICATIONS AND USAGE-------------------------- Meropenem for Injection is a penem antibacterial indicated for the treatment of bacterial meningitis in pediatric patients 3 months of age and older only. (1.1) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for Injection and other antibacterial drugs, Meropenem for Injection should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. (1.2) ------------------------DOSAGE AND ADMINISTRATION--------------------­ • Pediatric patients 3 months of age and older with bacterial meningitis (2.1) Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Bacterial Meningitis and Normal Renal Function (2.1) Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Bacterial Meningitis 40 2 grams Every 8 hours Intravenous infusion is to be given over approximately 15 minutes to 30 minutes. There is no experience with the use of Meropenem for Injection in pediatric patients with renal impairment. -----------------------DOSAGE FORMS AND STRENGTHS-------------------- Meropenem for Injection: 2 grams of meropenem as a powder in a single- dose vial for reconstitution (3) ------------------------------CONTRAINDICATIONS-----------------------------­ Known hypersensitivity to product components or other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta (β)­ lactams. (4) --------------------------WARNINGS AND PRECAUTIONS--------------------­ • Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactams. (5.1) • Severe cutaneous adverse reactions have been reported in patients receiving meropenem for injection. (5.2) • Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue meropenem for injection and initiate appropriate therapy. (5.3) • Seizures and other adverse CNS experiences have been reported during treatment. (5.4) • Co-administration of meropenem for injection with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. (5.5, 7.2) • Clostridioides difficile-associated diarrhea (ranging from mild diarrhea to fatal colitis) has been reported. Evaluate if diarrhea occurs. (5.6) • In patients with renal dysfunction, thrombocytopenia has been observed (5.9) ------------------------------ADVERSE REACTIONS-----------------------------­ Most common adverse reactions (incidence ≥ 1%) are diarrhea, rash (mostly diaper area moniliasis), oral moniliasis, and glossitis (6.1) To report SUSPECTED ADVERSE REACTIONS, contact WG Critical Care, LLC at 1-866-562-4708 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------------------DRUG INTERACTIONS---------------------------­ • Co-administration of meropenem for injection with probenecid inhibits renal excretion of meropenem and therefore Meropenem for Injection is not recommended. (7.1) • The concomitant use of Meropenem for Injection and valproic acid or divalproex sodium is generally not recommended. Antibacterial drugs other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium (5.4, 7.2) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Bacterial Meningitis (Pediatric Patients 3 Months of Age and Older Only) 1.2 Usage 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Pediatric Patients 3 Months of Age and Older with Bacterial Meningitis 2.2 Preparation and Administration of Meropenem for Injection 2.3 Compatibility 2.4 Stability and Storage 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Severe Cutaneous Adverse Reactions 5.3 Rhabdomyolysis 5.4 Seizure Potential 5.5 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid 5.6 Clostridioides difficile–associated Diarrhea 5.7 Development of Drug-Resistant Bacteria 5.8 Overgrowth of Nonsusceptible Organisms 5.9 Thrombocytopenia 5.10 Potential for Neuromotor Impairment 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-marketing Experience 7 DRUG INTERACTIONS 7.1 Probenecid 7.2 Valproic Acid 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Bacterial Meningitis 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5488116 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Bacterial Meningitis (Pediatric Patients 3 Months of Age and Older Only) Meropenem for Injection is indicated for the treatment of bacterial meningitis caused by Haemophilus influenzae, Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae, in pediatric patients 3 months of age and older. Meropenem for injection has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis. 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for Injection and other antibacterial drugs, Meropenem for Injection should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Pediatric Patients 3 Months of Age and Older with Bacterial Meningitis • For pediatric patients 3 months of age and older with bacterial meningitis, the Meropenem for Injection recommended dosage is 40 mg/kg every 8 hours (maximum dosage is 2 grams every 8 hours). • For pediatric patients weighing over 50 kg administer Meropenem for Injection at a dosage of 2 grams every 8 hours for bacterial meningitis. • Administer diluted Meropenem for Injection as an intravenous infusion over approximately 15 minutes to 30 minutes [see Dosage and Administration (2.2)]. • There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 grams) intravenous bolus injection. • There is no experience with the use of Meropenem for Injection in pediatric patients with renal impairment [see Clinical Pharmacology (12.3)]. 2.2 Preparation and Administration of Meropenem for Injection Preparation instructions for Intravenous Infusion (Reconstitution and Dilution) • Reconstitute Meropenem for Injection vial (2 grams) with Sterile Water for Injection according to the instructions in Table 1 below. • Shake well to dissolve and let stand until clear. Table 1: Volume of Sterile Water for Injection for Reconstitution of Injection Vials Vial Size Amount of Diluent Added (mL) Approximate Withdrawable Volume (mL) Approximate Average Concentration (mg/mL) 2 grams 40 mL 40 mL 50 mg/mL • Add the resulting reconstituted solution to an intravenous container and further dilute with an appropriate infusion fluid [see Dosage and Administration (2.3) and (2.4)]. • Discard unused portion. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When reconstituted, the solution varies from colorless to yellow depending on the concentration. • Do not use flexible container in series connections. Administration Instructions for Meropenem Intravenous Infusion Solution After reconstitution and dilution of Meropenem for Injection, administer the appropriate dose of diluted Meropenem solution as an intravenous infusion over approximately 15 minutes to 30 minutes [see Dosage and Administration (2.1)]. Reference ID: 5488116 2.3 Compatibility Compatibility of Meropenem for Injection with other drugs has not been established. Meropenem for Injection should not be mixed with or physically added to solutions containing other drugs. 2.4 Stability and Storage Reconstituted Solution with Sterile Water for Injection Use the reconstituted solution with Sterile Water for Injection immediately. However, re-constituted solutions of Meropenem for Injection maintain satisfactory potency under the conditions described below. Do not freeze reconstituted solutions of Meropenem for Injection. Reconstituted Solution Diluted with Sodium Chloride Injection, 0.9 % Solutions prepared for infusion (meropenem concentrations ranging from 1 mg/mL to 20 mg/mL) reconstituted with Water for Injection and further diluted with Sodium Chloride Injection 0.9% may be stored for 1 hour at up to 25°C (77°F) or 2 hours at up to 5°C (41°F). Reconstituted Solution Diluted with Dextrose Injection, 5 % Immediately use solutions (meropenem concentrations ranging from 1 mg/mL to 20 mg/mL) reconstituted with Water for Injection and subsequently diluted with Dextrose Injection 5%. 3 DOSAGE FORMS AND STRENGTHS For Injection: 2 grams of meropenem as a white to light yellow powder in a single-dose vial for reconstitution. 4 CONTRAINDICATIONS Meropenem for injection is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta (β)-lactams. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another β-lactam. Before initiating therapy with meropenem for injection, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to meropenem for injection occurs, discontinue the drug immediately. 5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving meropenem for injection [see Adverse Reactions (6.2)]. If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered. 5.3 Rhabdomyolysis Rhabdomyolysis has been reported with the use of meropenem [see Adverse Reactions (6.2)]. If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine, or elevated creatine phosphokinase are observed, discontinue meropenem for injection and initiate appropriate therapy. 5.4 Seizure Potential Seizures and other adverse CNS experiences have been reported during treatment with meropenem for injection. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function [see Adverse Reactions (6.1) and Drug Interactions (7.2)]. Reference ID: 5488116 During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall seizure rate being 0.7% (based on 20 patients with this adverse event). All meropenem-treated patients with seizures had pre-existing contributing factors. Among these included a prior history of seizures or CNS abnormality and concomitant medications with seizure potential. Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Continue anti-convulsant therapy in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate neurologically, placed on anti-convulsant therapy if not already instituted, and re­ examine the dosage of meropenem for injection to determine whether it should be decreased or discontinued. 5.5 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of meropenem for injection is necessary, consider supplemental anti-convulsant therapy [see Drug Interactions (7.2)]. 5.6 Clostridioides difficile–associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including meropenem for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.7 Development of Drug-Resistant Bacteria Prescribing meropenem for injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug- resistant bacteria. 5.8 Overgrowth of Nonsusceptible Organisms As with other broad-spectrum antibacterial drugs, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken. 5.9 Thrombocytopenia In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported [see Dosage and Administration (2.2), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)]. 5.10 Potential for Neuromotor Impairment Alert patients receiving meropenem for injection on an outpatient basis regarding adverse events such as seizures, Reference ID: 5488116 6 delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that meropenem for injection is well tolerated, advise patients not to operate machinery or motorized vehicles [see Adverse Reactions (6.1)]. ADVERSE REACTIONS The following are discussed in greater detail in other sections of labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.1)] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] • Rhabdomyolysis [see Warnings and Precautions (5.3)] • Seizure Potential [see Warnings and Precautions (5.4)] • Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid [see Warnings and Precautions (5.5)] • Clostridioides difficile – Associated Diarrhea [see Warnings and Precautions (5.6)] • Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.7)] • Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.8)] • Thrombocytopenia [see Warnings and Precautions (5.9)] • Potential for Neuromotor Impairment [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Pediatric Patients with Bacterial Meningitis Meropenem for injection was studied in 321 pediatric patients (3 months to less than 17 years of age) with bacterial meningitis at a dosage of 40 mg/kg every 8 hours. The most common adverse reactions and their rates of occurrence were as follows: Diarrhea 4.7% Rash (mostly diaper area moniliasis) 3.1% Oral Moniliasis 1.9% Glossitis 1% In these studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem for injection and those who received comparator agents (either cefotaxime or ceftriaxone). In the meropenem for injection-treated group, 12/15 patients with seizures had late onset seizures (seizures that occurred on day 3 or later) versus 7/20 patients in the comparator arm. The meropenem for injection group had a statistically higher number of patients than the comparator with transient elevation of liver enzymes. Adverse Reactions from Studies of Meropenem for Injection in Other Serious Bacterial Infections (not bacterial meningitis) The following adverse reactions occurred in studies of 2,904 immunocompetent adult patients who received meropenem for injection (500 mg or 1 gram every 8 hours) for the treatment of other serious bacterial infections (not bacterial meningitis). This meropenem for injection product is indicated only for the treatment of bacterial meningitis caused by certain organisms in pediatric patients 3 months of age and older [see Indications and Usage (1.1)]. Many patients in these studies were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with meropenem for injection. Deaths in 5 patients were assessed as possibly related to meropenem for injection; 36 (1.2%) patients had meropenem for injection discontinued because of adverse events. Reference ID: 5488116 Local Adverse Reactions Local adverse reactions that were reported with meropenem for injection were as follows: Inflammation at the injection site (2.4%), injection site reaction (0.9%), phlebitis/thrombophlebitis (0.8%), pain at the injection site (0.4%), and edema at the injection site (0.2%). Systemic Adverse Reactions Systemic adverse reactions that occurred in greater than 1% of the meropenem for injection-treated patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%), and pruritus (1.2%). Additional systemic adverse reactions that occurred in less than or equal to 1% but greater than 0.1% of the meropenem for injection-treated patients are listed below within each body system in order of decreasing frequency: Bleeding Events: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%). Body as a Whole: pain, abdominal pain, chest pain, fever, back pain, abdominal enlargement, chills, pelvic pain Cardiovascular: heart failure, heart arrest, tachycardia, hypertension, myocardial infarction, pulmonary embolus, bradycardia, hypotension, syncope Digestive System: oral moniliasis, anorexia, cholestatic jaundice/jaundice, flatulence, ileus, hepatic failure, dyspepsia, intestinal obstruction Hemic/Lymphatic: anemia, hypochromic anemia, hypervolemia Metabolic/Nutritional: peripheral edema, hypoxia Nervous System: insomnia, agitation, delirium, confusion, dizziness, seizure, nervousness, paresthesia, hallucinations, somnolence, anxiety, depression, asthenia Respiratory: respiratory disorder, dyspnea, pleural effusion, asthma, cough increased, lung edema Skin and Appendages: urticaria, sweating, skin ulcer Urogenital System: dysuria, kidney failure, vaginal moniliasis, urinary incontinence Laboratory Abnormalities Laboratory abnormalities that occurred in greater than 0.2% of the meropenem for injection-treated patients were as follows: Hepatic: increased alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), and bilirubin Hematologic: increased platelets, increased eosinophils, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased white blood cell (WBC), shortened prothrombin time and shortened partial thromboplastin time, leukocytosis, hypokalemia Renal: increased creatinine and increased blood urea nitrogen (BUN) Urinalysis: presence of red blood cells 6.2 Post-marketing Experience Reference ID: 5488116 The following adverse reactions have been identified during post-approval use of meropenem, including meropenem for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Worldwide post-marketing adverse reactions not otherwise listed under the Clinical Trials Experience subsection [see Adverse Reactions (6.1)] and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity. Blood and Lymphatic System Disorders: agranulocytosis, neutropenia, and leukopenia; a positive direct or indirect Coombs test, and hemolytic anemia. Immune System Disorders: angioedema. Skin and Subcutaneous Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme and acute generalized exanthematous pustulosis. Musculoskeletal Disorders: rhabdomyolysis 7 DRUG INTERACTIONS 7.1 Probenecid Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. Co-administration of probenecid with meropenem is not recommended. 7.2 Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. If administration of meropenem for injection is necessary, then supplemental anti-convulsant therapy should be considered [see Warnings and Precautions (5.4)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem in pregnant women. No fetal toxicity or malformations were observed in pregnant rats and Cynomolgus monkeys administered intravenous meropenem during organogenesis at doses up to 2.4 and 2.3 times the maximum recommended human dose (MRHD) based on body surface area comparison, respectively. In rats administered intravenous meropenem in late pregnancy and during the lactation period, there were no adverse effects on offspring at doses equivalent to approximately 3.2 times the MRHD based on body surface area comparison (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Meropenem administered to pregnant rats during organogenesis (Gestation Day 6 to Gestation Day 17) in intravenous Reference ID: 5488116 doses of 240, 500, and 750 mg/kg/day was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity. The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 2.4 times the MRHD of 1 gram every 8 hours based on body surface area comparison). Meropenem administered intravenously to pregnant Cynomolgus monkeys during organogenesis from Day 20 to 50 after mating at doses of 120, 240, and 360 mg/kg/day did not produce maternal or fetal toxicity at the NOAEL dose of 360 mg/kg/day (approximately 2.3 times the MRHD based on body surface area comparison). In a peri-postnatal study in rats described in the published literature1, intravenous meropenem was administered to dams from Gestation Day 17 until Lactation Day 21 at doses of 240, 500, and 1000 mg/kg/day. There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring. Second generation offspring showed no meropenem­ related effects. The NOAEL value was considered to be 1000 mg/kg/day (approximately 3.2 times the MRHD based on body surface area comparisons). 8.2 Lactation Risk Summary Meropenem has been reported to be excreted in human milk. No information is available on the effects of meropenem on the breast-fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for meropenem for injection and any potential adverse effects on the breast-fed child from meropenem for injection or from the underlying maternal conditions. 8.4 Pediatric Use The safety and effectiveness of Meropenem for Injection have been established for pediatric patients 3 months of age and older for the treatment of bacterial meningitis caused by Haemophilus influenzae, Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae, and the information on this use is discussed throughout the labeling. The safety and effectiveness of Meropenem for Injection have not been established in pediatric patients younger than 3 months of age. 10 OVERDOSAGE In mice and rats, large intravenous doses of meropenem (2200 mg/kg to 4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities. Intentional overdosing of meropenem for injection is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function. The largest dose of meropenem administered in clinical trials has been 2 grams given intravenously every 8 hours. At this dosage, no adverse pharmacological effects or increased safety risks have been observed. Limited postmarketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction. Consider symptomatic treatments. In individuals with normal renal function, rapid renal elimination takes place. Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage. 11 DESCRIPTION Meropenem for Injection contains meropenem a synthetic carbapenem antibacterial. Meropenem is (4R,5S,6S)-3­ [[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept­ 2-ene-2-carboxylic acid trihydrate. Its empirical formula is C17H25N3O5S•3H2O with a molecular weight of 437.52. Its structural formula is: Reference ID: 5488116 Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether. Meropenem for Injection, is a white to pale yellow sterile powder for intravenous administration. Each vial contains meropenem equivalent to 2 grams and 416 mg of sodium bicarbonate, anhydrous. When re-constituted as instructed Meropenem for Injection will deliver 2 grams of meropenem (on anhydrous basis) and approximately 180 mg of sodium as sodium carbonate (7.8 mEq) [see Dosage and Administration (2.2)]. The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Meropenem is an antibacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics The percentage of time of a dosing interval that unbound plasma concentration of meropenem exceeds the meropenem minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection. 12.3 Pharmacokinetics Plasma Concentrations At the end of a 30-minute intravenous infusion of a single dose of meropenem for injection in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 49 mcg/mL (range 39 to 58) for the 1 gram dose. Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 mcg/mL at 6 hours after administration. No accumulation of meropenem in plasma was observed with regimens using 1 gram administered every 6 hours in healthy volunteers with normal renal function. Distribution The plasma protein binding of meropenem is approximately 2%. After a single intravenous dose of meropenem for injection, the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour (0.5 hours to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in Table 2 below. Table 2: Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported) Tissue Intravenous Dose (gram) Number of Samples Mean [mcg/mL or mcg/(gram)]1 Range [mcg/mL or mcg/(gram)] Endometrium 0.5 7 4.2 1.7 to 10.2 Myometrium 0.5 15 3.8 0.4 to 8.1 Ovary 0.5 8 2.8 0.8 to 4.8 Cervix 0.5 2 7 5.4 to 8.5 Reference ID: 5488116 Fallopian tube 0.5 9 1.7 0.3 to 3.4 Skin 0.5 22 3.3 0.5 to 12.6 Interstitial fluid2 0.5 9 5.5 3.2 to 8.6 Skin 1 10 5.3 1.3 to 16.7 Interstitial fluid2 1 5 26.3 20.9 to 37.4 Colon 1 2 2.6 2.5 to 2.7 Bile 1 7 14.6 (3 hours) 4 to 25.7 Gall bladder 1 1 - 3.9 Peritoneal fluid 1 9 30.2 7.4 to 54.6 Lung 1 2 4.8 (2 hours) 1.4 to 8.2 Bronchial mucosa 1 7 4.5 1.3 to 11.1 Muscle 1 2 6. 1 (2 hours) 5.3 to 6.9 Fascia 1 9 8.8 1.5 to 20 Heart valves 1 7 9.7 6.4 to 12.1 Myocardium 1 10 15.5 5.2 to 25.5 CSF (inflamed) 20 mg/kg3 40 mg/kg4 8 5 1.1 (2 hours) 3.3 (3 hours) 0.2 to 2.8 0.9 to 6.5 CSF (uninflamed) 1 4 0.2 (2 hours) 0.1 to 0.3 1 at 1 hour unless otherwise noted 2 obtained from blister fluid 3 in pediatric patients of age 5 months to 8 years 4 in pediatric patients of age 1 month to 15 years (Meropenem for Injection is not approved for use in pediatric patients younger than 3 months of age) Elimination In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour. The elimination half-life for meropenem was approximately 1.5 hours in pediatric patients 3 months to 2 years of age. Metabolism There is one metabolite of meropenem that is microbiologically inactive. Excretion Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50% to 75%) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Fecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion. Urinary concentrations of meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose. Specific Populations Patients with Hepatic Impairment A pharmacokinetic study with meropenem for injection in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem. Patients with Renal Impairment Pharmacokinetic (PK) studies with meopenem for injection in adult patients with renal impairment have shown that the reduction in plasma clearance of meropenem correlates with creatinine clearance. The effect of renal impairment on the PK of meropenem has not been studied in the pediatric patients. Therefore, there is no experience in pediatric patients with renal impairment [see Dosage and Administration (2.3)]. Drug Interaction Studies Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38% [see Drug Interactions (7.1)]. Reference ID: 5488116 12.4 Microbiology Mechanism of Action The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding-protein (PBP) targets. Meropenem binds to PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus. Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 hours to 24 hours) are typically 1-2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed. Meropenem does not have in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) or methicillin­ resistant Staphylococcus epidermidis (MRSE). Resistance There are several mechanisms of resistance to carbapenems: 1) decreased permeability of the outer membrane of gram- negative bacteria (due to diminished production of porins) causing reduced bacterial uptake, 2) reduced affinity of the target PBPs, 3) increased expression of efflux pump components, and 4) production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases). Cross-resistance is sometimes observed with isolates resistant to other carbapenems. Interaction with Other Antimicrobials In vitro tests show meropenem to act synergistically with aminoglycoside antibacterial drugs against some isolates of Pseudomonas aeruginosa. Antimicrobial Activity Meropenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]. Gram-positive bacteria Streptococcus pneumoniae (penicillin-susceptible isolates only) Gram-negative bacteria Haemophilus influenzae Neisseria meningitidis The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for meropenem against isolates of similar genus or organism group. However, the efficacy of meropenem in treating clinical infections caused by these bacteria have not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Staphylococcus epidermidis (methicillin-susceptible isolates only) Gram-negative bacteria Aeromonas hydrophila Campylobacter jejuni Citrobacter freundii Citrobacter koseri Enterobacter cloacae Hafnia alvei Klebsiella oxytoca Moraxella catarrhalis Morganella morganii Pasteurella multocida Proteus vulgaris Reference ID: 5488116 Serratia marcescens Anaerobic bacteria Bacteroides ovatus Bacteroides uniformis Bacteroides vulgatus Clostridium difficile Clostridium perfringens Eggerthella lenta Fusobacterium species Prevotella intermedia Prevotella melaninogenica Propionibacterium acnes Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenesis studies have not been performed. Mutagenesis Genetic toxicity studies were performed with meropenem using the bacterial reverse mutation test, the Chinese hamster ovary HGPRT assay, cultured human lymphocytes cytogenic assay, and the mouse micronucleus test. There was no evidence of mutagenic potential found in any of these tests. Impairment of Fertility In fertility studies, intravenous meropenem was administered to male rats beginning 11 weeks before mating and throughout mating and to female rats from 2 weeks before mating through Gestation Day 7 at doses of 240, 500, and 1000 mg/kg/day. There was no evidence of impaired fertility at doses up to 1000 mg/kg/day (on the basis of body surface area comparison, approximately 3.2 times to the MRHD of 1 gram every 8 hours). 14 CLINICAL STUDIES 14.1 Bacterial Meningitis Four hundred forty-six patients (397 pediatric patients 3 months to less than 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with meropenem for injection (n = 225) at a dosage of 40 mg/kg every 8 hours or a comparator drug, i.e., cefotaxime (n = 187) or ceftriaxone (n = 34), at the approved dosing regimens. A comparable number of patients were found to be clinically evaluable (ranging from 61 to 68%) and with a similar distribution of pathogens isolated on initial CSF culture. A patient was defined as clinically not cured if any one of the following three criteria were met: 1 At the 5–7-week post-completion of therapy visit, the patient had any one of the following: moderate to severe motor, behavior or development deficits; hearing loss of greater than 60 decibels in one or both ears; or blindness. 2 During therapy the patient’s clinical status necessitated the addition of other antibacterial drugs. 3 Either during or post-therapy, the patient developed a large subdural effusion needing surgical drainage, or a cerebral abscess, or a bacteriologic relapse. Using these criteria, the following efficacy rates were obtained, per organism (noted in Table 3). The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses. Sequelae Reference ID: 5488116 were the most common reason patients were assessed as clinically not cured. Table 3: Efficacy rates by Pathogen in the Clinically Evaluable Population with Bacterial Meningitis Microorganisms Meropenem for Injection Comparator S. pneumoniae 17/24 (71) 19/30 (63) H. influenzae (+)1 8/10 (80) 6/6 (100) H. influenzae (-/NT)2 44/59 (75) 44/60 (73) N. meningitidis 30/35 (86) 35/39 (90) Total (including others) 102/131 (78) 108/140 (77) 1 (+) β-lactamase-producing 2 (-/NT) non-β-lactamase-producing or not tested Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the meropenem for injection group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa). With respect to hearing loss, 263 of the 271 evaluable patients had at least one hearing test performed post-therapy. Table 4 shows the degree of hearing loss between the meropenem for injection-treated patients and comparator-treated patients. Table 4: Hearing Loss at Post-Therapy in the Evaluable Population Treated with Meropenem Degree of Hearing Loss (in one or both ears) Meropenem for injection n = 128 Comparator n = 135 No loss 61% 56% 20 to 40 decibels 20% 24% Greater than 40 to 60 decibels 8% 7% Greater than 60 decibels 9% 10% 15 REFERENCES 1. Kawamura S, AW Russell, SJ Freeman, and RA Siddall, 1992, Reproductive and Developmental Toxicity of Meropenem in Rats, Chemotherapy, 40:S238-250. 16 HOW SUPPLIED/STORAGE AND HANDLING Meropenem for Injection is supplied in a single-dose vial containing meropenem as a white to light yellow powder to deliver 2 grams of meropenem for intravenous administration after reconstitution. The dry powder should be stored at 20°C to 25ºC (68°F to 77ºF). Brief exposure to 15°C to 30°C (59°F to 86°F) is permitted [see USP Controlled Room Temperature]. NDC 44567-402-01 2 gram single-dose injection vial NDC 44567-402-06 2 gram single-dose injection vial packaged in a carton of 6 The container closure is not made with natural rubber latex. 17 PATIENT COUNSELING INFORMATION Antibacterial Resistance Reference ID: 5488116 Patients should be counseled that antibacterial drugs including Meropenem for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Meropenem for Injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Meropenem for Injection or other antibacterial drugs in the future [see Warnings and Precautions (5.7)]. Diarrhea Counsel patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.6)]. Risk of Breakthrough Seizures Counsel patients to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with Meropenem for Injection. If treatment with Meropenem for Injection is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed [see Warnings and Precautions (5.4)]. Potential of Neuromotor Impairment Patients receiving Meropenem for Injection on an outpatient basis must be alerted of adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that Meropenem for Injection is well tolerated, patients should not operate machinery or motorized vehicles [see Warnings and Precautions (5.10)]. Manufactured for: WG Critical Care, LLC Paramus, NJ 07652 Made in Italy Reference ID: 5488116
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2025-02-12T15:47:29.779285
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_________________ _________________ _________________ _____________ ______________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VABOMERE safely and effectively. See full prescribing information for VABOMERE. VABOMERE® (meropenem and vaborbactam) for injection, for intravenous use Initial U.S. Approval: 2017 RECENT MAJOR CHANGES Warnings and Precautions, Rhabdomyolysis (5.3) ------------------------12/2024 __________________INDICATIONS AND USAGE VABOMERE (meropenem and vaborbactam) is a combination of meropenem, a penem antibacterial, and vaborbactam, a beta-lactamase inhibitor, indicated for the treatment of patients 18 years and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by designated susceptible bacteria. (1.1) To reduce the development of drug-resistant bacteria and maintain the effectiveness of VABOMERE and other antibacterial drugs, VABOMERE should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. (1.2) _______________DOSAGE AND ADMINISTRATION ______________ • Administer VABOMERE 4 grams (meropenem 2 grams and vaborbactam 2 grams) every 8 hours by intravenous infusion over 3 hours for up to 14 days, in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73m2. (2.1) • Dosage adjustment is recommended in patients with renal impairment who have an eGFR less than 50 mL/min/ 1.73m2. (2.2) eGFRa (mL/min/ 1.73m2) Recommended Dosage Regimen for VABOMERE (meropenem and vaborbactam) b, c, d Dosing Interval 30 to 49 VABOMERE 2 grams (meropenem 1 gram and vaborbactam 1 gram) Every 8 hours 15 to 29 VABOMERE 2 grams (meropenem 1 gram and vaborbactam 1 gram) Every 12 hours Less than 15 VABOMERE 1 gram (meropenem 0.5 grams and vaborbactam 0.5 grams) Every 12 hours a As calculated using the Modification of Diet in Renal Disease (MDRD) formula; b All doses of VABOMERE are administered intravenously over 3 hours; c Doses adjusted for renal impairment should be administered after a hemodialysis session; d The total duration of treatment is for up to 14 days. • See Full Prescribing Information for instructions for constituting supplied dry powder and subsequent required dilution. (2.3) • See Full Prescribing Information for drug compatibilities. (2.4) DOSAGE FORMS AND STRENGTHS VABOMERE 2 grams (meropenem and vaborbactam) for injection, is supplied as a sterile powder for constitution in single-dose vials containing meropenem 1 gram (equivalent to 1.14 grams of meropenem trihydrate) and vaborbactam1 gram. (3) ___________________ CONTRAINDICATIONS ___________________ Known hypersensitivity to the components of VABOMERE (meropenem and vaborbactam) or anaphylactic reactions to beta-lactams. (4) _______________WARNINGS AND PRECAUTIONS _______________ • Hypersensitivity reactions were reported with the use of VABOMERE. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs. Discontinue infusion if signs of acute hypersensitivity occur. (5.1) • Seizures and other adverse Central Nervous System experiences have been reported during treatment with meropenem, a component of VABOMERE. (5.2) • Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue VABOMERE and initiate appropriate therapy. (5.3) • Clostridioides difficile-associated diarrhea has been reported with nearly all systemic antibacterial agents, including VABOMERE. Evaluate patients if diarrhea occurs. (5.4) • Co-administration of meropenem with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. (5.5, 7.1) ___________________ ADVERSE REACTIONS ___________________ The most frequently reported adverse reactions occurring in ≥3% of patients treated with VABOMERE were headache, phlebitis/infusion site reactions, and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Melinta Therapeutics at 1-844-633-6568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ___________________ DRUG INTERACTIONS____________________ Hormonal Contraceptives: Effectiveness may be reduced; use an effective alternative non-hormonal form of contraception or additional contraceptive method. (7.4, 12.3) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1. Complicated Urinary Tract Infections (cUTI), including Pyelonephritis 1.2. Usage 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Dosage Adjustments in Patients with Renal Impairment 2.3 Preparation and Administration of VABOMERE for Intravenous Infusion 2.4 Drug Compatibility 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Seizure Potential 5.3 Rhabdomyolysis 5.4 Clostridioides difficile-associated Diarrhea 5.5 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid 5.6 Thrombocytopenia 5.7 Potential for Neuromotor Impairment 5.8 Development of Drug-Resistant Bacteria 5.9 Overgrowth of Non-susceptible Organisms 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Valproic Acid 7.2 Probenecid 7.3 Potential for VABOMERE to Affect Other Drugs 7.4 Hormonal Contraceptives 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Childbearing Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Complicated Urinary Tract Infections (cUTI), including Pyelonephritis 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 5488109 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1. Complicated Urinary Tract Infections (cUTI), including Pyelonephritis VABOMERE® is indicated for the treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex. 1.2. Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of VABOMERE and other antibacterial drugs, VABOMERE should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage of VABOMERE is 4 grams (meropenem 2 grams and vaborbactam 2 grams) administered every 8 hours by intravenous (IV) infusion over 3 hours in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) greater than or equal to 50 mL/min/1.73m2. The duration of treatment is for up to 14 days. 2.2 Dosage Adjustments in Patients with Renal Impairment Dosage adjustment is recommended in patients with renal impairment who have an eGFR less than 50 mL/min/1.73m2. The recommended dosage of VABOMERE in patients with varying degrees of renal function is presented in Table 1. For patients with changing renal function, monitor serum creatinine concentrations and eGFR at least daily and adjust the dosage of VABOMERE accordingly [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Meropenem and vaborbactam are removed by hemodialysis [see Clinical Pharmacology (12.3)]. For patients maintained on hemodialysis, administer VABOMERE after a hemodialysis session. 2 Reference ID: 5488109 Table 1: Dosage of VABOMERE in Patients with Renal Impairment eGFRa (mL/min/ 1.73m2) Recommended Dosage Regimen for VABOMERE (meropenem and vaborbactam)b, c, d Dosing Interval 30 to 49 VABOMERE 2 grams (meropenem 1 gram and vaborbactam 1 gram) Every 8 hours 15 to 29 VABOMERE 2 grams (meropenem 1 gram and vaborbactam 1 gram) Every 12 hours Less than 15 VABOMERE 1 gram (meropenem 0.5 grams and vaborbactam 0.5 grams) Every 12 hours a As calculated using the Modification of Diet in Renal Disease (MDRD) formula as follows: eGFR (mL/min/1.73m2) = 175 x (serum creatinine)-1.154 x (age)-0.203x (0.742 if female) x (1.212 if African American) b All doses of VABOMERE are administered intravenously over 3 hours. c Doses adjusted for renal impairment should be administered after a hemodialysis session. d The total duration of treatment is for up to 14 days. 2.3 Preparation and Administration of VABOMERE for Intravenous Infusion Preparation VABOMERE is supplied as a dry powder in a single-dose vial that must be constituted and further diluted prior to intravenous infusion as outlined below. VABOMERE does not contain preservatives. Aseptic technique must be used for constitution and dilution. 1. To prepare the required dose for intravenous infusion, constitute the appropriate number of vials, as determined from Table 2 below. Withdraw 20 mL of 0.9% Sodium Chloride Injection, USP, from an infusion bag and constitute each vial of VABOMERE. 2. Mix gently to dissolve. The constituted VABOMERE solution will have an approximate meropenem concentration of 0.05 gram/mL and an approximate vaborbactam concentration of 0.05 gram/mL. The final volume is approximately 21.3 mL. The constituted solution is not for direct injection. 3. The constituted solution must be diluted further, immediately, in a 0.9% Sodium Chloride Injection, USP infusion bag before intravenous infusion. The intravenous infusion of the diluted solution must be completed within 4 hours if stored at room temperature or 22 hours if stored refrigerated at 2°C to 8°C (36°F to 46°F). 4. To dilute the constituted solution, withdraw the full or partial constituted vial contents from each vial and add it back into the infusion bag in accordance with Table 2 below. 3 Reference ID: 5488109 Table 2: Preparation of VABOMERE Doses VABOMERE Dose (meropenem and vaborbactam) Number of Vials to Constitute for Further Dilution Volume to Withdraw from Each Constituted Vial for Further Dilution Volume of Infusion Bag Final Infusion Concentration of VABOMERE 4 grams (2 grams-2 grams) 2 vials Entire contents (approximately 250 mL 16 mg/mL 21 mL) 500 mL 8 mg/mL 1,000 mL 4 mg/mL 2 grams (1 gram-1 gram) 1 vial Entire contents (approximately 125 mL 16 mg/mL 21 mL) 250 mL 8 mg/mL 500 mL 4 mg/mL 1 gram (0.5 gram-0.5 gram) 1 vial 10.5 mL (discard unused portion) 70 mL 14.3 mg/mL 125 mL 8 mg/mL 250 mL 4 mg/mL 5. Visually inspect the diluted VABOMERE solution for particulate matter and discoloration prior to administration (the color of the VABOMERE infusion solution for administration ranges from colorless to light yellow). Discard unused portion after use. 2.4 Drug Compatibility VABOMERE solution for administration by 3-hour infusion is only compatible with 0.9% Sodium Chloride Injection, USP. Compatibility of VABOMERE solution for administration with other drugs has not been established. 4 Reference ID: 5488109 3 DOSAGE FORMS AND STRENGTHS VABOMERE 2 grams (meropenem and vaborbactam) for injection, is supplied as a white to light yellow sterile powder for constitution in single-dose, clear glass vials containing meropenem 1 gram (equivalent to 1.14 grams meropenem trihydrate) and vaborbactam 1 gram. 4 CONTRAINDICATIONS VABOMERE is contraindicated in patients with known hypersensitivity to any components of VABOMERE (meropenem and vaborbactam), or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactam antibacterial drugs [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Hypersensitivity reactions were reported in patients treated with VABOMERE in the clinical trials [see Adverse Reactions (6.1)]. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving therapy with beta-lactam antibacterial drugs. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another beta-lactam antibacterial drug. Before initiating therapy with VABOMERE, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactam antibacterial drugs, and other allergens. If an allergic reaction to VABOMERE occurs, discontinue the drug immediately. 5.2 Seizure Potential Seizures and other adverse Central Nervous System (CNS) experiences have been reported during treatment with meropenem, which is a component of VABOMERE. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function [see Adverse Reactions (6.1) and Drug Interactions (7.1)]. Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Continue anti-convulsant therapy in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate neurologically, place on anti-convulsant therapy if not already instituted, and reexamine the dosage of VABOMERE to determine whether it should be decreased or discontinued. 5.3 Rhabdomyolysis Rhabdomyolysis has been reported with the use of meropenem, a component of VABOMERE [see Adverse Reactions (6.2)]. If signs or symptoms of rhabdomyolysis such as muscle pain, 5 Reference ID: 5488109 tenderness or weakness, dark urine, or elevated creatine phosphokinase are observed, discontinue VABOMERE and initiate appropriate therapy. 5.4 Clostridioides difficile-associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including VABOMERE, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.5 Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid The concomitant use of VABOMERE and valproic acid or divalproex sodium is generally not recommended. Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of VABOMERE is necessary, consider supplemental anticonvulsant therapy [see Drug Interactions (7.1)]. 5.6 Thrombocytopenia In patients with renal impairment, thrombocytopenia has been observed in patients treated with meropenem, but no clinical bleeding has been reported [see Dosage and Administration (2.2), Adverse Reactions (6.1), Use in Specific Populations (8.5) and (8.6), and Clinical Pharmacology (12.3)]. 5.7 Potential for Neuromotor Impairment Alert patients receiving VABOMERE on an outpatient basis regarding adverse reactions such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that VABOMERE is well 6 Reference ID: 5488109 tolerated, advise patients not to operate machinery or motorized vehicles [see Adverse Reactions (6.1)]. 5.8 Development of Drug-Resistant Bacteria Prescribing VABOMERE in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of drug-resistant bacteria [see Indications and Usage (1.2)]. 5.9 Overgrowth of Non-susceptible Organisms As with other antibacterial drugs, prolonged use of VABOMERE may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the Warnings and Precautions section: • Hypersensitivity Reactions [see Warnings and Precautions (5.1)] • Seizure Potential [see Warnings and Precautions (5.2)] • Rhabdomyolysis [see Warnings and Precautions (5.3)] • Clostridioides difficile-associated Diarrhea [see Warnings and Precautions (5.4)] • Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid [see Warnings and Precautions (5.5)] • Thrombocytopenia [see Warnings and Precautions (5.6)] • Potential for Neuromotor Impairment [see Warnings and Precautions (5.7)] • Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.8)] • Overgrowth of Non-susceptible Organisms [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. VABOMERE was evaluated in a Phase 3 comparator-controlled clinical trial in cUTI, including pyelonephritis, which included 272 patients treated with VABOMERE and 273 patients treated with the comparator piperacillin/tazobactam 4.5 grams (piperacillin 4 g/tazobactam 0.5 g) every 8 hours. After a minimum of 15 doses of IV therapy, patients could be switched to oral levofloxacin (500 mg daily every 24 hours) to complete the treatment course. Mean duration of IV therapy was 8 days in both treatment groups. Mean duration of IV and oral therapy was 10 days; patients with baseline bacteremia could receive up to 14 days of treatment. 7 Reference ID: 5488109 The mean age of patients treated with VABOMERE was 53 years (range 18 to 92 years), and 32% of patients were 65 years of age or older. Patients were predominantly female (66.5%) and White (93.4%). Most patients were enrolled in Europe (89.7%). Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation Treatment was discontinued due to adverse reactions in 2.9% (8/272) of patients receiving VABOMERE and in 5.1% (14/273) of patients receiving piperacillin/tazobactam. Most common adverse reactions resulting in discontinuation of VABOMERE included hypersensitivity, 1.1% (3/272) and infusion-related reactions, 0.7% (2/272). Death occurred in 2 (0.7%) patients who received VABOMERE and in 2 (0.7%) patients who received piperacillin/tazobactam. Common Adverse Reactions The most frequently reported adverse reactions (3% or greater) in patients receiving VABOMERE in the Phase 3 cUTI trial were headache, phlebitis/infusion site reactions, and diarrhea. Table 3 provides adverse reactions occurring in 1% or greater of patients receiving VABOMERE in the Phase 3 cUTI trial. Table 3: Adverse Reactions Occurring in 1% or Greater of Patients Receiving VABOMERE in the Phase 3 Clinical Trial in cUTI Adverse Reactions VABOMERE (N=272) % Piperacillin/Tazobactama (N=273) % Headache 8.8 4.4 Phlebitis/Infusion site reactionsb 4.4 0.7 Diarrhea 3.3 4.4 Hypersensitivityc 1.8 1.8 Nausea 1.8 1.5 Alanine aminotransferase increased 1.8 0.4 Aspartate aminotransferase increased 1.5 0.7 Pyrexia 1.5 0.7 Hypokalemia 1.1 1.5 a Piperacillin/tazobactam 4.5 grams (piperacillin 4 g/tazobactam 0.5 g) IV infused over 30 minutes every 8 hours. b Infusion site reactions include infusion/injection site phlebitis, infusion site thrombosis, and infusion site erythema. c Hypersensitivity includes hypersensitivity, drug hypersensitivity, anaphylactic reaction, rash urticaria, and bronchospasm. Adverse Reactions Occurring in Less Than 1% of Patients Receiving VABOMERE in the Phase 3 cUTI trial: Blood and lymphatic system disorders: leukopenia General disorders and administration site conditions: chest discomfort 8 Reference ID: 5488109 Infections and infestations: pharyngitis, vulvovaginal candidiasis, oral candidiasis Investigations: creatinine phosphokinase increase Metabolism and nutrition disorders: decreased appetite, hyperkalemia, hyperglycemia, hypoglycemia Nervous system disorders: dizziness, tremor, paresthesia, lethargy Psychiatric disorders: hallucination, insomnia Renal and urinary disorders: azotemia, renal impairment Vascular disorders: deep vein thrombosis, hypotension, vascular pain Other Adverse Reactions Associated with Meropenem Additionally, adverse reactions reported with meropenem alone that were not reported in VABOMERE-treated patients in the Phase 3 clinical trial are listed below: Blood and lymphatic system disorders: thrombocytosis, neutropenia, eosinophilia, thrombocytopenia, agranulocytosis, hemolytic anemia Gastrointestinal disorders: abdominal pain Hepatobiliary disorders: jaundice Nervous system disorders: convulsions Investigations: blood alkaline phosphatase increased, blood lactate dehydrogenase increased, blood bilirubin increased, blood creatinine increased, blood urea increased, blood thromboplastin decreased, prothrombin time decreased, Direct and Indirect Coombs test positive Skin and subcutaneous tissue disorders: pruritus, toxic epidermal necrolysis, Stevens Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, erythema multiforme Immune system disorders: angioedema General disorders and administration site conditions: pain 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of meropenem, a component of VABOMERE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal Disorders: rhabdomyolysis 9 Reference ID: 5488109 7 DRUG INTERACTIONS 7.1 Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. If administration of VABOMERE is necessary, then supplemental anti-convulsant therapy should be considered [see Warnings and Precautions (5.5)]. 7.2 Probenecid Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. Co-administration of probenecid with VABOMERE is not recommended [see Clinical Pharmacology (12.3)]. 7.3 Potential for VABOMERE to Affect Other Drugs When administering VABOMERE concomitantly with medicinal products that are predominantly metabolized by CYP1A2, CYP3A4, CYP2C, and/or are substrates of P-gp transporters, there is a potential risk of interaction which may result in decreased plasma concentrations and activity of the co-administered drug(s) [see Clinical Pharmacology (12.3)]. When VABOMERE is concomitantly administered with the substrates of CYP1A2, CYP3A4, CYP2C, and/or P-gp, refer to the prescribing information for these concomitant medications for guidance on need for dosage adjustments and/or need for frequent drug level monitoring when administered with a weak CYP inducer(s). When administering VABOMERE concomitantly with medicinal products that are substrate of OAT3 transporters, there is a potential risk of interaction which may result in increased plasma concentrations and activity of the co-administered drug(s) [see Clinical Pharmacology (12.3)]. When VABOMERE is concomitantly administered with OAT3 substrate(s), refer to the prescribing information for these concomitant medication(s) for guidance on need for dosage adjustments and/or need for frequent drug level monitoring when administered with an OAT3 inhibitor(s). 7.4 Hormonal Contraceptives Hormonal contraceptives (e.g., combined oral contraceptives containing a progestin and an estrogen) are metabolized by CYP3A and other pregnane X receptor (PXR)-regulated enzymes. Therefore, the blood concentration and the effectiveness of hormonal contraceptives may be reduced when used with VABOMERE [see Clinical Pharmacology (12.3)]. Effective alternative non-hormonal forms of contraception or additional contraceptive methods are recommended for patients taking hormonal contraceptives when treated concomitantly with VABOMERE [see Use in Specific Populations (8.3) and Clinical Pharmacology (12.3)]. 10 Reference ID: 5488109 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Fetal malformations were observed in vaborbactam-treated rabbits, therefore advise pregnant women of the potential risks to the fetus. There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with VABOMERE, meropenem, or vaborbactam in pregnant women. Malformations (supernumerary lung lobes, interventricular septal defect) were observed in offspring from pregnant rabbits administered intravenous vaborbactam during the period of organogenesis at doses approximately equivalent to or above the maximum recommended human dose (MRHD) based on plasma AUC comparison. The clinical relevance of the malformations is uncertain. No similar malformations or fetal toxicity were observed in offspring from pregnant rats administered intravenous vaborbactam during organogenesis or from late pregnancy and through lactation at a dose equivalent to approximately 1.6 times the MRHD based on body surface area comparison [see Data]. No fetal toxicity or malformations were observed in pregnant rats and cynomolgus monkeys administered intravenous meropenem during organogenesis at doses up to 1.6 and 1.2 times the MRHD based on body surface area comparison, respectively. In rats administered intravenous meropenem in late pregnancy and during the lactation period, there were no adverse effects on offspring at doses equivalent to approximately 1.6 times the MRHD based on body surface area comparison [see Data]. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Meropenem Reproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day and in cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of body surface area comparisons, approximately 1.6 times and 1.2 times higher, respectively, than the MRHD of 2 grams every 8 hours). These studies revealed no evidence of harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (equivalent to approximately 0.4 times the MRHD of 2 grams every 8 hours based on body surface area comparison) and above in rats. In a published study1, meropenem administered to pregnant rats from Gestation Day 6 to Gestation Day 17, was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity. The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 1.2 times the MRHD based on body surface area comparison). 11 Reference ID: 5488109 In a peri-postnatal study in rats described in the published literature1, intravenous meropenem was administered to dams from Gestation Day 17 until Postpartum Day 21. There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring. Second generation offspring showed no meropenem-related effects. The NOAEL value was considered to be 1000 mg/kg/day (approximately 1.6 times the MRHD based on body surface area comparisons). Vaborbactam In a rat embryo-fetal toxicology study, intravenous administration of vaborbactam during Gestation Days 6-17 showed no evidence of maternal or embryofetal toxicity at doses up to 1000 mg/kg, which is equivalent to approximately 1.6 times the MRHD based on body surface area comparisons. In the rabbit, intravenous administration of vaborbactam during Gestation Days 7–19 at doses up to 1000 mg/kg/day (approximately 5 times the MRHD based on AUC exposure comparison) was not associated with maternal toxicity or fetal weight loss. A low incidence of malformations occurred in the 300 mg/kg/day mid-dose group (two fetuses from different litters with interventricular septal defects, one fetus with a fused right lung lobe and one fetus with a supernumerary lung lobe), and in the 1000 mg/kg/day high-dose group (two fetuses from different litters with supernumerary lobes). The NOAEL was considered to be 100 mg/kg/day which is equivalent to 0.3 times the MRHD based on plasma AUC exposure comparison and 6-times the MRHD based on maximum plasma concentration (Cmax) comparison. The clinical relevance of the malformations is uncertain. Vaborbactam Cmax values may have influenced malformations in the rabbit study, and the recommended 3-hour infusion time for clinical administration of vaborbactam is associated with lower plasma Cmax values than the 30-minute infusions in rabbits. In a peri-postnatal study in rats, vaborbactam administered intravenously to pregnant dams from Gestation Day 6 to Lactation Day 20 caused no adverse effects on the dams, or in first and second generation offspring. The NOAEL was considered to be 1000 mg/kg/day (equivalent to approximately 1.6 times the MRHD based on body surface area comparison). 8.2 Lactation Meropenem has been reported to be excreted in human milk. It is unknown whether vaborbactam is excreted in human milk. No information is available on the effects of meropenem and vaborbactam on the breast-fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VABOMERE and any potential adverse effects on the breast-fed child from VABOMERE or from the underlying maternal condition. 8.3 Females and Males of Childbearing Potential Use of VABOMERE may reduce the effectiveness of hormonal contraceptives. Advise patients taking hormonal contraceptives to use an effective alternative non-hormonal contraception or additional contraceptive method (e.g., barrier method of contraception) during treatment with VABOMERE [see Drug Interactions (7.4)]. 12 Reference ID: 5488109 8.4 Pediatric Use The safety and effectiveness of VABOMERE in pediatric patients (younger than 18 years of age) has not been established. Studies of VABOMERE have not been conducted in patients younger than 18 years of age. 8.5 Geriatric Use Of the 272 patients treated with VABOMERE in the Phase 3 cUTI trial, 48 (18%) patients were 65 years of age and older, while 39 (14%) patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Meropenem, a component of VABOMERE, is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Population pharmacokinetic (PK) analysis found no clinically relevant change in pharmacokinetic parameters in elderly patients. No dosage adjustment based on age is required. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 8.6 Renal Impairment Pharmacokinetic studies conducted with meropenem and vaborbactam in subjects with renal impairment have shown that the plasma exposures of both meropenem and vaborbactam increased with decreasing renal function [see Clinical Pharmacology (12.3)]. Dosage adjustment for VABOMERE is recommended in patients with renal impairment (eGFR less than 50 mL/min/1.73m2) [see Dosage and Administration (2.2)]. For patients with changing renal function, monitor serum creatinine concentrations and eGFR at least daily and adjust the dosage of VABOMERE accordingly. Meropenem and vaborbactam are removed by hemodialysis. Following a single dose of VABOMERE, vaborbactam exposure was substantially greater when VABOMERE was administered after hemodialysis than before hemodialysis [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In the event of overdose, discontinue VABOMERE and institute general supportive treatment. Meropenem and vaborbactam can be removed by hemodialysis. In subjects with end-stage renal disease (ESRD) administered meropenem 1 gram and vaborbactam 1 gram, the mean total recovery in dialysate following a hemodialysis session was 38% and 53% of the administered dose of meropenem and vaborbactam, respectively. No clinical information is available on the use of hemodialysis to treat VABOMERE overdosage. 13 Reference ID: 5488109 11 DESCRIPTION VABOMERE (meropenem and vaborbactam) for injection is a combination product that contains meropenem, a synthetic penem antibacterial drug and vaborbactam, a cyclic boronic acid beta-lactamase inhibitor, for intravenous administration. Meropenem, present as a trihydrate, is a white to light yellow crystalline powder, with a molecular weight of 437.52. The chemical name for meropenem trihydrate is (4R,5S,6S)-3­ [[(3S,5S)-5-(dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo­ 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, trihydrate. The empirical formula of meropenem trihydrate is C17H25N3O5S·3H2O and its chemical structure is: Figure 1: Structure of Meropenem Trihydrate N S OH H H O O OH NH O NMe2 3H2O Vaborbactam is a white to off-white powder, with a molecular weight of 297.14. The chemical name for vaborbactam is (3R,6S)-2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-1,2-oxaborinane-6­ acetic acid. Its empirical formula is C12H16BNO5S and its chemical structure is: Figure 2: Structure of Vaborbactam B O H N O S HO OH O VABOMERE is supplied as a white to light yellow sterile powder for constitution that contains meropenem trihydrate, vaborbactam, and sodium carbonate. Each 50 mL glass vial contains 1 gram of meropenem (equivalent to 1.14 grams of meropenem trihydrate), 1 gram of vaborbactam, and 0.575 gram of sodium carbonate. The total sodium content of the mixture is approximately 0.25 grams (10.9 mEq)/vial. Each vial is constituted and further diluted with 0.9% Sodium Chloride Injection, USP. Both the constituted solution and the diluted solution for intravenous infusion should be a colorless to light yellow solution [see Dosage and Administration (2.3)]. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action VABOMERE is an antibacterial drug [see Microbiology (12.4)]. 14 Reference ID: 5488109 12.2 Pharmacodynamics Similar to other beta-lactam antibacterial drugs, the percentage of time of a dosing interval that unbound plasma concentration of meropenem exceeds the meropenem-vaborbactam minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection. The ratio of the 24-hour unbound plasma vaborbactam AUC to meropenem-vaborbactam MIC is the index that best predicts efficacy of vaborbactam in combination with meropenem in animal and in vitro models of infection. Cardiac Electrophysiology At a dose of 1 and 3 times the maximum approved recommended dose, Vabomere (meropenem and vaborbactam) does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Pharmacokinetic (PK) Parameters The mean PK parameters of meropenem and vaborbactam in healthy adults with normal renal function after single and multiple 3-hour infusions of VABOMERE 4 grams (meropenem 2 grams and vaborbactam 2 grams) administered every 8 hours are summarized in Table 4. The PK parameters of meropenem and vaborbactam were similar for single and multiple dose administration of VABOMERE. Table 4: Pharmacokinetic Parameters (Mean [SD]) of Meropenem and Vaborbactam Following Administration of VABOMERE 4 grams (meropenem 2 grams and vaborbactam 2 grams) by 3-hour Infusion in Healthy Adult Subjects Parameter Meropenem Vaborbactam Single VABOMERE 4 grama Dose (N=8) Multiple VABOMERE 4 grama Doses Administered Every 8 hours for 7 Days (N=8) Single VABOMERE 4 grama Dose (N=8) Multiple VABOMERE 4 grama Doses Administered Every 8 hours for 7 Days (N=8) Cmax (mg/L) 46.0 (5.7) 43.4 (8.8) 50.7 (8.4) 55.6 (11.0) CL (L/h) 14.6 (2.7) 15.1 (2.8) 12.3 (2.2) 10.9 (1.8) AUC (mg•h/L)b 142.0 (28.0) 138.0 (27.7) 168.0 (32.2) 196.0 (36.7) T1/2 (h) 1.50 (1.0) 1.22 (0.3) 1.99 (0.8) 1.68 (0.4) Cmax = maximum observed concentration; CL = plasma clearance; AUC = area under the concentration time curve; T½ = half-life. a Meropenem 2 grams and vaborbactam 2 grams administered as a 3-hour infusion b AUC0-inf reported for single-dose administration; AUC0-8 reported for multiple-dose administration; AUC0 – 24 is 414 mg•h/L for meropenem and 588 mg•h/L for vaborbactam. The maximum plasma concentration (Cmax) and area under the plasma drug concentration time curve (AUC) of meropenem and vaborbactam proportionally increased with dose across the dose range studied (1 gram to 2 grams for meropenem and 0.25 grams to 2 grams for vaborbactam) 15 Reference ID: 5488109 when administered as a single 3-hour intravenous infusion. There is no accumulation of meropenem or vaborbactam following multiple intravenous infusions administered every 8 hours for 7 days in subjects with normal renal function. The mean population PK parameters of meropenem and vaborbactam in 295 patients (including 35 patients with reduced renal function) after 3-hour infusions of VABOMERE 4 grams (meropenem 2 grams and vaborbactam 2 grams) administered every 8 hours (or dose adjusted based on renal function) are summarized in Table 5. Table 5: Population Pharmacokinetic Parameters (Mean [SD]) of Meropenem and Vaborbactam Following Administration of VABOMERE 4 grams (meropenem 2 grams and vaborbactam 2 grams) by 3-hour Infusion in Patientsa Parameter Meropenem Vaborbactam Cmax (mg/L) 57.3 (23.0) 71.3 (28.6) AUC0-24, Day 1 (mg•h/L) 637 (295) 821 (369) AUC0-24, steady-state (mg•h/L) 650 (364) 835 (508) CL (L/h) 10.5 (6.4) 7.95 (4.3) T1/2 (h) 2.30 (2.5) 2.25 (2.1) a Meropenem 2 grams and vaborbactam 2 grams administered as a 3-hour infusion. Distribution The plasma protein binding of meropenem is approximately 2%. The plasma protein binding of vaborbactam is approximately 33%. The steady-state volumes of distribution of meropenem and vaborbactam in patients were 20.2 L and 18.6 L, respectively. Elimination The clearance of meropenem in healthy subjects following multiple doses is 15.1 L/h and for vaborbactam is 10.9 L/h. The t1/2 is 1.22 hours and 1.68 hours for meropenem and vaborbactam, respectively. Metabolism A minor pathway of meropenem elimination is hydrolysis of the beta-lactam ring (meropenem open lactam), which accounts for 22% of a dose eliminated via the urine. Vaborbactam does not undergo metabolism. Excretion Both meropenem and vaborbactam are primarily excreted via the kidneys. Approximately 40–60% of a meropenem dose is excreted unchanged within 24-48 hours with a further 22% recovered as the microbiologically inactive hydrolysis product. The mean renal clearance for meropenem was 7.8 L/h. The mean non-renal clearance for meropenem was 7.3 L/h which comprises both fecal elimination (~2% of dose) and degradation due to hydrolysis. 16 Reference ID: 5488109 For vaborbactam, 75 to 95% of the dose was excreted unchanged in the urine over a 24 to 48 hour period. The mean renal clearance for vaborbactam was 8.9 L/h. The mean non-renal clearance for vaborbactam was 2.0 L/h indicating nearly complete elimination of vaborbactam by the renal route. Specific Populations Patients with Renal Impairment Following a single dose of VABOMERE, pharmacokinetic studies with meropenem and vaborbactam in subjects with renal impairment have shown that meropenem AUC0-inf ratios to subjects with normal renal function are 1.28, 2.07, and 4.63 for subjects with mild (eGFR of 60 to 89 mL/min/1.73m2), moderate (eGFR of 30 to 59 mL/min/1.73m2), and severe (eGFR <30 mL/min/1.73m2) renal impairment, respectively; vaborbactam AUC0-inf ratios to subjects with normal renal function are 1.18, 2.31, and 7.8 for subjects with mild, moderate, and severe renal impairment, respectively [see Dosing and Administration (2.2)]. Hemodialysis removed 38% of the meropenem dose and 53% of the vaborbactam dose. Vaborbactam exposure was high in subjects with ESRD (eGFR <15 ml/min/1.73 m2). Vaborbactam exposure was higher when VABOMERE was administered after hemodialysis (AUC0-inf ratio to subjects with normal renal function of 37.5) than when VABOMERE was administered before hemodialysis (AUC0-inf ratio to subjects with normal renal function of 10.2) [see Use in Specific Populations (8.6) and Dosing and Administration (2.2)]. Patients with Hepatic Impairment A pharmacokinetic study conducted with an intravenous formulation of meropenem in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem. Vaborbactam does not undergo hepatic metabolism. Therefore, the systemic clearance of meropenem and vaborbactam is not expected to be affected by hepatic impairment. Geriatric Patients In elderly patients with renal impairment, plasma clearances of meropenem and vaborbactam were reduced, correlating with age-associated reduction in renal function [see Dosage and Administration (2.2) and Use in Specific Populations (8.5)]. Male and Female Patients Meropenem and vaborbactam Cmax and AUC were similar between males and females using a population pharmacokinetic analysis. Racial or Ethnic Groups No significant difference in mean meropenem or vaborbactam clearance was observed across race groups using a population pharmacokinetic analysis. Drug Interaction Studies No drug-drug interaction was observed between meropenem and vaborbactam in clinical studies with healthy subjects. 17 Reference ID: 5488109 No clinical studies have been conducted to evaluate the potential for VABOMERE to affect other drugs. Meropenem and vaborbactam do not inhibit the following cytochrome P450 isoforms in vitro at clinically relevant concentrations: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human liver microsomes. In vitro data suggest a potential for weak induction of CYP1A2 (meropenem), CYP3A4 (meropenem and vaborbactam) and potentially other pregnane X receptor (PXR)-regulated enzymes and transporters [see Drug Interactions (7.3 and 7.4)]. In vitro data suggest a potential of meropenem and vaborbactam to inhibit OAT3 at the clinically relevant concentrations. Meropenem and vaborbactam do not inhibit the following hepatic and renal transporters in vitro at clinically relevant concentrations: P-gp, BCRP, OAT1, OCT1, OCT2, OATP1B1, OATP1B3 or BSEP. Meropenem and vaborbactam were not substrates of OAT1, OCT2, P-gp, BCRP, MATE1, and MATE2-K. Meropenem and vaborbactam are substrates of OAT3 and as such, probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem and the same mechanism could apply for vaborbactam. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38% [see Drug Interactions (7.2)]. Concomitant administration of meropenem and valproic acid has been associated with reductions in valproic acid concentrations with subsequent loss in seizure control [see Drug Interactions (7.1)]. 12.4 Microbiology Mechanism of Action The meropenem component of VABOMERE is a penem antibacterial drug. The bactericidal action of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding protein (PBP) targets. Meropenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria, with the exception of carbapenem hydrolyzing beta-lactamases. The vaborbactam component of VABOMERE is a non-suicidal beta-lactamase inhibitor that protects meropenem from degradation by certain serine beta-lactamases such as Klebsiella pneumoniae carbapenemase (KPC). Vaborbactam does not have any antibacterial activity. Vaborbactam does not decrease the activity of meropenem against meropenem-susceptible organisms. Resistance Mechanisms of beta-lactam resistance may include the production of beta-lactamases, modification of PBPs by gene acquisition or target alteration, up-regulation of efflux pumps, and loss of outer membrane porin. VABOMERE may not have activity against gram-negative bacteria that have porin mutations combined with overexpression of efflux pumps. Clinical isolates may produce multiple beta-lactamases, express varying levels of beta­ lactamases, or have amino acid sequence variations, and other resistance mechanisms that have not been identified. 18 Reference ID: 5488109 Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy. VABOMERE demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: KPC, SME, TEM, SHV, CTX-M, CMY, and ACT. VABOMERE is not active against bacteria that produce metallo-beta lactamases or oxacillinases with carbapenemase activity. In the Phase 3 cUTI trial with VABOMERE, some isolates of E. coli, K. pneumoniae, E. cloacae, C. freundii, P. mirabilis, P. stuartii that produced beta-lactamases, were susceptible to VABOMERE (minimum inhibitory concentration ≤4 mcg /mL). These isolates produced one or more beta-lactamases of the following enzyme groups: OXA (non-carbapenemases), KPC, CTX-M, TEM, SHV, CMY, and ACT. Some beta-lactamases were also produced by an isolate of K. pneumoniae that was not susceptible to VABOMERE (minimum inhibitory concentration ≥32 mcg/mL). This isolate produced beta-lactamases of the following enzyme groups: CTX-M, TEM, SHV, and OXA. No cross-resistance with other classes of antimicrobials has been identified. Some isolates resistant to carbapenems (including meropenem) and to cephalosporins may be susceptible to VABOMERE. Interaction with Other Antimicrobials In vitro synergy studies have not demonstrated antagonism between VABOMERE and levofloxacin, tigecycline, polymyxin, amikacin, vancomycin, azithromycin, daptomycin, or linezolid. Activity against Meropenem Non-susceptible Bacteria in Animal Infection Models Vaborbactam restored activity of meropenem in animal models of infection (e.g., mouse thigh infection, urinary tract infection and pulmonary infection) caused by some meropenem non- susceptible KPC-producing Enterobacteriaceae. Antimicrobial Activity VABOMERE has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1.1)]. Gram-negative bacteria: • Enterobacter cloacae species complex • Escherichia coli • Klebsiella pneumoniae The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro MIC less than or equal to the susceptible breakpoint for VABOMERE against isolates of a similar genus or organism group. However, the efficacy of VABOMERE in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials. 19 Reference ID: 5488109 Gram-negative bacteria: • Citrobacter freundii • Citrobacter koseri • Enterobacter aerogenes • Klebsiella oxytoca • Morganella morganii • Proteus mirabilis • Providencia spp. • Pseudomonas aeruginosa • Serratia marcescens Susceptibility Test Methods For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies have not been performed with VABOMERE, meropenem, or vaborbactam. Mutagenesis Meropenem Genetic toxicity studies were performed with meropenem using the bacterial reverse mutation test, the Chinese hamster ovary HGPRT assay, cultured human lymphocytes cytogenic assay, and the mouse micronucleus test. There was no evidence of mutation potential found in any of these tests. Vaborbactam Genetic toxicity studies were performed with vaborbactam using the bacterial reverse mutation test, chromosomal aberration test and the mouse micronucleus test. There was no evidence of mutagenic potential found in any of these tests. 20 Reference ID: 5488109 Impairment of Fertility Meropenem Reproductive studies were performed with meropenem in male and female rats at doses up to 1000 mg/kg/day with no evidence of impaired fertility (approximately equivalent to 1.6 times the MRHD based on body surface area comparison). In a reproductive study in cynomolgus monkeys at doses of meropenem up to 360 mg/kg/day (on the basis of body surface area comparison, approximately equivalent to 1.2 times the MRHD) no reproductive toxicity was seen. Vaborbactam Vaborbactam had no adverse effect on fertility in male and female rats at doses up to 1000 mg/kg/day, which is equivalent to approximately 1.6 times the MRHD based on body surface area comparison. 14 CLINICAL STUDIES 14.1 Complicated Urinary Tract Infections (cUTI), including Pyelonephritis A total of 545 adults with cUTI, including pyelonephritis were randomized into a double-blind, double dummy, multi-center trial comparing VABOMERE (meropenem 2 grams and vaborbactam 2 grams) to piperacillin/tazobactam (piperacillin 4 grams/tazobactam 0.5 grams) intravenously every 8 hours. Switch to an oral antibacterial drug, such as levofloxacin was allowed after a minimum of 15 doses of IV therapy. The microbiologically modified intent to treat population (m-MITT) included all randomized patients who received any study drug and had at least 1 baseline uropathogen. Clinical and microbiological response at the end of IV treatment (EOIVT) required both a clinical outcome of cure or improvement and a microbiologic outcome of eradication (all baseline uropathogens at >105 CFU/mL are to be reduced to <104 CFU/mL). Clinical and microbiological response was also assessed at the Test of Cure (TOC) visit (approximately 7 days after completion of treatment) in the m-MITT population and required both a clinical outcome of cure and a microbiological outcome of eradication. Patient demographic and baseline characteristics were balanced between treatment groups in the m-MITT population. Approximately 93% of patients were Caucasian and 66% were females in both treatment groups. The mean age was 54 years with 32% and 42% patients greater than 65 years of age in VABOMERE and piperacillin/tazobactam treatment groups, respectively. Mean body mass index was approximately 26.5 kg/m2 in both treatment groups. Concomitant bacteremia was identified in 12 (6%) and 15 (8%) patients at baseline in VABOMERE and piperacillin/tazobactam treatment groups respectively. The proportion of patients with diabetes mellitus at baseline was 17% and 19% in VABOMERE and piperacillin/tazobactam treatment groups, respectively. The majority of patients (approximately 90%) were enrolled from Europe, and approximately 2% of patients were enrolled from North America. Overall, in both treatment 21 Reference ID: 5488109 groups, 59% of patients had pyelonephritis and 40% had cUTI, with 21% and 19% of patients having a non-removable and removable source of infection, respectively. Mean duration of IV treatment in both treatment groups was 8 days and mean total treatment duration (IV and oral) was 10 days; patients with baseline bacteremia could receive up to 14 days of therapy. Approximately 10% of patients in each treatment group in the m-MITT population had a levofloxacin-resistant pathogen at baseline and received levofloxacin as the oral switch therapy. This protocol violation may have impacted the assessment of the outcomes at the TOC visit. These patients were not excluded from the analysis presented in Table 6, as the decision to switch to oral levofloxacin was based on post-randomization factors. VABOMERE demonstrated efficacy with regard to clinical and microbiological response at the EOIVT visit and TOC visits in the m-MITT population as shown in Table 6. Table 6: Clinical and Microbiological Response Rates in a Phase 3 Trial of cUTI Including Pyelonephritis (m-MITT Population) VABOMERE n/N (%) Piperacillin/ Tazobactam n/N (%) Difference (95% CI) Clinical cure or improvement AND microbiological eradication at the End of IV Treatment Visit* 183/186 (98.4) 165/175 (94.3) 4.1% (0.3%, 8.8%) Clinical cure AND microbiological eradication at the Test of Cure visit approximately 7 days after completion of treatment** 124/162 (76.5) 112/153 (73.2) 3.3% (-6.2%, 13.0%) CI = confidence interval; EOIVT = End of Intravenous Treatment; TOC = Test of Cure *End of IV Treatment visit includes patients with organisms resistant to piperacillin/tazobactam at baseline **Test of Cure visit excludes patients with organisms resistant to piperacillin/tazobactam at baseline In the m-MITT population, the rate of clinical and microbiological response in VABOMERE- treated patients with concurrent bacteremia at baseline was 10/12 (83.3%). In a subset of the E. coli and K. pneumoniae isolates, genotypic testing identified certain ESBL groups (e.g., TEM, CTX-M, SHV and OXA) in both treatment groups of the Phase 3 cUTI trial. The rates of clinical and microbiological response were similar in the ESBL-positive and ESBL- negative subset at EOIVT; at TOC, clinical and microbiological response was lower in the ESBL-positive as compared to ESBL-negative subset in both treatment groups. 15 REFERENCES 1. Kawamura S, Russell AW, Freeman SJ, and Siddall, RA: Reproductive and Developmental Toxicity of Meropenem in Rats. Chemotherapy, 40:S238-250 (1992). 22 Reference ID: 5488109 16 HOW SUPPLIED/STORAGE AND HANDLING VABOMERE 2 grams (meropenem and vaborbactam) for injection is supplied as a white to light yellow sterile powder for constitution in single-dose, clear glass vials (NDC 70842-120-01) sealed with a rubber stopper (not made with natural rubber latex) and an aluminum overseal. Each vial is supplied in cartons of 6 vials (NDC 70842-120-06). Each vial contains 1 gram of meropenem (equivalent to 1.14 grams of meropenem trihydrate), 1 gram of vaborbactam, and 0.575 gram of sodium carbonate. Store VABOMERE vials at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F) [see USP, Controlled Room Temperature (CRT)]. 17 PATIENT COUNSELING INFORMATION Serious Allergic Reactions Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask patient about any previous hypersensitivity reactions to VABOMERE (meropenem and vaborbactam), penicillins, cephalosporins, other beta-lactams, or other allergens [see Warnings and Precautions (5.1)]. Seizures Patients receiving VABOMERE on an outpatient basis must be alerted of adverse events such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well established that VABOMERE is well tolerated, patients should not operate machinery or motorized vehicles [see Warnings and Precautions (5.2)]. Potentially Serious Diarrhea Counsel patients that diarrhea is a common problem caused by antibacterial drugs including VABOMERE, which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.4)]. Interaction with Valproic Acid Counsel patients to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co- administration with VABOMERE. If treatment with VABOMERE is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed [see Warnings and Precautions (5.5)]. Interaction with Hormonal Contraceptives Advise patients that administration of VABOMERE may reduce the efficacy of hormonal contraceptives. Instruct patients to use effective alternative or back-up methods of contraception 23 Reference ID: 5488109 (such as condoms and spermicides) during treatment with VABOMERE [see Drug Interactions (7.4) and Use in Specific Populations (8.3)]. Antibacterial Resistance Counsel patients that antibacterial drugs, including VABOMERE, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When VABOMERE is prescribed to treat a bacterial infection, tell patients that although it is common to feel better early in the course of therapy, take the medication exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by VABOMERE or other antibacterial drugs in the future [see Warnings and Precautions (5.8)]. Marketed by: Melinta Therapeutics, LLC Parsippany, NJ 07054 USA MEL040-R00x 24 Reference ID: 5488109
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2025-02-12T15:47:29.972900
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H 0 I II H-C-C-OH I 0 H Acetic Acid Chemically, hydrocortisone is: Pregn-4-ene-3, 20-dione, 11, 17, 21-trihydroxy-, (11~)- . Hydrocortisone and Acetic Acid Otic Solution, USP Rx only DESCRIPTION: Hydrocortisone and Acetic Acid Otic Solution, USP is a solution containing hydrocortisone (1%) and acetic acid (2%), in a propylene glycol vehicle containing benzethonium chloride (0.02%), citric acid (0.05%), propylene glycol diacetate (3%) and sodium acetate (0.015%). The empirical formulas for acetic acid and hydrocortisone are CH3COOH, and C21H30O5, with a molecular weight of 60.05 and 362.46, respectively. The structural formulas are: Hydrocortisone and Acetic Acid is available as a nonaqueous otic solution buffered at pH 3 for use in the external ear canal. CLINICAL PHARMACOLOGY: Acetic acid is antibacterial and antifungal; hydrocortisone is antiinflammatory, antiallergic and antipruritic; propylene glycol is hydrophilic and provides a low surface tension; benzethonium chloride is a surface active agent that promotes contact of the solution with tissues. INDICATIONS AND USAGE: For the treatment of superficial infections of the external auditory canal caused by organisms susceptible to the action of the antimicrobial, complicated by inflammation. CONTRAINDICATIONS: Hypersensitivity to Hydrocortisone and Acetic Acid or any of the ingredients; herpes simplex, vaccinia and varicella. Perforated tympanic membrane is considered a contraindication to the use of any medication in the external ear canal. WARNINGS: Discontinue promptly if sensitization or irritation occurs. PRECAUTIONS: Transient stinging or burning may be noted occasionally when the solution is first instilled into the acutely inflamed ear. PEDIATRIC USE: Safety and effectiveness in pediatric patients below the age of 3 years have not been established. ADVERSE REACTIONS: Stinging or burning may be noted occasionally; local irritation has occurred very rarely. To report SUSPECTED ADVERSE REACTIONS, contact Saptalis Pharmaceuticals, LLC at 1-833-727-8254 or FDA at 1­800­FDA­1088 or www.fda.gov/medwatch. Reference ID: 5488725 DOSAGE AND ADMINISTRATION: Carefully remove all cerumen and debris to allow Hydrocortisone and Acetic Acid to contact infected surfaces directly. To promote continuous contact, insert a wick of cotton saturated with Hydrocortisone and Acetic Acid into the ear canal; the wick may also be saturated after insertion. Instruct the patient to keep the wick in for at least 24 hours and to keep it moist by adding 3 to 5 drops of Hydrocortisone and Acetic Acid every 4 to 6 hours. The wick may be removed after 24 hours but the patient should continue to instill 5 drops of Hydrocortisone and Acetic Acid 3 or 4 times daily thereafter, for as long as indicated. In pediatric patients, 3 to 4 drops may be sufficient due to the smaller capacity of the ear canal. HOW SUPPLIED: Hydrocortisone and Acetic Acid Otic Solution, USP, containing hydrocortisone (1%) and acetic acid (2%), is available in 10 mL, measured-drop, safety-tip plastic bottles (NDC 71656-064-10). STORAGE: Store at room temperature, 20°C to 25°C (68°F to 77°F). Keep container tightly closed. Rx only Distributed by: Saptalis Pharmaceuticals, LLC. Hauppauge, NY 11788 MADE IN USA MAY 2024-R3 PPM-0082 Reference ID: 5488725
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2025-02-12T15:47:30.256803
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_______________________________________________________________________________________________________________________________________ _______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------WARNINGS AND PRECAUTIONS------------------------­ These highlights do not include all the information needed to use • Gastrointestinal Toxicity: Monitor and manage as necessary. Withhold, BOSULIF safely and effectively. See full prescribing information for dose reduce, or discontinue BOSULIF. (2.3, 5.1) BOSULIF. • Myelosuppression: Monitor blood counts and manage as necessary. Withhold, dose reduce, or discontinue BOSULIF. (2.4, 5.2) BOSULIF® (bosutinib) tablets, for oral use • Hepatic Toxicity: Monitor liver enzymes at least monthly for the first BOSULIF® (bosutinib) capsules, for oral use 3 months and as needed. Withhold, dose reduce, or discontinue BOSULIF. Initial U.S. Approval: 2012 (2.3, 5.3) • Cardiovascular Toxicity: Monitor and manage as necessary. Interrupt, dose ----------------------------INDICATIONS AND USAGE-------------------------- reduce, or discontinue BOSULIF. (5.4) BOSULIF is a kinase inhibitor indicated for the treatment of • Fluid Retention: Monitor patients and manage using standard of care treatment. Interrupt, dose reduce, or discontinue BOSULIF. (2.3, 5.5) • adult and pediatric patients 1 year of age and older with chronic phase Ph+ • Renal Toxicity: Monitor patients for renal function at baseline and during chronic myelogenous leukemia (CML), newly-diagnosed or resistant or therapy with BOSULIF. (5.6) intolerant to prior therapy. (1) • Embryo-Fetal Toxicity: BOSULIF can cause fetal harm. Advise female • adult patients with accelerated, or blast phase Ph+ CML with resistance or patients of reproductive potential of potential risk to a fetus and to use intolerance to prior therapy. (1) effective contraception. (5.7) ----------------------DOSAGE AND ADMINISTRATION---------------------- ------------------------------ADVERSE REACTIONS-----------------------------­ • Adult patients with newly-diagnosed chronic phase Ph+ CML: 400 mg • Most common adverse reactions (≥20%), in adult and pediatric patients orally once daily with food. (2.1) with CML are diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, • Adult patients with chronic, accelerated, or blast phase Ph+ CML with hepatic dysfunction, headache, pyrexia, decreased appetite respiratory tract resistance or intolerance to prior therapy: 500 mg orally once daily with infection, and constipation. The most common laboratory abnormalities food. (2.1) (≥20%) in adult and pediatric patients are creatinine increased, hemoglobin • Pediatric patients with newly-diagnosed chronic phase Ph+ CML: decreased, lymphocyte count decreased, platelets decreased, ALT 300 mg/m2 orally once daily with food. (2.1) increased, calcium decreased, white blood cell count decreased, AST • Pediatric patients with chronic phase Ph+ CML with resistance or increased, absolute neutrophil count decreased, glucose increased, intolerance to prior therapy: 400 mg/m2 orally once daily with food. (2.1) phosphorus decreased, urate increased, alkaline phosphatase increased, • Consider dose escalation by increments of 100 mg once daily to a lipase increased, creatine kinase increased, and amylase increased. (6.1) maximum of 600 mg daily in adult patients who do not reach complete hematologic, cytogenetic, or molecular response and do not have Grade 3 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at or greater adverse reactions. (2.2) 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. • Consider dose escalation by increments of 50 mg for those with a BSA <1.1 m2 and 100 mg for those with a BSA ≥1.1 m2 to a maximum of 600 ------------------------------DRUG INTERACTIONS------------------------------­ mg daily in pediatric patients who do not reach sufficient response after 3 • Strong and Moderate CYP3A Inhibitors: Avoid concomitant use with months. (2.2) BOSULIF. (7.1) • Adjust dosage for toxicity and organ impairment (2) • Strong CYP3A Inducers: Avoid concomitant use with BOSULIF. (7.1) • Proton Pump Inhibitors: Use short-acting antacids or H2 blockers as an ---------------------DOSAGE FORMS AND STRENGTHS--------------------- alternative to proton pump inhibitors. (7.1) • Tablets: 100 mg, 400 mg, and 500 mg. (3) • Capsules 50 mg, 100 mg. (3) ----------------------------USE IN SPECIFIC POPULATIONS------------------­ Lactation: Advise women not to breastfeed. (8.2) -------------------------------CONTRAINDICATIONS---------------------------­ See 17 for PATIENT COUNSELING INFORMATION and Hypersensitivity to BOSULIF. (4) FDA-approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 8.2 Lactation 1 INDICATIONS AND USAGE 8.3 Females and Males of Reproductive Potential 2 DOSAGE AND ADMINISTRATION 8.4 Pediatric Use 2.1 Recommended Dosage 8.5 Geriatric Use 2.2 Dose Escalation 8.6 Renal Impairment 2.3 Dosage Adjustments for Non-Hematologic Adverse Reactions 8.7 Hepatic Impairment 2.4 Dosage Adjustments for Myelosuppression 10 OVERDOSAGE 2.5 Dosage Adjustments for Renal Impairment or Hepatic Impairment 11 DESCRIPTION 3 DOSAGE FORMS AND STRENGTHS 12 CLINICAL PHARMACOLOGY 4 CONTRAINDICATIONS 12.1 Mechanism of Action 5 WARNINGS AND PRECAUTIONS 12.2 Pharmacodynamics 5.1 Gastrointestinal Toxicity 12.3 Pharmacokinetics 5.2 Myelosuppression 13 NONCLINICAL TOXICOLOGY 5.3 Hepatic Toxicity 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.4 Cardiovascular Toxicity 14 CLINICAL STUDIES 5.5 Fluid Retention 14.1 Adult Patients with Newly-Diagnosed CP Ph+ CML 5.6 Renal Toxicity 14.2 Adult Patients with Imatinib-Resistant or -Intolerant Ph+ CP, AP, 5.7 Embryo-Fetal Toxicity and BP CML 6 ADVERSE REACTIONS 14.3 Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP 6.1 Clinical Trials Experience Ph+ CML with Resistance or Intolerance to Prior Therapy 6.2 Postmarketing Experience 16 HOW SUPPLIED/STORAGE AND HANDLING 7 DRUG INTERACTIONS 17 PATIENT COUNSELING INFORMATION 7.1 Effect of Other Drugs on BOSULIF 8 USE IN SPECIFIC POPULATIONS * Sections or subsections omitted from the Full Prescribing Information are 8.1 Pregnancy not listed. 1 Reference ID: 5488737 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE BOSULIF is indicated for the treatment of: • Adult and pediatric patients 1 year of age and older with chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML), newly-diagnosed or resistant or intolerant to prior therapy [see Clinical Studies (14.1, 14.2, 14.3)]. • Adult patients with accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior therapy [see Clinical Studies (14.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage is taken orally once daily with food. Swallow tablets whole. Do not cut, crush, break or chew tablets. Continue treatment with BOSULIF until disease progression or intolerance to therapy. Capsules may be swallowed whole. For patients who are unable to swallow a whole capsule(s), each capsule can be opened and the contents mixed with applesauce or yogurt. Mixing the capsule contents with applesauce or yogurt cannot be considered a substitute of a proper meal. If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Dosage in Adult Patients with Newly-Diagnosed CP Ph+ CML The recommended dosage of BOSULIF is 400 mg orally once daily with food. Dosage in Adult Patients with CP, AP, or BP Ph+ CML with Resistance or Intolerance to Prior Therapy The recommended dosage of BOSULIF is 500 mg orally once daily with food. Dosage in Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy The recommended dose of BOSULIF for pediatric patients with newly-diagnosed CP Ph+ CML is 300 mg/m2 orally once daily with food and the recommended dosage for pediatric patients with CP Ph+ CML that is resistant or intolerant to prior therapy is 400 mg/m2 orally once daily with food and dose recommendations are provided in Table 1. As appropriate, the desired dose can be attained by combining different strengths of BOSULIF tablets or capsules. Table 1: Dosing of BOSULIF for Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy BSA1 Newly-Diagnosed Recommended Dose (Once Daily) Resistant or Intolerant Recommended Dose (Once Daily) < 0.55 m2 150 mg 200 mg 0.55 to < 0.63 m2 200 mg 250 mg 0.63 to < 0.75 m2 200 mg 300 mg 0.75 to < 0.9 m2 250 mg 350 mg 0.9 to < 1.1 m2 300 mg 400 mg ≥ 1.1 m2 400 mg* 500 mg* * maximum starting dose (corresponding to maximum starting dose in adult indication) 1 BSA=Body Surface Area 2 Reference ID: 5488737 Preparation Instructions for BOSULIF Capsules Mixed with Applesauce or Yogurt For patients who are unable to swallow capsules, the contents of the capsules can be mixed with applesauce or yogurt. Remove the required number of capsules from the container to prepare the dose as instructed and the amount of either room temperature applesauce or yogurt in a clean container. Carefully open each capsule, add the entire capsule content of each capsule into the applesauce or yogurt, then mix the entire dose into the applesauce or yogurt. Patients should immediately consume the full mixture in its entirety, without chewing. Do not store the mixture for later use. If the entire preparation is not swallowed do not take an additional dose. Wait until the next day to resume dosing. Table 2: BOSULIF Dose Using Capsules and Soft Food Volumes Dose Volume of Applesauce or Yogurt 100 mg 10 mL (2 teaspoons) 150 mg 15 mL (3 teaspoons) 200 mg 20 mL (4 teaspoons) 250 mg 25 mL (5 teaspoons) 300 mg 30 mL (6 teaspoons) 350 mg 30 mL (6 teaspoons) 400 mg 35 mL (7 teaspoons) 450 mg 40 mL (8 teaspoons) 500 mg 45 mL (9 teaspoons) 550 mg 45 mL (9 teaspoons) 600 mg 50 mL (10 teaspoons) 2.2 Dose Escalation In clinical studies of adult patients with Ph+ CML, dose escalation by increments of 100 mg once daily to a maximum of 600 mg once daily was allowed in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response and who did not have Grade 3 or higher adverse reactions at the recommended starting dosage. In pediatric patients with BSA <1.1 m2 and an insufficient response after 3 months consider increasing dose by 50 mg increments up to maximum of 100 mg above starting dose. Dose increases for insufficient response in pediatric patients with BSA ≥1.1 m2 can be conducted similarly to adult recommendations in 100 mg increments. The maximum dose in pediatric and adult patients is 600 mg once daily. 2.3 Dosage Adjustments for Non-Hematologic Adverse Reactions Elevated liver transaminases: If elevations in liver transaminases greater than 5×institutional upper limit of normal (ULN) occur, withhold BOSULIF until recovery to less than or equal to 2.5×ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinue BOSULIF. If transaminase elevations greater than or equal to 3×ULN occur concurrently with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 2×ULN (Hy’s law case definition), discontinue BOSULIF [see Warnings and Precautions (5.3)]. Diarrhea: For National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 3-4 diarrhea (increase of greater than or equal to 7 stools/day over baseline/pretreatment), withhold BOSULIF until recovery to Grade less than or equal to 1. BOSULIF may be resumed at 400 mg once daily [see Warnings and Precautions (5.1)]. For other clinically significant, moderate or severe non-hematological toxicity, withhold BOSULIF until the toxicity has resolved, then consider resuming BOSULIF at a dose reduced by 100 mg taken once daily. If clinically appropriate, consider re-escalating the dose of BOSULIF to the starting dose taken once daily. In pediatric patients, dose adjustments for non-hematologic toxicities can be conducted similarly to adults, however the dose reduction increments may differ. For pediatric patients with BSA <1.1 m2, reduce dose by 50 mg initially followed 3 Reference ID: 5488737 by additional 50 mg increment if the adverse reaction (AR) persists. For pediatric patients with BSA ≥1.1 m2 or greater, reduce dose similarly to adults. 2.4 Dosage Adjustments for Myelosuppression Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 3). Table 3: Dose Adjustments for Neutropenia and Thrombocytopenia in Adult and Pediatric Patients ANCa less than 1000×106/L or Platelets less than 50,000×106/L Withhold BOSULIF until ANC greater than or equal to1000×106/L and platelets greater than or equal to 50,000×106/L. Resume treatment with BOSULIF at the same dose if recovery occurs within 2 weeks. If blood counts remain low for greater than 2 weeks, upon recovery, reduce dose by 100 mg and resume treatment, or by 50 mg in pediatric patients with BSA <1.1 m2 and resume treatment. If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment, or by an additional 50 mg in pediatric patients with BSA <1.1 m2 and resume treatment. a Absolute Neutrophil Count 2.5 Dosage Adjustments for Renal Impairment or Hepatic Impairment The recommended starting doses for patients with renal and hepatic impairment are described in Table 4 below. Table 4: Dose Adjustments for Renal and Hepatic Impairment in Adult Patients Recommended Starting Dosage Newly-diagnosed chronic phase Ph+ CML Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy Normal renal and hepatic function 400 mg daily 500 mg daily Renal impairment Creatinine clearance 30 to 50 mL/min 300 mg daily 400 mg daily Creatinine clearance less than 30 mL/min 200 mg daily 300 mg daily Hepatic impairment Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child- Pugh C) 200 mg daily 200 mg daily [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)]. 4 Reference ID: 5488737 Table 5: Dosage Adjustments for Renal and Hepatic Impairment in Pediatric Patients Newly-Diagnosed CP Ph+ CML Recommended Starting Dose (Once Daily) By Organ Function Pediatric Patients by Separated BSA1 Band Normal renal and hepatic function Renal Impairment: Creatinine clearance 30 to 50 mL/min Renal Impairment: Creatinine clearance less than 30 mL/min Hepatic Impairment: Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C) Pediatric < 0.55 m2 150 mg 100 mg 100 mg 100 mg Pediatric 0.55 to < 0.63 m2 200 mg 150 mg 100 mg 100 mg Pediatric 0.63 to < 0.75 m2 200 mg 150 mg 100 mg 100 mg Pediatric 0.75 to < 0.9 m2 250 mg 200 mg 150 mg 100 mg Pediatric 0.9 to < 1.1 m2 300 mg 200 mg 200 mg 150 mg Pediatric ≥ 1.1 m2 400 mg 300 mg 200 mg 200 mg CP Ph+ CML with Resistance or Intolerance to Prior Therapy Recommended Starting Dose (Once Daily) By Organ Function Pediatric Patients by Separated BSA1 Band Normal renal and hepatic function Renal Impairment: Creatinine clearance 30 to 50 mL/min Renal Impairment: Creatinine clearance less than 30 mL/min Hepatic Impairment: Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C) Pediatric < 0.55 m2 200 mg 150 mg 100 mg 100 mg Pediatric 0.55 to < 0.63 m2 250 mg 200 mg 150 mg 100 mg Pediatric 0.63 to < 0.75 m2 300 mg 200 mg 200 mg 150 mg Pediatric 0.75 to < 0.9 m2 350 mg 250 mg 200 mg 150 mg Pediatric 0.9 to < 1.1 m2 400 mg 300 mg 250 mg 200 mg Pediatric ≥ 1.1 m2 500 mg 400 mg 300 mg 200 mg 1 BSA=Body Surface Area [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS Tablets: • 100 mg: yellow, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “100” on the other. • 400 mg: orange, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “400” on the other. • 500 mg: red, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “500” on the other. Capsules: • 50 mg: white body/orange cap with “BOS 50” printed on the body and “Pfizer” printed on the cap in black ink. • 100 mg: white body/brownish-red cap with “BOS 100” printed on the body and “Pfizer” printed on the cap in black ink. 4 CONTRAINDICATIONS BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included anaphylaxis [see Adverse Reactions (6.1)]. 5 Reference ID: 5488737 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Toxicity Diarrhea, nausea, vomiting, and abdominal pain occur with BOSULIF treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and fluid replacement. In the randomized clinical trial in adult patients with newly-diagnosed Ph+ CML, the median time to onset for diarrhea (all grades) was 4 days and the median duration per event was 3 days. Among 546 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 2 days. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range 1-268). Among 49 pediatric patients with newly-diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the duration was 2 days. Among patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 2 (range 1 – 198). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.2 Myelosuppression Thrombocytopenia, anemia and neutropenia occur with BOSULIF treatment. Perform complete blood counts weekly for the first month of therapy and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.4) and Adverse Reactions (6)]. 5.3 Hepatic Toxicity Bosutinib may cause elevations in serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]). Two cases consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3×ULN with total bilirubin greater than 2×ULN and alkaline phosphatase less than 2×ULN) have occurred without alternative causes. This represented 2 out 1711 patients in BOSULIF clinical trials. In the 268 adult patients from the safety population in the randomized clinical trial in patients with newly-diagnosed CML in the BOSULIF treatment group, the incidence of ALT elevation was 68.3% and increased AST was 56%. Of patients who experienced increased transaminases of any grade, 73% experienced their first increase within the first 3 months. The median time to onset of increased ALT and AST was 29 and 56 days, respectively, and the median duration was 19 and 15 days, respectively. Among the 546 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the incidence of increased ALT was 53.3% and AST elevation was 46.7%. Sixty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations in this study occurred early in treatment; of patients who experienced increased transaminases of any grade, more than 81% experienced their first increase within the first 3 months. The median time to onset of increased ALT and AST was 22 and 29 days, respectively, and the median duration for each was 21 days. Among 49 pediatric patients with newly-diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, the incidence based on laboratory data that worsened from baseline of increased ALT was 59% and of increased AST 51%. Seventy-six percent of the patients experienced an increase in either ALT or AST. Most cases of increased transaminases occurred early in treatment; of patients who experienced increased transaminases of any grade, 6 Reference ID: 5488737 84% of patients experienced their first increases within the first 3 months. The median time to onset for adverse reactions of increased ALT and AST was 22 and 15 days, respectively. The median duration for adverse reactions of Grade 3 or 4 increased ALT or AST was 26 and 12 days, respectively. Perform hepatic enzyme tests monthly for the first 3 months of BOSULIF treatment and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.4 Cardiovascular Toxicity BOSULIF can cause cardiovascular toxicity including cardiac failure, left ventricular dysfunction, and cardiac ischemic events. Cardiac failure events occurred more frequently in previously treated patients than in patients with newly diagnosed CML and were more frequent in patients with advanced age or risk factors, including previous medical history of cardiac failure. Cardiac ischemic events occurred in both previously treated patients and in patients with newly diagnosed CML and were more common in patients with coronary artery disease risk factors, including history of diabetes, body mass index greater than 30, hypertension, and vascular disorders. In a randomized study of adult patients with newly diagnosed CML, cardiac failure occurred in 1.9% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib. Cardiac ischemic events occurred in 4.9% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib. In a single-arm study in adult patients with CML who were resistant or intolerant to prior therapy, cardiac failure was observed in 5.3% of patients and cardiac ischemic events were observed in 5.1% of patients treated with BOSULIF. Among 49 pediatric patients with newly diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, 4 (8%) patients had Grade 1-2 cardiac events, including tachycardia (n=2), angina pectoris, right bundle branch block, and sinus tachycardia (n=1 each). Monitor patients for signs and symptoms consistent with cardiac failure and cardiac ischemia and treat as clinically indicated. Interrupt, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.5 Fluid Retention Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. In the randomized clinical trial of 268 adult patients with newly-diagnosed CML in the bosutinib treatment group, 3 patients (1.1%) experienced severe fluid retention of Grade 3, 1 patient experienced Grade 3 pericardial effusion, and 2 patients experienced Grade 3 pleural effusion. Among 546 adult patients in a single-arm study in patients with Ph+ CML who were resistant or intolerant to prior therapy, Grade 3 or 4 fluid retention was reported in 30 patients (6%). Some patients experienced more than one fluid retention event. Specifically, 24 patients experienced Grade 3 or 4 pleural effusions, 9 patients experienced Grade 3 or Grade 4 pericardial effusions, and 6 patients experienced Grade 3 edema. Among 49 pediatric patients with newly diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, Grade 1-2 pericardial effusion, peripheral edema, and face edema were reported in 1 patient each. Monitor and manage patients using standards of care. Interrupt, dose reduce or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.6 Renal Toxicity An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in patients treated with BOSULIF. Table 6 identifies the shift from baseline to lowest observed eGFR during BOSULIF therapy for patients in the pooled 7 Reference ID: 5488737 6 leukemia studies regardless of line of therapy. The median duration of therapy with BOSULIF was approximately 24 months (range, 0.03 to 155) for patients in these studies. Table 6: Shift From Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies (N=1372)* Baseline Follow-Up Renal Function Status N Normal n (%) Mild n (%) Mild to Moderate n (%) Moderate to Severe n (%) Severe n (%) Kidney Failure n (%) Normal 527 115 (21.8) 330 (62.6) 50 (9.5) 23 (4.4) 3 (0.6) 5 (0.9) Mild 672 10 (1.5) 259 (38.5) 271 (40.3) 96 (14.3) 26 (3.9) 6 (0.9) Mild to Moderate 137 0 6 (4.4) 40 (29.2) 66 (48.2) 24 (17.5) 1 (0.7) Moderate to Severe 33 0 1 (3.0) 1 (3.0) 8 (24.2) 19 (57.6) 4 (12.1) Severe 1 0 0 0 0 0 1 (100) Total 1370 125 (9.1) 596 (43.5) 362 (26.4) 193 (14.1) 72 (5.2) 17 (1.2) Abbreviations: eGFR=estimated glomerular filtration rate; N/n=number of patients. Notes: eGFR was calculated using Modification in Diet in Renal Disease method (MDRD). Notes: Grading is based on Kidney Disease Improving Global Outcomes (KDIGO) Classification by eGFR: Normal: greater than or equal to 90, Mild: 60 to less than 90, Mild to Moderate: 45 to less than 60, Moderate to Severe: 30 to less than 45, Severe: 15 to less than 30, Kidney Failure: less than 15 ml/min/1.73 m2 . *Among the 1372 patients, eGFR was missing in 7 patients at baseline or on-therapy. There were no patients with kidney failure at baseline. Overall, 45% of the pediatric patients with newly diagnosed CP Ph+ CML or resistant or intolerant CP Ph+ CML who had normal eGFR at baseline shifted to a maximum of mild, and 40% pediatric patients who had mild eGFR at baseline shifted to a maximum of moderate during treatment. Monitor renal function at baseline and during therapy with BOSULIF, with particular attention to those patients who have preexisting renal impairment or risk factors for renal dysfunction. Consider dose adjustment in patients with baseline and treatment emergent renal impairment [see Dosage and Administration (2.5)]. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, BOSULIF can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Gastrointestinal toxicity [see Warnings and Precautions (5.1)]. • Myelosuppression [see Warnings and Precautions (5.2)]. • Hepatic toxicity [see Warnings and Precautions (5.3)]. • Cardiovascular toxicity [see Warnings and Precautions (5.4)]. • Fluid retention [see Warnings and Precautions (5.5)]. • Renal toxicity [see Warnings and Precautions (5.6)]. 8 Reference ID: 5488737 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions, in ≥20% of adults with newly diagnosed CP Ph+ CML or CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy (N=814) were diarrhea (80%), rash (44%), nausea (44%), abdominal pain (43%), vomiting (33%), fatigue (33%), hepatic dysfunction (33%), respiratory tract infection (25%), pyrexia (24%), and headache (21%). The most common laboratory abnormalities that worsened from baseline in ≥20% of adults were creatinine increased (93%), hemoglobin decreased (90%), lymphocyte count decreased (72%), platelets decreased (69%), ALT increased (58%), calcium decreased (53%), white blood cell count decreased (52%), absolute neutrophils count decreased (50%), AST increased (50%), glucose increased (46%), phosphorus decreased (44%), urate increased (41%), alkaline phosphatase increased (40%), lipase increased (36%), creatine kinase increased (29%), and amylase increased (24%). The most common adverse reactions, in ≥20% of pediatric patients (N=49) were diarrhea (82%), abdominal pain (73%), vomiting (55%), nausea (49%), rash (49%), fatigue (37%), hepatic dysfunction (37%), headache (35%), pyrexia (31%), decreased appetite (27%), and constipation (20%). The most common laboratory abnormalities that worsened from baseline in ≥20% of pediatric patients were creatinine increased (92%), alanine aminotransferase increased (59%), white blood cell count decreased (53%), aspartate aminotransferase increased (51%), platelet count decreased (49%), glucose increased (41%), calcium decreased (31%), hemoglobin decreased (31%), neutrophil count decreased (31%), lymphocyte count decreased (29%), serum amylase increased (27%), and CPK increased (25%). Adverse Reactions in Adult Patients With Newly-Diagnosed CP CML The clinical trial randomized and treated 533 patients with newly-diagnosed CP CML to receive BOSULIF 400 mg daily or imatinib 400 mg daily as single agents (Newly-Diagnosed CP CML Study) [see Clinical Studies (14.1)]. The safety population (received at least 1 dose of BOSULIF) included: • two hundred sixty-eight (268) patients with newly-diagnosed CP CML had a median duration of BOSULIF treatment of 55 months (range: 0.3 to 60 months) and a median dose intensity of 394 mg/day. Serious adverse reactions occurred in 22% of patients with newly-diagnosed CP CML who received bosutinib. Serious adverse reactions reported in >2% of patients included hepatic dysfunction (4.1%), pneumonia (3.4%), coronary artery disease (3.4%), and gastroenteritis (2.2%). Fatal adverse reactions occurred in 3 patients (1.1%) due to coronary artery disease (0.4%), cardiac failure acute (0.4%), and renal failure (0.4%). Permanent discontinuation of bosutinib due to an adverse reaction occurred in 20% of patients with newly-diagnosed CP CML who received bosutinib. Adverse reactions which resulted in permanent discontinuation in > 2% of patients included hepatic dysfunction (9%). Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 68% of patients with newly-diagnosed CP CML. Adverse reactions which required dose interruptions or reductions in >5% of patients included hepatic dysfunction (27%), thrombocytopenia (16%), diarrhea (16%), lipase increased (10%), neutropenia (7%), abdominal pain (6%), rash (5%). The most common adverse reactions, in >20% of bosutinib-treated patients with newly-diagnosed CML (N=268) were diarrhea (75%), hepatic dysfunction (45%), rash (40%), abdominal pain (39%), nausea (37%), fatigue (33%), respiratory tract infection (27%), headache (22%), and vomiting (21%). The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine increased (94%), hemoglobin decreased (89%), lymphocyte count decreased (84%), ALT increased (68%), platelet count decreased 9 Reference ID: 5488737 (68%), glucose increased (57%), AST increased (56%), calcium decreased (55%), phosphorus decreased (54%), lipase increased (53%), white blood cell count decreased (50%), absolute neutrophil count decreased (42%), alkaline phosphatase increased (41%), creatine kinase increased (36%), and amylase increased (32%). Table 7 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 (3/4) for the Phase 3 CP CML safety population. Table 7: Adverse Reactions (10% or Greater) in Patients With Newly-Diagnosed CML in Bosutinib 400 mg Study* System Organ Class Preferred Term Bosutinib 400 mg Chronic Phase CML (N=268) Imatinib 400 mg Chronic Phase CML (N=265) All Grades % Grade 3/4 % All Grades % Grade 3/4 % Gastrointestinal disorders Diarrhea 75 9 40 1 Abdominal paina 39 2 27 1 Nausea 37 0 42 0 Vomiting 21 1 20 0 Constipation 13 0 6 0 Hepatobiliary disorders Hepatic dysfunctionf 45 27 15 4 Skin and subcutaneous tissue disorders Rashd 40 2 30 2 Pruritus 11 <1 4 0 General disorders and administration- site conditions Fatigueb 33 1 30 <1 Pyrexia 17 1 11 0 Edemag 15 0 46 2 Infections and infestations Respiratory tract infectione 27 1 25 <1 Nervous system disorders Headache 22 1 15 1 Musculoskeletal and connective tissue disorders Arthralgia 18 1 18 <1 Back pain 12 <1 9 <1 Respiratory, thoracic, and mediastinal disorders Cough 11 0 10 0 Dyspnea 11 1 6 1 Metabolism and nutrition disorders Decreased appetite 11 <1 6 0 Vascular disorders Hypertensionc 10 5 11 5 *Based on a Minimum of 57 Months of Follow-up. Adverse drug reactions are based on all-causality treatment-emergent adverse events. The commonality stratification is based on 'All Grades' under Total column. 'Grade 3', 'Grade 4' columns indicate maximum toxicity. a Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain. b Fatigue includes the following preferred terms: Asthenia, Fatigue, Malaise. c Hypertension* includes the preferred terms: Blood pressure systolic increased, Hypertension, Hypertensive crisis, Hypertensive heart disease, Retinopathy hypertensive. f Hepatic dysfunction includes the preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Drug-induced liver injury, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic steatosis, Hepatitis, Hepatitis toxic, Hepatocellular injury, Hepatotoxicity, Hyperbilirubinemia, Jaundice, Liver disorder, Liver function test increased, Ocular icterus, Transaminases increased. g Edema includes the following preferred terms: Eye edema, Eyelid edema, Face edema, Edema, Edema peripheral, Orbital 10 Reference ID: 5488737 edema, Periorbital edema, Periorbital swelling, Peripheral swelling, Swelling, Swelling face, Swelling of eyelid, Swollen tongue. d Rash includes the following preferred terms: Acne, Blister, Dermatitis, Dermatitis acneiform, Dermatitis bullous, Dermatitis exfoliative generalized, Drug reaction with eosinophilia and systemic symptoms, Dyshidrotic eczema, Eczema, Eczema asteatotic, Erythema, Erythema nodosum, Genital rash, Lichen planus, Perivascular dermatitis, Photosensitivity reaction, Psoriasis, Rash, Rash erythematous, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Seborrhoeic keratosis, Skin discoloration, Skin exfoliation, Skin hypopigmentation, Skin irritation, Skin lesion, Stasis dermatitis. e Respiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection. In the randomized study in patients with newly-diagnosed CP CML, one patient in the group treated with BOSULIF experienced a Grade 3 QTcF prolongation (>500 msec). Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol. Table 8 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 3 newly-diagnosed CML safety population. Table 8: Select Laboratory Abnormalities (>20%) That Worsened From Baseline in Patients with NewlyDiagnosed CML in Bosutinib 400 mg Study* Bosutinib N=268 % Imatinib N=265 % All Grade Grade 3-4 All Grade Grade 3-4 Hematology Parameters Platelet Count decreased 68 14 60 6 Absolute Neutrophil Count decreased 42 9 65 20 Hemoglobin decreased 89 9 90 7 White Blood Cell Count decreased 50 6 70 8 Lymphocyte Count decreased 84 12 82 14 Biochemistry Parameters SGPT/ALT increased 68 26 28 3 SGOT/AST increased 56 13 29 3.4 Lipase increased 53 19 35 8 Phosphorus decreased 54 9 69 21 Amylase increased 32 3.4 18 2.3 Alkaline Phosphatase increased 41 0 43 0.4 Calcium decreased 55 1.5 57 1.1 Glucose increased 57 3 65 3.4 Creatine Kinase increased 36 3 65 5 Creatinine increased 94 1.1 98 0.8 *Based on a Minimum of 57 Months of Follow-up. Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; SGPT=serum glutamic-pyruvic transaminase; SGOT=serum glutamic-oxaloacetic transaminase; N/n=number of patients; ULN=upper limit of normal. Graded using CTCAE v 4.03 Adverse Reactions in Adult Patients With Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CML The single-arm clinical trial enrolled patients with Ph+ CP, AP, or BP CML and with resistance or intolerance to prior therapy [see Clinical Studies (14.2)]. The safety population (received at least 1 dose of BOSULIF) included 546 CML patients: • two hundred eighty-four (284) patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF treatment of 26 months (range: 0.2 to 155 months), and a median dose intensity of 437 mg/day. 11 Reference ID: 5488737 • one hundred nineteen (119) patients with CP CML previously treated with both imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) who had a median duration of BOSULIF treatment of 9 months (range: 0.2 to 148 months) and a median dose intensity of 427 mg/day. • one hundred forty-three (143) patients with advanced phase (AdvP) CML including 79 patients with AP CML and 64 patients with BP CML. In the patients with AP CML and BP CML, the median duration of BOSULIF treatment was 10 months (range: 0.1 to 140 months) and 3 months (range: 0.03 to 71 months), respectively. The median dose intensity was 406 mg/day, and 456 mg/day, in the AP CML and BP CML cohorts, respectively. Serious adverse reactions occurred in 30% of patients in the safety population of the single-arm trial in patients with CML (N=546) who were resistant or intolerant to prior therapy. Serious adverse reactions reported in >2% of patients included pneumonia (7%), pleural effusion (6%), pyrexia (3.7%), coronary artery disease (3.5%), dyspnea (2.6%), rash (2.2%), thrombocytopenia (2%), abdominal pain (2%), and diarrhea (2%). Fatal adverse reactions occurred in 12 patients (2.2%) due to coronary artery disease (0.9%), pneumonia (0.4%), respiratory failure (0.4%), gastrointestinal hemorrhage (0.2%), acute kidney injury (0.2%), and acute pulmonary edema (0.2%). Permanent discontinuation of bosutinib due to an adverse reaction occurred in 22% of patients with CML who were resistant or intolerant to prior therapy. Adverse reactions which resulted in permanent discontinuation in >2% of patients included thrombocytopenia (6%), hepatic dysfunction (3.3%), and neutropenia (2%). Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 66% of patients with CML who were resistant or intolerant to prior therapy. Adverse reactions which required dose interruptions or reductions in >5% of patients included thrombocytopenia (24%), diarrhea (14%), rash (13%), hepatic dysfunction (10%), neutropenia (9%), pleural effusion (8%), vomiting (7%), anemia (6%), and abdominal pain (6%). The most common adverse reactions, in ≥20% of patients in the safety population of the single-arm trial in patients with CML (N=546) who were resistant or intolerant to prior therapy were diarrhea (83%), nausea (47%), rash (46%), abdominal pain (45%), vomiting (39%), fatigue (33%), pyrexia (28%), hepatic dysfunction (27%), respiratory tract infection (24%), cough (23%), and headache (21%). The most common laboratory abnormalities that worsened from baseline in ≥20% were creatinine increased (93%), hemoglobin decreased (91%), lymphocyte decreased (80%), platelets decreased (69%), absolute neutrophil count (54%), ALT increased (53%), calcium decreased (53%), white blood cell count decreased (52%), urate increased (48%), AST increased (47%), phosphorus decreased (39%), alkaline phosphatase increased (39%), lipase increased (28%), magnesium increased (25%), potassium decreased (24%), potassium increased (23%). See Table 10 for Grade 3/4 laboratory abnormalities. Table 9 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 for the Phase 1/2 CML safety population based on long-term follow-up. 12 Reference ID: 5488737 Table 9: Adverse Reactions (10% or Greater) in Patients With CML Who Were Resistant or Intolerant to Prior Therapy in Single-Arm Trial* System Organ Class Preferred Term CP CML (N=403) AdvP CML (N=143) All Grades % Grade 3/4 % All Grades % Grade 3/4 % Gastrointestinal disorders Diarrhea 85 10 76 4 Abdominal paina 49 2 36 7 Nausea 47 1 48 2 Vomiting 38 3 43 3 Constipation 15 <1 17 1 Skin and subcutaneous tissue disorders Rashe 48 9 42 5 Pruritus 12 1 7 0 General disorders and administration- site conditions Fatigue 35 3 27 6 Pyrexia 25 1 37 3 Edemac 19 <1 17 1 Chest paing 8 1 12 1 Hepatobiliary disorders Hepatic dysfunctionh 29 11 21 10 Infections and infestations Respiratory tract infectionf 27 <1 17 0 Influenzai 11 1 3 0 Pneumoniad 10 4 18 12 Respiratory, thoracic, and mediastinal disorders Cough 24 0 22 0 Pleural effusion 14 4 9 4 Dyspnea 12 2 20 6 Nervous system disorders Headache 21 1 18 4 Dizziness 11 0 14 1 Musculoskeletal and connective tissue disorders Arthralgia 19 1 15 0 Back pain 14 1 8 1 Metabolism and nutrition disorders Decreased appetite 14 1 14 0 Vascular disorders Hypertensionb 11 3 8 3 ADR Definition *Based on a Minimum of 105 Months of Follow-up. Adverse drug reactions are based on all-causality treatment-emergent adverse events. The commonality stratification is based on 'All Grades' under Total column. 'Grade 3', 'Grade 4' columns indicate maximum toxicity a Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain, Hepatic pain. g Chest pain includes the following preferred terms: Chest discomfort, Chest pain. h Hepatic dysfunction includes the following preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Hepatic steatosis, Hepatitis toxic, Hepatomegaly, Hepatotoxicity, Hyperbilirubinemia, Liver disorder, Liver function test abnormal, Liver function test increased, Transaminases increased. b Hypertension* includes the following preferred terms: Blood pressure increased, Blood pressure systolic increased, Essential hypertension, Hypertension, Hypertensive crisis, Retinopathy hypertensive. i Influenza includes the following preferred terms: H1N1 influenza, Influenza. c Edema includes the following preferred terms: Eye edema, Eyelid edema, Face edema, Generalized edema, Localized edema, Edema, Edema peripheral, Penile edema, Periorbital edema, Periorbital swelling, Peripheral swelling, Scrotal edema, Scrotal swelling, Swelling, Swelling 13 Reference ID: 5488737 face, Swelling of eyelid, Testicular edema, Tongue edema. d Pneumonia includes the following preferred terms: Atypical pneumonia, Lower respiratory tract congestion, Lower respiratory tract infection, Pneumonia, Pneumonia aspiration, Pneumonia bacterial, Pneumonia fungal, Pneumonia necrotising, Pneumonia streptococcal. e Rash includes the following preferred terms: Acarodermatitis, Acne, Angular cheilitis, Blister, Dermatitis, Dermatitis acneiform, Dermatitis psoriasiform, Drug eruption, Eczema, Eczema asteatotic, Erythema, Erythema annulare, Exfoliative rash, Lichenoid keratosis, Palmar erythema, Photosensitivity reaction, Pigmentation disorder, Psoriasis, Pyoderma gangrenosum, Pyogenic granuloma, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash pruritic, Rash pustular, Seborrhoeic dermatitis, Seborrhoeic keratosis, Skin depigmentation, Skin discoloration, Skin disorder, Skin exfoliation, Skin hyperpigmentation, Skin hypopigmentation, Skin irritation, Skin lesion, Skin plaque, Skin toxicity, Stasis dermatitis. f Respiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection. *ADR identified post-marketing In the single-arm study in patients with CML who were resistant or intolerant to prior therapy, 2 patients (0.4%) experienced QTcF interval of greater than 500 milliseconds. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol. Table 10 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the safety population of the study in patients with CML who were resistant or intolerant to prior therapy based on long-term follow-up. Table 10: Number (%) of Patients With Clinically Relevant All Grade or Grade 3/4 Laboratory Test Abnormalities in the Safety Population of the Study of Patients With CML Who Were Resistant or Intolerant to Prior Therapy* CP CML N=403 % AdvP CML N=143 % All grade Grade 3/4 All grade Grade 3/4 Hematology Parameters Platelet Count decreased 66 26 80 57 Absolute Neutrophil Count decreased 50 16 66 39 Hemoglobin decreased 89 13 97 38 Lymphocyte decreased 79 14 82 21 White Blood Cell Count decreased 51 7 57 27 Biochemistry Parameters SGPT/ALT increased 58 11 39 6 SGOT/AST increased 50 5 37 3.5 Lipase increased 32 12 19 6 Phosphorus decreased 41 8 33 7 Total Bilirubin increased 16 0.7 22 2.8 Creatinine increased 95 3 87 1.4 Alkaline Phosphatase increased 39 0 39 1.4 Glucose increased 42 2.7 39 6 Sodium increased 23 0.5 11 0 Sodium decreased 18 2.2 27 6 Calcium decreased 55 4.7 45 3.5 Urate increased 49 6 43 6 Magnesium increased 27 7 18 4.9 Potassium decreased 22 1.7 29 4.9 Potassium increased 25 2.7 19 2.1 14 Reference ID: 5488737 *Based on a Minimum of 105 Months of Follow-up. Abbreviations: AdvP=advanced phase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; CP=chronic phase; N/n=number of patients; SGPT=serum glutamate-pyruvate transaminase; SGOT=serum glutamate-oxaloacetate aminotransferase; ULN=upper limit of normal. Pediatric Patients with Newly-Diagnosed CP Ph+ CML or CP Ph+ CML that is Resistant or Intolerant to Prior Therapy The safety of BOSULIF was evaluated in BCHILD, a single-arm trial for the treatment of pediatric patients aged 1 year and older with newly-diagnosed CP Ph+ CML or in patients with CP Ph+ CML who are resistant or intolerant to prior therapy [see Clinical Studies (14.3)]. Patients received BOSULIF (n = 49) 300 mg/m2 to 400 mg/m2 orally once daily until disease progression or unacceptable toxicity. The median time on treatment with BOSULIF was 12.2 months (range, 0.2 to 60.9 months). Among patients who received BOSULIF, 77.6% were exposed for 6 months or longer and 51% were exposed for one year or longer. Permanent discontinuation of BOSULIF due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation in 2 or more patients included ALT increased (6%), AST increased (4%), diarrhea (4%), fatigue (4%) and rash maculo-papular (4%). The most common adverse reactions, in ≥20% of BOSULIF-treated pediatric patients were diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, and constipation. Table 11 summarizes the adverse reactions in BCHILD. Table 11: Adverse Reactions (10% or Greater) in Pediatric Patients with Newly Diagnosed CP Ph+ CML or CP Ph+ CML Resistant or Intolerant to Prior Therapy Who Received BOSULIF in BCHILD System Organ Class Preferred Term BOSULIF Total (N=49) % All Grades Grade 3/4 Gastrointestinal disorders Diarrhea 82 12 Abdominal paina 73 4 Vomiting 55 6 Nausea 49 2 Constipation 20 0 Skin and subcutaneous tissue disorders Rashb 49 8 Hepatobiliary disorders Hepatic dysfunctionc 37 14 General disorders and administration-site conditions Fatigued 37 4 Pyrexia 31 4 Nervous system disorders Headache 35 2 Metabolism and nutrition disorders Decreased appetite 27 2 Infections and infestations Respiratory tract infectione 12 2 Adverse drug reactions are based on all-causality treatment-emergent adverse reactions. The commonality stratification is based on 'All Grades' under Bosutinib 400 mg column. 'Grade 3/4 columns indicate maximum toxicity. a Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain, Hepatic pain. b Rash includes the following preferred terms: Acarodermatitis, Acne, Angular cheilitis, Blister, Dermatitis, Dermatitis acneiform, Dermatitis bullous, Dermatitis exfoliative generalized, Dermatitis psoriasiform, Drug eruption, Drug reaction with eosinophilia and systemic symptoms, Dyshidrotic eczema, Eczema, Eczema asteatotic, Erythema, Erythema annulare, Erythema nodosum, Exfoliative rash, Genital rash, Lichen planus, Lichenoid keratosis, Palmar erythema, Palmar-plantar erythrodysesthesia syndrome, Perivascular dermatitis, Photosensitivity reaction, Pigmentation disorder, Pruritus allergic, Psoriasis, Punctate keratitis, Pyoderma gangrenosum, Pyogenic granuloma, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, 15 Reference ID: 5488737 c Rash pustular, Rash vesicular, Seborrheic dermatitis, Seborrhoeic keratosis, Skin depigmentation, Skin discoloration, Skin disorder, Skin exfoliation, Skin hyperpigmentation, Skin hypopigmentation, Skin irritation, Skin lesion, Skin plaque, Skin reaction, Skin toxicity, Stasis dermatitis. Hepatic dysfunction includes the following preferred terms: Alanine aminotransferase abnormal, Alanine aminotransferase increased, Aspartate aminotransferase, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatomegaly, Hepatosplenomegaly, Hyperbilirubinaemia, Jaundice, Liver function test abnormal, Liver function test increased, Ocular icterus, Transaminases increased, Hepatic function abnormal, Drug-induced liver injury, Hepatic steatosis, Hepatitis, Hepatitis toxic, Hepatobiliary disease, Hepatocellular injury, Hepatotoxicity, Liver disorder, Liver injury. d Fatigue includes the following preferred terms: Asthenia, Fatigue, Malaise. e Respiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract congestion, Upper respiratory tract infection, Upper respiratory tract inflammation, Viral upper respiratory tract infection. The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine increased, alanine aminotransferase increased, white blood cell count decreased, aspartate aminotransferase increased, platelet count decreased, glucose increased, calcium decreased, hemoglobin decreased, neutrophil count decreased, lymphocyte count decreased, serum amylase increased and CPK increased. Table 12 summarizes laboratory test abnormalities in BCHILD. Table 12: Laboratory Abnormalities (≥ 20%) That Worsened From Baseline in Pediatric Patients with Newly- Diagnosed CP Ph+ CML or CP Ph+ CML Resistant or Intolerant to Prior Therapy Who Received BOSULIF in BCHILD BOSULIF (N= 49) All Grade Grade 3/4 % % Creatinine increased 92 0 Alanine aminotransferase increased 59 14 White blood cell count decreased 53 4 Aspartate aminotransferase increased 51 6 Platelet count decreased 49 18 Glucose increased 41 0 Calcium decreased 31 0 Hemoglobin decreased 31 8 Neutrophil count decreased 31 12 Lymphocyte count decreased 29 2 Serum amylase increased 27 4 CPK increased 25 0 Grades are defined using CTCAE V4.03. Based on CTCAE grading without regard to fasting status for 'Hyperglycemia' lab parameter. Includes data up to 28 days after last dose of study treatment. Additional Adverse Reactions From Multiple Clinical Trials The following adverse reactions were reported in patients in clinical trials with BOSULIF (less than 10% of BOSULIF- treated patients). They represent an evaluation of the adverse reaction data from all 1372 patients with leukemia who received at least 1 dose of single-agent BOSULIF. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. Blood and Lymphatic System Disorders: 0.1% and less than 1% - Febrile neutropenia Cardiac Disorders: 1% and less than 10% - Cardiac ischemia (includes Acute coronary syndrome, Acute myocardial infarction, Angina pectoris, Angina unstable, Arteriosclerosis coronary artery, Coronary artery disease, Coronary artery 16 Reference ID: 5488737 occlusion, Coronary artery stenosis, Myocardial infarction, Myocardial ischemia, Troponin increased), Pericardial effusion, Cardiac failure (includes Cardiac failure, Cardiac failure acute, Cardiac failure chronic, Cardiac failure congestive, Cardiogenic shock, Cardiorenal syndrome, Ejection fraction decreased, Left ventricular failure); 0.1% and less than 1% - Pericarditis Ear and Labyrinth Disorders: 1% and less than 10% - Tinnitus Endocrine Disorders: 1% and less than 10% - Hypothyroidism; 0.1% and less than 1% - Hyperthyroidism Gastrointestinal Disorders: 1% and less than 10% - Gastritis, Pancreatitis (includes Edematous pancreatitis, Pancreatic enzymes increased, Pancreatitis, Pancreatitis acute, Pancreatitis chronic), Gastrointestinal hemorrhage (includes Anal hemorrhage, Gastric hemorrhage, Gastrointestinal hemorrhage, Intestinal hemorrhage, Lower gastrointestinal hemorrhage, Rectal hemorrhage, Upper gastrointestinal hemorrhage) General Disorders and Administrative Site Conditions: 1% and less than 10% - Pain Immune System Disorders: 1% and less than 10% - Drug hypersensitivity; 0.1% and less than 1% - Anaphylactic shock Infections and Infestations: 1% and less than 10% - Bronchitis Investigations: 1% and less than 10% - Electrocardiogram QT prolonged (includes Electrocardiogram QT prolonged, Long QT syndrome) Metabolism and Nutrition Disorders: 1% and less than 10% - Dehydration Musculoskeletal and Connective Tissue Disorders: 1% and less than 10% - Myalgia Nervous System Disorders: 1% and less than 10% - Dysgeusia Renal and Urinary Disorders: 1% and less than 10% - Acute kidney injury, Renal impairment, Renal failure Respiratory, Thoracic and Mediastinal Disorders: 1% and less than 10% - Pulmonary hypertension (includes Pulmonary hypertension, Pulmonary arterial hypertension, Pulmonary arterial pressure increased); 0.1% and less than 1% - Acute pulmonary edema (includes Acute pulmonary edema, Pulmonary edema), Interstitial lung disease, Respiratory failure Skin and Subcutaneous Disorders: 0.1% and less than 1% - Erythema multiforme 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of BOSULIF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Thrombotic microangiopathy Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome 17 Reference ID: 5488737 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on BOSULIF Strong or Moderate CYP3A Inhibitors Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF. Bosutinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inhibitor increases bosutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may increase the risk of toxicities. Strong CYP3A Inducers Avoid the concomitant use of strong CYP3A inducers with BOSULIF. Bosutinib is a CYP3A substrate. Concomitant use with a strong CYP3A inducer decreases bosutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce BOSULIF efficacy. Proton Pump Inhibitors (PPI) As an alternative to PPIs, use short-acting antacids or H2 blockers and separate dosing by more than 2 hours from BOSULIF dosing. Bosutinib displays pH dependent aqueous solubility, Concomitant use with a PPI decreases bosutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce BOSULIF efficacy. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, BOSULIF can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day (see Data). Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Animal Data In a rat fertility and early embryonic development study, bosutinib was administered orally to female rats for approximately 3 to 6 weeks, depending on day of mating (2 weeks prior to cohabitation with untreated breeder males until gestation day [GD] 7). Increased embryonic resorptions occurred at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). In an embryo-fetal development study conducted in rabbits, bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of 3, 10, and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and 2 fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 5.1 and 3.8 times the human exposures at the recommended doses of 400 and 500 mg/day, respectively. 18 Reference ID: 5488737 Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. In a rat pre- and postnatal development study, bosutinib was administered orally to pregnant animals during the period of organogenesis through lactation day 20 at doses of 10, 30, and 70 mg/kg/day. Reduced number of pups born occurred at greater than or equal to 30 mg/kg/day bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day bosutinib (6.9 and 5.1 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). 8.2 Lactation Risk Summary No data are available regarding the presence of bosutinib or its metabolites in human milk or its effects on a breastfed child or on milk production. However, bosutinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in a nursing child, breastfeeding is not recommended during treatment with BOSULIF and for 2 weeks after the last dose. Animal Data After a single radiolabeled bosutinib dose to lactating rats, radioactivity was present in the plasma of suckling offspring for 24 to 48 hours. 8.3 Females and Males of Reproductive Potential Based on findings from animal studies, BOSULIF can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Females of reproductive potential should have a pregnancy test prior to starting treatment with BOSULIF. Contraception Females Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with BOSULIF and for 2 weeks after the last dose. Infertility The risk of infertility in females or males of reproductive potential has not been studied in humans. Based on findings from animal studies, BOSULIF may cause reduced fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of BOSULIF have been established in pediatric patients 1 year of age and older with newly-diagnosed CP Ph+ CML and CP Ph+ CML that is resistant or intolerant to prior therapy. Use of BOSULIF for these indications is based on data from BCHILD [NCT04258943]. The study included pediatric patients with newly diagnosed CP Ph+ CML in the following age groups: 2 patients 1 year of age to less than 6 years of age, 3 patients 6 years of age to less than 12 years of age, and 10 patients 12 years of age to less than 17 years of age. The study also included pediatric patients with CP Ph+ CML that was resistant or intolerant to prior therapy in the following age groups: 4 patients 1 year of age to less than 6 years of age, 10 patients 6 years of age to less than 12 years of age, and 10 patients 12 years of age to less than 17 years of age. [see Adverse Reactions (6.1) and Clinical Studies (14.3)]. BSA-normalized apparent clearance in 27 pediatric patients aged 4 to <17 years (141.3 L/h/m2) was 29% higher than BSA-normalized apparent clearance in adult patients with CP Ph+ CML (109.2 L/h/m2) [see Clinical Pharmacology (12.3)]. The recommended dosage of BOSULIF in pediatric patients is based on body surface area (BSA) [see Dosage and Administration (2.1)]. 19 Reference ID: 5488737 xx The safety and effectiveness of BOSULIF in pediatric patients younger than 1 year of age with newly diagnosed CP Ph+ CML, pediatric patients younger than 1 year of age with CP Ph+ CML that is resistant or intolerant to prior therapy, and pediatric patients with AP Ph+ CML or BP Ph+ CML have not been established. 8.5 Geriatric Use In the single-arm study in patients with CML who were resistant or intolerant to prior therapy of BOSULIF in patients with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. Of the 268 patients who received bosutinib in the study for newly diagnosed CML, 20% were age 65 and over, 5% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment Reduce the BOSULIF starting dose in patients with moderate (creatinine clearance [CLcr] 30 to 50 mL/min, estimated by Cockcroft-Gault (C-G)) and severe (CLcr less than 30 mL/min, C-G) renal impairment at baseline. For patients who have declining renal function while on BOSULIF who cannot tolerate the starting dose, follow dose adjustment recommendations for toxicity [see Dosage and Administration (2.3, 2.5) and Clinical Pharmacology (12.3)]. BOSULIF has not been studied in patients undergoing hemodialysis. 8.7 Hepatic Impairment Reduce the BOSULIF dosage in patients with hepatic impairment (Child-Pugh A, B, or C) [see Dosage and Administration (2.3, 2.5) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Experience with BOSULIF overdose in clinical studies was limited to isolated cases. There were no reports of any serious adverse events associated with the overdoses. Patients who take an overdose of BOSULIF should be observed and given appropriate supportive treatment. 11 DESCRIPTION BOSULIF contains bosutinib, a kinase inhibitor. Bosutinib is present as a monohydrate with a chemical name of 3­ Quinolinecarbonitrile, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl) propoxy]-, hydrate (1:1). Its chemical formula is C26H29Cl2N5O3•H2O (monohydrate); its molecular weight is 548.46 (monohydrate), equivalent to 530.46 (anhydrous). Bosutinib monohydrate has the following chemical structure: Cl Cl HN OMe MeO N CN • H 2O N O N Me Bosutinib monohydrate is a white to yellowish-tan powder. Bosutinib monohydrate has a pH dependent solubility across the physiological pH range. At or below pH 5, bosutinib monohydrate behaves as a highly soluble compound. Above pH 5, the solubility of bosutinib monohydrate reduces rapidly. 20 Reference ID: 5488737 BOSULIF® (bosutinib) tablets are supplied for oral administration in 3 strengths: 100 mg, 400 mg and 500 mg. Each strength reflects the equivalent amount of bosutinib content (on anhydrous basis). The tablets contain the following inactive ingredients: croscarmellose sodium, iron oxide red (for 400 mg, and 500 mg tablet) and iron oxide yellow (for 100 mg, and 400 mg tablet), magnesium stearate, microcrystalline cellulose, poloxamer, polyethylene glycol, polyvinyl alcohol, povidone, talc and titanium dioxide. BOSULIF® (bosutinib) capsules are supplied for oral administration in 2 strengths: 50 mg and 100 mg. Each strength reflects the equivalent amount of bosutinib (on anhydrous basis). The capsules contain the following inactive ingredients: croscarmellose sodium, gelatin, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer, povidone, red iron oxide, titanium dioxide, yellow iron oxide. The printing ink contains black iron oxide, potassium hydroxide, propylene glycol, shellac, strong ammonia solution. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Bosutinib is a TKI. Bosutinib inhibits the BCR-ABL kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of BCR-ABL kinase expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells. 12.2 Pharmacodynamics A greater likelihood of response and a greater likelihood of safety events were observed with higher bosutinib exposure in clinical studies. The time course of bosutinib pharmacodynamic response has not been fully characterized. Cardiac Electrophysiology At a single oral dose of 500 mg BOSULIF with ketoconazole (a strong CYP3A inhibitor), BOSULIF does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Bosutinib pharmacokinetics were assessed following oral dosing with food in adult patients with CML and were presented as geometric mean (CV%), unless otherwise specified. Bosutinib exhibits dose proportional increases in Cmax and AUC over the oral dose range of 200 to 800 mg (0.33 to 1.3 times the maximum approved recommended dosage of 600 mg). Bosutinib steady state Cmax was 127 ng/mL (31%), Ctrough was 68 ng/mL (39%) and AUC was 2370 ng•h/mL (34%) following multiple oral doses of BOSULIF 400 mg; Bosutinib steady state Cmax was 171 ng/mL (38%), Ctrough was 91 ng/mL (42%) and AUC was 3150 ng•h/mL (38%) following multiple oral doses of BOSULIF 500 mg. No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of either the tablet or capsule dosage forms of BOSULIF at the same dose, under fed conditions. Absorption The median bosutinib (minimum, maximum) time--to-Cmax (tmax) was 6.0 (6.0, 6.0) hours following oral administration of a single oral dose of BOSULIF 500 mg with food. The absolute bioavailability was 34% in healthy subjects. Effect of Food Bosutinib Cmax increased 1.8-fold and AUC increased 1.7-fold when BOSULIF tablets were given with a high fat meal to healthy subjects compared to administration under fasted condition. Bosutinib Cmax increased 1.6-fold and AUC increased 1.5-fold when BOSULIF capsules were given with a high fat meal to healthy subjects compared to administration under fasted condition. The high-fat meal (800-1000 total calories) consisted of approximately 150 protein calories, 250 carbohydrate calories, and 500-600 fat calories. No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of a BOSULIF capsule that was opened and the contents mixed with applesauce or yogurt immediately before use. 21 Reference ID: 5488737 Distribution The mean (SD) apparent bosutinib volume of distribution is 6080 (1230) L after an oral dose of 500 mg of BOSULIF. Bosutinib protein binding is 94% in vitro and 96% ex vivo, and is independent of concentration. Elimination The mean (SD) bosutinib terminal phase elimination half life (t½) was 22.5 (1.7) hours, and the mean (SD) apparent clearance was 189 (48) L/h following a single oral dose of BOSULIF. Metabolism Bosutinib is primarily metabolized by CYP3A4. Excretion Following a single oral dose of [14C] radiolabeled bosutinib without food, 91.3% of the dose was recovered in feces and 3.3% of the dose recovered in urine. Specific Populations Patients with Renal Impairment Bosutinib AUC increased 1.4-fold in subjects with moderate renal impairment (CLcr: 30 to 50 mL/min, estimated by Cockcroft-Gault (C-G)) and increased 1.6-fold in subjects with severe renal impairment (CLcr less than 30 mL/min) following a single oral dose of BOSULIF 200 mg (0.33 times the maximum approved recommended dosage of 600 mg). No clinically significant difference in the pharmacokinetics of bosutinib was observed in subjects with mild renal impairment (CLcr: 51 to 80 mL/min, C-G). BOSULIF has not been studied in patients undergoing hemodialysis. Patients with Hepatic Impairment Bosutinib Cmax increased 2.4-fold, 2-fold, and 1.5-fold, and AUC increased 2.3-fold, 2-fold, and 1.9-fold in hepatic impairment Child-Pugh A, B, and C, respectively, following a single oral dose of BOSULIF 200 mg (0.33 times the maximum approved recommended dosage of 600 mg). Pediatric Patients The pharmacokinetics of bosutinib in 27 pediatric patients aged 4 to less than 17 years with newly diagnosed CP Ph+ CML or resistant/intolerant CP Ph+ CML were evaluated over the dose range of 300 mg/m2 to 400 mg/m2 administered orally once daily with food. Exposures increased in a dose proportional manner over the dose range of 300 mg/m2 to 400 mg/m2. The bosutinib median (min, max) tmax is approximately 3 hours post-dose (1, 8 hours). In 15 pediatric patients aged 4 to less than 17 years who received 300 mg/m2 daily, steady state Cmax was 159 ng/mL (42%), Ctrough was 49 ng/mL (53%) and AUC was 2027 ng•h/mL (47%). In 6 pediatric patients aged 6 to less than 17 years who received 400 mg/m2 daily, steady state Cmax was 198 ng/mL (37%), Ctrough was 42 ng/mL (105%), and AUC was 2514 ng•h/mL (35%). An increase in BSA correlated with an increase in apparent clearance and exposure metrics did not significantly differ across BSA or age in pediatric patients following the approved recommended BSA-based dosage. Drug Interaction Studies Clinical Studies Strong CYP3A Inhibitors: Bosutinib Cmax increased 5.2-fold and AUC increased 8.6-foldfollowing a single dose of BOSULIF 100 mg (0.17 times the maximum approved recommended dosage) without food when used concomitantly with 400 mg ketoconazole (a strong CYP3A inhibitor) administered over multiple daily doses. Moderate CYP3A Inhibitors: Bosutinib Cmax increased 1.5-fold and AUC increased 2.0-fold following a single dose of BOSULIF 500 mg with food when administered concomitantly with 125 mg aprepitant (a moderate CYP3A inhibitor). 22 Reference ID: 5488737 Strong CYP3A Inducers: Bosutinib Cmax decreased by 86% and AUC decreased by 94% following a single dose of BOSULIF 500 mg with food administered concomitantly with multiple daily doses of 600 mg of rifampin (a strong CYP3A inducer). Proton Pump Inhibitors: Lansoprazole decreased bosutinib Cmax by 46% and AUC by 26% following a single oral dose of BOSULIF 400 mg without food when used concomitantly with lansoprazole 60 mg (proton pump inhibitor) administered over multiple daily doses. Bosutinib displays pH-dependent aqueous solubility, in vitro [see Description (11)]. P-gp Substrates: No clinically significant differences in bosutinib pharmacokinetics were observed when used concomitantly with dabigatran etexilate mesylate (a P-glycoprotein (P-gp) substrate). In Vitro Studies Transporters Systems: Bosutinib inhibits breast cancer resistance protein (BCRP)but, does not inhibit organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, and OCT2. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Bosutinib was not carcinogenic in rats or transgenic mice. The rat 2-year carcinogenicity study was conducted at bosutinib oral doses up to 25 mg/kg in males and 15 mg/kg in females. Exposures at these doses were approximately 1.5 times (males) and 3.1 times (females) the human exposure at the 400 mg dose and 1.2 times (males) and 2.4 times (females) exposure in humans at the 500 mg dose. The 6-month RasH2 transgenic mouse carcinogenicity study was conducted at bosutinib oral doses up to 60 mg/kg. Bosutinib was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames Test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated male mice. In a rat fertility study, drug-treated males were mated with untreated females, or untreated males were mated with drug- treated females. Females were administered the drug from pre-mating through early embryonic development. The dose of 70 mg/kg/day of bosutinib resulted in reduced fertility in males as demonstrated by 16% reduction in the number of pregnancies. There were no lesions in the male reproductive organs at this dose. This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats approximately 1.5 times and equal to the human exposure at the recommended doses of 400 and 500 mg/day, respectively. Fertility (number of pregnancies) was not affected when female rats were treated with bosutinib. However, there were increased embryonic resorptions at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 and 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). 14 CLINICAL STUDIES 14.1 Adult Patients with Newly-Diagnosed CP Ph+ CML The efficacy of BOSULIF in patients with newly-diagnosed chronic phase Ph+ CML was evaluated in the Bosutinib trial in First-line chrOnic myelogenous leukemia tREatment (BFORE) Trial: “A Multicenter Phase 3, Open-Label Study of Bosutinib Versus Imatinib in Adult Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia” [NCT02130557]. The BFORE Trial is a 2-arm, open-label, randomized, multicenter trial conducted to investigate the efficacy and safety of BOSULIF 400 mg once daily alone compared with imatinib 400 mg once daily alone in adult patients with newly-diagnosed CP Ph+ CML. The trial randomized 536 patients (268 in each arm) with Ph+ or Ph- newly-diagnosed CP CML (intent-to-treat [ITT] population) including 487 patients with Ph+ CML harboring b2a2 and/or b3a2 transcripts at baseline and baseline BCR-ABL copies >0 (modified intent-to-treat [mITT] population). Randomization was stratified 23 Reference ID: 5488737 by Sokal score and geographical region. All patients are being treated and/or followed for up to 5 years (240 weeks). Efficacy was evaluated in the mITT population. The major efficacy outcome measure was major molecular response (MMR) at 12 months (48 weeks) defined as ≤0.1% BCR-ABL ratio on international scale (corresponding to ≥3 log reduction from standardized baseline) with a minimum of 3000 ABL transcripts as assessed by the central laboratory. Additional efficacy outcomes included CCyR by 12 months, defined as the absence of Ph+ metaphases in chromosome banding analysis of ≥20 metaphases derived from bone marrow aspirate or MMR if an adequate cytogenetic assessment was unavailable and MMR by 18 months (72 weeks). In the mITT population in this study, 57% of patients were males, 78% were Caucasian, and 19% were 65 years or older. The median age was 53 years. At baseline, the distribution of Sokal risk scores was similar in bosutinib and imatinib­ treated patients (low risk: 35% and 39%; intermediate risk: 44% and 38%; high risk: 22% and 22%, respectively). After a minimum of 12 months follow-up, 78% of the 246 bosutinib -treated patients and 72% of the 239 imatinib-treated patients were still receiving treatment and with a minimum of 60 months of follow-up, 60% and 60% of patients, respectively, were still receiving treatment. The median treatment duration was 55.1 months for BOSULIF and 55.0 months for imatinib. The efficacy results from the BFORE trial are summarized in Table 13. Table 13: Summary of Major Molecular Response (MMR) and Complete Cytogenetic Response (CCyR), by Treatment Group in the Modified Intent-to-Treat (mITT) Population Response Bosutinib N=246 n (%) Imatinib N=241 n (%) 2-sided p-value MMR at Month 12 (Week 48) MMR (%) (95% CI) 116 (47) (41, 53) 89 (37) (31, 43) 0.0200* CCyR by Month 12 (Week 48) CCyR (%) (95% CI) 190 (77) (72, 83) 160 (66) (60, 72) 0.0075* MMR by Month 18 (Week 72) MMR (%) (95% CI) 150 (61) (55, 67) 127 (53) (46, 59) 0.0606* Abbreviations: CCyR=complete cytogenetic response; CI=confidence interval; CMH=Cochran-Mantel-Haenszel; MMR=major molecular response; N/n=number of patients. *Derived from CMH test stratified by Geographical region and Sokal score at randomization. The MMR rate at Month 12 for all randomized patients (ITT population) was consistent with the mITT population (47% [95% CI: 41, 53] in the bosutinib treatment group and 36% [95% CI: 30, 42] in the imatinib treatment group; odds ratio of 1.57 [95% CI: 1.10, 2.22]). MMR by Month 60 (Week 240) in the mITT population was 74% (95% CI: 69, 80) in the bosutinib treatment group and 66% (95% CI: 60, 72) in the imatinib treatment group; odds ratio of 1.52 (95% CI: 1.02, 2.25). MMR by Month 60 in the ITT population was also consistent with the mITT population (1.57 [95% CI: 1.08, 2.28]). After 60 months of follow-up, the median time to MMR in responders was 9.0 months for bosutinib and 11.9 months for imatinib. By 60 months, the MMR rates in each Sokal risk group for the bosutinib and imatinib-treated patients, respectively, were 78% and 72% for low risk, 74% and 67% for intermediate risk and 68% and 52% for high risk. After 60 months of follow-up, 6 (2%) bosutinib patients and 7 (3%) imatinib patients transformed to AP CML or BP CML while on treatment. At 60 months, the estimated overall survival rate was 95% (95% CI: 91, 97) in the bosutinib group and 94% (95% CI: 90, 96) in the imatinib group. 24 Reference ID: 5488737 14.2 Adult Patients with Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CML Study 200 (NCT00261846), a single-arm, open-label, multicenter study in patients with CML who were resistant or intolerant to prior therapy was conducted to evaluate the efficacy and safety of BOSULIF 500 mg once daily in patients with imatinib-resistant or -intolerant CML with separate cohorts for CP, AP, and BP disease previously treated with 1 prior TKI (imatinib) or more than 1 TKI (imatinib followed by dasatinib and/or nilotinib). The definition of imatinib resistance included (1) failure to achieve or maintain any hematologic improvement within 4 weeks; (2) failure to achieve a CHR by 3 months, cytogenetic response by 6 months or major cytogenetic response (MCyR) by 12 months; (3) progression of disease after a previous cytogenetic or hematologic response; or (4) presence of a genetic mutation in the BCR-ABL gene associated with imatinib resistance. Imatinib intolerance was defined as inability to tolerate imatinib due to toxicity, or progression on imatinib and inability to receive a higher dose due to toxicity. The definitions of resistance and intolerance to both dasatinib and nilotinib were similar to those for imatinib. The protocol was amended to exclude patients with a known history of the T315I mutation after 396 patients were enrolled in the trial. The efficacy endpoints for patients with CP CML previously treated with 1 prior TKI (imatinib) were the rate of attaining MCyR by Week 24 and the duration of MCyR. The efficacy endpoints for patients with CP CML previously treated with both imatinib and at least 1 additional TKI were the cumulative rate of attaining MCyR by Week 24 and the duration of MCyR. The efficacy endpoints for patients with previously treated AP and BP CML were confirmed CHR and overall hematologic response (OHR). The study enrolled 546 patients with CP, AP or BP CML. Of the total patient population 73% were imatinib resistant and 27% were imatinib intolerant. In this trial, 53% of patients were males, 65% were Caucasian, and 20% were 65 years old or older. Of the 546 treated patients, 506 were considered evaluable for cytogenetic or hematologic efficacy assessment. Patients were evaluable for efficacy if they had received at least 1 dose of BOSULIF and had a valid baseline efficacy assessment. Among evaluable patients, there were 262 patients with CP CML previously treated with 1 prior TKI (imatinib), 112 patients with CP CML previously treated with both imatinib and at least 1 additional TKI, and 132 patients with advanced phase CML previously treated with at least 1 TKI. Median duration of BOSULIF treatment was 26 months in patients with CP CML previously treated with 1 TKI (imatinib), 9 months in patients with CP CML previously treated with imatinib and at least 1 additional TKI, 10 months in patients with AP CML previously treated with at least imatinib, and 3 months in patients with BP CML previously treated with at least imatinib. The 24 week efficacy and MCyR at any time results are summarized in Table 14. Table 14: Efficacy Results in Patients with Ph+ CP CML With Resistance to or Intolerance to Imatinib Prior Treatment With Imatinib Only (N=262 evaluable) n (%) Prior Treatment With Imatinib and Dasatinib or Nilotinib (N=112 evaluable) n (%) By Week 24 MCyR (95% CI) 105 (40.1) (34.1, 46.3) 29 (25.9) (18.1, 35.0) MCyR any time 156 (59.5) (53.3, 65.5) 45 (40.2) (31.0, 49.9) Abbreviations: CI=confidence interval; CML=chronic myelogenous leukemia; CP=chronic phase; MCyR=major cytogenetic response; N/n=number of patients; Ph+=Philadelphia chromosome positive. The long-term follow-up data analysis was based on a minimum of 60 months for patients with CP CML treated with 1 prior TKI (imatinib) and a minimum of 48 months for patients with CP CML treated with imatinib and at least 1 additional TKI. For the 59.5% of patients with CP CML treated with 1 prior TKI (imatinib) who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these patients, 65.4% and 42.9% had a MCyR lasting at least 18 and 54 months, respectively. For the 40.2% of patients with CP CML treated with imatinib and at least 1 additional TKI who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these 25 Reference ID: 5488737 patients, 64.4% and 35.6% had a MCyR lasting at least 9 and 42 months, respectively. Of the 403 treated patients with CP CML, 20 patients had confirmed disease transformation to AP or BP while on treatment with BOSULIF. The 48-week efficacy results in patients with accelerated and blast phases CML previously treated with at least imatinib are summarized in Table 15. Table 15: Efficacy Results in Patients With Accelerated Phase and Blast Phase CML Previously Treated With at Least Imatinib AP CML (N=72 evaluable) n (%) BP CML (N=60 evaluable) n (%) CHRa by Week 48 22 (30.6) 10 (16.7) (95% CI) (20.2, 42.5) (8.3, 28.5) OHRa by Week 48 (95% CI) 41 (56.9) (44.7, 68.6) 17 (28.3) (17.5, 41.4) Abbreviations: AP=accelerated phase; BP=blast phase; CHR=complete hematologic response; CI=confidence interval; CML=chronic myelogenous leukemia; CI=confidence interval, OHR=overall hematologic response, CHR=complete hematologic response, N/n=number of patients a Overall hematologic response (OHR) = major hematologic response (complete hematologic response + no evidence of leukemia) or return to chronic phase (RCP). All responses were confirmed after 4 weeks. Complete hematologic response (CHR) for AP and BP CML: WBC less than or equal to institutional ULN, platelets greater than or equal to 100,000/mm3 and less than 450,000/mm3, absolute neutrophil count (ANC) greater than or equal to 1.0×109 /L, no blasts or promyelocytes in peripheral blood, less than 5% myelocytes + metamyelocytes in bone marrow, less than 20% basophils in peripheral blood, and no extramedullary involvement. No evidence of leukemia (NEL): Meets all other criteria for CHR except may have thrombocytopenia (platelets greater than or equal to 20,000/mm3 and less than 100,000/mm3) and/or neutropenia (ANC greater than or equal to 0.5×109 /L and less than 1.0×109 /L). Return to chronic phase (RCP) = disappearance of features defining accelerated or blast phases but still in chronic phase. The long-term follow-up data analysis was based on a minimum of 48 months for patients with AP CML and BP CML. Of the 79 treated patients with AP CML, 3 patients had confirmed disease transformation to BP while on BOSULIF treatment. 14.3 Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy The efficacy of BOSULIF in pediatric patients with newly-diagnosed (ND) chronic phase (CP) Ph+ CML and patients with resistant/intolerant (R/I) CP Ph+ CML was evaluated in the BCHILD trial [NCT04258943]. The BCHILD trial is a multicenter, non-randomized, open-label study conducted to identify a recommended dose of bosutinib administered orally once daily in pediatric patients with ND CP Ph+ CML and pediatric patients with R/I CP Ph+ CML who have received at least one prior TKI therapy, to estimate the safety and tolerability and efficacy, and to evaluate the PK of bosutinib in this patient population. The study enrolled 28 patients with R/I CP Ph+ CML treated with BOSULIF at 300 mg/m2 to 400 mg/m2 orally once daily, and 21 patients with ND CP Ph+ CML treated at 300 mg/m2 orally once daily. Efficacy outcomes included CCyR (defined as the absence of Ph+ metaphases in chromosome banding analysis of ≥20 metaphases, or <1% BCR-ABL1–positive nuclei of at least 200 peripheral blood interphase nuclei analyzed by Fluorescence In Situ Hybridization (FISH), or MMR if an adequate cytogenetic assessment was unavailable), MCyR (defined as CCyR or partial cytogenetic response of 1% to 35% Ph+ metaphases), and MMR (defined as ≤0.1% BCR-ABL ratio on international scale [IS]) at any time on study. Patients with ND CP Ph+ CML had a median age of 14 years (range 5 to 17 years); 68% were male; 81% were White, 14% were Black/African American, and 5% were race not reported. The major (MCyR) and complete (CCyR) cytogenetic responses among patients with ND CP Ph+ CML were 76.2% (95% CI: 52.8, 91.8) and 71.4% (95% CI: 47.8, 88.7), respectively. The MMR among patients with ND CP Ph+ CML was 26 Reference ID: 5488737 28.6% (95% CI: 11.3, 52.3). The median duration of follow-up was 14.2 months (range: 1.1, 26.3 months) in patients with ND CP CML. Patients with R/I CP Ph+ CML included n=6 treated at 300 mg/m2 (0.75 times the recommended dose), n=11 treated at 350 mg/m2 (0.875 times the recommended dose), and n=11 at 400 mg/m2. Overall (n=28), patients had a median age of 11.5 years (range: 1 to 17 years); 57% were male; 43% were White, 7% were Black/African American, 14% were Asian, and 36% were race not reported. The major (MCyR) and complete (CCyR) cytogenetic responses among patients with R/I CP Ph+ CML were 82.1% (95% CI: 63.1, 93.9) and 78.6% (95% CI: 59.0, 91.7), respectively. The MMR among patients with R/I CP Ph+ CML was 50.0% (95% CI: 30.6, 69.4). The MR4.5 (defined as BCR-ABL/ABL IS ≤ 0.0032%) was 17.9% (95% CI: 6.1, 36.9). Among 14 patients who achieved MMR, two patients lost MMR after 13.6 months and 24.7 months on treatment. The median duration of follow-up for overall survival was 23.2 months (range: 1.0, 61.5 months) in patients with R/I CP Ph+ CML. 16 HOW SUPPLIED/STORAGE AND HANDLING Tablets – How Supplied BOSULIF (bosutinib) tablets are supplied for oral administration in 3 strengths: a 100 mg yellow, oval, biconvex, film- coated tablet debossed with “Pfizer” on one side and “100” on the other; a 400 mg orange, oval, biconvex, film coated tablet debossed with “Pfizer” on one side and “400” on the other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with “Pfizer” on one side and “500” on the other. BOSULIF (bosutinib) tablets are available in the following packaging configurations with a child-resistant (CR) closure (Table 17). Bottles contain a desiccant. Table 17: Tablet Presentations BOSULIF Tablets Package Configuration Tablet Strength (mg) NDC Tablet Description 120 tablets per bottle 100 mg 0069-0135-01 Yellow, oval, biconvex, film-coated tablets, debossed “Pfizer” on one side and “100” on the other. 30 tablets per bottle 400 mg 0069-0193-01 Orange, oval, biconvex, film-coated tablet debossed with “Pfizer” on one side and “400” on the other. 30 tablets per bottle 500 mg 0069-0136-01 Red, oval, biconvex, film-coated tablets, debossed “Pfizer” on one side and “500” on the other. Abbreviation: NDC=National drug code. Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Handling and Disposal Procedures for proper disposal of anticancer drugs should be considered. Touching or handling crushed or broken tablets is to be avoided. Any unused product or waste material should be disposed of in accordance with local requirements, or drug take back programs. Capsules - How Supplied BOSULIF (bosutinib) capsules are supplied for oral administration in 2 strengths: 50 mg capsule: size 2 capsule, white body/orange cap with “BOS 50” printed on the body and “Pfizer” printed on the cap in black ink. 100 mg capsule: size 0 capsule, white body/brownish-red cap with “BOS 100” printed on the body and 27 Reference ID: 5488737 “Pfizer” printed on the cap in black ink. BOSULIF (bosutinib) capsules are available in the following packaging configurations with a CR closure (Table 18). Table 18: Capsule Presentations BOSULIF Capsules Package Configuration Count Capsule Strength (mg) NDC Capsule Description 30 capsules per bottle 50  0069-0504-30 Size 2 capsule, white body/orange cap with “BOS 50” printed on the body and “Pfizer” printed on the cap in black ink. 150 capsules per bottle 100  0069-1014-15 Size 0 capsule, white body/brownish­ red cap with “BOS 100” printed on the body and “Pfizer” printed on the cap in black ink. Abbreviation: NDC=National drug code. Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] and Store and Dispense in Original Container. Handling and Disposal Procedures for proper disposal of anticancer drugs should be considered. Patients and/or caregivers must wear gloves while handling the drug product, and wash their hands once finished. Any unused product or waste material should be disposed of in accordance with local requirements. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). • Dosage and Administration Instruct patients to take BOSULIF exactly as prescribed, not to change their dose or to stop taking BOSULIF unless they are told to do so by their doctor. If patients miss a dose beyond 12 hours, they should be advised to take the next scheduled dose at its regular time. A double dose should not be taken to make up for any missed dose. Advise patients to take BOSULIF with food. Patients should be advised: “Swallow tablets whole. Do not crush, break, or cut tablet. Do not touch or handle crushed or broken tablets.” Patients should be advised: “Capsules may be swallowed whole. For those that cannot swallow the capsule whole, the capsule can be opened and the contents mixed with applesauce or yogurt.” • Gastrointestinal Toxicity Advise patients that they may experience diarrhea, nausea, vomiting, abdominal pain, or blood in their stools with BOSULIF and to seek medical attention promptly for these symptoms [see Warnings and Precautions (5.1)]. • Myelosuppression Advise patients of the possibility of developing low blood cell counts and to immediately report fever, any suggestion of infection, or signs or symptoms suggestive of bleeding or easy bruising [see Warnings and Precautions (5.2)]. • Hepatic Toxicity Advise patients of the possibility of developing liver function abnormalities and to immediately report jaundice [see Warnings and Precautions (5.3)]. • Cardiovascular Toxicity Advise patients that cardiac failure, left ventricular dysfunction, and cardiac ischemic events have been reported. Advise patients to seek immediate medical attention if any symptoms suggestive of cardiac failure and cardiac ischemia occur, such as shortness of breath, weight gain, or fluid retention [see Warnings and Precautions (5.4)]. 28 Reference ID: 5488737 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 • Fluid Retention Advise patients of the possibility of developing fluid retention (swelling, weight gain, or shortness of breath) and to seek medical attention promptly if these symptoms arise [see Warnings and Precautions (5.5)]. • Renal Toxicity Advise patients of the possibility of developing renal problems and to immediately report frequent urination, polyuria or oliguria [see Warnings and Precautions (5.6)]. • Adverse Reactions Advise patients that they may experience other adverse reactions such as respiratory tract infections, rash, fatigue, loss of appetite, headache, dizziness, back pain, arthralgia, pruritus or constipation with BOSULIF and to seek medical attention if symptoms are significant. There is a possibility of anaphylactic shock [see Contraindications (4) and Adverse Reactions (6)]. • Embryo-Fetal Toxicity Advise females to inform their healthcare provider if they are pregnant or become pregnant. Advise female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive potential, to use effective contraception during treatment and for 2 weeks after receiving the last dose of BOSULIF [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1, 8.3)]. Advise lactating women not to breastfeed during treatment with BOSULIF and for 2 weeks after the last dose [see Use in Specific Populations (8.2)]. • Drug Interactions Advise patients that BOSULIF and certain other medicines, including over the counter medications or herbal supplements (such as St. John’s wort) can interact with each other and may alter the effects of BOSULIF [see Drug Interactions (7)]. LAB-0443-18.2 29 Reference ID: 5488737 PATIENT INFORMATION BOSULIF® (BAH-su-lif) BOSULIF® (BAH-su-lif) (bosutinib) (bosutinib) tablets capsules What is BOSULIF? BOSULIF is a prescription medicine used to treat: • adults and children 1 year of age and older who have a certain type of leukemia called chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) who are newly-diagnosed or who no longer benefit from or did not tolerate other treatment. • adults with accelerated phase (AP), or blast phase (BP) Ph+ CML who can no longer benefit from or did not tolerate other treatment. It is not known if BOSULIF is safe and effective in children less than 1 year of age with CP Ph+ CML who are newly-diagnosed or who no longer benefit from or did not tolerate other treatment or in children with AP Ph+ CML or BP Ph+ CML. Do not take BOSULIF if you are allergic to bosutinib or any of the ingredients in BOSULIF. See the end of this leaflet for a complete list of ingredients of BOSULIF. Before taking BOSULIF, tell your doctor about all of your medical conditions, including if you: • have liver problems • have heart problems • have kidney problems • have high blood pressure • have diabetes • are pregnant or plan to become pregnant. BOSULIF can harm your unborn baby. Females who are able to become pregnant should have a pregnancy test before starting treatment with BOSULIF. Tell your doctor right away if you become pregnant during treatment with BOSULIF. o Females who are able to become pregnant should use effective birth control (contraception) during treatment with BOSULIF and for 2 weeks after the last dose. Talk to your doctor about birth control methods that may be right for you. • are breastfeeding or plan to breastfeed. It is not known if BOSULIF passes into your breast milk or if it can harm your baby. Do not breastfeed during treatment with BOSULIF and for 2 weeks after the last dose. Tell your doctor about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. When taken together, BOSULIF and certain other medicines can affect each other. Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. How should I take BOSULIF? • Take BOSULIF exactly as prescribed by your doctor. • Do not change your dose or stop taking BOSULIF without first talking with your doctor. • If your child takes BOSULIF, your healthcare provider will change the dose as your child grows. • Take BOSULIF with food. • Swallow BOSULIF tablets whole. Do not crush, break, chew or cut BOSULIF tablets. Do not touch or handle crushed or broken BOSULIF tablets. • Swallow BOSULIF capsules whole. If you cannot swallow BOSULIF capsules whole, tell your healthcare provider. • If you cannot swallow BOSULIF capsules whole, see the “Instructions for Use” for detailed instructions on how to prepare and give a dose of BOSULIF capsules by opening the capsules and mixing the capsule contents with applesauce or yogurt. • If you take an antacid or H2 blocker medicine, take it at least 2 hours before or 2 hours after BOSULIF. If you take a Proton Pump Inhibitor (PPI) medicine, talk to your doctor or pharmacist. • You should avoid grapefruit, grapefruit juice, and supplements that contain grapefruit extract during treatment with BOSULIF. Grapefruit products increase the amount of BOSULIF in your body. 1 Reference ID: 5488737 • If you miss a dose of BOSULIF, take it as soon as you remember. If you miss a dose by more than 12 hours, skip that dose and take your next dose at your regular time. Do not take 2 doses at the same time. • If you take too much BOSULIF, call your doctor or go to the nearest hospital emergency room right away. What are the possible side effects of BOSULIF? BOSULIF may cause serious side effects, including: • Stomach problems. BOSULIF may cause stomach (abdomen) pain, nausea, diarrhea, vomiting, or blood in your stools. Get medical help right away for any stomach problems. • Low blood cell counts. BOSULIF may cause low platelet counts (thrombocytopenia), low red blood cell counts (anemia) and low white blood cell counts (neutropenia). Your doctor should do blood tests to check your blood cell counts regularly during your treatment with BOSULIF. Call your doctor right away if you have unexpected bleeding or bruising, blood in your urine or stools, fever, or any signs of an infection. • Liver problems. Your doctor should do blood tests to check your liver function regularly during your treatment with BOSULIF. Call your doctor right away if your skin or the white part of your eyes turns yellow (jaundice) or you have dark “tea color” urine. • Heart problems. BOSULIF may cause heart problems, including heart failure and decreased blood flow to the heart which can lead to heart attack. Get medical help right away if you get shortness of breath, weight gain, chest pain, or swelling in your hands, ankles or feet. • Your body may hold too much fluid (fluid retention). Fluid may build up in the lining of your lungs, the sac around your heart, or your stomach cavity. Get medical help right away if you get any of the following symptoms during your treatment with BOSULIF: o shortness of breath and cough o swelling all over your body o chest pain o weight gain o swelling in your hands, ankles, or feet • Kidney problems. Your doctor should do tests to check your kidney function when you start treatment with BOSULIF and during your treatment. Call your doctor right away if you get any of the following symptoms during your treatment with BOSULIF: o you urinate more often than normal o you urinate less often than normal o you make a much larger amount of urine than normal o you make a much smaller amount of urine than normal The most common side effects of BOSULIF in adults and children with CML include: • diarrhea • headache • stomach (abdominal) pain • fever • vomiting • decreased appetite • nausea • respiratory tract infections (infections in nose, throat or lungs) • rash • constipation • tiredness • changes in certain blood tests. Your doctor may do • liver problems blood tests during treatment with BOSULIF to check for changes Tell your doctor or get medical help right away if you get respiratory tract infections, loss of appetite, headache, dizziness, back pain, joint pain, rash or itching while taking BOSULIF. These may be symptoms of a severe allergic reaction. Your doctor may change your dose, temporarily stop, or permanently stop treatment with BOSULIF if you have certain side effects. BOSULIF may cause fertility problems in females and males. This may affect your ability to have a child. Talk to your doctor if this is a concern for you. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of BOSULIF. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. 2 Reference ID: 5488737 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 How should I store BOSULIF? • Store BOSULIF tablets and capsules at room temperature between 68°F to 77°F (20°C to 25°C). • The BOSULIF tablets and capsules bottle has a child-resistant closure. • The BOSULIF tablets bottle contains a desiccant to help keep your medicine dry (protect it from moisture). Keep the desiccant in the bottle. Do not eat the desiccant. • Store the BOSULIF capsules in the original bottle. • Ask your doctor or pharmacist about the right way to throw away outdated or unused BOSULIF. Keep BOSULIF and all medicines out of the reach of children. General information about the safe and effective use of BOSULIF. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use BOSULIF for a condition for which it is not prescribed. Do not give BOSULIF to other people even if they have the same symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about BOSULIF that is written for health professionals. What are the ingredients in BOSULIF? Active ingredient: bosutinib. Inactive ingredients: Tablets: croscarmellose sodium, iron oxide red (for 400 mg, and 500 mg tablet) and iron oxide yellow (for 100 mg, and 400 mg tablet), magnesium stearate, microcrystalline cellulose, poloxamer, polyethylene glycol, polyvinyl alcohol, povidone, talc and titanium dioxide. Capsules: croscarmellose sodium, gelatin, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer, povidone, red iron oxide, titanium dioxide, yellow iron oxide. The printing ink contains black iron oxide, potassium hydroxide, propylene glycol, shellac, strong ammonia solution. For more information, go to www.Bosulif.com or www.pfizermedicalinformation.com or call 1-800-438-1985. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised 12/2024 3 Reference ID: 5488737 INSTRUCTIONS FOR USE BOSULIF® (BAH-su-lif) (bosutinib) capsules This Instructions for Use contains information on how to prepare and give a dose of BOSULIF capsules by opening the capsules and mixing the contents with applesauce or yogurt for people who cannot swallow capsules whole. Read this Instructions for Use before you prepare or give the first dose of BOSULIF, and each time you get a refill. Ask your healthcare provider or pharmacist if you have any questions. Important information you need to know before preparing a dose of BOSULIF capsules: • BOSULIF capsules can be opened and the capsules contents mixed with room temperature applesauce or yogurt. • Only use applesauce or yogurt. Do not mix BOSULIF with other foods. • Swallow all of the mixture right away, without chewing. Do not store the mixture for later use. • If you do not swallow the entire BOSULIF mixture, do not mix another dose. Wait until the next day to take your regularly scheduled dose. • Take the BOSULIF mixture with a full meal. Preparing a dose of BOSULIF capsules: Gather the following supplies: • BOSULIF capsules • small, clean container • yogurt or applesauce • teaspoon for mixing • disposable gloves Giving a dose of BOSULIF capsules: Step 1: Choose a clean, flat work surface. Place all supplies on the work surface. Step 2: Wash and dry your hands well. Step 3: Put on disposable gloves Step 4: Get the prescribed number of BOSULIF capsule(s) needed to prepare the dose. Step 5: Add the amount of applesauce or yogurt needed for the prescribed dose to the container. Dose Amount of Applesauce or Yogurt 100 mg 10 mL (2 teaspoons) 150 mg 15 mL (3 teaspoons) 200 mg 20 mL (4 teaspoons) 250 mg 25 mL (5 teaspoons) 300 mg 30 mL (6 teaspoons) 350 mg 30 mL (6 teaspoons) 400 mg 35 mL (7 teaspoons) 450 mg 40 mL (8 teaspoons) 500 mg 45 mL (9 teaspoons) 550 mg 45 mL (9 teaspoons) 600 mg 50 mL (10 teaspoons) 1 Reference ID: 5488737 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 1 0001 Step 6: Carefully open each of the BOSULIF capsule(s) needed for the dose and empty the entire contents into the applesauce or yogurt. Mix the entire capsule contents with the applesauce or yogurt in the container. Step 7: Swallow all of the mixture right away, without chewing. Step 8: Dispose of (throw away) the empty BOSULIF capsule shell(s) in the household trash. Step 9: Wash teaspoon and the container with soap and warm water. Step 10: Remove disposable gloves and throw them away in the household trash. Step 11: Wash and dry your hands. How should I store BOSULIF capsules? • Store BOSULIF at room temperature between 68°F to 77°F (20°C to 25°C). • Store the BOSULIF capsules in the original bottle. • Ask your doctor or pharmacist about the right way to throw away outdated or unused BOSULIF. Keep BOSULIF and all medicines out of the reach of children. LAB-0639-12.1 For more information, go to www.Bosulif.com or www.pfizermedicalinformation.com or call 1 800 438 1985. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 9 2023 2 Reference ID: 5488737
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2025-02-12T15:47:30.572704
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_______________________________________________________________________________________________________________________________________ _______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------WARNINGS AND PRECAUTIONS------------------------­ These highlights do not include all the information needed to use • Gastrointestinal Toxicity: Monitor and manage as necessary. Withhold, BOSULIF safely and effectively. See full prescribing information for dose reduce, or discontinue BOSULIF. (2.3, 5.1) BOSULIF. • Myelosuppression: Monitor blood counts and manage as necessary. Withhold, dose reduce, or discontinue BOSULIF. (2.4, 5.2) BOSULIF® (bosutinib) tablets, for oral use • Hepatic Toxicity: Monitor liver enzymes at least monthly for the first BOSULIF® (bosutinib) capsules, for oral use 3 months and as needed. Withhold, dose reduce, or discontinue BOSULIF. Initial U.S. Approval: 2012 (2.3, 5.3) • Cardiovascular Toxicity: Monitor and manage as necessary. Interrupt, dose ----------------------------INDICATIONS AND USAGE-------------------------- reduce, or discontinue BOSULIF. (5.4) BOSULIF is a kinase inhibitor indicated for the treatment of • Fluid Retention: Monitor patients and manage using standard of care treatment. Interrupt, dose reduce, or discontinue BOSULIF. (2.3, 5.5) • adult and pediatric patients 1 year of age and older with chronic phase Ph+ • Renal Toxicity: Monitor patients for renal function at baseline and during chronic myelogenous leukemia (CML), newly-diagnosed or resistant or therapy with BOSULIF. (5.6) intolerant to prior therapy. (1) • Embryo-Fetal Toxicity: BOSULIF can cause fetal harm. Advise female • adult patients with accelerated, or blast phase Ph+ CML with resistance or patients of reproductive potential of potential risk to a fetus and to use intolerance to prior therapy. (1) effective contraception. (5.7) ----------------------DOSAGE AND ADMINISTRATION---------------------- ------------------------------ADVERSE REACTIONS-----------------------------­ • Adult patients with newly-diagnosed chronic phase Ph+ CML: 400 mg • Most common adverse reactions (≥20%), in adult and pediatric patients orally once daily with food. (2.1) with CML are diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, • Adult patients with chronic, accelerated, or blast phase Ph+ CML with hepatic dysfunction, headache, pyrexia, decreased appetite respiratory tract resistance or intolerance to prior therapy: 500 mg orally once daily with infection, and constipation. The most common laboratory abnormalities food. (2.1) (≥20%) in adult and pediatric patients are creatinine increased, hemoglobin • Pediatric patients with newly-diagnosed chronic phase Ph+ CML: decreased, lymphocyte count decreased, platelets decreased, ALT 300 mg/m2 orally once daily with food. (2.1) increased, calcium decreased, white blood cell count decreased, AST • Pediatric patients with chronic phase Ph+ CML with resistance or increased, absolute neutrophil count decreased, glucose increased, intolerance to prior therapy: 400 mg/m2 orally once daily with food. (2.1) phosphorus decreased, urate increased, alkaline phosphatase increased, • Consider dose escalation by increments of 100 mg once daily to a lipase increased, creatine kinase increased, and amylase increased. (6.1) maximum of 600 mg daily in adult patients who do not reach complete hematologic, cytogenetic, or molecular response and do not have Grade 3 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at or greater adverse reactions. (2.2) 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. • Consider dose escalation by increments of 50 mg for those with a BSA <1.1 m2 and 100 mg for those with a BSA ≥1.1 m2 to a maximum of 600 ------------------------------DRUG INTERACTIONS------------------------------­ mg daily in pediatric patients who do not reach sufficient response after 3 • Strong and Moderate CYP3A Inhibitors: Avoid concomitant use with months. (2.2) BOSULIF. (7.1) • Adjust dosage for toxicity and organ impairment (2) • Strong CYP3A Inducers: Avoid concomitant use with BOSULIF. (7.1) • Proton Pump Inhibitors: Use short-acting antacids or H2 blockers as an ---------------------DOSAGE FORMS AND STRENGTHS--------------------- alternative to proton pump inhibitors. (7.1) • Tablets: 100 mg, 400 mg, and 500 mg. (3) • Capsules 50 mg, 100 mg. (3) ----------------------------USE IN SPECIFIC POPULATIONS------------------­ Lactation: Advise women not to breastfeed. (8.2) -------------------------------CONTRAINDICATIONS---------------------------­ See 17 for PATIENT COUNSELING INFORMATION and Hypersensitivity to BOSULIF. (4) FDA-approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 8.2 Lactation 1 INDICATIONS AND USAGE 8.3 Females and Males of Reproductive Potential 2 DOSAGE AND ADMINISTRATION 8.4 Pediatric Use 2.1 Recommended Dosage 8.5 Geriatric Use 2.2 Dose Escalation 8.6 Renal Impairment 2.3 Dosage Adjustments for Non-Hematologic Adverse Reactions 8.7 Hepatic Impairment 2.4 Dosage Adjustments for Myelosuppression 10 OVERDOSAGE 2.5 Dosage Adjustments for Renal Impairment or Hepatic Impairment 11 DESCRIPTION 3 DOSAGE FORMS AND STRENGTHS 12 CLINICAL PHARMACOLOGY 4 CONTRAINDICATIONS 12.1 Mechanism of Action 5 WARNINGS AND PRECAUTIONS 12.2 Pharmacodynamics 5.1 Gastrointestinal Toxicity 12.3 Pharmacokinetics 5.2 Myelosuppression 13 NONCLINICAL TOXICOLOGY 5.3 Hepatic Toxicity 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.4 Cardiovascular Toxicity 14 CLINICAL STUDIES 5.5 Fluid Retention 14.1 Adult Patients with Newly-Diagnosed CP Ph+ CML 5.6 Renal Toxicity 14.2 Adult Patients with Imatinib-Resistant or -Intolerant Ph+ CP, AP, 5.7 Embryo-Fetal Toxicity and BP CML 6 ADVERSE REACTIONS 14.3 Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP 6.1 Clinical Trials Experience Ph+ CML with Resistance or Intolerance to Prior Therapy 6.2 Postmarketing Experience 16 HOW SUPPLIED/STORAGE AND HANDLING 7 DRUG INTERACTIONS 17 PATIENT COUNSELING INFORMATION 7.1 Effect of Other Drugs on BOSULIF 8 USE IN SPECIFIC POPULATIONS * Sections or subsections omitted from the Full Prescribing Information are 8.1 Pregnancy not listed. 1 Reference ID: 5488743 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE BOSULIF is indicated for the treatment of: • Adult and pediatric patients 1 year of age and older with chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML), newly-diagnosed or resistant or intolerant to prior therapy [see Clinical Studies (14.1, 14.2, 14.3)]. • Adult patients with accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior therapy [see Clinical Studies (14.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage is taken orally once daily with food. Swallow tablets whole. Do not cut, crush, break or chew tablets. Continue treatment with BOSULIF until disease progression or intolerance to therapy. Capsules may be swallowed whole. For patients who are unable to swallow a whole capsule(s), each capsule can be opened and the contents mixed with applesauce or yogurt. Mixing the capsule contents with applesauce or yogurt cannot be considered a substitute of a proper meal. If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Dosage in Adult Patients with Newly-Diagnosed CP Ph+ CML The recommended dosage of BOSULIF is 400 mg orally once daily with food. Dosage in Adult Patients with CP, AP, or BP Ph+ CML with Resistance or Intolerance to Prior Therapy The recommended dosage of BOSULIF is 500 mg orally once daily with food. Dosage in Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy The recommended dose of BOSULIF for pediatric patients with newly-diagnosed CP Ph+ CML is 300 mg/m2 orally once daily with food and the recommended dosage for pediatric patients with CP Ph+ CML that is resistant or intolerant to prior therapy is 400 mg/m2 orally once daily with food and dose recommendations are provided in Table 1. As appropriate, the desired dose can be attained by combining different strengths of BOSULIF tablets or capsules. Table 1: Dosing of BOSULIF for Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy BSA1 Newly-Diagnosed Recommended Dose (Once Daily) Resistant or Intolerant Recommended Dose (Once Daily) < 0.55 m2 150 mg 200 mg 0.55 to < 0.63 m2 200 mg 250 mg 0.63 to < 0.75 m2 200 mg 300 mg 0.75 to < 0.9 m2 250 mg 350 mg 0.9 to < 1.1 m2 300 mg 400 mg ≥ 1.1 m2 400 mg* 500 mg* * maximum starting dose (corresponding to maximum starting dose in adult indication) 1 BSA=Body Surface Area 2 Reference ID: 5488743 Preparation Instructions for BOSULIF Capsules Mixed with Applesauce or Yogurt For patients who are unable to swallow capsules, the contents of the capsules can be mixed with applesauce or yogurt. Remove the required number of capsules from the container to prepare the dose as instructed and the amount of either room temperature applesauce or yogurt in a clean container. Carefully open each capsule, add the entire capsule content of each capsule into the applesauce or yogurt, then mix the entire dose into the applesauce or yogurt. Patients should immediately consume the full mixture in its entirety, without chewing. Do not store the mixture for later use. If the entire preparation is not swallowed do not take an additional dose. Wait until the next day to resume dosing. Table 2: BOSULIF Dose Using Capsules and Soft Food Volumes Dose Volume of Applesauce or Yogurt 100 mg 10 mL (2 teaspoons) 150 mg 15 mL (3 teaspoons) 200 mg 20 mL (4 teaspoons) 250 mg 25 mL (5 teaspoons) 300 mg 30 mL (6 teaspoons) 350 mg 30 mL (6 teaspoons) 400 mg 35 mL (7 teaspoons) 450 mg 40 mL (8 teaspoons) 500 mg 45 mL (9 teaspoons) 550 mg 45 mL (9 teaspoons) 600 mg 50 mL (10 teaspoons) 2.2 Dose Escalation In clinical studies of adult patients with Ph+ CML, dose escalation by increments of 100 mg once daily to a maximum of 600 mg once daily was allowed in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response and who did not have Grade 3 or higher adverse reactions at the recommended starting dosage. In pediatric patients with BSA <1.1 m2 and an insufficient response after 3 months consider increasing dose by 50 mg increments up to maximum of 100 mg above starting dose. Dose increases for insufficient response in pediatric patients with BSA ≥1.1 m2 can be conducted similarly to adult recommendations in 100 mg increments. The maximum dose in pediatric and adult patients is 600 mg once daily. 2.3 Dosage Adjustments for Non-Hematologic Adverse Reactions Elevated liver transaminases: If elevations in liver transaminases greater than 5×institutional upper limit of normal (ULN) occur, withhold BOSULIF until recovery to less than or equal to 2.5×ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinue BOSULIF. If transaminase elevations greater than or equal to 3×ULN occur concurrently with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 2×ULN (Hy’s law case definition), discontinue BOSULIF [see Warnings and Precautions (5.3)]. Diarrhea: For National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 3-4 diarrhea (increase of greater than or equal to 7 stools/day over baseline/pretreatment), withhold BOSULIF until recovery to Grade less than or equal to 1. BOSULIF may be resumed at 400 mg once daily [see Warnings and Precautions (5.1)]. For other clinically significant, moderate or severe non-hematological toxicity, withhold BOSULIF until the toxicity has resolved, then consider resuming BOSULIF at a dose reduced by 100 mg taken once daily. If clinically appropriate, consider re-escalating the dose of BOSULIF to the starting dose taken once daily. In pediatric patients, dose adjustments for non-hematologic toxicities can be conducted similarly to adults, however the dose reduction increments may differ. For pediatric patients with BSA <1.1 m2, reduce dose by 50 mg initially followed 3 Reference ID: 5488743 by additional 50 mg increment if the adverse reaction (AR) persists. For pediatric patients with BSA ≥1.1 m2 or greater, reduce dose similarly to adults. 2.4 Dosage Adjustments for Myelosuppression Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 3). Table 3: Dose Adjustments for Neutropenia and Thrombocytopenia in Adult and Pediatric Patients ANCa less than 1000×106/L or Platelets less than 50,000×106/L Withhold BOSULIF until ANC greater than or equal to1000×106/L and platelets greater than or equal to 50,000×106/L. Resume treatment with BOSULIF at the same dose if recovery occurs within 2 weeks. If blood counts remain low for greater than 2 weeks, upon recovery, reduce dose by 100 mg and resume treatment, or by 50 mg in pediatric patients with BSA <1.1 m2 and resume treatment. If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment, or by an additional 50 mg in pediatric patients with BSA <1.1 m2 and resume treatment. a Absolute Neutrophil Count 2.5 Dosage Adjustments for Renal Impairment or Hepatic Impairment The recommended starting doses for patients with renal and hepatic impairment are described in Table 4 below. Table 4: Dose Adjustments for Renal and Hepatic Impairment in Adult Patients Recommended Starting Dosage Newly-diagnosed chronic phase Ph+ CML Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy Normal renal and hepatic function 400 mg daily 500 mg daily Renal impairment Creatinine clearance 30 to 50 mL/min 300 mg daily 400 mg daily Creatinine clearance less than 30 mL/min 200 mg daily 300 mg daily Hepatic impairment Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child- Pugh C) 200 mg daily 200 mg daily [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)]. 4 Reference ID: 5488743 Table 5: Dosage Adjustments for Renal and Hepatic Impairment in Pediatric Patients Newly-Diagnosed CP Ph+ CML Recommended Starting Dose (Once Daily) By Organ Function Pediatric Patients by Separated BSA1 Band Normal renal and hepatic function Renal Impairment: Creatinine clearance 30 to 50 mL/min Renal Impairment: Creatinine clearance less than 30 mL/min Hepatic Impairment: Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C) Pediatric < 0.55 m2 150 mg 100 mg 100 mg 100 mg Pediatric 0.55 to < 0.63 m2 200 mg 150 mg 100 mg 100 mg Pediatric 0.63 to < 0.75 m2 200 mg 150 mg 100 mg 100 mg Pediatric 0.75 to < 0.9 m2 250 mg 200 mg 150 mg 100 mg Pediatric 0.9 to < 1.1 m2 300 mg 200 mg 200 mg 150 mg Pediatric ≥ 1.1 m2 400 mg 300 mg 200 mg 200 mg CP Ph+ CML with Resistance or Intolerance to Prior Therapy Recommended Starting Dose (Once Daily) By Organ Function Pediatric Patients by Separated BSA1 Band Normal renal and hepatic function Renal Impairment: Creatinine clearance 30 to 50 mL/min Renal Impairment: Creatinine clearance less than 30 mL/min Hepatic Impairment: Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C) Pediatric < 0.55 m2 200 mg 150 mg 100 mg 100 mg Pediatric 0.55 to < 0.63 m2 250 mg 200 mg 150 mg 100 mg Pediatric 0.63 to < 0.75 m2 300 mg 200 mg 200 mg 150 mg Pediatric 0.75 to < 0.9 m2 350 mg 250 mg 200 mg 150 mg Pediatric 0.9 to < 1.1 m2 400 mg 300 mg 250 mg 200 mg Pediatric ≥ 1.1 m2 500 mg 400 mg 300 mg 200 mg 1 BSA=Body Surface Area [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS Tablets: • 100 mg: yellow, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “100” on the other. • 400 mg: orange, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “400” on the other. • 500 mg: red, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “500” on the other. Capsules: • 50 mg: white body/orange cap with “BOS 50” printed on the body and “Pfizer” printed on the cap in black ink. • 100 mg: white body/brownish-red cap with “BOS 100” printed on the body and “Pfizer” printed on the cap in black ink. 4 CONTRAINDICATIONS BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included anaphylaxis [see Adverse Reactions (6.1)]. 5 Reference ID: 5488743 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Toxicity Diarrhea, nausea, vomiting, and abdominal pain occur with BOSULIF treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and fluid replacement. In the randomized clinical trial in adult patients with newly-diagnosed Ph+ CML, the median time to onset for diarrhea (all grades) was 4 days and the median duration per event was 3 days. Among 546 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 2 days. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range 1-268). Among 49 pediatric patients with newly-diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the duration was 2 days. Among patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 2 (range 1 – 198). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.2 Myelosuppression Thrombocytopenia, anemia and neutropenia occur with BOSULIF treatment. Perform complete blood counts weekly for the first month of therapy and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.4) and Adverse Reactions (6)]. 5.3 Hepatic Toxicity Bosutinib may cause elevations in serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]). Two cases consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3×ULN with total bilirubin greater than 2×ULN and alkaline phosphatase less than 2×ULN) have occurred without alternative causes. This represented 2 out 1711 patients in BOSULIF clinical trials. In the 268 adult patients from the safety population in the randomized clinical trial in patients with newly-diagnosed CML in the BOSULIF treatment group, the incidence of ALT elevation was 68.3% and increased AST was 56%. Of patients who experienced increased transaminases of any grade, 73% experienced their first increase within the first 3 months. The median time to onset of increased ALT and AST was 29 and 56 days, respectively, and the median duration was 19 and 15 days, respectively. Among the 546 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the incidence of increased ALT was 53.3% and AST elevation was 46.7%. Sixty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations in this study occurred early in treatment; of patients who experienced increased transaminases of any grade, more than 81% experienced their first increase within the first 3 months. The median time to onset of increased ALT and AST was 22 and 29 days, respectively, and the median duration for each was 21 days. Among 49 pediatric patients with newly-diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, the incidence based on laboratory data that worsened from baseline of increased ALT was 59% and of increased AST 51%. Seventy-six percent of the patients experienced an increase in either ALT or AST. Most cases of increased transaminases occurred early in treatment; of patients who experienced increased transaminases of any grade, 6 Reference ID: 5488743 84% of patients experienced their first increases within the first 3 months. The median time to onset for adverse reactions of increased ALT and AST was 22 and 15 days, respectively. The median duration for adverse reactions of Grade 3 or 4 increased ALT or AST was 26 and 12 days, respectively. Perform hepatic enzyme tests monthly for the first 3 months of BOSULIF treatment and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.4 Cardiovascular Toxicity BOSULIF can cause cardiovascular toxicity including cardiac failure, left ventricular dysfunction, and cardiac ischemic events. Cardiac failure events occurred more frequently in previously treated patients than in patients with newly diagnosed CML and were more frequent in patients with advanced age or risk factors, including previous medical history of cardiac failure. Cardiac ischemic events occurred in both previously treated patients and in patients with newly diagnosed CML and were more common in patients with coronary artery disease risk factors, including history of diabetes, body mass index greater than 30, hypertension, and vascular disorders. In a randomized study of adult patients with newly diagnosed CML, cardiac failure occurred in 1.9% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib. Cardiac ischemic events occurred in 4.9% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib. In a single-arm study in adult patients with CML who were resistant or intolerant to prior therapy, cardiac failure was observed in 5.3% of patients and cardiac ischemic events were observed in 5.1% of patients treated with BOSULIF. Among 49 pediatric patients with newly diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, 4 (8%) patients had Grade 1-2 cardiac events, including tachycardia (n=2), angina pectoris, right bundle branch block, and sinus tachycardia (n=1 each). Monitor patients for signs and symptoms consistent with cardiac failure and cardiac ischemia and treat as clinically indicated. Interrupt, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.5 Fluid Retention Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. In the randomized clinical trial of 268 adult patients with newly-diagnosed CML in the bosutinib treatment group, 3 patients (1.1%) experienced severe fluid retention of Grade 3, 1 patient experienced Grade 3 pericardial effusion, and 2 patients experienced Grade 3 pleural effusion. Among 546 adult patients in a single-arm study in patients with Ph+ CML who were resistant or intolerant to prior therapy, Grade 3 or 4 fluid retention was reported in 30 patients (6%). Some patients experienced more than one fluid retention event. Specifically, 24 patients experienced Grade 3 or 4 pleural effusions, 9 patients experienced Grade 3 or Grade 4 pericardial effusions, and 6 patients experienced Grade 3 edema. Among 49 pediatric patients with newly diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, Grade 1-2 pericardial effusion, peripheral edema, and face edema were reported in 1 patient each. Monitor and manage patients using standards of care. Interrupt, dose reduce or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.6 Renal Toxicity An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in patients treated with BOSULIF. Table 6 identifies the shift from baseline to lowest observed eGFR during BOSULIF therapy for patients in the pooled 7 Reference ID: 5488743 6 leukemia studies regardless of line of therapy. The median duration of therapy with BOSULIF was approximately 24 months (range, 0.03 to 155) for patients in these studies. Table 6: Shift From Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies (N=1372)* Baseline Follow-Up Renal Function Status N Normal n (%) Mild n (%) Mild to Moderate n (%) Moderate to Severe n (%) Severe n (%) Kidney Failure n (%) Normal 527 115 (21.8) 330 (62.6) 50 (9.5) 23 (4.4) 3 (0.6) 5 (0.9) Mild 672 10 (1.5) 259 (38.5) 271 (40.3) 96 (14.3) 26 (3.9) 6 (0.9) Mild to Moderate 137 0 6 (4.4) 40 (29.2) 66 (48.2) 24 (17.5) 1 (0.7) Moderate to Severe 33 0 1 (3.0) 1 (3.0) 8 (24.2) 19 (57.6) 4 (12.1) Severe 1 0 0 0 0 0 1 (100) Total 1370 125 (9.1) 596 (43.5) 362 (26.4) 193 (14.1) 72 (5.2) 17 (1.2) Abbreviations: eGFR=estimated glomerular filtration rate; N/n=number of patients. Notes: eGFR was calculated using Modification in Diet in Renal Disease method (MDRD). Notes: Grading is based on Kidney Disease Improving Global Outcomes (KDIGO) Classification by eGFR: Normal: greater than or equal to 90, Mild: 60 to less than 90, Mild to Moderate: 45 to less than 60, Moderate to Severe: 30 to less than 45, Severe: 15 to less than 30, Kidney Failure: less than 15 ml/min/1.73 m2 . *Among the 1372 patients, eGFR was missing in 7 patients at baseline or on-therapy. There were no patients with kidney failure at baseline. Overall, 45% of the pediatric patients with newly diagnosed CP Ph+ CML or resistant or intolerant CP Ph+ CML who had normal eGFR at baseline shifted to a maximum of mild, and 40% pediatric patients who had mild eGFR at baseline shifted to a maximum of moderate during treatment. Monitor renal function at baseline and during therapy with BOSULIF, with particular attention to those patients who have preexisting renal impairment or risk factors for renal dysfunction. Consider dose adjustment in patients with baseline and treatment emergent renal impairment [see Dosage and Administration (2.5)]. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, BOSULIF can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Gastrointestinal toxicity [see Warnings and Precautions (5.1)]. • Myelosuppression [see Warnings and Precautions (5.2)]. • Hepatic toxicity [see Warnings and Precautions (5.3)]. • Cardiovascular toxicity [see Warnings and Precautions (5.4)]. • Fluid retention [see Warnings and Precautions (5.5)]. • Renal toxicity [see Warnings and Precautions (5.6)]. 8 Reference ID: 5488743 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions, in ≥20% of adults with newly diagnosed CP Ph+ CML or CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy (N=814) were diarrhea (80%), rash (44%), nausea (44%), abdominal pain (43%), vomiting (33%), fatigue (33%), hepatic dysfunction (33%), respiratory tract infection (25%), pyrexia (24%), and headache (21%). The most common laboratory abnormalities that worsened from baseline in ≥20% of adults were creatinine increased (93%), hemoglobin decreased (90%), lymphocyte count decreased (72%), platelets decreased (69%), ALT increased (58%), calcium decreased (53%), white blood cell count decreased (52%), absolute neutrophils count decreased (50%), AST increased (50%), glucose increased (46%), phosphorus decreased (44%), urate increased (41%), alkaline phosphatase increased (40%), lipase increased (36%), creatine kinase increased (29%), and amylase increased (24%). The most common adverse reactions, in ≥20% of pediatric patients (N=49) were diarrhea (82%), abdominal pain (73%), vomiting (55%), nausea (49%), rash (49%), fatigue (37%), hepatic dysfunction (37%), headache (35%), pyrexia (31%), decreased appetite (27%), and constipation (20%). The most common laboratory abnormalities that worsened from baseline in ≥20% of pediatric patients were creatinine increased (92%), alanine aminotransferase increased (59%), white blood cell count decreased (53%), aspartate aminotransferase increased (51%), platelet count decreased (49%), glucose increased (41%), calcium decreased (31%), hemoglobin decreased (31%), neutrophil count decreased (31%), lymphocyte count decreased (29%), serum amylase increased (27%), and CPK increased (25%). Adverse Reactions in Adult Patients With Newly-Diagnosed CP CML The clinical trial randomized and treated 533 patients with newly-diagnosed CP CML to receive BOSULIF 400 mg daily or imatinib 400 mg daily as single agents (Newly-Diagnosed CP CML Study) [see Clinical Studies (14.1)]. The safety population (received at least 1 dose of BOSULIF) included: • two hundred sixty-eight (268) patients with newly-diagnosed CP CML had a median duration of BOSULIF treatment of 55 months (range: 0.3 to 60 months) and a median dose intensity of 394 mg/day. Serious adverse reactions occurred in 22% of patients with newly-diagnosed CP CML who received bosutinib. Serious adverse reactions reported in >2% of patients included hepatic dysfunction (4.1%), pneumonia (3.4%), coronary artery disease (3.4%), and gastroenteritis (2.2%). Fatal adverse reactions occurred in 3 patients (1.1%) due to coronary artery disease (0.4%), cardiac failure acute (0.4%), and renal failure (0.4%). Permanent discontinuation of bosutinib due to an adverse reaction occurred in 20% of patients with newly-diagnosed CP CML who received bosutinib. Adverse reactions which resulted in permanent discontinuation in > 2% of patients included hepatic dysfunction (9%). Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 68% of patients with newly-diagnosed CP CML. Adverse reactions which required dose interruptions or reductions in >5% of patients included hepatic dysfunction (27%), thrombocytopenia (16%), diarrhea (16%), lipase increased (10%), neutropenia (7%), abdominal pain (6%), rash (5%). The most common adverse reactions, in >20% of bosutinib-treated patients with newly-diagnosed CML (N=268) were diarrhea (75%), hepatic dysfunction (45%), rash (40%), abdominal pain (39%), nausea (37%), fatigue (33%), respiratory tract infection (27%), headache (22%), and vomiting (21%). The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine increased (94%), hemoglobin decreased (89%), lymphocyte count decreased (84%), ALT increased (68%), platelet count decreased 9 Reference ID: 5488743 (68%), glucose increased (57%), AST increased (56%), calcium decreased (55%), phosphorus decreased (54%), lipase increased (53%), white blood cell count decreased (50%), absolute neutrophil count decreased (42%), alkaline phosphatase increased (41%), creatine kinase increased (36%), and amylase increased (32%). Table 7 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 (3/4) for the Phase 3 CP CML safety population. Table 7: Adverse Reactions (10% or Greater) in Patients With Newly-Diagnosed CML in Bosutinib 400 mg Study* System Organ Class Preferred Term Bosutinib 400 mg Chronic Phase CML (N=268) Imatinib 400 mg Chronic Phase CML (N=265) All Grades % Grade 3/4 % All Grades % Grade 3/4 % Gastrointestinal disorders Diarrhea 75 9 40 1 Abdominal paina 39 2 27 1 Nausea 37 0 42 0 Vomiting 21 1 20 0 Constipation 13 0 6 0 Hepatobiliary disorders Hepatic dysfunctionf 45 27 15 4 Skin and subcutaneous tissue disorders Rashd 40 2 30 2 Pruritus 11 <1 4 0 General disorders and administration- site conditions Fatigueb 33 1 30 <1 Pyrexia 17 1 11 0 Edemag 15 0 46 2 Infections and infestations Respiratory tract infectione 27 1 25 <1 Nervous system disorders Headache 22 1 15 1 Musculoskeletal and connective tissue disorders Arthralgia 18 1 18 <1 Back pain 12 <1 9 <1 Respiratory, thoracic, and mediastinal disorders Cough 11 0 10 0 Dyspnea 11 1 6 1 Metabolism and nutrition disorders Decreased appetite 11 <1 6 0 Vascular disorders Hypertensionc 10 5 11 5 *Based on a Minimum of 57 Months of Follow-up. Adverse drug reactions are based on all-causality treatment-emergent adverse events. The commonality stratification is based on 'All Grades' under Total column. 'Grade 3', 'Grade 4' columns indicate maximum toxicity. a Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain. b Fatigue includes the following preferred terms: Asthenia, Fatigue, Malaise. c Hypertension* includes the preferred terms: Blood pressure systolic increased, Hypertension, Hypertensive crisis, Hypertensive heart disease, Retinopathy hypertensive. f Hepatic dysfunction includes the preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Drug-induced liver injury, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic steatosis, Hepatitis, Hepatitis toxic, Hepatocellular injury, Hepatotoxicity, Hyperbilirubinemia, Jaundice, Liver disorder, Liver function test increased, Ocular icterus, Transaminases increased. g Edema includes the following preferred terms: Eye edema, Eyelid edema, Face edema, Edema, Edema peripheral, Orbital 10 Reference ID: 5488743 edema, Periorbital edema, Periorbital swelling, Peripheral swelling, Swelling, Swelling face, Swelling of eyelid, Swollen tongue. d Rash includes the following preferred terms: Acne, Blister, Dermatitis, Dermatitis acneiform, Dermatitis bullous, Dermatitis exfoliative generalized, Drug reaction with eosinophilia and systemic symptoms, Dyshidrotic eczema, Eczema, Eczema asteatotic, Erythema, Erythema nodosum, Genital rash, Lichen planus, Perivascular dermatitis, Photosensitivity reaction, Psoriasis, Rash, Rash erythematous, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Seborrhoeic keratosis, Skin discoloration, Skin exfoliation, Skin hypopigmentation, Skin irritation, Skin lesion, Stasis dermatitis. e Respiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection. In the randomized study in patients with newly-diagnosed CP CML, one patient in the group treated with BOSULIF experienced a Grade 3 QTcF prolongation (>500 msec). Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol. Table 8 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 3 newly-diagnosed CML safety population. Table 8: Select Laboratory Abnormalities (>20%) That Worsened From Baseline in Patients with NewlyDiagnosed CML in Bosutinib 400 mg Study* Bosutinib N=268 % Imatinib N=265 % All Grade Grade 3-4 All Grade Grade 3-4 Hematology Parameters Platelet Count decreased 68 14 60 6 Absolute Neutrophil Count decreased 42 9 65 20 Hemoglobin decreased 89 9 90 7 White Blood Cell Count decreased 50 6 70 8 Lymphocyte Count decreased 84 12 82 14 Biochemistry Parameters SGPT/ALT increased 68 26 28 3 SGOT/AST increased 56 13 29 3.4 Lipase increased 53 19 35 8 Phosphorus decreased 54 9 69 21 Amylase increased 32 3.4 18 2.3 Alkaline Phosphatase increased 41 0 43 0.4 Calcium decreased 55 1.5 57 1.1 Glucose increased 57 3 65 3.4 Creatine Kinase increased 36 3 65 5 Creatinine increased 94 1.1 98 0.8 *Based on a Minimum of 57 Months of Follow-up. Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; SGPT=serum glutamic-pyruvic transaminase; SGOT=serum glutamic-oxaloacetic transaminase; N/n=number of patients; ULN=upper limit of normal. Graded using CTCAE v 4.03 Adverse Reactions in Adult Patients With Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CML The single-arm clinical trial enrolled patients with Ph+ CP, AP, or BP CML and with resistance or intolerance to prior therapy [see Clinical Studies (14.2)]. The safety population (received at least 1 dose of BOSULIF) included 546 CML patients: • two hundred eighty-four (284) patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF treatment of 26 months (range: 0.2 to 155 months), and a median dose intensity of 437 mg/day. 11 Reference ID: 5488743 • one hundred nineteen (119) patients with CP CML previously treated with both imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) who had a median duration of BOSULIF treatment of 9 months (range: 0.2 to 148 months) and a median dose intensity of 427 mg/day. • one hundred forty-three (143) patients with advanced phase (AdvP) CML including 79 patients with AP CML and 64 patients with BP CML. In the patients with AP CML and BP CML, the median duration of BOSULIF treatment was 10 months (range: 0.1 to 140 months) and 3 months (range: 0.03 to 71 months), respectively. The median dose intensity was 406 mg/day, and 456 mg/day, in the AP CML and BP CML cohorts, respectively. Serious adverse reactions occurred in 30% of patients in the safety population of the single-arm trial in patients with CML (N=546) who were resistant or intolerant to prior therapy. Serious adverse reactions reported in >2% of patients included pneumonia (7%), pleural effusion (6%), pyrexia (3.7%), coronary artery disease (3.5%), dyspnea (2.6%), rash (2.2%), thrombocytopenia (2%), abdominal pain (2%), and diarrhea (2%). Fatal adverse reactions occurred in 12 patients (2.2%) due to coronary artery disease (0.9%), pneumonia (0.4%), respiratory failure (0.4%), gastrointestinal hemorrhage (0.2%), acute kidney injury (0.2%), and acute pulmonary edema (0.2%). Permanent discontinuation of bosutinib due to an adverse reaction occurred in 22% of patients with CML who were resistant or intolerant to prior therapy. Adverse reactions which resulted in permanent discontinuation in >2% of patients included thrombocytopenia (6%), hepatic dysfunction (3.3%), and neutropenia (2%). Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 66% of patients with CML who were resistant or intolerant to prior therapy. Adverse reactions which required dose interruptions or reductions in >5% of patients included thrombocytopenia (24%), diarrhea (14%), rash (13%), hepatic dysfunction (10%), neutropenia (9%), pleural effusion (8%), vomiting (7%), anemia (6%), and abdominal pain (6%). The most common adverse reactions, in ≥20% of patients in the safety population of the single-arm trial in patients with CML (N=546) who were resistant or intolerant to prior therapy were diarrhea (83%), nausea (47%), rash (46%), abdominal pain (45%), vomiting (39%), fatigue (33%), pyrexia (28%), hepatic dysfunction (27%), respiratory tract infection (24%), cough (23%), and headache (21%). The most common laboratory abnormalities that worsened from baseline in ≥20% were creatinine increased (93%), hemoglobin decreased (91%), lymphocyte decreased (80%), platelets decreased (69%), absolute neutrophil count (54%), ALT increased (53%), calcium decreased (53%), white blood cell count decreased (52%), urate increased (48%), AST increased (47%), phosphorus decreased (39%), alkaline phosphatase increased (39%), lipase increased (28%), magnesium increased (25%), potassium decreased (24%), potassium increased (23%). See Table 10 for Grade 3/4 laboratory abnormalities. Table 9 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 for the Phase 1/2 CML safety population based on long-term follow-up. 12 Reference ID: 5488743 Table 9: Adverse Reactions (10% or Greater) in Patients With CML Who Were Resistant or Intolerant to Prior Therapy in Single-Arm Trial* System Organ Class Preferred Term CP CML (N=403) AdvP CML (N=143) All Grades % Grade 3/4 % All Grades % Grade 3/4 % Gastrointestinal disorders Diarrhea 85 10 76 4 Abdominal paina 49 2 36 7 Nausea 47 1 48 2 Vomiting 38 3 43 3 Constipation 15 <1 17 1 Skin and subcutaneous tissue disorders Rashe 48 9 42 5 Pruritus 12 1 7 0 General disorders and administration- site conditions Fatigue 35 3 27 6 Pyrexia 25 1 37 3 Edemac 19 <1 17 1 Chest paing 8 1 12 1 Hepatobiliary disorders Hepatic dysfunctionh 29 11 21 10 Infections and infestations Respiratory tract infectionf 27 <1 17 0 Influenzai 11 1 3 0 Pneumoniad 10 4 18 12 Respiratory, thoracic, and mediastinal disorders Cough 24 0 22 0 Pleural effusion 14 4 9 4 Dyspnea 12 2 20 6 Nervous system disorders Headache 21 1 18 4 Dizziness 11 0 14 1 Musculoskeletal and connective tissue disorders Arthralgia 19 1 15 0 Back pain 14 1 8 1 Metabolism and nutrition disorders Decreased appetite 14 1 14 0 Vascular disorders Hypertensionb 11 3 8 3 ADR Definition *Based on a Minimum of 105 Months of Follow-up. Adverse drug reactions are based on all-causality treatment-emergent adverse events. The commonality stratification is based on 'All Grades' under Total column. 'Grade 3', 'Grade 4' columns indicate maximum toxicity a Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain, Hepatic pain. g Chest pain includes the following preferred terms: Chest discomfort, Chest pain. h Hepatic dysfunction includes the following preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Hepatic steatosis, Hepatitis toxic, Hepatomegaly, Hepatotoxicity, Hyperbilirubinemia, Liver disorder, Liver function test abnormal, Liver function test increased, Transaminases increased. b Hypertension* includes the following preferred terms: Blood pressure increased, Blood pressure systolic increased, Essential hypertension, Hypertension, Hypertensive crisis, Retinopathy hypertensive. i Influenza includes the following preferred terms: H1N1 influenza, Influenza. c Edema includes the following preferred terms: Eye edema, Eyelid edema, Face edema, Generalized edema, Localized edema, Edema, Edema peripheral, Penile edema, Periorbital edema, Periorbital swelling, Peripheral swelling, Scrotal edema, Scrotal swelling, Swelling, Swelling 13 Reference ID: 5488743 face, Swelling of eyelid, Testicular edema, Tongue edema. d Pneumonia includes the following preferred terms: Atypical pneumonia, Lower respiratory tract congestion, Lower respiratory tract infection, Pneumonia, Pneumonia aspiration, Pneumonia bacterial, Pneumonia fungal, Pneumonia necrotising, Pneumonia streptococcal. e Rash includes the following preferred terms: Acarodermatitis, Acne, Angular cheilitis, Blister, Dermatitis, Dermatitis acneiform, Dermatitis psoriasiform, Drug eruption, Eczema, Eczema asteatotic, Erythema, Erythema annulare, Exfoliative rash, Lichenoid keratosis, Palmar erythema, Photosensitivity reaction, Pigmentation disorder, Psoriasis, Pyoderma gangrenosum, Pyogenic granuloma, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash pruritic, Rash pustular, Seborrhoeic dermatitis, Seborrhoeic keratosis, Skin depigmentation, Skin discoloration, Skin disorder, Skin exfoliation, Skin hyperpigmentation, Skin hypopigmentation, Skin irritation, Skin lesion, Skin plaque, Skin toxicity, Stasis dermatitis. f Respiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection. *ADR identified post-marketing In the single-arm study in patients with CML who were resistant or intolerant to prior therapy, 2 patients (0.4%) experienced QTcF interval of greater than 500 milliseconds. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol. Table 10 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the safety population of the study in patients with CML who were resistant or intolerant to prior therapy based on long-term follow-up. Table 10: Number (%) of Patients With Clinically Relevant All Grade or Grade 3/4 Laboratory Test Abnormalities in the Safety Population of the Study of Patients With CML Who Were Resistant or Intolerant to Prior Therapy* CP CML N=403 % AdvP CML N=143 % All grade Grade 3/4 All grade Grade 3/4 Hematology Parameters Platelet Count decreased 66 26 80 57 Absolute Neutrophil Count decreased 50 16 66 39 Hemoglobin decreased 89 13 97 38 Lymphocyte decreased 79 14 82 21 White Blood Cell Count decreased 51 7 57 27 Biochemistry Parameters SGPT/ALT increased 58 11 39 6 SGOT/AST increased 50 5 37 3.5 Lipase increased 32 12 19 6 Phosphorus decreased 41 8 33 7 Total Bilirubin increased 16 0.7 22 2.8 Creatinine increased 95 3 87 1.4 Alkaline Phosphatase increased 39 0 39 1.4 Glucose increased 42 2.7 39 6 Sodium increased 23 0.5 11 0 Sodium decreased 18 2.2 27 6 Calcium decreased 55 4.7 45 3.5 Urate increased 49 6 43 6 Magnesium increased 27 7 18 4.9 Potassium decreased 22 1.7 29 4.9 Potassium increased 25 2.7 19 2.1 14 Reference ID: 5488743 *Based on a Minimum of 105 Months of Follow-up. Abbreviations: AdvP=advanced phase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; CP=chronic phase; N/n=number of patients; SGPT=serum glutamate-pyruvate transaminase; SGOT=serum glutamate-oxaloacetate aminotransferase; ULN=upper limit of normal. Pediatric Patients with Newly-Diagnosed CP Ph+ CML or CP Ph+ CML that is Resistant or Intolerant to Prior Therapy The safety of BOSULIF was evaluated in BCHILD, a single-arm trial for the treatment of pediatric patients aged 1 year and older with newly-diagnosed CP Ph+ CML or in patients with CP Ph+ CML who are resistant or intolerant to prior therapy [see Clinical Studies (14.3)]. Patients received BOSULIF (n = 49) 300 mg/m2 to 400 mg/m2 orally once daily until disease progression or unacceptable toxicity. The median time on treatment with BOSULIF was 12.2 months (range, 0.2 to 60.9 months). Among patients who received BOSULIF, 77.6% were exposed for 6 months or longer and 51% were exposed for one year or longer. Permanent discontinuation of BOSULIF due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation in 2 or more patients included ALT increased (6%), AST increased (4%), diarrhea (4%), fatigue (4%) and rash maculo-papular (4%). The most common adverse reactions, in ≥20% of BOSULIF-treated pediatric patients were diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, and constipation. Table 11 summarizes the adverse reactions in BCHILD. Table 11: Adverse Reactions (10% or Greater) in Pediatric Patients with Newly Diagnosed CP Ph+ CML or CP Ph+ CML Resistant or Intolerant to Prior Therapy Who Received BOSULIF in BCHILD System Organ Class Preferred Term BOSULIF Total (N=49) % All Grades Grade 3/4 Gastrointestinal disorders Diarrhea 82 12 Abdominal paina 73 4 Vomiting 55 6 Nausea 49 2 Constipation 20 0 Skin and subcutaneous tissue disorders Rashb 49 8 Hepatobiliary disorders Hepatic dysfunctionc 37 14 General disorders and administration-site conditions Fatigued 37 4 Pyrexia 31 4 Nervous system disorders Headache 35 2 Metabolism and nutrition disorders Decreased appetite 27 2 Infections and infestations Respiratory tract infectione 12 2 Adverse drug reactions are based on all-causality treatment-emergent adverse reactions. The commonality stratification is based on 'All Grades' under Bosutinib 400 mg column. 'Grade 3/4 columns indicate maximum toxicity. a Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain, Hepatic pain. b Rash includes the following preferred terms: Acarodermatitis, Acne, Angular cheilitis, Blister, Dermatitis, Dermatitis acneiform, Dermatitis bullous, Dermatitis exfoliative generalized, Dermatitis psoriasiform, Drug eruption, Drug reaction with eosinophilia and systemic symptoms, Dyshidrotic eczema, Eczema, Eczema asteatotic, Erythema, Erythema annulare, Erythema nodosum, Exfoliative rash, Genital rash, Lichen planus, Lichenoid keratosis, Palmar erythema, Palmar-plantar erythrodysesthesia syndrome, Perivascular dermatitis, Photosensitivity reaction, Pigmentation disorder, Pruritus allergic, Psoriasis, Punctate keratitis, Pyoderma gangrenosum, Pyogenic granuloma, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, 15 Reference ID: 5488743 c Rash pustular, Rash vesicular, Seborrheic dermatitis, Seborrhoeic keratosis, Skin depigmentation, Skin discoloration, Skin disorder, Skin exfoliation, Skin hyperpigmentation, Skin hypopigmentation, Skin irritation, Skin lesion, Skin plaque, Skin reaction, Skin toxicity, Stasis dermatitis. Hepatic dysfunction includes the following preferred terms: Alanine aminotransferase abnormal, Alanine aminotransferase increased, Aspartate aminotransferase, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatomegaly, Hepatosplenomegaly, Hyperbilirubinaemia, Jaundice, Liver function test abnormal, Liver function test increased, Ocular icterus, Transaminases increased, Hepatic function abnormal, Drug-induced liver injury, Hepatic steatosis, Hepatitis, Hepatitis toxic, Hepatobiliary disease, Hepatocellular injury, Hepatotoxicity, Liver disorder, Liver injury. d Fatigue includes the following preferred terms: Asthenia, Fatigue, Malaise. e Respiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract congestion, Upper respiratory tract infection, Upper respiratory tract inflammation, Viral upper respiratory tract infection. The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine increased, alanine aminotransferase increased, white blood cell count decreased, aspartate aminotransferase increased, platelet count decreased, glucose increased, calcium decreased, hemoglobin decreased, neutrophil count decreased, lymphocyte count decreased, serum amylase increased and CPK increased. Table 12 summarizes laboratory test abnormalities in BCHILD. Table 12: Laboratory Abnormalities (≥ 20%) That Worsened From Baseline in Pediatric Patients with Newly- Diagnosed CP Ph+ CML or CP Ph+ CML Resistant or Intolerant to Prior Therapy Who Received BOSULIF in BCHILD BOSULIF (N= 49) All Grade Grade 3/4 % % Creatinine increased 92 0 Alanine aminotransferase increased 59 14 White blood cell count decreased 53 4 Aspartate aminotransferase increased 51 6 Platelet count decreased 49 18 Glucose increased 41 0 Calcium decreased 31 0 Hemoglobin decreased 31 8 Neutrophil count decreased 31 12 Lymphocyte count decreased 29 2 Serum amylase increased 27 4 CPK increased 25 0 Grades are defined using CTCAE V4.03. Based on CTCAE grading without regard to fasting status for 'Hyperglycemia' lab parameter. Includes data up to 28 days after last dose of study treatment. Additional Adverse Reactions From Multiple Clinical Trials The following adverse reactions were reported in patients in clinical trials with BOSULIF (less than 10% of BOSULIF- treated patients). They represent an evaluation of the adverse reaction data from all 1372 patients with leukemia who received at least 1 dose of single-agent BOSULIF. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. Blood and Lymphatic System Disorders: 0.1% and less than 1% - Febrile neutropenia Cardiac Disorders: 1% and less than 10% - Cardiac ischemia (includes Acute coronary syndrome, Acute myocardial infarction, Angina pectoris, Angina unstable, Arteriosclerosis coronary artery, Coronary artery disease, Coronary artery 16 Reference ID: 5488743 occlusion, Coronary artery stenosis, Myocardial infarction, Myocardial ischemia, Troponin increased), Pericardial effusion, Cardiac failure (includes Cardiac failure, Cardiac failure acute, Cardiac failure chronic, Cardiac failure congestive, Cardiogenic shock, Cardiorenal syndrome, Ejection fraction decreased, Left ventricular failure); 0.1% and less than 1% - Pericarditis Ear and Labyrinth Disorders: 1% and less than 10% - Tinnitus Endocrine Disorders: 1% and less than 10% - Hypothyroidism; 0.1% and less than 1% - Hyperthyroidism Gastrointestinal Disorders: 1% and less than 10% - Gastritis, Pancreatitis (includes Edematous pancreatitis, Pancreatic enzymes increased, Pancreatitis, Pancreatitis acute, Pancreatitis chronic), Gastrointestinal hemorrhage (includes Anal hemorrhage, Gastric hemorrhage, Gastrointestinal hemorrhage, Intestinal hemorrhage, Lower gastrointestinal hemorrhage, Rectal hemorrhage, Upper gastrointestinal hemorrhage) General Disorders and Administrative Site Conditions: 1% and less than 10% - Pain Immune System Disorders: 1% and less than 10% - Drug hypersensitivity; 0.1% and less than 1% - Anaphylactic shock Infections and Infestations: 1% and less than 10% - Bronchitis Investigations: 1% and less than 10% - Electrocardiogram QT prolonged (includes Electrocardiogram QT prolonged, Long QT syndrome) Metabolism and Nutrition Disorders: 1% and less than 10% - Dehydration Musculoskeletal and Connective Tissue Disorders: 1% and less than 10% - Myalgia Nervous System Disorders: 1% and less than 10% - Dysgeusia Renal and Urinary Disorders: 1% and less than 10% - Acute kidney injury, Renal impairment, Renal failure Respiratory, Thoracic and Mediastinal Disorders: 1% and less than 10% - Pulmonary hypertension (includes Pulmonary hypertension, Pulmonary arterial hypertension, Pulmonary arterial pressure increased); 0.1% and less than 1% - Acute pulmonary edema (includes Acute pulmonary edema, Pulmonary edema), Interstitial lung disease, Respiratory failure Skin and Subcutaneous Disorders: 0.1% and less than 1% - Erythema multiforme 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of BOSULIF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Thrombotic microangiopathy Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome 17 Reference ID: 5488743 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on BOSULIF Strong or Moderate CYP3A Inhibitors Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF. Bosutinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inhibitor increases bosutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may increase the risk of toxicities. Strong CYP3A Inducers Avoid the concomitant use of strong CYP3A inducers with BOSULIF. Bosutinib is a CYP3A substrate. Concomitant use with a strong CYP3A inducer decreases bosutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce BOSULIF efficacy. Proton Pump Inhibitors (PPI) As an alternative to PPIs, use short-acting antacids or H2 blockers and separate dosing by more than 2 hours from BOSULIF dosing. Bosutinib displays pH dependent aqueous solubility, Concomitant use with a PPI decreases bosutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce BOSULIF efficacy. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, BOSULIF can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day (see Data). Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Animal Data In a rat fertility and early embryonic development study, bosutinib was administered orally to female rats for approximately 3 to 6 weeks, depending on day of mating (2 weeks prior to cohabitation with untreated breeder males until gestation day [GD] 7). Increased embryonic resorptions occurred at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). In an embryo-fetal development study conducted in rabbits, bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of 3, 10, and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and 2 fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 5.1 and 3.8 times the human exposures at the recommended doses of 400 and 500 mg/day, respectively. 18 Reference ID: 5488743 Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. In a rat pre- and postnatal development study, bosutinib was administered orally to pregnant animals during the period of organogenesis through lactation day 20 at doses of 10, 30, and 70 mg/kg/day. Reduced number of pups born occurred at greater than or equal to 30 mg/kg/day bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day bosutinib (6.9 and 5.1 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). 8.2 Lactation Risk Summary No data are available regarding the presence of bosutinib or its metabolites in human milk or its effects on a breastfed child or on milk production. However, bosutinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in a nursing child, breastfeeding is not recommended during treatment with BOSULIF and for 2 weeks after the last dose. Animal Data After a single radiolabeled bosutinib dose to lactating rats, radioactivity was present in the plasma of suckling offspring for 24 to 48 hours. 8.3 Females and Males of Reproductive Potential Based on findings from animal studies, BOSULIF can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Females of reproductive potential should have a pregnancy test prior to starting treatment with BOSULIF. Contraception Females Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with BOSULIF and for 2 weeks after the last dose. Infertility The risk of infertility in females or males of reproductive potential has not been studied in humans. Based on findings from animal studies, BOSULIF may cause reduced fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of BOSULIF have been established in pediatric patients 1 year of age and older with newly-diagnosed CP Ph+ CML and CP Ph+ CML that is resistant or intolerant to prior therapy. Use of BOSULIF for these indications is based on data from BCHILD [NCT04258943]. The study included pediatric patients with newly diagnosed CP Ph+ CML in the following age groups: 2 patients 1 year of age to less than 6 years of age, 3 patients 6 years of age to less than 12 years of age, and 10 patients 12 years of age to less than 17 years of age. The study also included pediatric patients with CP Ph+ CML that was resistant or intolerant to prior therapy in the following age groups: 4 patients 1 year of age to less than 6 years of age, 10 patients 6 years of age to less than 12 years of age, and 10 patients 12 years of age to less than 17 years of age. [see Adverse Reactions (6.1) and Clinical Studies (14.3)]. BSA-normalized apparent clearance in 27 pediatric patients aged 4 to <17 years (141.3 L/h/m2) was 29% higher than BSA-normalized apparent clearance in adult patients with CP Ph+ CML (109.2 L/h/m2) [see Clinical Pharmacology (12.3)]. The recommended dosage of BOSULIF in pediatric patients is based on body surface area (BSA) [see Dosage and Administration (2.1)]. 19 Reference ID: 5488743 xx The safety and effectiveness of BOSULIF in pediatric patients younger than 1 year of age with newly diagnosed CP Ph+ CML, pediatric patients younger than 1 year of age with CP Ph+ CML that is resistant or intolerant to prior therapy, and pediatric patients with AP Ph+ CML or BP Ph+ CML have not been established. 8.5 Geriatric Use In the single-arm study in patients with CML who were resistant or intolerant to prior therapy of BOSULIF in patients with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. Of the 268 patients who received bosutinib in the study for newly diagnosed CML, 20% were age 65 and over, 5% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment Reduce the BOSULIF starting dose in patients with moderate (creatinine clearance [CLcr] 30 to 50 mL/min, estimated by Cockcroft-Gault (C-G)) and severe (CLcr less than 30 mL/min, C-G) renal impairment at baseline. For patients who have declining renal function while on BOSULIF who cannot tolerate the starting dose, follow dose adjustment recommendations for toxicity [see Dosage and Administration (2.3, 2.5) and Clinical Pharmacology (12.3)]. BOSULIF has not been studied in patients undergoing hemodialysis. 8.7 Hepatic Impairment Reduce the BOSULIF dosage in patients with hepatic impairment (Child-Pugh A, B, or C) [see Dosage and Administration (2.3, 2.5) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Experience with BOSULIF overdose in clinical studies was limited to isolated cases. There were no reports of any serious adverse events associated with the overdoses. Patients who take an overdose of BOSULIF should be observed and given appropriate supportive treatment. 11 DESCRIPTION BOSULIF contains bosutinib, a kinase inhibitor. Bosutinib is present as a monohydrate with a chemical name of 3­ Quinolinecarbonitrile, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl) propoxy]-, hydrate (1:1). Its chemical formula is C26H29Cl2N5O3•H2O (monohydrate); its molecular weight is 548.46 (monohydrate), equivalent to 530.46 (anhydrous). Bosutinib monohydrate has the following chemical structure: Cl Cl HN OMe MeO N CN • H 2O N O N Me Bosutinib monohydrate is a white to yellowish-tan powder. Bosutinib monohydrate has a pH dependent solubility across the physiological pH range. At or below pH 5, bosutinib monohydrate behaves as a highly soluble compound. Above pH 5, the solubility of bosutinib monohydrate reduces rapidly. 20 Reference ID: 5488743 BOSULIF® (bosutinib) tablets are supplied for oral administration in 3 strengths: 100 mg, 400 mg and 500 mg. Each strength reflects the equivalent amount of bosutinib content (on anhydrous basis). The tablets contain the following inactive ingredients: croscarmellose sodium, iron oxide red (for 400 mg, and 500 mg tablet) and iron oxide yellow (for 100 mg, and 400 mg tablet), magnesium stearate, microcrystalline cellulose, poloxamer, polyethylene glycol, polyvinyl alcohol, povidone, talc and titanium dioxide. BOSULIF® (bosutinib) capsules are supplied for oral administration in 2 strengths: 50 mg and 100 mg. Each strength reflects the equivalent amount of bosutinib (on anhydrous basis). The capsules contain the following inactive ingredients: croscarmellose sodium, gelatin, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer, povidone, red iron oxide, titanium dioxide, yellow iron oxide. The printing ink contains black iron oxide, potassium hydroxide, propylene glycol, shellac, strong ammonia solution. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Bosutinib is a TKI. Bosutinib inhibits the BCR-ABL kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of BCR-ABL kinase expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells. 12.2 Pharmacodynamics A greater likelihood of response and a greater likelihood of safety events were observed with higher bosutinib exposure in clinical studies. The time course of bosutinib pharmacodynamic response has not been fully characterized. Cardiac Electrophysiology At a single oral dose of 500 mg BOSULIF with ketoconazole (a strong CYP3A inhibitor), BOSULIF does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Bosutinib pharmacokinetics were assessed following oral dosing with food in adult patients with CML and were presented as geometric mean (CV%), unless otherwise specified. Bosutinib exhibits dose proportional increases in Cmax and AUC over the oral dose range of 200 to 800 mg (0.33 to 1.3 times the maximum approved recommended dosage of 600 mg). Bosutinib steady state Cmax was 127 ng/mL (31%), Ctrough was 68 ng/mL (39%) and AUC was 2370 ng•h/mL (34%) following multiple oral doses of BOSULIF 400 mg; Bosutinib steady state Cmax was 171 ng/mL (38%), Ctrough was 91 ng/mL (42%) and AUC was 3150 ng•h/mL (38%) following multiple oral doses of BOSULIF 500 mg. No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of either the tablet or capsule dosage forms of BOSULIF at the same dose, under fed conditions. Absorption The median bosutinib (minimum, maximum) time--to-Cmax (tmax) was 6.0 (6.0, 6.0) hours following oral administration of a single oral dose of BOSULIF 500 mg with food. The absolute bioavailability was 34% in healthy subjects. Effect of Food Bosutinib Cmax increased 1.8-fold and AUC increased 1.7-fold when BOSULIF tablets were given with a high fat meal to healthy subjects compared to administration under fasted condition. Bosutinib Cmax increased 1.6-fold and AUC increased 1.5-fold when BOSULIF capsules were given with a high fat meal to healthy subjects compared to administration under fasted condition. The high-fat meal (800-1000 total calories) consisted of approximately 150 protein calories, 250 carbohydrate calories, and 500-600 fat calories. No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of a BOSULIF capsule that was opened and the contents mixed with applesauce or yogurt immediately before use. 21 Reference ID: 5488743 Distribution The mean (SD) apparent bosutinib volume of distribution is 6080 (1230) L after an oral dose of 500 mg of BOSULIF. Bosutinib protein binding is 94% in vitro and 96% ex vivo, and is independent of concentration. Elimination The mean (SD) bosutinib terminal phase elimination half life (t½) was 22.5 (1.7) hours, and the mean (SD) apparent clearance was 189 (48) L/h following a single oral dose of BOSULIF. Metabolism Bosutinib is primarily metabolized by CYP3A4. Excretion Following a single oral dose of [14C] radiolabeled bosutinib without food, 91.3% of the dose was recovered in feces and 3.3% of the dose recovered in urine. Specific Populations Patients with Renal Impairment Bosutinib AUC increased 1.4-fold in subjects with moderate renal impairment (CLcr: 30 to 50 mL/min, estimated by Cockcroft-Gault (C-G)) and increased 1.6-fold in subjects with severe renal impairment (CLcr less than 30 mL/min) following a single oral dose of BOSULIF 200 mg (0.33 times the maximum approved recommended dosage of 600 mg). No clinically significant difference in the pharmacokinetics of bosutinib was observed in subjects with mild renal impairment (CLcr: 51 to 80 mL/min, C-G). BOSULIF has not been studied in patients undergoing hemodialysis. Patients with Hepatic Impairment Bosutinib Cmax increased 2.4-fold, 2-fold, and 1.5-fold, and AUC increased 2.3-fold, 2-fold, and 1.9-fold in hepatic impairment Child-Pugh A, B, and C, respectively, following a single oral dose of BOSULIF 200 mg (0.33 times the maximum approved recommended dosage of 600 mg). Pediatric Patients The pharmacokinetics of bosutinib in 27 pediatric patients aged 4 to less than 17 years with newly diagnosed CP Ph+ CML or resistant/intolerant CP Ph+ CML were evaluated over the dose range of 300 mg/m2 to 400 mg/m2 administered orally once daily with food. Exposures increased in a dose proportional manner over the dose range of 300 mg/m2 to 400 mg/m2. The bosutinib median (min, max) tmax is approximately 3 hours post-dose (1, 8 hours). In 15 pediatric patients aged 4 to less than 17 years who received 300 mg/m2 daily, steady state Cmax was 159 ng/mL (42%), Ctrough was 49 ng/mL (53%) and AUC was 2027 ng•h/mL (47%). In 6 pediatric patients aged 6 to less than 17 years who received 400 mg/m2 daily, steady state Cmax was 198 ng/mL (37%), Ctrough was 42 ng/mL (105%), and AUC was 2514 ng•h/mL (35%). An increase in BSA correlated with an increase in apparent clearance and exposure metrics did not significantly differ across BSA or age in pediatric patients following the approved recommended BSA-based dosage. Drug Interaction Studies Clinical Studies Strong CYP3A Inhibitors: Bosutinib Cmax increased 5.2-fold and AUC increased 8.6-foldfollowing a single dose of BOSULIF 100 mg (0.17 times the maximum approved recommended dosage) without food when used concomitantly with 400 mg ketoconazole (a strong CYP3A inhibitor) administered over multiple daily doses. Moderate CYP3A Inhibitors: Bosutinib Cmax increased 1.5-fold and AUC increased 2.0-fold following a single dose of BOSULIF 500 mg with food when administered concomitantly with 125 mg aprepitant (a moderate CYP3A inhibitor). 22 Reference ID: 5488743 Strong CYP3A Inducers: Bosutinib Cmax decreased by 86% and AUC decreased by 94% following a single dose of BOSULIF 500 mg with food administered concomitantly with multiple daily doses of 600 mg of rifampin (a strong CYP3A inducer). Proton Pump Inhibitors: Lansoprazole decreased bosutinib Cmax by 46% and AUC by 26% following a single oral dose of BOSULIF 400 mg without food when used concomitantly with lansoprazole 60 mg (proton pump inhibitor) administered over multiple daily doses. Bosutinib displays pH-dependent aqueous solubility, in vitro [see Description (11)]. P-gp Substrates: No clinically significant differences in bosutinib pharmacokinetics were observed when used concomitantly with dabigatran etexilate mesylate (a P-glycoprotein (P-gp) substrate). In Vitro Studies Transporters Systems: Bosutinib inhibits breast cancer resistance protein (BCRP)but, does not inhibit organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, and OCT2. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Bosutinib was not carcinogenic in rats or transgenic mice. The rat 2-year carcinogenicity study was conducted at bosutinib oral doses up to 25 mg/kg in males and 15 mg/kg in females. Exposures at these doses were approximately 1.5 times (males) and 3.1 times (females) the human exposure at the 400 mg dose and 1.2 times (males) and 2.4 times (females) exposure in humans at the 500 mg dose. The 6-month RasH2 transgenic mouse carcinogenicity study was conducted at bosutinib oral doses up to 60 mg/kg. Bosutinib was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames Test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated male mice. In a rat fertility study, drug-treated males were mated with untreated females, or untreated males were mated with drug- treated females. Females were administered the drug from pre-mating through early embryonic development. The dose of 70 mg/kg/day of bosutinib resulted in reduced fertility in males as demonstrated by 16% reduction in the number of pregnancies. There were no lesions in the male reproductive organs at this dose. This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats approximately 1.5 times and equal to the human exposure at the recommended doses of 400 and 500 mg/day, respectively. Fertility (number of pregnancies) was not affected when female rats were treated with bosutinib. However, there were increased embryonic resorptions at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 and 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). 14 CLINICAL STUDIES 14.1 Adult Patients with Newly-Diagnosed CP Ph+ CML The efficacy of BOSULIF in patients with newly-diagnosed chronic phase Ph+ CML was evaluated in the Bosutinib trial in First-line chrOnic myelogenous leukemia tREatment (BFORE) Trial: “A Multicenter Phase 3, Open-Label Study of Bosutinib Versus Imatinib in Adult Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia” [NCT02130557]. The BFORE Trial is a 2-arm, open-label, randomized, multicenter trial conducted to investigate the efficacy and safety of BOSULIF 400 mg once daily alone compared with imatinib 400 mg once daily alone in adult patients with newly-diagnosed CP Ph+ CML. The trial randomized 536 patients (268 in each arm) with Ph+ or Ph- newly-diagnosed CP CML (intent-to-treat [ITT] population) including 487 patients with Ph+ CML harboring b2a2 and/or b3a2 transcripts at baseline and baseline BCR-ABL copies >0 (modified intent-to-treat [mITT] population). Randomization was stratified 23 Reference ID: 5488743 by Sokal score and geographical region. All patients are being treated and/or followed for up to 5 years (240 weeks). Efficacy was evaluated in the mITT population. The major efficacy outcome measure was major molecular response (MMR) at 12 months (48 weeks) defined as ≤0.1% BCR-ABL ratio on international scale (corresponding to ≥3 log reduction from standardized baseline) with a minimum of 3000 ABL transcripts as assessed by the central laboratory. Additional efficacy outcomes included CCyR by 12 months, defined as the absence of Ph+ metaphases in chromosome banding analysis of ≥20 metaphases derived from bone marrow aspirate or MMR if an adequate cytogenetic assessment was unavailable and MMR by 18 months (72 weeks). In the mITT population in this study, 57% of patients were males, 78% were Caucasian, and 19% were 65 years or older. The median age was 53 years. At baseline, the distribution of Sokal risk scores was similar in bosutinib and imatinib­ treated patients (low risk: 35% and 39%; intermediate risk: 44% and 38%; high risk: 22% and 22%, respectively). After a minimum of 12 months follow-up, 78% of the 246 bosutinib -treated patients and 72% of the 239 imatinib-treated patients were still receiving treatment and with a minimum of 60 months of follow-up, 60% and 60% of patients, respectively, were still receiving treatment. The median treatment duration was 55.1 months for BOSULIF and 55.0 months for imatinib. The efficacy results from the BFORE trial are summarized in Table 13. Table 13: Summary of Major Molecular Response (MMR) and Complete Cytogenetic Response (CCyR), by Treatment Group in the Modified Intent-to-Treat (mITT) Population Response Bosutinib N=246 n (%) Imatinib N=241 n (%) 2-sided p-value MMR at Month 12 (Week 48) MMR (%) (95% CI) 116 (47) (41, 53) 89 (37) (31, 43) 0.0200* CCyR by Month 12 (Week 48) CCyR (%) (95% CI) 190 (77) (72, 83) 160 (66) (60, 72) 0.0075* MMR by Month 18 (Week 72) MMR (%) (95% CI) 150 (61) (55, 67) 127 (53) (46, 59) 0.0606* Abbreviations: CCyR=complete cytogenetic response; CI=confidence interval; CMH=Cochran-Mantel-Haenszel; MMR=major molecular response; N/n=number of patients. *Derived from CMH test stratified by Geographical region and Sokal score at randomization. The MMR rate at Month 12 for all randomized patients (ITT population) was consistent with the mITT population (47% [95% CI: 41, 53] in the bosutinib treatment group and 36% [95% CI: 30, 42] in the imatinib treatment group; odds ratio of 1.57 [95% CI: 1.10, 2.22]). MMR by Month 60 (Week 240) in the mITT population was 74% (95% CI: 69, 80) in the bosutinib treatment group and 66% (95% CI: 60, 72) in the imatinib treatment group; odds ratio of 1.52 (95% CI: 1.02, 2.25). MMR by Month 60 in the ITT population was also consistent with the mITT population (1.57 [95% CI: 1.08, 2.28]). After 60 months of follow-up, the median time to MMR in responders was 9.0 months for bosutinib and 11.9 months for imatinib. By 60 months, the MMR rates in each Sokal risk group for the bosutinib and imatinib-treated patients, respectively, were 78% and 72% for low risk, 74% and 67% for intermediate risk and 68% and 52% for high risk. After 60 months of follow-up, 6 (2%) bosutinib patients and 7 (3%) imatinib patients transformed to AP CML or BP CML while on treatment. At 60 months, the estimated overall survival rate was 95% (95% CI: 91, 97) in the bosutinib group and 94% (95% CI: 90, 96) in the imatinib group. 24 Reference ID: 5488743 14.2 Adult Patients with Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CML Study 200 (NCT00261846), a single-arm, open-label, multicenter study in patients with CML who were resistant or intolerant to prior therapy was conducted to evaluate the efficacy and safety of BOSULIF 500 mg once daily in patients with imatinib-resistant or -intolerant CML with separate cohorts for CP, AP, and BP disease previously treated with 1 prior TKI (imatinib) or more than 1 TKI (imatinib followed by dasatinib and/or nilotinib). The definition of imatinib resistance included (1) failure to achieve or maintain any hematologic improvement within 4 weeks; (2) failure to achieve a CHR by 3 months, cytogenetic response by 6 months or major cytogenetic response (MCyR) by 12 months; (3) progression of disease after a previous cytogenetic or hematologic response; or (4) presence of a genetic mutation in the BCR-ABL gene associated with imatinib resistance. Imatinib intolerance was defined as inability to tolerate imatinib due to toxicity, or progression on imatinib and inability to receive a higher dose due to toxicity. The definitions of resistance and intolerance to both dasatinib and nilotinib were similar to those for imatinib. The protocol was amended to exclude patients with a known history of the T315I mutation after 396 patients were enrolled in the trial. The efficacy endpoints for patients with CP CML previously treated with 1 prior TKI (imatinib) were the rate of attaining MCyR by Week 24 and the duration of MCyR. The efficacy endpoints for patients with CP CML previously treated with both imatinib and at least 1 additional TKI were the cumulative rate of attaining MCyR by Week 24 and the duration of MCyR. The efficacy endpoints for patients with previously treated AP and BP CML were confirmed CHR and overall hematologic response (OHR). The study enrolled 546 patients with CP, AP or BP CML. Of the total patient population 73% were imatinib resistant and 27% were imatinib intolerant. In this trial, 53% of patients were males, 65% were Caucasian, and 20% were 65 years old or older. Of the 546 treated patients, 506 were considered evaluable for cytogenetic or hematologic efficacy assessment. Patients were evaluable for efficacy if they had received at least 1 dose of BOSULIF and had a valid baseline efficacy assessment. Among evaluable patients, there were 262 patients with CP CML previously treated with 1 prior TKI (imatinib), 112 patients with CP CML previously treated with both imatinib and at least 1 additional TKI, and 132 patients with advanced phase CML previously treated with at least 1 TKI. Median duration of BOSULIF treatment was 26 months in patients with CP CML previously treated with 1 TKI (imatinib), 9 months in patients with CP CML previously treated with imatinib and at least 1 additional TKI, 10 months in patients with AP CML previously treated with at least imatinib, and 3 months in patients with BP CML previously treated with at least imatinib. The 24 week efficacy and MCyR at any time results are summarized in Table 14. Table 14: Efficacy Results in Patients with Ph+ CP CML With Resistance to or Intolerance to Imatinib Prior Treatment With Imatinib Only (N=262 evaluable) n (%) Prior Treatment With Imatinib and Dasatinib or Nilotinib (N=112 evaluable) n (%) By Week 24 MCyR (95% CI) 105 (40.1) (34.1, 46.3) 29 (25.9) (18.1, 35.0) MCyR any time 156 (59.5) (53.3, 65.5) 45 (40.2) (31.0, 49.9) Abbreviations: CI=confidence interval; CML=chronic myelogenous leukemia; CP=chronic phase; MCyR=major cytogenetic response; N/n=number of patients; Ph+=Philadelphia chromosome positive. The long-term follow-up data analysis was based on a minimum of 60 months for patients with CP CML treated with 1 prior TKI (imatinib) and a minimum of 48 months for patients with CP CML treated with imatinib and at least 1 additional TKI. For the 59.5% of patients with CP CML treated with 1 prior TKI (imatinib) who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these patients, 65.4% and 42.9% had a MCyR lasting at least 18 and 54 months, respectively. For the 40.2% of patients with CP CML treated with imatinib and at least 1 additional TKI who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these 25 Reference ID: 5488743 patients, 64.4% and 35.6% had a MCyR lasting at least 9 and 42 months, respectively. Of the 403 treated patients with CP CML, 20 patients had confirmed disease transformation to AP or BP while on treatment with BOSULIF. The 48-week efficacy results in patients with accelerated and blast phases CML previously treated with at least imatinib are summarized in Table 15. Table 15: Efficacy Results in Patients With Accelerated Phase and Blast Phase CML Previously Treated With at Least Imatinib AP CML (N=72 evaluable) n (%) BP CML (N=60 evaluable) n (%) CHRa by Week 48 22 (30.6) 10 (16.7) (95% CI) (20.2, 42.5) (8.3, 28.5) OHRa by Week 48 (95% CI) 41 (56.9) (44.7, 68.6) 17 (28.3) (17.5, 41.4) Abbreviations: AP=accelerated phase; BP=blast phase; CHR=complete hematologic response; CI=confidence interval; CML=chronic myelogenous leukemia; CI=confidence interval, OHR=overall hematologic response, CHR=complete hematologic response, N/n=number of patients a Overall hematologic response (OHR) = major hematologic response (complete hematologic response + no evidence of leukemia) or return to chronic phase (RCP). All responses were confirmed after 4 weeks. Complete hematologic response (CHR) for AP and BP CML: WBC less than or equal to institutional ULN, platelets greater than or equal to 100,000/mm3 and less than 450,000/mm3, absolute neutrophil count (ANC) greater than or equal to 1.0×109 /L, no blasts or promyelocytes in peripheral blood, less than 5% myelocytes + metamyelocytes in bone marrow, less than 20% basophils in peripheral blood, and no extramedullary involvement. No evidence of leukemia (NEL): Meets all other criteria for CHR except may have thrombocytopenia (platelets greater than or equal to 20,000/mm3 and less than 100,000/mm3) and/or neutropenia (ANC greater than or equal to 0.5×109 /L and less than 1.0×109 /L). Return to chronic phase (RCP) = disappearance of features defining accelerated or blast phases but still in chronic phase. The long-term follow-up data analysis was based on a minimum of 48 months for patients with AP CML and BP CML. Of the 79 treated patients with AP CML, 3 patients had confirmed disease transformation to BP while on BOSULIF treatment. 14.3 Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy The efficacy of BOSULIF in pediatric patients with newly-diagnosed (ND) chronic phase (CP) Ph+ CML and patients with resistant/intolerant (R/I) CP Ph+ CML was evaluated in the BCHILD trial [NCT04258943]. The BCHILD trial is a multicenter, non-randomized, open-label study conducted to identify a recommended dose of bosutinib administered orally once daily in pediatric patients with ND CP Ph+ CML and pediatric patients with R/I CP Ph+ CML who have received at least one prior TKI therapy, to estimate the safety and tolerability and efficacy, and to evaluate the PK of bosutinib in this patient population. The study enrolled 28 patients with R/I CP Ph+ CML treated with BOSULIF at 300 mg/m2 to 400 mg/m2 orally once daily, and 21 patients with ND CP Ph+ CML treated at 300 mg/m2 orally once daily. Efficacy outcomes included CCyR (defined as the absence of Ph+ metaphases in chromosome banding analysis of ≥20 metaphases, or <1% BCR-ABL1–positive nuclei of at least 200 peripheral blood interphase nuclei analyzed by Fluorescence In Situ Hybridization (FISH), or MMR if an adequate cytogenetic assessment was unavailable), MCyR (defined as CCyR or partial cytogenetic response of 1% to 35% Ph+ metaphases), and MMR (defined as ≤0.1% BCR-ABL ratio on international scale [IS]) at any time on study. Patients with ND CP Ph+ CML had a median age of 14 years (range 5 to 17 years); 68% were male; 81% were White, 14% were Black/African American, and 5% were race not reported. The major (MCyR) and complete (CCyR) cytogenetic responses among patients with ND CP Ph+ CML were 76.2% (95% CI: 52.8, 91.8) and 71.4% (95% CI: 47.8, 88.7), respectively. The MMR among patients with ND CP Ph+ CML was 26 Reference ID: 5488743 28.6% (95% CI: 11.3, 52.3). The median duration of follow-up was 14.2 months (range: 1.1, 26.3 months) in patients with ND CP CML. Patients with R/I CP Ph+ CML included n=6 treated at 300 mg/m2 (0.75 times the recommended dose), n=11 treated at 350 mg/m2 (0.875 times the recommended dose), and n=11 at 400 mg/m2. Overall (n=28), patients had a median age of 11.5 years (range: 1 to 17 years); 57% were male; 43% were White, 7% were Black/African American, 14% were Asian, and 36% were race not reported. The major (MCyR) and complete (CCyR) cytogenetic responses among patients with R/I CP Ph+ CML were 82.1% (95% CI: 63.1, 93.9) and 78.6% (95% CI: 59.0, 91.7), respectively. The MMR among patients with R/I CP Ph+ CML was 50.0% (95% CI: 30.6, 69.4). The MR4.5 (defined as BCR-ABL/ABL IS ≤ 0.0032%) was 17.9% (95% CI: 6.1, 36.9). Among 14 patients who achieved MMR, two patients lost MMR after 13.6 months and 24.7 months on treatment. The median duration of follow-up for overall survival was 23.2 months (range: 1.0, 61.5 months) in patients with R/I CP Ph+ CML. 16 HOW SUPPLIED/STORAGE AND HANDLING Tablets – How Supplied BOSULIF (bosutinib) tablets are supplied for oral administration in 3 strengths: a 100 mg yellow, oval, biconvex, film- coated tablet debossed with “Pfizer” on one side and “100” on the other; a 400 mg orange, oval, biconvex, film coated tablet debossed with “Pfizer” on one side and “400” on the other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with “Pfizer” on one side and “500” on the other. BOSULIF (bosutinib) tablets are available in the following packaging configurations with a child-resistant (CR) closure (Table 17). Bottles contain a desiccant. Table 17: Tablet Presentations BOSULIF Tablets Package Configuration Tablet Strength (mg) NDC Tablet Description 120 tablets per bottle 100 mg 0069-0135-01 Yellow, oval, biconvex, film-coated tablets, debossed “Pfizer” on one side and “100” on the other. 30 tablets per bottle 400 mg 0069-0193-01 Orange, oval, biconvex, film-coated tablet debossed with “Pfizer” on one side and “400” on the other. 30 tablets per bottle 500 mg 0069-0136-01 Red, oval, biconvex, film-coated tablets, debossed “Pfizer” on one side and “500” on the other. Abbreviation: NDC=National drug code. Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Handling and Disposal Procedures for proper disposal of anticancer drugs should be considered. Touching or handling crushed or broken tablets is to be avoided. Any unused product or waste material should be disposed of in accordance with local requirements, or drug take back programs. Capsules - How Supplied BOSULIF (bosutinib) capsules are supplied for oral administration in 2 strengths: 50 mg capsule: size 2 capsule, white body/orange cap with “BOS 50” printed on the body and “Pfizer” printed on the cap in black ink. 100 mg capsule: size 0 capsule, white body/brownish-red cap with “BOS 100” printed on the body and 27 Reference ID: 5488743 “Pfizer” printed on the cap in black ink. BOSULIF (bosutinib) capsules are available in the following packaging configurations with a CR closure (Table 18). Table 18: Capsule Presentations BOSULIF Capsules Package Configuration Count Capsule Strength (mg) NDC Capsule Description 30 capsules per bottle 50  0069-0504-30 Size 2 capsule, white body/orange cap with “BOS 50” printed on the body and “Pfizer” printed on the cap in black ink. 150 capsules per bottle 100  0069-1014-15 Size 0 capsule, white body/brownish­ red cap with “BOS 100” printed on the body and “Pfizer” printed on the cap in black ink. Abbreviation: NDC=National drug code. Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] and Store and Dispense in Original Container. Handling and Disposal Procedures for proper disposal of anticancer drugs should be considered. Patients and/or caregivers must wear gloves while handling the drug product, and wash their hands once finished. Any unused product or waste material should be disposed of in accordance with local requirements. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). • Dosage and Administration Instruct patients to take BOSULIF exactly as prescribed, not to change their dose or to stop taking BOSULIF unless they are told to do so by their doctor. If patients miss a dose beyond 12 hours, they should be advised to take the next scheduled dose at its regular time. A double dose should not be taken to make up for any missed dose. Advise patients to take BOSULIF with food. Patients should be advised: “Swallow tablets whole. Do not crush, break, or cut tablet. Do not touch or handle crushed or broken tablets.” Patients should be advised: “Capsules may be swallowed whole. For those that cannot swallow the capsule whole, the capsule can be opened and the contents mixed with applesauce or yogurt.” • Gastrointestinal Toxicity Advise patients that they may experience diarrhea, nausea, vomiting, abdominal pain, or blood in their stools with BOSULIF and to seek medical attention promptly for these symptoms [see Warnings and Precautions (5.1)]. • Myelosuppression Advise patients of the possibility of developing low blood cell counts and to immediately report fever, any suggestion of infection, or signs or symptoms suggestive of bleeding or easy bruising [see Warnings and Precautions (5.2)]. • Hepatic Toxicity Advise patients of the possibility of developing liver function abnormalities and to immediately report jaundice [see Warnings and Precautions (5.3)]. • Cardiovascular Toxicity Advise patients that cardiac failure, left ventricular dysfunction, and cardiac ischemic events have been reported. Advise patients to seek immediate medical attention if any symptoms suggestive of cardiac failure and cardiac ischemia occur, such as shortness of breath, weight gain, or fluid retention [see Warnings and Precautions (5.4)]. 28 Reference ID: 5488743 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 • Fluid Retention Advise patients of the possibility of developing fluid retention (swelling, weight gain, or shortness of breath) and to seek medical attention promptly if these symptoms arise [see Warnings and Precautions (5.5)]. • Renal Toxicity Advise patients of the possibility of developing renal problems and to immediately report frequent urination, polyuria or oliguria [see Warnings and Precautions (5.6)]. • Adverse Reactions Advise patients that they may experience other adverse reactions such as respiratory tract infections, rash, fatigue, loss of appetite, headache, dizziness, back pain, arthralgia, pruritus or constipation with BOSULIF and to seek medical attention if symptoms are significant. There is a possibility of anaphylactic shock [see Contraindications (4) and Adverse Reactions (6)]. • Embryo-Fetal Toxicity Advise females to inform their healthcare provider if they are pregnant or become pregnant. Advise female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive potential, to use effective contraception during treatment and for 2 weeks after receiving the last dose of BOSULIF [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1, 8.3)]. Advise lactating women not to breastfeed during treatment with BOSULIF and for 2 weeks after the last dose [see Use in Specific Populations (8.2)]. • Drug Interactions Advise patients that BOSULIF and certain other medicines, including over the counter medications or herbal supplements (such as St. John’s wort) can interact with each other and may alter the effects of BOSULIF [see Drug Interactions (7)]. LAB-0443-18.2 29 Reference ID: 5488743 PATIENT INFORMATION BOSULIF® (BAH-su-lif) BOSULIF® (BAH-su-lif) (bosutinib) (bosutinib) tablets capsules What is BOSULIF? BOSULIF is a prescription medicine used to treat: • adults and children 1 year of age and older who have a certain type of leukemia called chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) who are newly-diagnosed or who no longer benefit from or did not tolerate other treatment. • adults with accelerated phase (AP), or blast phase (BP) Ph+ CML who can no longer benefit from or did not tolerate other treatment. It is not known if BOSULIF is safe and effective in children less than 1 year of age with CP Ph+ CML who are newly-diagnosed or who no longer benefit from or did not tolerate other treatment or in children with AP Ph+ CML or BP Ph+ CML. Do not take BOSULIF if you are allergic to bosutinib or any of the ingredients in BOSULIF. See the end of this leaflet for a complete list of ingredients of BOSULIF. Before taking BOSULIF, tell your doctor about all of your medical conditions, including if you: • have liver problems • have heart problems • have kidney problems • have high blood pressure • have diabetes • are pregnant or plan to become pregnant. BOSULIF can harm your unborn baby. Females who are able to become pregnant should have a pregnancy test before starting treatment with BOSULIF. Tell your doctor right away if you become pregnant during treatment with BOSULIF. o Females who are able to become pregnant should use effective birth control (contraception) during treatment with BOSULIF and for 2 weeks after the last dose. Talk to your doctor about birth control methods that may be right for you. • are breastfeeding or plan to breastfeed. It is not known if BOSULIF passes into your breast milk or if it can harm your baby. Do not breastfeed during treatment with BOSULIF and for 2 weeks after the last dose. Tell your doctor about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. When taken together, BOSULIF and certain other medicines can affect each other. Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. How should I take BOSULIF? • Take BOSULIF exactly as prescribed by your doctor. • Do not change your dose or stop taking BOSULIF without first talking with your doctor. • If your child takes BOSULIF, your healthcare provider will change the dose as your child grows. • Take BOSULIF with food. • Swallow BOSULIF tablets whole. Do not crush, break, chew or cut BOSULIF tablets. Do not touch or handle crushed or broken BOSULIF tablets. • Swallow BOSULIF capsules whole. If you cannot swallow BOSULIF capsules whole, tell your healthcare provider. • If you cannot swallow BOSULIF capsules whole, see the “Instructions for Use” for detailed instructions on how to prepare and give a dose of BOSULIF capsules by opening the capsules and mixing the capsule contents with applesauce or yogurt. • If you take an antacid or H2 blocker medicine, take it at least 2 hours before or 2 hours after BOSULIF. If you take a Proton Pump Inhibitor (PPI) medicine, talk to your doctor or pharmacist. • You should avoid grapefruit, grapefruit juice, and supplements that contain grapefruit extract during treatment with BOSULIF. Grapefruit products increase the amount of BOSULIF in your body. 1 Reference ID: 5488743 • If you miss a dose of BOSULIF, take it as soon as you remember. If you miss a dose by more than 12 hours, skip that dose and take your next dose at your regular time. Do not take 2 doses at the same time. • If you take too much BOSULIF, call your doctor or go to the nearest hospital emergency room right away. What are the possible side effects of BOSULIF? BOSULIF may cause serious side effects, including: • Stomach problems. BOSULIF may cause stomach (abdomen) pain, nausea, diarrhea, vomiting, or blood in your stools. Get medical help right away for any stomach problems. • Low blood cell counts. BOSULIF may cause low platelet counts (thrombocytopenia), low red blood cell counts (anemia) and low white blood cell counts (neutropenia). Your doctor should do blood tests to check your blood cell counts regularly during your treatment with BOSULIF. Call your doctor right away if you have unexpected bleeding or bruising, blood in your urine or stools, fever, or any signs of an infection. • Liver problems. Your doctor should do blood tests to check your liver function regularly during your treatment with BOSULIF. Call your doctor right away if your skin or the white part of your eyes turns yellow (jaundice) or you have dark “tea color” urine. • Heart problems. BOSULIF may cause heart problems, including heart failure and decreased blood flow to the heart which can lead to heart attack. Get medical help right away if you get shortness of breath, weight gain, chest pain, or swelling in your hands, ankles or feet. • Your body may hold too much fluid (fluid retention). Fluid may build up in the lining of your lungs, the sac around your heart, or your stomach cavity. Get medical help right away if you get any of the following symptoms during your treatment with BOSULIF: o shortness of breath and cough o swelling all over your body o chest pain o weight gain o swelling in your hands, ankles, or feet • Kidney problems. Your doctor should do tests to check your kidney function when you start treatment with BOSULIF and during your treatment. Call your doctor right away if you get any of the following symptoms during your treatment with BOSULIF: o you urinate more often than normal o you urinate less often than normal o you make a much larger amount of urine than normal o you make a much smaller amount of urine than normal The most common side effects of BOSULIF in adults and children with CML include: • diarrhea • headache • stomach (abdominal) pain • fever • vomiting • decreased appetite • nausea • respiratory tract infections (infections in nose, throat or lungs) • rash • constipation • tiredness • changes in certain blood tests. Your doctor may do • liver problems blood tests during treatment with BOSULIF to check for changes Tell your doctor or get medical help right away if you get respiratory tract infections, loss of appetite, headache, dizziness, back pain, joint pain, rash or itching while taking BOSULIF. These may be symptoms of a severe allergic reaction. Your doctor may change your dose, temporarily stop, or permanently stop treatment with BOSULIF if you have certain side effects. BOSULIF may cause fertility problems in females and males. This may affect your ability to have a child. Talk to your doctor if this is a concern for you. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of BOSULIF. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. 2 Reference ID: 5488743 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 10001 How should I store BOSULIF? • Store BOSULIF tablets and capsules at room temperature between 68°F to 77°F (20°C to 25°C). • The BOSULIF tablets and capsules bottle has a child-resistant closure. • The BOSULIF tablets bottle contains a desiccant to help keep your medicine dry (protect it from moisture). Keep the desiccant in the bottle. Do not eat the desiccant. • Store the BOSULIF capsules in the original bottle. • Ask your doctor or pharmacist about the right way to throw away outdated or unused BOSULIF. Keep BOSULIF and all medicines out of the reach of children. General information about the safe and effective use of BOSULIF. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use BOSULIF for a condition for which it is not prescribed. Do not give BOSULIF to other people even if they have the same symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about BOSULIF that is written for health professionals. What are the ingredients in BOSULIF? Active ingredient: bosutinib. Inactive ingredients: Tablets: croscarmellose sodium, iron oxide red (for 400 mg, and 500 mg tablet) and iron oxide yellow (for 100 mg, and 400 mg tablet), magnesium stearate, microcrystalline cellulose, poloxamer, polyethylene glycol, polyvinyl alcohol, povidone, talc and titanium dioxide. Capsules: croscarmellose sodium, gelatin, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer, povidone, red iron oxide, titanium dioxide, yellow iron oxide. The printing ink contains black iron oxide, potassium hydroxide, propylene glycol, shellac, strong ammonia solution. For more information, go to www.Bosulif.com or www.pfizermedicalinformation.com or call 1-800-438-1985. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised 12/2024 3 Reference ID: 5488743 INSTRUCTIONS FOR USE BOSULIF® (BAH-su-lif) (bosutinib) capsules This Instructions for Use contains information on how to prepare and give a dose of BOSULIF capsules by opening the capsules and mixing the contents with applesauce or yogurt for people who cannot swallow capsules whole. Read this Instructions for Use before you prepare or give the first dose of BOSULIF, and each time you get a refill. Ask your healthcare provider or pharmacist if you have any questions. Important information you need to know before preparing a dose of BOSULIF capsules: • BOSULIF capsules can be opened and the capsules contents mixed with room temperature applesauce or yogurt. • Only use applesauce or yogurt. Do not mix BOSULIF with other foods. • Swallow all of the mixture right away, without chewing. Do not store the mixture for later use. • If you do not swallow the entire BOSULIF mixture, do not mix another dose. Wait until the next day to take your regularly scheduled dose. • Take the BOSULIF mixture with a full meal. Preparing a dose of BOSULIF capsules: Gather the following supplies: • BOSULIF capsules • small, clean container • yogurt or applesauce • teaspoon for mixing • disposable gloves Giving a dose of BOSULIF capsules: Step 1: Choose a clean, flat work surface. Place all supplies on the work surface. Step 2: Wash and dry your hands well. Step 3: Put on disposable gloves Step 4: Get the prescribed number of BOSULIF capsule(s) needed to prepare the dose. Step 5: Add the amount of applesauce or yogurt needed for the prescribed dose to the container. Dose Amount of Applesauce or Yogurt 100 mg 10 mL (2 teaspoons) 150 mg 15 mL (3 teaspoons) 200 mg 20 mL (4 teaspoons) 250 mg 25 mL (5 teaspoons) 300 mg 30 mL (6 teaspoons) 350 mg 30 mL (6 teaspoons) 400 mg 35 mL (7 teaspoons) 450 mg 40 mL (8 teaspoons) 500 mg 45 mL (9 teaspoons) 550 mg 45 mL (9 teaspoons) 600 mg 50 mL (10 teaspoons) 1 Reference ID: 5488743 ~Pfizer Distributed by Pfizer Labs Division of Pfizer Inc. New York, NY 1 0001 Step 6: Carefully open each of the BOSULIF capsule(s) needed for the dose and empty the entire contents into the applesauce or yogurt. Mix the entire capsule contents with the applesauce or yogurt in the container. Step 7: Swallow all of the mixture right away, without chewing. Step 8: Dispose of (throw away) the empty BOSULIF capsule shell(s) in the household trash. Step 9: Wash teaspoon and the container with soap and warm water. Step 10: Remove disposable gloves and throw them away in the household trash. Step 11: Wash and dry your hands. How should I store BOSULIF capsules? • Store BOSULIF at room temperature between 68°F to 77°F (20°C to 25°C). • Store the BOSULIF capsules in the original bottle. • Ask your doctor or pharmacist about the right way to throw away outdated or unused BOSULIF. Keep BOSULIF and all medicines out of the reach of children. LAB-0639-12.1 For more information, go to www.Bosulif.com or www.pfizermedicalinformation.com or call 1 800 438 1985. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 9 2023 2 Reference ID: 5488743
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2025-02-12T15:47:31.269280
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PHYRAGO safely and effectively. See full prescribing information for PHYRAGO. PHYRAGO® (dasatinib) tablets, for oral use Initial U.S. Approval: 2006 --------------------------RECENT MAJOR CHANGES--------------------------­ Dosage and Administration, Dosage Modifications (2.2) 12/2024 -----------------------------INDICATIONS AND USAGE-------------------------­ PHYRAGO® is a kinase inhibitor indicated for the treatment of • newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. (1, 14) • adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. (1, 14) • adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. (1, 14) -------------------------DOSAGE AND ADMINISTRATION-------------------­ • Chronic phase CML in adults: 100 mg orally once daily. (2) • Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults: 140 mg orally once daily. (2) • Administer with or without a meal. Do not crush, cut, or chew tablets. (2) ------------------------DOSAGE FORMS AND STRENGTHS------------------­ Tablets: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg. (3) ---------------------------------CONTRAINDICATIONS--------------------------­ None. (4) -------------------------WARNINGS AND PRECAUTIONS---------------------­ • Myelosuppression and Bleeding Events: Severe thrombocytopenia, neutropenia, and anemia may occur. Use caution if used concomitantly with medications that inhibit platelet function or anticoagulants. Monitor complete blood counts regularly. Transfuse and interrupt PHYRAGO when indicated. (2.5, 5.1, 5.2) • Fluid Retention: Fluid retention, sometimes severe, including pleural effusions. Manage with supportive care measures and/or dose modification. (2.5, 5.3) • Cardiovascular Toxicity: Monitor patients for signs or symptoms and treat appropriately. (5.4) • Pulmonary Arterial Hypertension (PAH): PHYRAGO may increase the risk of developing PAH which may be reversible on discontinuation. Consider baseline risk and evaluate patients for signs and symptoms of PAH during treatment. Stop PHYRAGO if PAH is confirmed. (5.5) • QT Prolongation: Use PHYRAGO with caution in patients who have or may develop prolongation of the QT interval. (5.6) • Severe Dermatologic Reactions: Individual cases of severe mucocutaneous dermatologic reactions have been reported. (5.7) • Tumor Lysis Syndrome: Tumor lysis syndrome has been reported. Maintain adequate hydration and correct uric acid levels prior to initiating therapy with PHYRAGO. (5.8) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of potential risk to fetus and to use effective contraception. (5.9, 8.1, 8.3) • Effects on Growth and Development in Pediatric Patients: Epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia have been reported. Monitor bone growth and development in pediatric patients. (5.10) • Hepatotoxicity: Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. (5.11) ----------------------------ADVERSE REACTIONS-----------------------------­ Most common adverse reactions (≥15%) in patients receiving dasatinib as single-agent therapy included myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain. (6) To report SUSPECTED ADVERSE REACTIONS, contact Nanocopoeia LLC at 1-844-784-1807 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------------DRUG INTERACTIONS-----------------------------­ • Strong CYP3A4 Inhibitors: Dose reduction may be necessary. (2.2, 7.1) • Strong CYP3A4 Inducers: Dose increase may be necessary. (2.2, 7.1) • Antacids: Avoid concomitant use . (2.2, 7.1) -----------------------USE IN SPECIFIC POPULATIONS--------------------­ Lactation: Advise women not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling. Pediatric use information is approved for Bristol-Myers Squibb Company’s SPRYCEL (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Revised 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Adult Patients 2.2 Dosage Modifications 2.3 Dose Escalation in Adults with CML and Ph+ ALL 2.4 Dosage Adjustment for Adverse Reactions 2.5 Duration of Treatment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression 5.2 Bleeding-Related Events 5.3 Fluid Retention 5.4 Cardiovascular Toxicity 5.5 Pulmonary Arterial Hypertension 5.6 QT Prolongation 5.7 Severe Dermatologic Reactions 5.8 Tumor Lysis Syndrome 5.9 Embryo-Fetal Toxicity 5.10 Effects on Growth and Development in Pediatric Patients 5.11 Hepatotoxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Dasatinib 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Newly Diagnosed Chronic Phase CML in Adults 14.2 Imatinib-resistant or -Intolerant CML or Ph+ ALL in Adults 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5489006 FULL PRESCRIBING INFORMATION 1. INDICATIONS AND USAGE PHYRAGO is indicated for the treatment of adult patients with • newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. • chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. • Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. Pediatric use information is approved for Bristol-Myers Squibb Company’s SPRYCEL (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Adult Patients The recommended starting dosage of PHYRAGO for chronic phase CML in adults is 100 mg administered orally once daily. The recommended starting dosage of PHYRAGO for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL in adults is 140 mg administered orally once daily. Swallow PHYRAGO whole. Do not crush, cut, or chew the tablets. PHYRAGO can be taken with or without a meal, either in the morning or in the evening. 2.2 Dosage Modifications Strong CYP3A4 Inducers Avoid the use of concomitant strong CYP3A4 inducers. If patients must be coadministered a strong CYP3A4 inducer, consider a PHYRAGO dose increase. If the dose of PHYRAGO is increased, monitor the patient carefully for toxicity [see Drug Interactions (7.1)]. Strong CYP3A4 Inhibitors Avoid the use of concomitant strong CYP3A4 inhibitors and grapefruit juice. Recommend selecting an alternate concomitant medication with no or minimal enzyme inhibition potential, if possible. If PHYRAGO must be administered with a strong CYP3A4 inhibitor, consider a dose decrease to: • 40 mg daily for patients taking PHYRAGO 140 mg daily. • 20 mg daily for patients taking PHYRAGO 100 mg daily. • 20 mg daily for patients taking PHYRAGO 70 mg daily. For patients taking PHYRAGO 60 mg or 40 mg daily, consider interrupting PHYRAGO until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before reinitiating PHYRAGO. These reduced doses of PHYRAGO are predicted to adjust the area under the curve (AUC) to the range observed without CYP3A4 inhibitors; however, clinical data are not available with these dose adjustments in patients receiving strong CYP3A4 inhibitors. If PHYRAGO is not tolerated after dose reduction, either discontinue the strong CYP3A4 inhibitor or interrupt PHYRAGO Reference ID: 5489006 until the inhibitor is discontinued. Allow a washout period of approximately 1 week after the inhibitor is stopped before the PHYRAGO dose is increased [see Drug Interactions (7.1)]. Antacids Avoid concomitant use of PHYRAGO with antacids. If concomitant use of an antacid cannot be avoided, administer the antacid at least 2 hours prior to or 2 hours after the dose of PHYRAGO [see Drug Interactions (7.1)]. 2.3 Dose Escalation in Adults with CML and Ph+ ALL For adult patients with CML and Ph+ ALL, consider dose escalation to 140 mg once daily (chronic phase CML) or 180 mg once daily (advanced phase CML and Ph+ ALL) in patients who do not achieve a hematologic or cytogenetic response at the recommended starting dosage. 2.4 Dosage Adjustment for Adverse Reactions Myelosuppression In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy. Hematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dose modifications for adult patients are summarized in Table 1. Table 1: Dosage Adjustments for Neutropenia and Thrombocytopenia in Adults Chronic Phase CML (starting dose 100 mg once daily) ANC* <0.5 × 109/L or Platelets <50 × 109/L 1. Stop PHYRAGO until ANC ≥1 × 109/L and platelets ≥50 × 109/L. 2. Resume treatment with PHYRAGO at the original starting dose if recovery occurs in ≤7 days. 3. If platelets <25 × 109/L or recurrence of ANC <0.5 ×109/L for >7 days, repeat Step 1 and resume PHYRAGO at a reduced dose of 80 mg once daily for second episode. For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue PHYRAGO (for patients resistant or intolerant to prior therapy including imatinib). Accelerated Phase CML, Blast Phase CML and Ph+ ALL (starting dose 140 mg once daily) ANC* <0.5 × 109/L or Platelets <10 × 109/L 1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukemia, stop PHYRAGO until ANC ≥1 × 109/L and platelets ≥20 × 109/L and resume at the original starting dose. 3. If recurrence of cytopenia, repeat Step 1 and resume PHYRAGO at a reduced dose of 100 mg once daily (second episode) or 80 mg once daily (third episode). 4. If cytopenia is related to leukemia, consider dose escalation to 180 mg once daily. *ANC: absolute neutrophil count Non-Hematologic Adverse Reactions For adults with Ph+ CML and ALL, if a severe non-hematologic adverse reaction develops with PHYRAGO use, treatment must be withheld until the adverse reaction has resolved or improved. Thereafter, treatment can be resumed as appropriate at a reduced dose depending on the severity and recurrence [see Warnings and Precautions (5)]. 2.5 Duration of Treatment Reference ID: 5489006 In clinical studies, treatment with dasatinib in adults with chronic phase CML was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic response (including complete cytogenetic response [CCyR]) or major molecular response (MMR and MR4.5) has not been established. PHYRAGO is a hazardous product. Follow applicable special handling and disposal procedures.1 Pediatric use information is approved for Bristol-Myers Squibb Company’s SPRYCEL (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 3. DOSAGE FORMS AND STRENGTHS PHYRAGO is available as 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg white to light yellow, biconvex, immediate release tablets. 4. CONTRAINDICATIONS None. 5. WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with dasatinib is associated with severe (NCI CTCAE Grade 3 or 4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML [see Adverse Reactions (6.1)]. In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated. In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression is generally reversible; withhold, reduce, or discontinue PHYRAGO based on severity [see Dosage and Administration (2.5)]. 5.2 Bleeding-Related Events PHYRAGO can cause serious and fatal bleeding. In all CML or Ph+ ALL clinical studies, Grade ≥3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving dasatinib. The incidence of Grade 3/4 hemorrhage occurred in 5.8% of adult patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The most frequent site of hemorrhage was gastrointestinal [see Adverse Reactions (6.1)]. Most bleeding events in clinical studies were associated with severe thrombocytopenia. In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage. 5.3 Fluid Retention Reference ID: 5489006 PHYRAGO may cause fluid retention [see Adverse Reactions (6.1)]. After 5 years of follow-up in the adult randomized newly diagnosed chronic phase CML study (n=258), Grade 3 or 4 fluid retention was reported in 5% of patients, including 3% of patients with Grade 3 or 4 pleural effusion. In adult patients with newly diagnosed or imatinib-resistant or -intolerant chronic phase CML, Grade 3 or 4 fluid retention occurred in 6% of patients treated with dasatinib at the recommended dose (n=548). In adult patients with advanced phase CML or Ph+ ALL treated with dasatinib, the recommended dose (n=304), Grade 3 or 4 fluid retention was reported in 8% of patients, including Grade 3 or 4 pleural effusion reported in 7% of patients. Evaluate patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough, promptly with a chest x-ray or additional diagnostic imaging as appropriate. Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids. Severe pleural effusion may require thoracentesis and oxygen therapy. Consider dose reduction or treatment interruption [see Dosage and Administration (2.5)]. 5.4 Cardiovascular Toxicity PHYRAGO can cause cardiac dysfunction [see Adverse Reactions (6.1)]. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial in adults (n=258), the following cardiac adverse reactions occurred: cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac-related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. 5.5 Pulmonary Arterial Hypertension PHYRAGO may increase the risk of developing pulmonary arterial hypertension (PAH) in adult and pediatric patients which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention [see Adverse Reactions (6.1)]. PAH may be reversible on discontinuation of PHYRAGO. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating PHYRAGO and during treatment. If PAH is confirmed, PHYRAGO should be permanently discontinued. 5.6 QT Prolongation PHYRAGO may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy [see Adverse Reactions (6.1)]. Correct hypokalemia or hypomagnesemia prior to and during PHYRAGO administration. 5.7 Severe Dermatologic Reactions Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome [see Adverse Reactions (6.2)] and erythema multiforme, have been reported in patients treated with dasatinib. Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified. 5.8 Tumor Lysis Syndrome Reference ID: 5489006 Tumor lysis syndrome has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease. Due to potential for tumor lysis syndrome, maintain adequate hydration, correct uric acid levels prior to initiating therapy with PHYRAGO and monitor electrolyte levels. Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently [see Adverse Reactions (6.2)]. 5.9 Embryo-Fetal Toxicity Based on limited human data, dasatinib can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects of dasatinib, including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to dasatinib. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with PHYRAGO and for 30 days after the last dose [see Use in Specific Populations (8.1, 8.3)]. 5.10 Effects on Growth and Development in Pediatric Patients In pediatric trials of dasatinib in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 5 cases included cases of epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia [see Adverse Reactions (6.1)]. Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment. Monitor bone growth and development in pediatric patients. 5.11 Hepatotoxicity PHYRAGO may cause hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase [see Adverse Reactions (6.1)]. Monitor transaminases at baseline and monthly or as clinically indicated during treatment. Reduce dose, withhold, or permanently discontinue PHYRAGO based on severity [see Dosage and Administration (2.4)]. When dasatinib is administered in combination with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Monitor hepatic function when PHYRAGO is used in combination with chemotherapy. Pediatric use information is approved for Bristol-Myers Squibb Company’s SPRYCEL (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, the drug product is not labeled with that pediatric information. 6. ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)]. • Bleeding-related events [see Warnings and Precautions (5.2)]. • Fluid retention [see Warnings and Precautions (5.3)]. • Cardiovascular toxicity [see Warnings and Precautions (5.4)]. Reference ID: 5489006 • Pulmonary arterial hypertension [see Warnings and Precautions (5.5)]. • QT prolongation [see Warnings and Precautions (5.6)]. • Severe dermatologic reactions [see Warnings and Precautions (5.7)]. • Tumor lysis syndrome [see Warnings and Precautions (5.8)]. • Effects on growth and development in pediatric patients [see Warnings and Precautions (5.10)]. • Hepatotoxicity [see Warnings and Precautions (5.11)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to dasatinib administered as single-agent therapy at all doses tested in clinical studies, including 324 adult patients with newly diagnosed chronic phase CML and 2388 adult patients with imatinib-resistant or -intolerant chronic or advanced phase CML or Ph+ ALL. The median duration of therapy in a total of 2712 adult patients was 19.2 months (range 0 to 93.2 months). In a randomized trial in patients with newly diagnosed chronic phase CML, the median duration of therapy was approximately 60 months. The median duration of therapy in 1618 adult patients with chronic phase CML was 29 months (range 0 to 92.9 months). The median duration of therapy in 1094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0 to 93.2 months). In the overall population of 2712 adult patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation. In the randomized trial in adult patients with newly diagnosed chronic phase CML, drug was discontinued for adverse reactions in 16% of patients with a minimum of 60 months of follow­ up. After a minimum of 60 months of follow-up, the cumulative discontinuation rate was 39%. Among the 1618 patients with chronic phase CML, drug-related adverse reactions leading to discontinuation were reported in 329 (20.3%) patients; among the 1094 patients with advanced phase CML or Ph+ ALL, drug-related adverse reactions leading to discontinuation were reported in 191 (17.5%) patients. Adverse reactions reported in ≥10% of adult patients, and other adverse reactions of interest, in a randomized trial in patients with newly diagnosed chronic phase CML at a median follow-up of approximately 60 months are presented in Table 2. Adverse reactions reported in ≥10% of adult patients treated at the recommended dose of 100 mg once daily (n=165), and other adverse reactions of interest, in a randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy at a median follow-up of approximately 84 months are presented in Table 4. Drug-related serious adverse reactions (SARs) were reported for 16.7% of adult patients in the randomized trial of patients with newly diagnosed chronic phase CML. Serious adverse reactions reported in ≥5% of patients included pleural effusion (5%). Drug-related SARs were reported for 26.1% of patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of adult patients with chronic phase Reference ID: 5489006 CML resistant or intolerant to prior imatinib therapy. Serious adverse reactions reported in ≥5% of patients included pleural effusion (10%). Chronic Myeloid Leukemia (CML) Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of adult patients are shown in Table 2 for newly diagnosed patients with chronic phase CML and Tables 4 and 6 for CML patients with resistance or intolerance to prior imatinib therapy. Table 2: Adverse Reactions Reported in ≥10% of Adult Patients with Newly Diagnosed Chronic Phase CML (Minimum of 60 Months Follow-up) All Grades Grade 3/4 Dasatinib (n=258) Imatinib (n=258) Dasatinib (n=258) Imatinib (n=258) Adverse Reaction Percent (%) of Patients Fluid retention 38 45 5 1 Pleural effusion 28 1 3 0 Superficial localized edema 14 38 0 <1 Pulmonary hypertension 5 <1 1 0 Generalized edema 4 7 0 0 Pericardial effusion 4 1 1 0 Congestive heart failure/ Cardiac dysfunctiona 2 1 <1 <1 Pulmonary edema 1 0 0 0 Diarrhea 22 23 1 1 Musculoskeletal pain 14 17 0 <1 Rashb 14 18 0 2 Headache 14 11 0 0 Abdominal pain 11 8 0 1 Fatigue 11 12 <1 0 Nausea 10 25 0 0 Myalgia 7 12 0 0 Arthralgia 7 10 0 <1 Hemorrhagec 8 8 1 1 Gastrointestinal bleeding 2 2 1 0 Other bleedingd 6 6 0 <1 CNS bleeding <1 <1 0 <1 Reference ID: 5489006 All Grades Grade 3/4 Dasatinib (n=258) Imatinib (n=258) Dasatinib (n=258) Imatinib (n=258) Adverse Reaction Percent (%) of Patients Vomiting 5 12 0 0 Muscle spasms 5 21 0 <1 a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage. A comparison of cumulative rates of adverse reactions reported in ≥10% of patients with minimum follow-up of 1 and 5 years in a randomized trial of newly diagnosed patients with chronic phase CML treated with dasatinib are shown in Table 3. Reference ID: 5489006 Table 3: Adverse Reactions Reported in ≥10% of Adult Patients with Newly Diagnosed Chronic Phase CML in the Dasatinib-Treated Arm (n=258) Minimum of 1 Year Follow-up Minimum of 5 Years Follow-up All Grades Grade 3/4 All Grades Grade 3/4 Adverse Reaction Percent (%) of Patients Fluid retention 19 1 38 5 Pleural effusion 10 0 28 3 Superficial localized edema 9 0 14 0 Pulmonary hypertension 1 0 5 1 Generalized edema 2 0 4 0 Pericardial effusion 1 <1 4 1 Congestive heart failure/cardiac dysfunctiona 2 <1 2 <1 Pulmonary edema <1 0 1 0 Diarrhea 17 <1 22 1 Musculoskeletal pain 11 0 14 0 Rashb 11 0 14 0 Headache 12 0 14 0 Abdominal pain 7 0 11 0 Fatigue 8 <1 11 <1 Nausea 8 0 10 0 a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. At 60 months, there were 26 deaths in dasatinib-treated patients (10.1%) and 26 deaths in imatinib-treated patients (10.1%); 1 death in each group was assessed by the investigator as related to study therapy. Table 4: Adverse Reactions Reported in ≥10% of Adult Patients with Chronic Phase CML Resistant or Intolerant to Prior Imatinib Therapy (minimum of 84 months follow-up) 100 mg Once Daily Chronic (n=165) All Grades Grade 3/4 Adverse Reaction Percent (%) of Patients Fluid retention 48 7 Superficial localized edema 22 0 Pleural effusion 28 5 Reference ID: 5489006 100 mg Once Daily Chronic (n=165) All Grades Grade 3/4 Adverse Reaction Percent (%) of Patients Generalized edema 4 0 Pericardial effusion 3 1 Pulmonary hypertension 2 1 Headache 33 1 Diarrhea 28 2 Fatigue 26 4 Dyspnea 24 2 Musculoskeletal pain 22 2 Nausea 18 1 Skin rasha 18 2 Myalgia 13 0 Arthralgia 13 1 Infection (including bacterial, viral, fungal, and non-specified) 13 1 Abdominal pain 12 1 Hemorrhage 12 1 Gastrointestinal bleeding 2 1 Pruritus 12 1 Pain 11 1 Constipation 10 1 a Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular. Cumulative rates of selected adverse reactions that were reported over time in patients treated with the 100 mg once daily recommended starting dose in a randomized dose-optimization trial of imatinib-resistant or -intolerant patients with chronic phase CML are shown in Table 5. Reference ID: 5489006 I I Table 5: Selected Adverse Reactions Reported in Adult Dose Optimization Trial (Imatinib-Intolerant or -Resistant Chronic Phase CML)a Minimum of 2 Years Follow-up Minimum of 5 Years Follow-up Minimum of 7 Years Follow-up All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Adverse Reaction Percent (%) of Patients Diarrhea 27 2 28 2 28 2 Fluid retention 34 4 42 6 48 7 Superficial edema 18 0 21 0 22 0 Pleural effusion 18 2 24 4 28 5 Generalized edema 3 0 4 0 4 0 Pericardial effusion 2 1 2 1 3 1 Pulmonary hypertension 0 0 0 0 2 1 Hemorrhage 11 1 11 1 12 1 Gastrointestinal bleeding 2 1 2 1 2 1 a Randomized dose-optimization trial results reported in the recommended starting dose of 100 mg once daily (n=165) population. Table 6: Adverse Reactions Reported in ≥10% of Adult Patients with Advanced Phase CML Resistant or Intolerant to Prior Imatinib Therapy 140 mg Once Daily Accelerated (n=157) Myeloid Blast (n=74) Lymphoid Blast (n=33) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Adverse Reaction Percent (%) of Patients Fluid retention 35 8 34 7 21 6 Superficial localized edema 18 1 14 0 3 0 Pleural effusion 21 7 20 7 21 6 Generalized edema 1 0 3 0 0 0 Pericardial effusion 3 1 0 0 0 0 Congestive heart failure/cardiac dysfunctiona 0 0 4 0 0 0 Pulmonary edema 1 0 4 3 0 0 Headache 27 1 18 1 15 3 Diarrhea 31 3 20 5 18 0 Fatigue 19 2 20 1 9 3 Dyspnea 20 3 15 3 3 3 Reference ID: 5489006 I I 140 mg Once Daily Accelerated (n=157) Myeloid Blast (n=74) Lymphoid Blast (n=33) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Adverse Reaction Percent (%) of Patients Musculoskeletal pain 11 0 8 1 0 0 Nausea 19 1 23 1 21 3 Skin rashb 15 0 16 1 21 0 Arthralgia 10 0 5 1 0 0 Infection (including bacterial, viral, fungal, and non-specified) 10 6 14 7 9 0 Hemorrhage 26 8 19 9 24 9 Gastrointestinal bleeding 8 6 9 7 9 3 CNS bleeding 1 1 0 0 3 3 Vomiting 11 1 12 0 15 0 Pyrexia 11 2 18 3 6 0 Febrile neutropenia 4 4 12 12 12 12 a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure. b Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular. Adverse reactions associated with bone growth and development were reported in 5 (5.2%) of pediatric patients with chronic phase CML [see Warnings and Precautions (5.10)]. Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML (Tables 7 and 8). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities. In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of adult patients with newly diagnosed chronic phase CML and 5% of adult patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions (5.1)]. Grade 3 or 4 elevations of transaminases or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during dasatinib therapy often had recovery with oral calcium supplementation. Reference ID: 5489006 Laboratory abnormalities reported in adult patients with newly diagnosed chronic phase CML are shown in Table 7. There were no discontinuations of dasatinib therapy in this patient population due to biochemical laboratory parameters. Table 7: CTC Grade 3/4 Laboratory Abnormalities in Adult Patients with Newly Diagnosed Chronic Phase CML (Minimum of 60 Months Follow-up) Dasatinib (n=258) Imatinib (n=258) Percent (%) of Patients Hematology Parameters Neutropenia 29 24 Thrombocytopenia 22 14 Anemia 13 9 Biochemistry Parameters Hypophosphatemia 7 31 Hypokalemia 0 3 Hypocalcemia 4 3 Elevated SGPT (ALT) <1 2 Elevated SGOT (AST) <1 1 Elevated Bilirubin 1 0 Elevated Creatinine 1 1 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of dasatinib are shown by disease phase in Table 8. Table 8: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML in Adults: Resistance or Intolerance to Prior Imatinib Therapy Reference ID: 5489006 Chronic Phase CML 100 mg Once Daily Advanced Phase CML 140 mg Once Daily (n=165) Accelerated Phase (n=157) Myeloid Blast Phase (n=74) Lymphoid Blast Phase (n=33) Percent (%) of Patients Hematology Parameters* Neutropenia 36 58 77 79 Thrombocytopenia 24 63 78 85 Anemia 13 47 74 52 Biochemistry Parameters Hypophosphatemia 10 13 12 18 Hypokalemia 2 7 11 15 Hypocalcemia <1 4 9 12 Elevated SGPT (ALT) 0 2 5 3 Elevated SGOT (AST) <1 0 4 3 Elevated Bilirubin <1 1 3 6 Elevated Creatinine 0 2 8 0 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia (Grade 3≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). *Hematology parameters for 100 mg once-daily dosing in chronic phase CML reflects 60-month minimum follow­ up. Among adult patients with chronic phase CML with resistance or intolerance to prior imatinib therapy, cumulative Grade 3 or 4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%). Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) in Adults A total of 135 adult patients with Ph+ ALL were treated with dasatinib in clinical studies. The median duration of treatment was 3 months (range 0.03–31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention events, such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders, such as diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. Serious adverse reactions reported in ≥5% of patients included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), and infection (5%). Additional Pooled Data from Clinical Trials Reference ID: 5489006 The following additional adverse reactions were reported in patients in dasatinib CML clinical studies and adult patients in Ph+ ALL clinical studies at a frequency of ≥10%, 1%–<10%, 0.1%– <1%, or <0.1%. These adverse reactions are included based on clinical relevance. Gastrointestinal Disorders: 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1%–<1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis, gastroesophageal reflux disease; <0.1% – protein losing gastroenteropathy, ileus, acute pancreatitis, anal fistula. General Disorders and Administration-Site Conditions: ≥10% – peripheral edema, face edema; 1%–<10% – asthenia, chest pain, chills; 0.1%–<1% – malaise, other superficial edema, peripheral swelling; <0.1% – gait disturbance. Skin and Subcutaneous Tissue Disorders: 1%–<10% – alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome, hair disorder; <0.1% – leukocytoclastic vasculitis, skin fibrosis. Respiratory, Thoracic, and Mediastinal Disorders: 1%–<10% – lung infiltration, pneumonitis, cough; 0.1%–<1% – asthma, bronchospasm, dysphonia, pulmonary arterial hypertension; <0.1% – acute respiratory distress syndrome, pulmonary embolism. Nervous System Disorders: 1%–<10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1%–<1% – amnesia, tremor, syncope, balance disorder; <0.1% – convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis, VIIth nerve paralysis, dementia, ataxia. Blood and Lymphatic System Disorders: 0.1%–<1% – lymphadenopathy, lymphopenia; <0.1%– aplasia pure red cell. Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular weakness, musculoskeletal stiffness; 0.1%–<1% – rhabdomyolysis, tendonitis, muscle inflammation, osteonecrosis, arthritis; <0.1% – epiphyses delayed fusion (reported at 1%–<10% in the pediatric studies), growth retardation (reported at 1%–<10% in the pediatric studies). Investigations: 1%–<10% – weight increased, weight decreased; 0.1%–<1% – blood creatine phosphokinase increased, gamma-glutamyltransferase increased. Infections and Infestations: 1%–<10% – pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection, sepsis (including fatal outcomes [0.2%]). Metabolism and Nutrition Disorders: 1%–<10% – appetite disturbances, hyperuricemia; 0.1%– <1% – hypoalbuminemia, tumor lysis syndrome, dehydration, hypercholesterolemia; <0.1% – diabetes mellitus. Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia), electrocardiogram T-wave abnormal, troponin increased; <0.1% – cor pulmonale, myocarditis, acute coronary syndrome, cardiac arrest, electrocardiogram PR prolongation, coronary artery disease, pleuropericarditis. Reference ID: 5489006 Eye Disorders: 1%–<10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye; 0.1%–<1% – conjunctivitis, visual impairment, lacrimation increased, <0.1% – photophobia. Vascular Disorders: 1%–<10% – flushing, hypertension; 0.1%–<1% – hypotension, thrombophlebitis, thrombosis; <0.1% – livedo reticularis, deep vein thrombosis, embolism. Psychiatric Disorders: 1%–<10% – insomnia, depression; 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased. Pregnancy, Puerperium, and Perinatal Conditions: <0.1% – abortion. Reproductive System and Breast Disorders: 0.1%–<1% – gynecomastia, menstrual disorder. Injury, Poisoning, and Procedural Complications: 1%–<10% – contusion. Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% – vertigo, hearing loss. Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis. Renal and Urinary Disorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria; <0.1%– renal impairment. Immune System Disorders: 0.1%–<1% – hypersensitivity (including erythema nodosum). Endocrine Disorders: 0.1%–<1% – hypothyroidism; <0.1% – hyperthyroidism, thyroiditis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of dasatinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections: hepatitis B virus reactivation Cardiac disorders: atrial fibrillation/atrial flutter Respiratory, thoracic, and mediastinal disorders: interstitial lung disease, chylothorax Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome Renal and urinary disorders: nephrotic syndrome Blood and lymphatic system disorders: thrombotic microangiopathy Hepatobiliary disorders: hepatotoxicity Pediatric use information is approved for Bristol-Myers Squibb Company’s SPRYCEL (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 7. DRUG INTERACTIONS 7.1 Effect of Other Drugs on Dasatinib Strong CYP3A4 Inhibitors The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations [see Clinical Pharmacology (12.3)]. Increased dasatinib concentrations may increase the risk of Reference ID: 5489006 toxicity. Avoid concomitant use of strong CYP3A4 inhibitors. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a dose reduction [see Dosage and Administration (2.2)]. Strong CYP3A4 Inducers The coadministration of PHYRAGO with strong CYP3A inducers may decrease dasatinib concentrations [see Clinical Pharmacology (12.3)]. Decreased dasatinib concentrations may reduce efficacy. Consider alternative drugs with less enzyme induction potential. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a dose increase. Antacids Avoid concomitant use of PHYRAGO with antacids. If concomitant use of an antacid cannot be avoided, administer the antacid at least 2 hours prior to or 2 hours after the dose of PHYRAGO [see Dosage and Administration (2.2)]. Concomitant use with antacids decreases dasatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce PHYRAGO efficacy. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on limited human data, PHYRAGO can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to dasatinib. Animal reproduction studies in rats have demonstrated extensive mortality during organogenesis, the fetal period, and in neonates. Skeletal malformations were observed in a limited number of surviving rat and rabbit conceptuses. These findings occurred at dasatinib plasma concentrations below those in humans receiving therapeutic doses of dasatinib [see Data]. Advise a pregnant woman of the potential risk to a fetus. The estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Clinical Considerations Fetal/Neonatal Adverse Reactions Transplacental transfer of dasatinib has been reported. Dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma. Hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported with maternal exposure to dasatinib. These adverse pharmacologic effects on the fetus are similar to adverse reactions observed in adult patients and may result in fetal harm or neonatal death [see Warnings and Precautions (5.1, 5.3)]. Data Human Data Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and harmful pharmacological effects on the fetus when administered during pregnancy. Reference ID: 5489006 Animal Data In nonclinical studies at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m2/day] and rabbit: 0.5 mg/kg/day [6 mg/m2/day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 ng•h/mL and 44 ng•h/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, and clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia. In a pre- and postnatal development study in rats, administration of dasatinib from gestation day (GD) 16 through lactation day (LD) 20, GD 21 through LD 20, or LD 4 through LD 20 resulted in extensive pup mortality at maternal exposures that were below the exposures in patients treated with dasatinib at the recommended labeling dose. 8.2 Lactation Risk Summary No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. However, dasatinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in nursing children from dasatinib, breastfeeding is not recommended during treatment with PHYRAGO and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential PHYRAGO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Contraception Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with PHYRAGO and for 30 days after the last dose. Infertility Based on animal data, PHYRAGO may result in damage to female and male reproductive tissues [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Monitor bone growth and development in pediatric patients [see Warnings and Precautions (5.10)]. Pediatric use information is approved for Bristol-Myers Squibb Company’s SPRYCEL (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 8.5 Geriatric Use Reference ID: 5489006 ~----<N~ H Cl 0 S N HO_r 'L_/N N--( 0 )) Of the 2712 patients in clinical studies of dasatinib, 617 (23%) were 65 years of age and older, and 123 (5%) were 75 years of age and older. No differences in confirmed Complete Cytogenetic Response (cCCyR) and MMR were observed between older and younger patients. While the safety profile of dasatinib in the geriatric population was similar to that in the younger population, patients aged 65 years and older are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease, and should be monitored closely. 10. OVERDOSAGE Experience with overdose of dasatinib in clinical studies is limited to isolated cases. The highest overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding. Since dasatinib is associated with severe myelosuppression [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)], monitor patients who ingest more than the recommended dosage closely for myelosuppression and give appropriate supportive treatment. Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m2). 11. DESCRIPTION PHYRAGO (dasatinib) is a kinase inhibitor. The chemical name for dasatinib (anhydrous) is N­ (2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4­ pyrimidinyl]amino]-5-thiazolecarboxamide. The molecular formula is C22H26ClN7O2S, which corresponds to a formula weight of 488.01. Dasatinib (anhydrous) has the following chemical structure: Dasatinib (anhydrous) is a white to light yellow powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol. PHYRAGO is supplied as white to light yellow, biconvex, immediate release tablets for oral use containing dasatinib (anhydrous), with the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, methacrylic acid-ethyl acrylate copolymer, microcrystalline cellulose, propyl gallate, and silica dimethyl silylate. 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Reference ID: 5489006 Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase. In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate­ sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib could overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression. 12.2 Pharmacodynamics Cardiac Electrophysiology Of 2440 patients treated with dasatinib at all doses tested in clinical trials, 16 patients (<1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF > 500 ms. In 865 patients with leukemia treated with dasatinib 70 mg BID in five Phase 2 studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7 ms to 13.4 ms. An analysis of the data from five Phase 2 studies in patients (70 mg BID) and a Phase 1 study in healthy subjects (100 mg single dose) suggests that there is a maximum increase of 3 to 6 milliseconds in Fridericia corrected QTc interval from baseline for subjects receiving therapeutic doses of dasatinib, with associated upper 95% confidence intervals <10 msec. 12.3 Pharmacokinetics The pharmacokinetics of dasatinib exhibits dose proportional increases in AUC and linear elimination characteristics over the dose range of 15 mg/day (0.15 times the lowest approved recommended dose) to 240 mg/day (1.7 times the highest approved recommended dose). At 100 mg QD, the maximum concentration at steady state (Cmax) is 82.2 ng/mL (CV% 69%), area under the plasma drug concentration time curve (AUC) is 397 ng/mL*hr (CV% 55%). The clearance of dasatinib is found to be time-invariant. Absorption The maximum plasma concentration (Cmax) of dasatinib was observed at a median Tmax (range) of 1.25 hours (0.5 – 3.5 hours) following administration of a single oral 100 mg dose of PHYRAGO. Effect of Food No clinically significant differences in dasatinib pharmacokinetics were observed following PHYRAGO administration with a high-fat meal (approximately 900 calories, 50% fat). Distribution The geometric mean (%CV) apparent volume of distribution for PHYRAGO is 1850 L (59.3%). Binding of dasatinib to human plasma proteins in vitro was approximately 96% and of its active metabolite was 93%, with no concentration dependence over the range of 100 ng/mL to 500 ng/mL. Reference ID: 5489006 Dasatinib is a P-gp substrate in vitro. Elimination The mean terminal half-life of PHYRAGO is 5 hours and the geometric mean (%CV) apparent clearance is 241 L/hr (54.4%). Metabolism Dasatinib is metabolized in humans, primarily by CYP3A4. CYP3A4 is the primary enzyme responsible for the formation of the active metabolite. Flavin-containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites. The exposure of the active metabolite, which is equipotent to dasatinib, represents approximately 5% of the AUC of dasatinib. The active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also has several other inactive oxidative metabolites. Excretion Elimination is primarily via the feces. Following a single radiolabeled dose of oral dasatinib, 4% of the administered radioactivity was recovered in the urine and 85% in the feces within 10 days. Unchanged dasatinib accounted for 0.1% of the administered dose in the urine and 19% of the administered dose in the feces with the remainder of the dose being metabolites. Specific Populations Age, sex, and renal impairment (creatinine clearance 21.6 mL/min to 342.3 mL/min as estimated by Cockcroft Gault) have no clinically relevant effect on the pharmacokinetics of dasatinib. Pediatric Patients Pediatric use information is approved for Bristol Myers Squibb Company’s SPRYCEL (dasatinib) tablets. However, due to Bristol Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Patients with Hepatic Impairment Compared to subjects with normal liver function, patients with moderate hepatic impairment (Child Pugh B) had decreases in mean Cmax by 47% and mean AUC by 8%. Patients with severe hepatic impairment (Child Pugh C) had decreases in mean Cmax by 43% and in mean AUC by 28% compared to the subjects with normal liver function. Drug Interaction Studies Cytochrome P450 Enzymes The coadministration of ketoconazole (strong CYP3A4 inhibitor) twice daily increased the mean Cmax of dasatinib by 4-fold and the mean AUC of dasatinib by 5-fold following a single oral dose of 20 mg. The coadministration of rifampin (strong CYP3A4 inducer) once daily decreased the mean Cmax of dasatinib by 81% and the mean AUC of dasatinib by 82%. Dasatinib is a time-dependent inhibitor of CYP3A4. Dasatinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. Dasatinib does not induce CYP enzymes. Reference ID: 5489006 Gastric Acid Reducing Agents The dasatinib Cmax decreased by 47.9% and AUC by 31.7% following concomitant use with a calcium carbonate antacid. No clinically significant differences in the pharmacokinetics of PHYRAGO were observed following concomitant use with omeprazole (proton pump inhibitor) or famotidine (H2 receptor antagonist). Transporters Dasatinib is not an inhibitor of P-gp in vitro. 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) level approximately 60% of the human exposure at 100 mg once daily. Dasatinib induced a statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose females and prostate adenoma in low-dose males. Dasatinib was clastogenic when tested in vitro in Chinese hamster ovary cells, with and without metabolic activation. Dasatinib was not mutagenic when tested in an in vitro bacterial cell assay (Ames test) and was not genotoxic in an in vivo rat micronucleus study. Dasatinib did not affect mating or fertility in male and female rats at plasma drug exposure (AUC) similar to the human exposure at 100 mg daily. In repeat dose studies, administration of dasatinib resulted in reduced size and secretion of seminal vesicles, and immature prostate, seminal vesicle, and testis. The administration of dasatinib resulted in uterine inflammation and mineralization in monkeys, and cystic ovaries and ovarian hypertrophy in rodents. 14. CLINICAL STUDIES 14.1 Newly Diagnosed Chronic Phase CML in Adults DASISION (Dasatinib vs Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients) (NCT00481247) was an open-label, multicenter, international, randomized trial conducted in adult patients with newly diagnosed chronic phase CML. A total of 519 patients were randomized to receive either dasatinib 100 mg once daily or imatinib 400 mg once daily. Patients with a history of cardiac disease were included in this trial except those who had a myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation. The primary endpoint was the rate of confirmed complete cytogenetic response (CCyR) within 12 months. Confirmed CCyR was defined as a CCyR noted on two consecutive occasions (at least 28 days apart). Median age was 46 years in the dasatinib group and 49 years in the imatinib groups, with 10% and 11% of patients ≥65 years of age, respectively. There were slightly more male than female patients in both groups (59% vs 41%). Fifty-three percent of all patients were Caucasian and 39% were Asian. At baseline, the distribution of Hasford scores was similar in the dasatinib and imatinib treatment groups (low risk: 33% and 34%; intermediate risk: 48% and 47%; high risk: Reference ID: 5489006 19% and 19%, respectively). With a minimum of 12 months follow-up, 85% of patients randomized to dasatinib and 81% of patients randomized to imatinib were still on study. With a minimum of 24 months follow-up, 77% of patients randomized to dasatinib and 75% of patients randomized to imatinib were still on study and with a minimum of 60 months follow-up, 61% and 62% of patients, respectively, were still on treatment at the time of study closure. Efficacy results are summarized in Table 9. Table 9: Efficacy Results in a Randomized Newly Diagnosed Chronic Phase CML Trial Dasatinib (n=259) Imatinib (n=260) Confirmed CCyRa Within 12 months (95%CI) P-value 76.8% (71.2–81.8) 0.007* 66.2% (60.1–71.9) Major Molecular Responseb 12 months (95% CI) P-value 60 months (95% CI) 52.1% (45.9–58.3) 76.4% (70.8–81.5) <0.0001 33.8% (28.1–39.9) 64.2% (58.1–70.1) a Confirmed CCyR is defined as a CCyR noted on two consecutive occasions at least 28 days apart. b Major molecular response (at any time) was defined as BCR-ABL ratios ≤0.1% by RQ-PCR in peripheral blood samples standardized on the International scale. These are cumulative rates representing minimum follow up for the time frame specified. * Adjusted for Hasford score and indicated statistical significance at a pre-defined nominal level of significance. CI = confidence interval. The confirmed CCyR within 24, 36, and 60 months for dasatinib versus imatinib arms were 80% versus 74%, 83% versus 77%, and 83% versus 79%, respectively. The MMR at 24 and 36 months for dasatinib versus imatinib arms were 65% versus 50% and 69% versus 56%, respectively. After 60 months follow-up, median time to confirmed CCyR was 3.1 months in 215 dasatinib responders and 5.8 months in 204 imatinib responders. Median time to MMR after 60 months follow-up was 9.3 months in 198 dasatinib responders and 15.0 months in 167 imatinib responders. At 60 months, 8 patients (3%) on the dasatinib arm progressed to either accelerated phase or blast crisis while 15 patients (6%) on the imatinib arm progressed to either accelerated phase or blast crisis. The estimated 60-month survival rates for dasatinib- and imatinib-treated patients were 90.9% (CI: 86.6%–93.8%) and 89.6% (CI: 85.2%–92.8%), respectively. Based on data 5 years after the last patient was enrolled in the trial, 83% and 77% of patients were known to be alive in the dasatinib and imatinib treatment groups, respectively, 10% were known to have died in both treatment groups, and 7% and 13% had unknown survival status in the dasatinib and imatinib treatment groups, respectively. Reference ID: 5489006 At 60 months follow-up in the dasatinib arm, the rate of MMR at any time in each risk group determined by Hasford score was 90% (low risk), 71% (intermediate risk) and 67% (high risk). In the imatinib arm, the rate of MMR at any time in each risk group determined by Hasford score was 69% (low risk), 65% (intermediate risk), and 54% (high risk). BCR-ABL sequencing was performed on blood samples from patients in the newly diagnosed trial who discontinued dasatinib or imatinib therapy. Among dasatinib-treated patients the mutations detected were T315I, F317I/L, and V299L. Dasatinib does not appear to be active against the T315I mutation, based on in vitro data. 14.2 Imatinib-Resistant or -Intolerant CML or Ph+ ALL in Adults The efficacy and safety of dasatinib were investigated in adult patients with CML or Ph+ ALL whose disease was resistant to or who were intolerant to imatinib: 1158 patients had chronic phase CML, 858 patients had accelerated phase, myeloid blast phase, or lymphoid blast phase CML, and 130 patients had Ph+ ALL. In a clinical trial in chronic phase CML, resistance to imatinib was defined as failure to achieve a complete hematologic response (CHR; after 3 months), major cytogenetic response (MCyR; after 6 months), or complete cytogenetic response (CCyR; after 12 months); or loss of a previous molecular response (with concurrent ≥10% increase in Ph+ metaphases), cytogenetic response, or hematologic response. Imatinib intolerance was defined as inability to tolerate 400 mg or more of imatinib per day or discontinuation of imatinib because of toxicity. Results described below are based on a minimum of 2 years follow-up after the start of dasatinib therapy in patients with a median time from initial diagnosis of approximately 5 years. Across all studies, 48% of patients were women, 81% were white, 15% were black or Asian, 25% were 65 years of age or older, and 5% were 75 years of age or older. Most patients had long disease histories with extensive prior treatment, including imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant. Overall, 80% of patients had imatinib-resistant disease and 20% of patients were intolerant to imatinib. The maximum imatinib dose had been 400–600 mg/day in about 60% of the patients and >600 mg/day in 40% of the patients. The primary efficacy endpoint in chronic phase CML was MCyR, defined as elimination (CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary efficacy endpoint in accelerated phase, myeloid blast phase, lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a CHR or no evidence of leukemia (NEL). Chronic Phase CML Dose-Optimization Trial: A randomized, open-label trial (NCT00123474) was conducted in adult patients with chronic phase CML to evaluate the efficacy and safety of dasatinib administered once daily compared with dasatinib administered twice daily. Patients with significant cardiac diseases, including myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation were excluded from the trial. The primary efficacy endpoint was MCyR in patients with imatinib-resistant CML. A total of 670 patients, of whom 497 had imatinib-resistant disease, were randomized to the dasatinib 100 mg once-daily, 140 mg once-daily, 50 mg twice-daily, or 70 mg twice-daily group. Median duration of treatment was 22 months. Reference ID: 5489006 Efficacy was achieved across all dasatinib treatment groups with the once-daily schedule demonstrating comparable efficacy (non-inferiority) to the twice-daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% CI [−6.8%–10.6%]); however, the 100-mg once-daily regimen demonstrated improved safety and tolerability. Efficacy results are presented in Tables 10 and 11 for adult patients with chronic phase CML who received the recommended starting dose of 100 mg once daily. Table 10: Efficacy of Dasatinib in Adult Patients with Imatinib-Resistant or ­ Intolerant Chronic Phase CML (minimum of 24 months follow-up) All Patients 100 mg Once Daily (n=167) Hematologic Response Rate % (95% CI) CHRa 92% (86–95) Cytogenetic Response Rate % (95% CI) MCyRb 63% (56–71) CCyR 50% (42–58) a CHR (response confirmed after 4 weeks): WBC ≤ institutional ULN, platelets <450,000/mm3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement. b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses. Table 11: Long-Term MMR of Dasatinib in the Dose Optimization Trial: Adult Patients with Imatinib-Resistant or -Intolerant Chronic Phase CMLa Minimum Follow-up Period 2 Years 5 Years 7 Years Major Molecular Responseb % (n/N) All Patients Randomized 34% (57/167) 43% (71/167) 44% (73/167) Imatinib-Resistant Patients 33% (41/124) 40% (50/124) 41% (51/124) Imatinib-Intolerant Patients 37% (16/43) 49% (21/43) 51% (22/43) a Results reported in recommended starting dose of 100 mg once daily. bMajor molecular response criteria: Defined as BCR-ABL/control transcripts ≤0.1% by RQ-PCR in peripheral blood samples. Based on data 7 years after the last patient was enrolled in the trial, 44% were known to be alive, 31% were known to have died, and 25% had an unknown survival status. By 7 years, transformation to either accelerated or blast phase occurred in nine patients on treatment in the 100 mg once-daily treatment group. Advanced Phase CML and Ph+ ALL Dose-Optimization Trial: One randomized open-label trial (NCT00123487) was conducted in patients with advanced phase CML (accelerated phase CML, myeloid blast phase CML, or lymphoid blast phase CML) to evaluate the efficacy and safety of dasatinib administered once Reference ID: 5489006 daily compared with dasatinib administered twice daily. The primary efficacy endpoint was MaHR. A total of 611 patients were randomized to either the dasatinib 140 mg once-daily or 70 mg twice-daily group. Median duration of treatment was approximately 6 months for both treatment groups. The once-daily schedule demonstrated comparable efficacy (non-inferiority) to the twice-daily schedule on the primary efficacy endpoint; however, the 140-mg once-daily regimen demonstrated improved safety and tolerability. Response rates for patients in the 140 mg once-daily group are presented in Table 12. Table 12: Efficacy of Dasatinib in Imatinib-Resistant or -Intolerant Advanced Phase CML and Ph+ ALL (Two-Year Results) 140 mg Once Daily Accelerated (n=158) Myeloid Blast (n=75) Lymphoid Blast (n=33) Ph+ ALL (n=40) MaHRa 66% 28% 42% 38% (95% CI) (59–74) (18–40) (26–61) (23–54) CHRa (95% CI) 47% (40–56) 17% (10–28) 21% (9–39) 33% (19–49) NELa 19% 11% 21% 5% (95% CI) (13–26) (5–20) (9–39) (1–17) MCyRb 39% 28% 52% 70% (95% CI) (31–47) (18–40) (34–69) (54–83) CCyR 32% 17% 39% 50% (95% CI) (25–40) (10–28) (23–58) (34–66) a Hematologic response criteria (all responses confirmed after 4 weeks): Major hematologic response: (MaHR) = complete hematologic response (CHR) + no evidence of leukemia (NEL). CHR: WBC ≤ institutional ULN, ANC ≥1000/mm3, platelets ≥100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement. NEL: same criteria as for CHR but ANC ≥500/mm3 and <1000/mm3, or platelets ≥20,000/mm3 and ≤100,000/mm3. b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses. CI = confidence interval ULN = upper limit of normal range. In the dasatinib 140 mg once-daily group, the median time to MaHR was 1.9 months (min-max: 0.7-14.5) for patients with accelerated phase CML, 1.9 months (min-max: 0.9-6.2) for patients with myeloid blast phase CML, and 1.8 months (min-max: 0.9-2.8) for patients with lymphoid blast phase CML. In patients with myeloid blast phase CML, the median duration of MaHR was 8.1 months (min­ max: 2.7-21.1) and 9.0 (min-max: 1.8-23.1) months for the 140 mg once-daily group and the 70 mg twice-daily group, respectively. In patients with lymphoid blast phase CML, the median duration of MaHR was 4.7 months (min-max: 3.0-9.0) and 7.9 months (min-max: 1.6-22.1) for the 140 mg once-daily group and the 70 mg twice-daily group, respectively. In patients with Ph+ ALL who were treated with dasatinib 140 mg once-daily, the median duration of MaHR was 4.6 months (min-max: 1.4-10.2). The medians of progression-free survival for patients with Ph+ Reference ID: 5489006 ALL treated with dasatinib 140 mg once-daily and 70 mg twice-daily were 4.0 months (min­ max: 0.4-11.1) and 3.1 months (min-max: 0.3-20.8), respectively. Pediatric use information is approved for Bristol-Myers Squibb Company’s SPRYCEL (dasatinib) tablets. However, due to Bristol-Myers Squibb Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 15. REFERENCES 1. http://www.osha.gov/SLTC/hazardousdrugs/index.html 16. HOW SUPPLIED/STORAGE AND HANDLING How Supplied PHYRAGO (dasatinib) tablets are available in bottles with a child-resistant closure and desiccant container(s) as described in Table 13. The desiccant container(s) should remain within the bottle after opening and should not be swallowed or eaten. Table 13: PHYRAGO Trade Presentations NDC Number Strength Description Tablets per Bottle 83858-101-60 20 mg white to light-yellow, biconvex, round shaped tablet with “NC 2” debossed on one side and plain on the other side 60 83858-102-60 50 mg white to light-yellow, biconvex, oval shaped tablet with “NC 5” debossed on one side and plain on the other side 60 83858-103-60 70 mg white to light-yellow, biconvex, round shaped tablet with “NC 7” debossed on one side and plain on the other side 60 83858-104-30 80 mg white to light-yellow, biconvex, triangular shaped tablet with “NC 8” debossed on one side and plain on the other side 30 83858-105-30 100 mg white to light-yellow, biconvex, oval shaped tablet with “NC 10” debossed on one side and plain on the other side 30 83858-106-30 140 mg white to light-yellow, biconvex, round shaped tablet with “NC 14” debossed on one side and plain on the other side 30 Storage PHYRAGO should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Handling and Disposal Reference ID: 5489006 PHYRAGO is a hazardous product. Follow special handling and disposal procedures. Personnel who are pregnant should avoid exposure to tablets. To prevent exposure of healthcare professionals to the active substance, the use of latex or nitrile gloves for appropriate disposal when handling tablets is recommended, to minimize the risk of dermal exposure. 17. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myelosuppression Inform patients of the possibility of developing low blood cell counts. Advise patients to immediately report fever particularly in association with any suggestion of infection [see Warnings and Precautions (5.1)]. Bleeding Inform patients of the possibility of serious bleeding and to report immediately any signs or symptoms suggestive of hemorrhage (unusual bleeding or easy bruising) [see Warnings and Precautions (5.2)]. Fluid Retention Inform patients of the possibility of developing fluid retention (swelling, weight gain, dry cough, chest pain on respiration, or shortness of breath) and advise them to seek medical attention promptly if those symptoms arise [see Warnings and Precautions (5.3)]. Cardiovascular Toxicity Inform patients of the possibility of developing cardiovascular toxicity, including cardiac ischemic events, cardiac-related fluid retention, conduction abnormalities, and TIAs. Advise patients to seek immediate medical attention if symptoms suggestive of cardiovascular toxicity occur, such as chest pain, shortness of breath, palpitations, transient vision problems, or slurred speech [see Warnings and Precautions (5.4)]. Pulmonary Arterial Hypertension Inform patients of the possibility of developing pulmonary arterial hypertension (dyspnea, fatigue, hypoxia, and fluid retention) and advise them to seek medical attention promptly if those symptoms arise [see Warnings and Precautions (5.5)]. Tumor Lysis Syndrome Inform patients to immediately report and seek medical attention for any symptoms such as nausea, vomiting, weakness, edema, shortness of breath, muscle cramps, and seizures, which may indicate tumor lysis syndrome [see Warnings and Precautions (5.8)]. Growth and Development in Pediatric Patients Inform pediatric patients and their caregivers of the possibility of developing bone growth abnormalities, bone pain, or gynecomastia and advise them to seek medical attention promptly if those symptoms arise [see Warnings and Precautions (5.10)]. Embryo-Fetal Toxicity Reference ID: 5489006 • Advise pregnant women of the potential risk to a fetus [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with PHYRAGO and for 30 days after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking PHYRAGO [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1, 8.3)]. Lactation • Advise women not to breastfeed during treatment with PHYRAGO and for 2 weeks after the last dose [see Use in Specific Populations (8.2)]. Gastrointestinal Complaints Inform patients that they may experience nausea, vomiting, or diarrhea with PHYRAGO. Advise patients to seek medical attention if these symptoms are bothersome or persistent. Advise patients using antacids to avoid taking PHYRAGO and antacids less than 2 hours apart [see Drug Interactions (7.1)]. Pain Inform patients that they may experience headache or musculoskeletal pain with PHYRAGO. Advise patients to seek medical attention if these symptoms are bothersome or persistent. Fatigue Inform patients that they may experience fatigue with PHYRAGO. Advise patients to seek medical attention if this symptom is bothersome or persistent. Rash Inform patients that they may experience skin rash with PHYRAGO. Advise patients to seek medical attention if this symptom is bothersome or persistent. Lactose PHYRAGO does not contain lactose. Hepatotoxicity Advise patients that PHYRAGO can cause hepatotoxicity and that patients with previous history of liver diseases may be at risk. Advise patients to seek immediate medical attention if any symptoms suggestive of hepatotoxicity occur, such as abdominal pain, jaundice and scleral icterus, anorexia, bleeding, bruising, and dark-colored urine [see Warnings and Precautions (5.11)]. Instructions for Taking PHYRAGO • Missed Dose Advise patients that if they miss a dose of PHYRAGO they should take the next scheduled dose at its regular time. The patient should not take two doses at the same time. • Grapefruit Juice Reference ID: 5489006 Advise patients not to drink grapefruit juice as it may increase the amount of dasatinib in their blood and therefore increase their risk of adverse reactions. Manufactured for: Nanocopoeia, LLC 639 Campus Dr. New Brighton, MN 55112 PHYRAGO® is a trademark of Nanocopoeia, LLC For patent information, please refer to www.phyrago.com/patents Reference ID: 5489006
custom-source
2025-02-12T15:47:31.352664
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TYENNE safely and effectively. See full prescribing information for TYENNE. TYENNE® (tocilizumab-aazg) injection, for intravenous or subcutaneous use. Initial U.S. Approval: 2024 TYENNE® (tocilizumab-aazg) is biosimilar* to ACTEMRA® (tocilizumab). WARNING: RISK OF SERIOUS INFECTIONS See full prescribing information for complete boxed warning. • Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections have occurred in patients receiving tocilizumab products. (5.1) • If a serious infection develops, interrupt TYENNE until the infection is controlled. (5.1) • Perform test for latent TB; if positive, start treatment for TB prior to starting TYENNE. (5.1) • Monitor all patients for active TB during treatment, even if initial latent TB test is negative. (5.1) --------------------------RECENT MAJOR CHANGES------------------­ Warnings and Precautions (5.6) 12/2024 --------------------------INDICATIONS AND USAGE-------------------­ TYENNE® (tocilizumab-aazg) is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of: Rheumatoid Arthritis (RA) (1.1) • Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). Giant Cell Arteritis (GCA) (1.2) • Adult patients with giant cell arteritis. Polyarticular Juvenile Idiopathic Arthritis (PJIA) (1.3) • Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis. Systemic Juvenile Idiopathic Arthritis (SJIA) (1.4) • Patients 2 years of age and older with active systemic juvenile idiopathic arthritis. ------------------DOSAGE AND ADMINISTRATION----------------­ For RA, pJIA and sJIA, TYENNE may be used alone or in combination with methotrexate; and in RA, other DMARDs may be used. (2) General Administration and Dosing Information (2.1) • RA, GCA, PJIA and SJIA – It is recommended that TYENNE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or ALT or AST above 1.5 times the upper limit of normal (ULN)(5.3, 5.4). • In RA patients, TYENNE doses exceeding 800 mg per infusion are not recommended. (2.2, 2.7, 12.3) • In GCA patients, TYENNE doses exceeding 600 mg per infusion are not recommended. (2.3, 12.3) Rheumatoid Arthritis (2.2) Recommended Adult Intravenous Dosage: When used in combination with DMARDs or as monotherapy the recommended starting dose is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response. Recommended Adult Subcutaneous Dosage: Patients less than 100 kg 162 mg administered subcutaneously weight every other week, followed by an increase to every week based on clinical response Patients at or above 100 kg 162 mg administered subcutaneously weight every week Giant Cell Arteritis (2.3) Recommended Adult Intravenous Dosage: The recommended dose is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids. TYENNE can be used alone following discontinuation of glucocorticoids. Recommended Adult Subcutaneous Dosage: The recommended dose is 162 mg given once every week as a subcutaneous injection, in combination with a tapering course of glucocorticoids. A dose of 162 mg given once every other week as a subcutaneous injection, in combination with a tapering course of glucocorticoids, may be prescribed based on clinical considerations. TYENNE can be used alone following discontinuation of glucocorticoids. Polyarticular Juvenile Idiopathic Arthritis (2.4) Recommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous PJIA Dosage Patients less than 30 kg weight 162 mg once every three weeks Patients at or above 30 kg weight 162 mg once every two weeks Systemic Juvenile Idiopathic Arthritis (2.5) Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous SJIA Dosage Patients less than 30 kg weight 162 mg every two weeks Patients at or above 30 kg weight 162 mg every week Administration of Intravenous formulation (2.6) • For patients with RA, GCA,, PJIA and SJIA patients at or above 30 kg, dilute to 100 mL in 0.9% or 0.45% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique. • For PJIA, and SJIA patients less than 30 kg, dilute to 50 mL in 0.9% or 0.45% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique. • Administer as a single intravenous drip infusion over 1 hour; do not administer as bolus or push. Administration of Subcutaneous formulation (2.7) • Follow the Instructions for Use for prefilled syringe and prefilled autoinjector Dose Modifications (2.8) Recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia. ------------------DOSAGE FORMS AND STRENGTHS-----------------­ Intravenous Infusion Injection: 80 mg/4 mL (20 mg/mL), 200 mg/10 mL (20 mg/mL), 400 mg/20 mL (20 mg/mL) in single-dose vials for further dilution prior to intravenous infusion (3) Subcutaneous Injection Injection: 162 mg/0.9 mL in a single-dose prefilled syringe or single-dose prefilled autoinjector (3) ---------------------------CONTRAINDICATIONS-----------------------­ Known hypersensitivity to tocilizumab products. (4) --------------------WARNINGS AND PRECAUTIONS----------------­ • Serious Infections – do not administer TYENNE during an active infection, including localized infections. If a serious infection develops, interrupt TYENNE until the infection is controlled. (5.1) • Gastrointestinal (GI) perforation—use with caution in patients who may be at increased risk. (5.2) • Hepatotoxicity- monitor patients for signs and symptoms of hepatic injury. Modify or discontinue TYENNE if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (, 5.3) Reference ID: 5489050 1 • Laboratory monitoring—recommended due to potential consequences of treatment-related changes in neutrophils, platelets, lipids, and liver function tests. (2.8, 5.4) • Hypersensitivity reactions, including anaphylaxis and death, and serious cutaneous reactions including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)- discontinue TYENNE, treat promptly, and monitor until reaction resolves (5.6) • Live vaccines—Avoid use with TYENNE (5.9, 7.3) -------------------------ADVERSE REACTIONS-------------------------­ Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, injection site reactions. (6) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch -----------------USE IN SPECIFIC POPULATIONS-----------------­ • Pregnancy: Based on animal data, may cause fetal harm. (8.1) • Lactation: Discontinue drug or nursing taking into consideration importance of drug to mother. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of TYENNE has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s), strength(s), dosage form(s), and route(s) of administration) described in its Full Prescribing Information. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS INFECTIONS 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis (RA) 1.2 Giant Cell Arteritis (GCA) 1.3 Polyarticular Juvenile Idiopathic Arthritis (PJIA) 1.4 Systemic Juvenile Idiopathic Arthritis (SJIA) 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations for administration 2.2 Recommended Dosage for Rheumatoid Arthritis 2.3 Recommended Dosage for Giant Cell Arteritis 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis 2.5 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis 2.6 Preparation and Administration Instructions for Intravenous Infusion 2.7 Preparation and Administration Instructions for Subcutaneous Injection 2.8 Dosage Modifications due to Serious Infections or Laboratory Abnormalities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections 5.2 Gastrointestinal Perforations 5.3 Hepatotoxicity 5.4 Changes in Laboratory Parameters 5.5 Immunosuppression 5.6 Hypersensitivity Reactions, Including Anaphylaxis 5.7 Demyelinating Disorders 5.8 Active Hepatic Disease and Hepatic Impairment 5.9 Vaccinations 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) 6.2 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Subcutaneous Tocilizumab (Tocilizumab-SC) 6.3 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Subcutaneous Tocilizumab (Tocilizumab-SC) 6.4 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) 6.5 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated Patients with Intravenous Tocilizumab (Tocilizumab-IV) 6.6 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Subcutaneous Tocilizumab (Tocilizumab-SC) 6.7 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) 6.8 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Subcutaneous Tocilizumab (Tocilizumab-SC) 6.9 Post marketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Drugs for Treatment of Adult Indications 7.2 Interactions with CYP450 Substrates 7.3 Live Vaccines 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 9 DRUG ABUSE AND DEPENDENCE 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICALPHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis – Intravenous Administration 14.2 Rheumatoid Arthritis – Subcutaneous Administration 14.3 Giant Cell Arteritis – Subcutaneous Administration 14.4 Giant Cell Arteritis – Intravenous Administration 14.5 Polyarticular Juvenile Idiopathic Arthritis – Intravenous Administration 14.6 Polyarticular Juvenile Idiopathic Arthritis – Subcutaneous Administration 14.7 Systemic Juvenile Idiopathic Arthritis – Intravenous Administration 14.8 Systemic Juvenile Idiopathic Arthritis – Subcutaneous Administration 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5489050 2 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS INFECTIONS Patients treated with tocilizumab products including TYENNE are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt TYENNE until the infection is controlled. Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before TYENNE use and during therapy. Treatment for latent infection should be initiated prior to TYENNE use. • Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. • Bacterial, viral and other infections due to opportunistic pathogens. The risks and benefits of treatment with TYENNE should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with TYENNE including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)]. Reference ID: 5489050 3 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis (RA) TYENNE® (tocilizumab-aazg) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). 1.2 Giant Cell Arteritis (GCA) TYENNE® (tocilizumab-aazg) is indicated for the treatment of giant cell arteritis (GCA) in adult patients. 1.3 Polyarticular Juvenile Idiopathic Arthritis (PJIA) TYENNE® (tocilizumab-aazg) is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. 1.4 Systemic Juvenile Idiopathic Arthritis (SJIA) TYENNE® (tocilizumab-aazg) is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older. 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations for Administration Not Recommended for Concomitant Use with Biological DMARDs Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection. Avoid using TYENNE with biological DMARDs. Baseline Laboratory Evaluation Prior to Treatment Obtain and assess baseline complete blood count (CBC) and liver function tests prior to treatment. RA, GCA, PJIA and SJIA – It is recommended that TYENNE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or ALT or AST above 1.5 times the upper limit of normal (ULN) [see Warnings and Precautions (5.3, 5.4)]. 2.2 Recommended Dosage for Rheumatoid Arthritis TYENNE may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection. Recommended Intravenous Dosage Regimen: The recommended dosage of TYENNE for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response. • Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.1)]. • Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology (12.3)]. Recommended Subcutaneous Dosage Regimen: Patients less than 100 kg weight 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response Patients at or above 100 kg weight 162 mg administered subcutaneously every week Reference ID: 5489050 4 I I When transitioning from TYENNE intravenous therapy to subcutaneous administration administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.2)]. 2.3 Recommended Dosage for Giant Cell Arteritis Recommended Intravenous Dosage Regimen: The recommended dosage of TYENNE for adult patients given as a 60-minute single intravenous drip infusion is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids. TYENNE can be used alone following discontinuation of glucocorticoids. • Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)]. • Doses exceeding 600 mg per infusion are not recommended in GCA patients [see Clinical Pharmacology (12.3)]. Recommended Subcutaneous Dosage Regimen: The recommended dose of TYENNE for adult patients with GCA is 162 mg given once every week as a subcutaneous injection in combination with a tapering course of glucocorticoids. A dose of 162 mg given once every other week as a subcutaneous injection in combination with a tapering course of glucocorticoids may be prescribed based on clinical considerations. TYENNE can be used alone following discontinuation of glucocorticoids. When transitioning from TYENNE intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)]. 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis TYENNE may be used as an intravenous infusion or as a subcutaneous injection alone or in combination with methotrexate. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. Recommended Intravenous Dosage Regimen: The recommended dosage of TYENNE for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is: Recommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous Dosage Regimen: Recommended Subcutaneous PJIA Dosage Patients less than 30 kg weight 162 mg once every 3 weeks Patients at or above 30 kg weight 162 mg once every 2 weeks When transitioning from TYENNE intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Reference ID: 5489050 5 I I Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)]. 2.5 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis TYENNE may be used as an intravenous infusion or as a subcutaneous injection alone or in combination with methotrexate. Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate. Recommended Intravenous Dosage Regimen: The recommended dose of TYENNE for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is: Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous Dosage Regimen: Recommended Subcutaneous SJIA Dosage Patients less than 30 kg weight 162 mg once every two weeks Patients at or above 30 kg weight 162 mg once every week When transitioning from TYENNE intravenous therapy to subcutaneous administration, administer the first subcutaneous dose when the next scheduled intravenous dose is due. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)]. 2.6 Preparation and Administration Instructions for Intravenous Infusion TYENNE for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows: • Use a sterile needle and syringe to prepare TYENNE. • Patients less than 30 kg: use a 50 mL infusion bag or bottle of 0.9% or 0.45% Sodium Chloride Injection, USP, and then follow steps 1 and 2 below. • Patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps 1 and 2 below. – Step 1. Withdraw a volume of 0.9% or 0.45% Sodium Chloride Injection, USP, equal to the volume of the TYENNE injection required for the patient’s dose from the infusion bag or bottle [see Dosage and Administration (2.2, 2.4, 2.5,)]. For Intravenous Use: Volume of TYENNE Injection per kg of Body Weight Dosage Indication Volume of TYENNE injection per kg of body weight 4 mg/kg Adult RA 0.2 mL/kg 6mg/kg Adult GCA 0.3 mL/kg 8 mg/kg Adult RA SJIA, and PJIA (greater than or equal to 30 kg of body weight) 0.4 mL/kg 10 mg/kg PJIA (less than 30 kg of body weight) 0.5 mL/kg 12 mg/kg SJIA (less than 30 kg of body weight) 0.6 mL/kg Reference ID: 5489050 6 – Step 2. Withdraw the amount of TYENNE for intravenous infusion from the vial(s) and add slowly into the 0.9% or 0.45% Sodium Chloride Injection, USP infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming. • The prepared solution for infusion should be used immediately. If not used immediately, the diluted tocilizumab solutions may be refrigerated at 36°F to 46°F (2°C to 8°C) up to 24 hours, or stored at room temperature at or below 77°F (25°C) for up to 4 hours and should be protected from light. Administration of diluted TYENNE solution must be completed within this period of time. • TYENNE solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used. • Allow the fully diluted TYENNE solution to reach room temperature prior to infusion. • The infusion should be administered over 60 minutes and must be administered with an infusion set. Do not administer as an intravenous push or bolus. • TYENNE should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of TYENNE with other drugs. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used. • Fully diluted TYENNE solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and bottles, and glass infusion bottles. 2.7 Preparation and Administration Instructions for Subcutaneous Injection • TYENNE for subcutaneous injection is not intended for intravenous drip infusion. • Assess suitability of patient for subcutaneous home use and instruct patients to inform a healthcare professional before administering the next dose if they experience any symptoms of allergic reaction. Patients should seek immediate medical attention if they develop symptoms of serious allergic reactions. TYENNE subcutaneous injection is intended for use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject TYENNE or the patient’s caregiver may administer TYENNE if a healthcare practitioner determines that it is appropriate. PJIA and SJIA patients may self-inject with the TYENNE prefilled syringe or autoinjector, or the patient’s caregiver may administer TYENNE if both the healthcare practitioner and the parent/legal guardian determine it is appropriate [see Use in Specific Populations (8.4)]. Patients, or patient caregivers, should be instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication administration. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use TYENNE prefilled syringes (PFS) or prefilled autoinjectors exhibiting particulate matter, cloudiness, or discoloration. TYENNE for subcutaneous administration should be clear and colorless to pale yellow. Do not use if any part of the PFS or autoinjector appears to be damaged. • Patients using TYENNE for subcutaneous administration should be instructed to inject the full amount in the syringe (0.9 mL) or full amount in the autoinjector (0.9 mL), which provides 162 mg of TYENNE, according to the directions provided in the IFU. • Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. Reference ID: 5489050 7 2.8 Dosage Modifications due to Serious Infections or Laboratory Abnormalities Serious Infections Hold TYENNE treatment if a patient develops a serious infection until the infection is controlled. Laboratory Abnormalities Rheumatoid Arthritis and Giant Cell Arteritis Liver Enzyme Abnormalities [see Warnings and Precautions (5.3, 5.4)] Lab Value Recommendation for RA Recommendation for GCA Greater than 1 to 3x Dose modify concomitant DMARDs if Dose modify immunomodulatory ULN appropriate For persistent increases in this range: • For patients receiving intravenous TYENNE, reduce dose to 4 mg per kg or hold TYENNE until ALT or AST have normalized • For patients receiving subcutaneous TYENNE, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume TYENNE at every other week and increase frequency to every week as clinically appropriate agents if appropriate For persistent increases in this range: • For patients receiving Intravenous TYENNE, hold TYENNE until ALT or AST have normalized • For patients receiving subcutaneous TYENNE, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume TYENNE at every other week and increase frequency to every week as clinically appropriate Greater than 3 to 5x Hold TYENNE dosing until less than 3x Hold TYENNE dosing until less than ULN (confirmed by ULN and follow recommendations above 3x ULN and follow recommendations repeat testing) for greater than 1 to 3x ULN For persistent increases greater than 3x ULN, discontinue TYENNE above for greater than 1 to 3x ULN For persistent increases greater than 3x ULN, discontinue TYENNE Greater than 5x ULN Discontinue TYENNE Discontinue TYENNE Reference ID: 5489050 8 Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5.4)] Lab Value (cells per mm3) Recommendation for RA Recommendation for GCA ANC greater than 1000 Maintain dose Maintain dose ANC 500 to 1000 Hold TYENNE dosing Hold TYENNE dosing When ANC greater than 1000 cells per mm3: • For patients receiving intravenous TYENNE, resume TYENNE at 4 mg per kg and increase to 8 mg per kg as clinically appropriate • For patients receiving subcutaneous TYENNE, resume TYENNE at every other week and increase frequency to every week as clinically appropriate When ANC greater than 1000 cells per mm3: • For patients receiving intravenous TYENNE, resume TYENNE at 6 mg per kg • For patients receiving subcutaneous TYENNE, resume TYENNE at every other week and increase frequency to every week as clinically appropriate ANC less than 500 Discontinue TYENNE Discontinue TYENNE Low Platelet Count [see Warnings and Precautions (5.4)] Lab Value (cells per mm3) Recommendation for RA Recommendation for GCA 50,000 to 100,000 Hold TYENNE dosing When platelet count is greater than 100,000 cells per mm3: • For patients receiving intravenous TYENNE, resume TYENNE at 4 mg per kg and increase to 8 mg per kg as clinically appropriate • For patients receiving subcutaneous TYENNE, resume TYENNE at every other week and increase frequency to every week as clinically appropriate Hold TYENNE dosing When platelet count is greater than 100,000 cells per mm3: • For patients receiving intravenous TYENNE, resume TYENNE at 6 mg per kg • For patients receiving subcutaneous TYENNE, resume TYENNE at every other week and increase frequency to every week as clinically appropriate Less than 50,000 Discontinue TYENNE Discontinue TYENNE Polyarticular and Systemic Juvenile Idiopathic Arthritis: Dose reduction of tocilizumab products has not been studied in the PJIA and SJIA populations. Dose interruptions of TYENNE are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined above for patients with RA and GCA. If appropriate, dose modify or stop concomitant methotrexate and/or other medications and hold TYENNE dosing until the clinical situation has been evaluated. In PJIA and SJIA the decision to discontinue TYENNE for a laboratory abnormality should be based upon the medical assessment of the individual patient. Reference ID: 5489050 9 3 DOSAGE FORMS AND STRENGTHS Intravenous Infusion Injection: 80 mg/4 mL (20 mg/mL), 200 mg/10 mL (20 mg/mL), 400 mg/20 mL (20 mg/mL) as a clear and colorless to pale yellow solution in single-dose vials for further dilution prior to intravenous infusion. Subcutaneous Injection Injection: 162 mg/0.9 mL clear and colorless to pale yellow solution in a single-dose prefilled syringe or single-dose prefilled autoinjector. 4 CONTRAINDICATIONS TYENNE is contraindicated in patients with known hypersensitivity to tocilizumab products [see Warnings and Precautions (5.6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including tocilizumab products. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with tocilizumab products. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections. Do not administer TYENNE in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating TYENNE in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of serious or an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with TYENNE, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.1), Adverse Reactions (6.1), and Patient Counseling Information (17)]. Hold TYENNE if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with TYENNE should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient. Tuberculosis Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating TYENNE. Consider anti-tuberculosis therapy prior to initiation of TYENNE in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested 10 Reference ID: 5489050 negative for latent tuberculosis infection prior to initiating therapy. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating TYENNE. Viral Reactivation Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with tocilizumab. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded. 5.2 Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with tocilizumab. Use TYENNE with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)]. 5.3 Hepatotoxicity Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous tocilizumab products. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from months to years after treatment initiation with tocilizumab products. While most cases presented with marked elevations of transaminases (> 5 times ULN), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases. During randomized controlled studies, treatment with tocilizumab was associated with a higher incidence of transaminase elevations [see Adverse Reactions (6.1, 6.2, 6.5, 6.7)]. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with tocilizumab. For RA and GCA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating TYENNE, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter. It is not recommended to initiate TYENNE treatment in RA or GCA patients with elevated transaminases ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than 5x ULN, discontinue TYENNE. For recommended modifications based upon increase in transaminases [see Dosage and Administration (2.8)]. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (e.g., ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range), TYENNE treatment should be interrupted and investigation done to establish the probable cause. TYENNE should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests. A similar pattern of liver enzyme elevation is noted with tocilizumab products treatment in the PJIA and SJIA populations. Monitor liver test panel at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. 5.4 Changes in Laboratory Parameters Patients with Rheumatoid Arthritis and Giant Cell Arteritis Neutropenia Treatment with tocilizumab products was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience. – It is not recommended to initiate TYENNE treatment in RA and GCA patients with a low neutrophil count, Reference ID: 5489050 11 i.e., absolute neutrophil count (ANC) less than 2000 per mm3. In patients who develop an absolute neutrophil count less than 500 per mm3 treatment is not recommended. – Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter [see Clinical Pharmacology (12.2)]. For recommended modifications based on ANC results [ see Dosage and Administration (2.8)]. Thrombocytopenia Treatment with tocilizumab products was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials [see Adverse Reactions (6.1, 6.2)]. – It is not recommended to initiate TYENNE treatment in RA and GCA patients with a platelet count below 100,000 per mm3. In patients who develop a platelet count less than 50,000 per mm3 treatment is not recommended. – Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts [see Dosage and Administration (2.8)]. Elevated Liver Enzymes Refer to 5.3 Hepatotoxicity. For recommended modifications [see Dosage and Administration (2.8)]. Lipid Abnormalities Treatment with tocilizumab products was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol [see Adverse Reactions (6.1, 6.2)]. – Assess lipid parameters approximately 4 to 8 weeks following initiation of TYENNE therapy. – Subsequently, manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia. Patients with Polyarticular and Systemic Juvenile Idiopathic Arthritis A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with tocilizumab products treatment in the PJIA and SJIA populations. Monitor neutrophils, platelets, ALT and AST at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Monitor lipids as above for approved adult indications [see Dosage and Administration (2.8)]. 5.5 Immunosuppression The impact of treatment with tocilizumab products on the development of malignancies is not known but malignancies were observed in clinical studies [see Adverse Reactions (6.1)]. TYENNE is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies. 5.6 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis, have been reported in association with tocilizumab products and anaphylactic events with a fatal outcome have been reported with intravenous infusion of tocilizumab products. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous tocilizumab, 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1465) of patients in the subcutaneous all- exposure population. In the SJIA controlled trial with intravenous tocilizumab, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous tocilizumab, 0 out of 188 patients (0%) in the tocilizumab all-exposure population experienced hypersensitivity reactions that required treatment discontinuation. Reactions that required treatment discontinuation included generalized erythema, rash, and urticaria. Injection site reactions were categorized Reference ID: 5489050 12 separately [see Adverse Reactions (6)]. In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous tocilizumab products, with or without concomitant therapies. Events have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of tocilizumab products. In addition, serious cutaneous reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported in patients with autoinflammatory conditions treated with tocilizumab products. TYENNE for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. For TYENNE subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If a hypersensitivity reaction occurs, immediately discontinue TYENNE; treat promptly and monitor until signs and symptoms resolve. 5.7 Demyelinating Disorders The impact of treatment with tocilizumab products on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of TYENNE in patients with preexisting or recent onset demyelinating disorders. 5.8 Active Hepatic Disease and Hepatic Impairment Treatment with TYENNE is not recommended in patients with active hepatic disease or hepatic impairment [see Adverse Reactions (6.1), Use in Specific Populations (8.6)]. 5.9 Vaccinations Avoid use of live vaccines concurrently with TYENNE as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab products. No data are available on the effectiveness of vaccination in patients receiving tocilizumab products. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly pediatric or elderly patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating TYENNE therapy. The interval between live vaccinations and initiation of TYENNE therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: • Serious Infections [see Warnings and Precautions (5.1)] • Gastrointestinal Perforations [see Warnings and Precautions (5.2)] • Laboratory Parameters [see Warnings and Precautions (5.4)] • Immunosuppression [see Warnings and Precautions (5.5)] • Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.6)] • Demyelinating Disorders [see Warnings and Precautions (5.7)] • Active Hepatic Disease and Hepatic Impairment [see Warnings and Precautions (5.8)] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the 13 Reference ID: 5489050 clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. 6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (tocilizumab-IV) The tocilizumab-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of tocilizumab-IV 8 mg per kg monotherapy (288 patients), tocilizumab-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or tocilizumab-IV 4 mg per kg in combination with methotrexate (774 patients). The all exposure population includes all patients in registration studies who received at least one dose of tocilizumab-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years. All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian. The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1)]. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with tocilizumab-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT. The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking tocilizumab-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of tocilizumab-IV were increased hepatic transaminase values (per protocol requirement) and serious infections. Overall Infections In the 24 week, controlled clinical studies, the rate of infections in the tocilizumab-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 133 and 127 events per 100 patient- years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis. The overall rate of infections with tocilizumab-IV in the all exposure population remained consistent with rates in the controlled periods of the studies. Serious Infections In the 24 week, controlled clinical studies, the rate of serious infections in the tocilizumab-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group. In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported [see Warnings and Precautions (5.1)]. In the cardiovascular outcomes Study WA25204, the rate of serious infections in the tocilizumab 8 mg/kg IV every 4 weeks group, with or without DMARD, was 4.5 per 100 patient-years, and the rate in the etanercept 50 mg weekly SC group, with or without DMARD, was 3.2 per 100 patient-years [see Clinical Studies (14.1)]. Gastrointestinal Perforations During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with tocilizumab-IV therapy. Reference ID: 5489050 14 In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti- inflammatory medications (NSAIDs), corticosteroids, or methotrexate [see Warnings and Precautions (5.2)]. The relative contribution of these concomitant medications versus tocilizumab-IV to the development of GI perforations is not known. Infusion Reactions In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting. Anaphylaxis Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with tocilizumab-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of tocilizumab-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction [see Warnings and Precautions 5.6)]. Laboratory Abnormalities Neutropenia In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm3 occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm3 occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm3 and the occurrence of serious infections. In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.4)]. Thrombocytopenia In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm3 occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events. In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions 5.4)]. Elevated Liver Enzymes Liver enzyme abnormalities are summarized in Table 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tocilizumab-IV, or reduction in tocilizumab-IV dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration (2.1)]. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency [see Warnings and Reference ID: 5489050 15 Precautions (5.3, 5.4)]. Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V* Tocilizumab 8 mg per kg MONOTHERAPY N = 288 (%) Methotrexate N = 284 (%) Tocilizumab 4 mg per kg + DMARDs N = 774 (%) Tocilizumab 8 mg per kg + DMARDs N = 1582 (%) Placebo + DMARDs N = 1170 (%) AST (U/L) > ULN to 3x ULN 22 26 34 41 17 > 3x ULN to 5x ULN 0.3 2 1 2 0.3 > 5x ULN 0.7 0.4 0.1 0.2 < 0.1 ALT (U/L) > ULN to 3x ULN 36 33 45 48 23 > 3x ULN to 5x ULN 1 4 5 5 1 > 5x ULN 0.7 1 1.3 1.5 0.3 ULN = Upper Limit of Normal *For a description of these studies [see Section 14, Clinical Studies]. In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials. In Study WA25204, of the 1538 patients with moderate to severe RA [see Clinical Studies (14.1)] and treated with tocilizumab, elevations in ALT or AST >3 x ULN occurred in 5.3% and 2.2% patients, respectively. One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with tocilizumab. Lipids Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of tocilizumab-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below: – Mean LDL increased by 13 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 20 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 25 mg per dL in tocilizumab 8 mg per kg monotherapy. – Mean HDL increased by 3 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 5 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 4 mg per dL in tocilizumab 8 mg per kg monotherapy. – Mean LDL/HDL ratio increased by an average of 0.14 in the tocilizumab 4 mg per kg+DMARD arm, 0.15 in the tocilizumab 8 mg per kg+DMARD, and 0.26 in tocilizumab 8 mg per kg monotherapy. – ApoB/ApoA1 ratios were essentially unchanged in tocilizumab-treated patients. – Elevated lipids responded to lipid lowering agents. In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials. Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of tocilizumab or of other tocilizumab products. Reference ID: 5489050 16 In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies. Malignancies During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving tocilizumab-IV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the tocilizumab-IV groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years). In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period [see Warnings and Precautions (5.5)]. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg tocilizumab-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2. Table 2 Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per kg Tocilizumab plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD 24 Week Phase 3 Controlled Study Population Preferred Term Tocilizumab 8 mg per kg MONOTHERAPY N = 288 (%) Methotrexate N = 284 (%) Tocilizumab 4 mg per kg + DMARDs N = 774 (%) Tocilizumab 8 mg per kg + DMARDs N = 1582 (%) Placebo + DMARDs N = 1170 (%) Upper Respiratory Tract Infection 7 5 6 8 6 Nasopharyngitis 7 6 4 6 4 Headache 7 2 6 5 3 Hypertension 6 2 4 4 3 ALT increased 6 4 3 3 1 Dizziness 3 1 2 3 2 Bronchitis 3 2 4 3 3 Rash 2 1 4 3 1 Mouth Ulceration 2 2 1 2 1 Abdominal Pain Upper 2 2 3 3 2 Gastritis 1 2 1 2 1 Transaminase increased 1 5 2 2 1 Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with tocilizumab-IV in controlled trials were: Infections and Infestations: oral herpes simplex Gastrointestinal disorders: stomatitis, gastric ulcer Investigations: weight increased, total bilirubin increased Blood and lymphatic system disorders: leukopenia General disorders and administration site conditions: edema peripheral Respiratory, thoracic, and mediastinal disorders: dyspnea, cough Eye disorders: conjunctivitis Renal disorders: nephrolithiasis Endocrine disorders: hypothyroidism Reference ID: 5489050 17 6.2 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Subcutaneous Tocilizumab (tocilizumab-SC) The tocilizumab-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously and 8 mg/kg intravenously every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo- controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week subcutaneously or placebo in 656 patients. All patients in both studies received background non-biologic DMARDs. The safety observed for tocilizumab-SC administered subcutaneously was consistent with the known safety profile of intravenous tocilizumab, with the exception of injection site reactions (ISRs), which were more common with tocilizumab-SC compared with placebo SC injections (IV arm). Injection Site Reactions In the 6-month control period, in SC-I, the frequency of ISRs was 10.1% (64/631) and 2.4% (15/631) for the weekly tocilizumab-SC and placebo SC (IV-arm) groups, respectively. In SC-II, the frequency of ISRs was 7.1% (31/437) and 4.1% (9/218) for the every other week tocilizumab-SC and placebo groups, respectively. These ISRs (including erythema, pruritus, pain and hematoma) were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation. Immunogenicity In the 6-month control period in SC-I, 0.8% (5/625) in the tocilizumab-SC arm and 0.8% (5/627) in the IV arm developed anti-tocilizumab antibodies; of these, all developed neutralizing antibodies. In SC-II, 1.6% (7/434) in the tocilizumab-SC arm compared with 1.4 % (3/217) in the placebo arm developed anti-tocilizumab antibodies; of these, 1.4% (6/434) in the tocilizumab-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies. A total of 1454 (>99%) patients who received tocilizumab-SC in the all exposure group have been tested for anti­ tocilizumab antibodies. Thirteen patients (0.9%) developed anti-tocilizumab antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies. The rate is consistent with previous intravenous experience. No correlation of antibody development to adverse events or loss of clinical response was observed. Laboratory Abnormalities Neutropenia During routine laboratory monitoring in the 6-month controlled clinical trials, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% and 3.7% of patients receiving tocilizumab-SC weekly and every other week, respectively. There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections. Thrombocytopenia During routine laboratory monitoring in the tocilizumab-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤ 50,000/mm3. Elevated Liver Enzymes During routine laboratory monitoring in the 6-month controlled clinical trials, elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively, receiving tocilizumab-SC weekly and 3.4% and 0.7% receiving tocilizumab-SC every other week. Lipid Parameters Elevations During routine laboratory monitoring in the tocilizumab-SC 6-month clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and 10.2% of patients on placebo experienced sustained elevations Reference ID: 5489050 18 in total cholesterol > 6.2 mmol/l (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l (160 mg/dL) receiving tocilizumab-SC weekly, every other week and placebo, respectively. 6.3 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Subcutaneous Tocilizumab (tocilizumab-SC) The safety of subcutaneous tocilizumab has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the tocilizumab-SC GCA all exposure population was 138.5 patient years during the 12-month double blind, placebo-controlled phase of the study. The overall safety profile observed in the tocilizumab-SC treatment groups was generally consistent with the known safety profile of tocilizumab. There was an overall higher incidence of infections in GCA patients relative to RA patients. The rate of infection/serious infection events was 200.2/9.7 events per 100 patient years in the tocilizumab-SC weekly group and 160.2/4.4 events per 100 patient years in the tocilizumab-SC every other week group as compared to 156.0/4.2 events per 100 patient years in the placebo + 26 week prednisone taper and 210.2/12.5 events per 100 patient years in the placebo + 52 week taper groups. 6.4 Clinical Trials Experience in Giant Cell Arteritis Patients Treated With Intravenous Tocilizumab (tocilizumab-IV) The safety of tocilizumab-IV was studied in an open label PK-PD and safety study in 24 patients with GCA who were in remission on tocilizumab-IV at time of enrollment. Patients received tocilizumab 7 mg/kg every 4 weeks for 20 weeks, followed by 6 mg/kg every 4 weeks for 20 weeks. The total patient years exposure to treatment was 17.5 years. The overall safety profile observed for tocilizumab administered intravenously in GCA patients was consistent with the known safety profile of tocilizumab. 6.5 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Intravenous Tocilizumab (tocilizumab-IV) The safety of tocilizumab-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the tocilizumab-IV all exposure population (defined as patients who received at least one dose of tocilizumab-IV) was 184.4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients [see Adverse Reactions (6.1 and 6.7)]. Infections The rate of infections in the tocilizumab-IV all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%). Infusion Reactions In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the tocilizumab-IV all exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and SJIA patients [see Adverse Reactions (6.1 and 6.7)]. No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported. Reference ID: 5489050 19 Immunogenicity One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study. Laboratory Abnormalities Neutropenia During routine laboratory monitoring in the tocilizumab-IV all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 3.7% of patients. There was no clear relationship between decreases in neutrophils below 1 x 109 per L and the occurrence of serious infections. Thrombocytopenia During routine laboratory monitoring in the tocilizumab-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50,000 per mm3 without associated bleeding events. Elevated Liver Enzymes During routine laboratory monitoring in the tocilizumab-IV all exposure population, elevation in ALT or AST at or greater than 3 x ULN occurred in 4% and less than 1% of patients, respectively. Lipids During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol greater than 1.5-2 x ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 x ULN occurred in one patient (0.5%). 6.6 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Subcutaneous Tocilizumab (tocilizumab-SC) The safety of tocilizumab-SC was studied in 52 pediatric patients 1 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the PJIA tocilizumab-SC population (defined as patients who received at least one dose of tocilizumab-SC and accounting for treatment discontinuation) was 49.5 patient years. In general, the safety observed for tocilizumab administered subcutaneously was consistent with the known safety profile of intravenous tocilizumab, with the exception of injection site reactions (ISRs), and neutropenia. Injection Site Reactions During the 1-year study, a frequency of 28.8% (15/52) ISRs was observed in tocilizumab-SC treated PJIA patients. These ISRs occurred in a greater proportion of patients at or above 30 kg (44.0%) compared with patients below 30 kg (14.8%). All ISRs were mild in severity and none of the ISRs required patient withdrawal from treatment or dose interruption. A higher frequency of ISRs was observed in tocilizumab-SC treated PJIA patients compared to what was seen in adult RA or GCA patients [see Adverse Reactions (6.2 and 6.3)]. Immunogenicity Three patients, 1 patient below 30 kg and 2 patients at or above 30 kg, developed positive anti-tocilizumab antibodies with neutralizing potential without developing a serious or clinically significant hypersensitivity reaction. One patient subsequently withdrew from the study. Neutropenia During routine laboratory monitoring in the tocilizumab-SC all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 15.4% of patients, and was more frequently observed in the patients less than 30 kg (25.9%) compared to patients at or above 30 kg (4.0%). There was no clear relationship between decreases in neutrophils below 1 x 109 per L and the occurrence of serious infections. Reference ID: 5489050 20 6.7 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (tocilizumab-IV) The data described below reflect exposure to tocilizumab-IV in one randomized, double-blind, placebo-controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy. At baseline, approximately half of the patients were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension. In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with tocilizumab-IV (8 or 12 mg per kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated with tocilizumab-IV in the open-label extension phase. The most common adverse events (at least 5%) seen in tocilizumab-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea. Infections In the 12 week controlled phase, the rate of all infections in the tocilizumab-IV group was 345 per 100 patient- years and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years. In the 12 week controlled phase, the rate of serious infections in the tocilizumab-IV group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media. Macrophage Activation Syndrome In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with tocilizumab-IV. One patient in the placebo group escaped to tocilizumab-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had tocilizumab-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the tocilizumab-IV SJIA clinical development experience; however no definitive conclusions can be made. Infusion Reactions Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA. Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of tocilizumab-IV and 0% of placebo treated patients experienced events occurring during infusion. One event (angioedema) was considered serious and life- threatening, and the patient was discontinued from study treatment. Within 24 hours after infusion, 16% of patients in the tocilizumab-IV treatment group and 5% of patients in the placebo group experienced an event. In the tocilizumab-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious. Anaphylaxis Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with tocilizumab-IV during the controlled and open label extension study [see Warnings and Precautions (5.6)]. Immunogenicity All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti­ tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage Reference ID: 5489050 21 activation syndrome while on escape therapy and was discontinued from the study. Laboratory Abnormalities Neutropenia During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 × 109 per L occurred in 7% of patients in the tocilizumab-IV group, and in no patients in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the tocilizumab-IV group. There was no clear relationship between decrease in neutrophils below 1 x 109 per L and the occurrence of serious infections. Thrombocytopenia During routine monitoring in the 12 week controlled phase, 1% of patients in the tocilizumab-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100,000 per mm3. In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the tocilizumab-IV group, with no associated bleeding. Elevated Liver Enzymes During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3x ULN occurred in 5% and 3% of patients, respectively in the tocilizumab-IV group and in 0% of placebo patients. In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3x ULN occurred in 13% and 5% of tocilizumab-IV treated patients, respectively. Lipids During routine laboratory monitoring in the 12 week controlled phase, elevation in total cholesterol greater than 1.5x ULN – 2x ULN occurred in 1.5% of the tocilizumab-IV group and in 0% of placebo patients. Elevation in LDL greater than 1.5x ULN – 2x ULN occurred in 1.9% of patients in the tocilizumab-IV group and 0% of the placebo group. In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data. 6.8 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Subcutaneous Tocilizumab (tocilizumab-SC) The safety profile of tocilizumab-SC was studied in 51 pediatric patients 1 to 17 years of age with SJIA who had an inadequate clinical response to NSAIDs and corticosteroids. In general, the safety observed for tocilizumab administered subcutaneously was consistent with the known safety profile of intravenous tocilizumab, with the exception of ISRs where a higher frequency was observed in tocilizumab-SC treated SJIA patients compared to PJIA patients and adult RA or GCA patients [see Adverse Reactions (6.2, 6.3 and 6.6)]. Injection Site Reactions (ISRs) A total of 41.2% (21/51) SJIA patients experienced ISRs to tocilizumab-SC. The most common ISRs were erythema, pruritus, pain, and swelling at the injection site. The majority of ISRs reported were Grade 1 events and all ISRs reported were non-serious and none required patient withdrawal from treatment or dose interruption. Immunogenicity Forty-six of the 51 (90.2%) patients who were tested for anti-tocilizumab antibodies at baseline had at least one post-baseline screening assay result. No patient developed positive anti-tocilizumab antibodies post-baseline. 6.9 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tocilizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Reference ID: 5489050 22 • Hypersensitivity Reactions: Fatal anaphylaxis, Stevens-Johnson Syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)] • Pancreatitis • Drug-induced liver injury, Hepatitis, Hepatic failure, Jaundice [see Warnings and Precautions (5.3)] 7 DRUG INTERACTIONS 7.1 Concomitant Drugs for Treatment of Adult Indications In RA patients, population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non- steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. Concomitant administration of a single intravenous dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration (2.2)]. In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed. 7.2 Interactions with CYP450 Substrates Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab products may restore CYP450 activities to higher levels than those in the absence of tocilizumab products leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effect on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of tocilizumab, respectively. The effect of tocilizumab products on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of TYENNE, in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise caution when coadministering TYENNE with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab products on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12.3)]. 7.3 Live Vaccines Avoid use of live vaccines concurrently with TYENNE [see Warnings and Precautions (5.9)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The limited available data with tocilizumab products in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as tocilizumab products, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant [see Clinical Considerations]. In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition [see Data]. Based on the animal data, there may be a potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized 23 Reference ID: 5489050 pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to TYENNE in utero [see Warnings and Precautions 5.9)]. Data Animal Data An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring. Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery. 8.2 Lactation Risk Summary No information is available on the presence of tocilizumab products in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab products are transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab products are unknown. The lack of clinical data during lactation precludes clear determination of the risk of tocilizumab products to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TYENNE and the potential adverse effects on the breastfed child from TYENNE or from the underlying maternal condition. 8.4 Pediatric Use TYENNE by intravenous use is indicated for the treatment of pediatric patients with: • Active systemic juvenile idiopathic arthritis in patients 2 years of age and older • Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older TYENNE by subcutaneous use is indicated for the treatment of pediatric patients with: • Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older • Active systemic juvenile idiopathic arthritis in patients 2 years of age and older The safety and effectiveness of TYENNE in pediatric patients with conditions other than PJIA or SJIA have not been established. The safety and effectiveness in pediatric patients below the age of 2 have not been established in PJIA or SJIA. Reference ID: 5489050 24 Systemic Juvenile Idiopathic Arthritis – Intravenous Use A multicenter, open-label, single arm study to evaluate the PK, safety and exploratory PD and efficacy of tocilizumab over 12-weeks in SJIA patients (N=11) under 2 years of age was conducted. Patients received intravenous tocilizumab 12 mg/kg every two weeks. Concurrent use of stable background treatment with corticosteroids, MTX, and/or non-steroidal anti-inflammatory drugs was permitted. Patients who completed the 12-week period could continue to the optional extension period (a total of 52-weeks or until the age of 2 years, whichever was longer). The primary PK endpoints (Cmax, Ctrough and AUC2weeks) of tocilizumab at steady-state in this study were within the ranges of these parameters observed in patients with SJIA aged 2 to 17 years. The safety and immunogenicity of tocilizumab for patients with SJIA under 2 years of age was assessed descriptively. SAEs, AEs leading to discontinuation, and infectious AEs were reported by 27.3%, 36.4%, and 81.8% of patients. Six patients (54.5%) experienced hypersensitivity reactions, defined as all adverse events occurring during or within 24 hours after an infusion considered related to tocilizumab. Three of these patients experienced serious hypersensitivity reactions and were withdrawn from the study. Three patients with hypersensitivity reactions (two with serious hypersensitivity reactions) developed treatment induced anti­ tocilizumab antibodies after the event. There were no cases of MAS based on the protocol-specified criteria, but 2 cases of suspected MAS based on Ravelli criteria1. 8.5 Geriatric Use Of the 2644 patients who received tocilizumab in Studies I to V [see Clinical Studies (14)], a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. Of the 1069 patients who received tocilizumab-SC in studies SC-I and SC-II there were 295 patients 65 years of age and older, including 41 patients 75 years and older. The frequency of serious infection among tocilizumab treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly. 8.6 Hepatic Impairment The safety and efficacy of tocilizumab products have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology [see Warnings and Precautions 5.8)]. 8.7 Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. Tocilizumab products have not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. 9 DRUG ABUSE AND DEPENDENCE No studies on the potential for tocilizumab products to cause dependence have been performed. However, there is no evidence from the available data that tocilizumab products treatment results in dependence. 10 OVERDOSAGE There are limited data available on overdoses with tocilizumab products. One case of accidental overdose was reported with intravenous tocilizumab in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse 1 Ravelli A, Minoia F, Davì S on behalf of the Paediatric Rheumatology International Trials Organisation, the Childhood Arthritis and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis. Annals of the Rheumatic Diseases 2016;75:481-489 25 Reference ID: 5489050 reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment. 11 DESCRIPTION Tocilizumab-aazg is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H2L2 polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids (excluding the C-terminal lysine), respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. Tocilizumab-aazg has a molecular weight of approximately 148 kDa. The antibody is produced in mammalian (Chinese hamster ovary) cells. Intravenous Infusion TYENNE (tocilizumab-aazg) injection is a sterile, clear and colorless to pale yellow, histidine buffered preservative-free solution with a pH of approximately 6 for further dilution prior to intravenous infusion. Each single-dose vial is available at a concentration of 20 mg/mL containing 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL of TYENNE. Each mL of solution contains arginine (17.4 mg), histidine (3.1 mg), lactic acid (0.9 mg), polysorbate 80 (0.2 mg), sodium chloride (0.6 mg), and Water for Injection, USP. Hydrochloric acid and sodium hydroxide are added to adjust the pH. Subcutaneous Injection TYENNE (tocilizumab-aazg) injection is a sterile, clear, colorless to pale yellow, preservative-free, histidine buffered solution with a pH of approximately 6 for subcutaneous use. It is supplied in a ready-to-use, single-dose 0.9 mL prefilled syringe (PFS) with a needle safety device or in a ready-to-use, single-dose 0.9 mL autoinjector that delivers 162 mg tocilizumab-aazg, arginine (16.7 mg), histidine (2.0 mg), lactic acid (0.9 mg), polysorbate 80 (0.2 mg), sodium chloride (0.6 mg), and Water for Injection, USP. Hydrochloric acid and sodium hydroxide are added to adjust the pH. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tocilizumab products bind to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and have been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis. 12.2 Pharmacodynamics In clinical studies in RA patients with the 4 mg per kg and 8 mg per kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of tocilizumab, decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen and increases in hemoglobin) with doses, however the greatest improvements were observed with 8 mg per kg tocilizumab. Pharmacodynamic changes were also observed to occur after tocilizumab administration in GCA, PJIA, and SJIA patients (decreases in CRP, ESR, and increases in hemoglobin). The relationship between these pharmacodynamic findings and clinical efficacy is not known. In healthy subjects administered tocilizumab in doses from 2 to 28 mg per kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to the nadir 3 to 5 days following tocilizumab administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis and GCA patients demonstrated a similar pattern of absolute neutrophil counts following tocilizumab administration [see Warnings and Precautions (5.4)]. Reference ID: 5489050 26 12.3 Pharmacokinetics PK of tocilizumab is characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of tocilizumab elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies. Rheumatoid Arthritis – Intravenous and Subcutaneous Administration The pharmacokinetics in healthy subjects and RA patients suggest that PK is similar between the two populations. The population PK model was developed from an analysis dataset composed of an IV dataset of 1793 patients from Study I, Study III, Study IV, and Study V, and from an IV and SC dataset of 1759 patients from Studies SC-I and SC-II. Cmean is included in place of AUCtau, since for dosing regimens with different inter-dose intervals, the mean concentration over the dosing period characterizes the comparative exposure better than AUCtau. At high serum concentrations, when total clearance of tocilizumab is dominated by linear clearance, a terminal half-life of approximately 21.5 days was derived from the population parameter estimates. For doses of 4 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab at steady state were 86.1 (44.8–202) mcg/mL, 0.1 (0.0–14.6) mcg/mL, and 18.0 (8.9– 50.7) mcg/mL, respectively. For doses of 8 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 176 (75.4–557) mcg/mL, 13.4 (0.1–154) mcg/mL, and 54.0 (17–260) mcg/mL, respectively. Cmax increased dose-proportionally between doses of 4 and 8 mg/kg IV every 4 weeks, while a greater than dose-proportional increase was observed in Cmean and Ctrough. At steady-state, Cmean and Ctrough were 3.0 and 134 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively. The accumulation ratios for AUC and Cmax after multiple doses of 4 and 8 mg/kg IV Q4W are low, while the accumulation ratios for Ctrough are higher (2.62 and 2.47, respectively). For Cmax, greater than 90% of the steady- state value was reached after the 1st IV infusion. For AUCtau and Cmean, 90% of the steady-state value was reached after the 1st and 3rd infusion for 4 mg/kg and 8 mg/kg IV, while for Ctrough, approximately 90% of the steady- state value was reached after the 4th IV infusion after both doses. For doses of 162 mg given every other week subcutaneously, the estimated median (range) steady-state Cmax, Ctrough, and Cmean of tocilizumab were 12.1 (0.4–49.3) mcg/mL, 4.1 (0.0–34.2) mcg/mL, and 9.2 (0.2– 43.6) mcg/mL, respectively. For doses of 162 mg given every week subcutaneously, the estimated median (range) steady-state Cmax, Ctrough, and Cmean of tocilizumab were 49.8 (3–150) mcg/mL, 42.9 (1.3–144) mcg/mL, and 47.3 (2.4–147) mcg/mL, respectively. Exposures after the 162 mg SC QW regimen were greater by 5.1 (Cmean) to 10.5 fold (Ctrough) compared to the 162 mg SC Q2W regimen. Accumulation ratios after multiple doses of either SC regimen were higher than after IV regimen with the highest ratios for Ctrough (6.02 and 6.30, for 162 mg SC Q2W and 162 mg SC QW, respectively). The higher accumulation for Ctrough was expected based on the nonlinear clearance contribution at lower concentrations. For Cmax, greater than 90% of the steady-state value was reached after the 5th SC and the 12th SC injection with the Q2W and QW regimens, respectively. For AUCtau and Cmean, 90% of the steady-state value was reached after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens, respectively. For Ctrough, approximately 90% of the steady- state value was reached after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens, respectively. Population PK analysis identified body weight as a significant covariate impacting the pharmacokinetics of tocilizumab. When given IV on a mg/kg basis, individuals with body weight ≥ 100 kg are predicted to have mean steady-state exposures higher than mean values for the patient population. Therefore, tocilizumab doses exceeding Reference ID: 5489050 27 - 800 mg per infusion are not recommended in patients with RA [see Dosage and Administration (2.2)]. Due to the flat dosing employed for SC administration of tocilizumab, no modifications are necessary by this dosing route. Giant Cell Arteritis – Subcutaneous and Intravenous Administration The pharmacokinetics of tocilizumab S C in GCA patients was determined using a population pharmacokinetic analysis on a dataset composed of 149 GCA patients treated with 162 mg subcutaneously every week or with 162 mg subcutaneously every other week. For the 162 mg every week dose, the estimated median (range) steady-state Cmax, Ctrough and Cmean of tocilizumab SC were 72.1 (12.2–151) mcg/mL, 67.2 (10.7–145) mcg/mL, and 70.6 (11.7–149) mcg/mL, respectively. The accumulation ratios for Cmean or AUCtau, Ctrough, and Cmax were 10.9, 9.6, and 8.9, respectively. Steady state was reached after 17 weeks. For the 162 mg every other week dose, the estimated median (range) steady-state Cmax, Ctrough, and Cmean of tocilizumab were 17.2 (1.1–56.2) mcg/mL, 7.7 (0.1–37.3) mcg/mL, and 13.7 (0.5– 49) mcg/mL, respectively. The accumulation ratios for Cmean or AUCtau, Ctrough, and Cmax were 2.8, 5.6, and 2.3 respectively. Steady-state was reached after 14 weeks. The pharmacokinetics of tocilizumab IV in GCA patients was characterized by a non-compartmental pharmacokinetic analysis which included 22 patients treated with 6 mg/kg intravenously every 4 weeks for 20 weeks. The median (range) Cmax, Ctrough and Cmean of tocilizumab at steady state were 178 (115-320) mcg/mL, 22.7 (3.38-54.5) mcg/mL and 57.5 (32.9-110) mcg/mL, respectively. Steady state trough concentrations were within the range observed in GCA patients treated with 162 mg TCZ SC administered every week or every other week. Based on pharmacokinetic exposure and extrapolation between RA and GCA patients, when given IV on a mg/kg basis, tocilizumab doses exceeding 600 mg per infusion are not recommended in patients with GCA [see Dosage and Administration (2.3)]. Polyarticular Juvenile Idiopathic Arthritis – Intravenous and Subcutaneous Administration The pharmacokinetics of tocilizumab (TCZ) in PJIA patients was characterized by a population pharmacokinetic analysis which included 188 patients who were treated with TCZ IV or 52 patients treated with TCZ SC. For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab at steady state were 181 (114– 331) mcg/mL, 3.28 (0.02–35.4) mcg/mL, and 38.6 (22.2–83.8) mcg/mL, respectively. For doses of 10 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 167 (125–220) mcg/mL, 0.35 (0– 11.8) mcg/mL, and 30.8 (16.0–48.0) mcg/mL, respectively. The accumulation ratios were 1.05 and 1.16 for AUC4weeks, and 1.43 and 2.22 for Ctrough for 10 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. No accumulation for Cmax was observed. Following 10 mg/kg and 8 mg/kg TCZ IV every 4 weeks doses in PJIA patients (aged 2 to 17 years), steady state concentrations (trough and average) were within the range of exposures in adult RA patients following 4 mg/kg and 8 mg/kg every 4 weeks, and steady state peak concentrations in PJIA patients were comparable to those following 8 mg/kg every 4 weeks in adult RA patients. For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks subcutaneously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 29.7 (7.56–50.3) mcg/mL, 12.7 (0.19–23.8) mcg/mL, and 23.0 (3.86–36.9) mcg/mL, respectively. For doses of 162 mg tocilizumab (patients with a body weight less than 30 kg) given every 3 weeks subcutaneously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 62.4 (39.4–121) mcg/mL, 13.4 (0.21–52.3) mcg/mL, and 35.7 (17.4– 91.8) mcg/mL, respectively. The accumulation ratios were 1.46 and 2.04 for AUC4weeks, 2.08 and 3.58 for Ctrough, and 1.32 and 1.72 for Cmax, for 162 mg given every 3 weeks (BW less than 30 kg) and 162 mg given every 2 weeks (BW at or above 30 kg) subcutaneous doses, respectively. Following subcutaneous dosing, steady state Ctrough was comparable for patients Reference ID: 5489050 28 in the two body weight groups, while steady-state Cmax and Cmean were higher for patients in the less than 30 kg group compared to the group at or above 30 kg. All patients treated with TCZ SC had steady-state Ctrough at or higher than that achieved with TCZ IV across the spectrum of body weights. The average and trough concentrations in patients after subcutaneous dosing were within the range of those achieved in adult patients with RA following the subcutaneous administration of the recommended regimens. Systemic Juvenile Idiopathic Arthritis – Intravenous and Subcutaneous Administration The pharmacokinetics of tocilizumab (TCZ) in SJIA patients was characterized by a population pharmacokinetic analysis which included 89 patients who were treated with TCZ IV or 51 patients treated with TCZ SC. For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 253 (120–404) mcg/mL, 70.7 (5.26–127) mcg/mL, and 117 (37.6–199) mcg/mL, respectively. For doses of 12 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 274 (149–444) mcg/mL, 65.9 (19.0–135) mcg/mL, and 124 (60–194) mcg/mL, respectively. The accumulation ratios were 1.95 and 2.01 for AUC4weeks, and 3.41 and 3.20 for Ctrough for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. Accumulation data for Cmax were 1.37 and 1.42 for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. Following every other week dosing with tocilizumab IV, steady state was reached by 8 weeks for both body weight groups. Mean estimated tocilizumab exposure parameters were similar between the two dose groups defined by body weight. For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every week subcutaneously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 89.8 (26.4– 190) mcg/mL, 72.4 (19.5–158) mcg/mL, and 82.4 (23.9–169) mcg/mL, respectively. For doses of 162 mg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks subcutaneously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 127 (51.7–266) mcg/mL, 64.2 (16.6–136) mcg/mL, and 92.7 (38.5–199) mcg/mL, respectively. The accumulation ratios were 2.27 and 4.28 for AUC4weeks, 3.21 and 4.39 for Ctrough, and 1.88 and 3.66 for Cmax, for 162 mg given every 2 weeks (BW less than 30 kg) and 162 mg given every week (BW at or above 30 kg) subcutaneous doses, respectively. Following subcutaneous dosing, steady state was reached by 12 weeks for both body weight groups. All patients treated with tocilizumab SC had steady-state Cmax lower than that achieved with tocilizumab IV across the spectrum of body weights. Trough and mean concentrations in patients after SC dosing were similar to those achieved with tocilizumab IV across body weights. Absorption Following subcutaneous dosing, the absorption half-life was around 4 days in RA and GCA patients. The bioavailability for the subcutaneous formulation was 80%. Following subcutaneous dosing in PJIA patients, the absorption half-life was around 2 days, and the bioavailability for the subcutaneous formulation in PJIA patients was 96%. Following subcutaneous dosing in SJIA patients, the absorption half-life was around 2 days, and the bioavailability for the SC formulation in SJIA patients was 95%. In RA patients the median values of Tmax were 2.8 days after the tocilizumab every week dose and 4.7 days after the tocilizumab every other week dose. In GCA patients, the median values of Tmax were 3 days after the tocilizumab every week dose and 4.5 days after the tocilizumab every other week dose. Reference ID: 5489050 29 Distribution Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L. In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution was 3.37 L resulting in a volume of distribution at steady state of 7.46 L. In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L. In pediatric patients with SJIA, the central volume of distribution was 1.87 L, the peripheral volume of distribution was 2.14 L resulting in a volume of distribution at steady state of 4.01 L. Elimination Tocilizumab is eliminated by a combination of linear clearance and nonlinear elimination. The concentration- dependent nonlinear elimination plays a major role at low tocilizumab concentrations. Once the nonlinear pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance. The saturation of the nonlinear elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies. The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA patients, 6.7 mL per h in GCA patients, 5.8 mL per h in pediatric patients with PJIA, and 5.7 mL per h in pediatric patients with SJIA. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. For intravenous administration in RA patients, the concentration-dependent apparent t1/2 is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For subcutaneous administration in RA patients, the concentration-dependent apparent t1/2 is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state. In GCA patients at steady state, the effective t1/2 of tocilizumab varied between 18.3 and 18.9 days for 162 mg subcutaneously every week dosing regimen and between 4.2 and 7.9 days for 162 mg subcutaneously every other week dosing regimen. For intravenous administration in GCA patients, the TCZ concentration-dependent apparent t1/2 was 13.2 days following 6 mg/kg every 4 weeks. The t1/2 of tocilizumab in children with PJIA is up to 17 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg or 10 mg/kg for body weight below 30 kg) during a dosing interval at steady state. For subcutaneous administration, the t1/2 of tocilizumab in PJIA patients is up to 10 days for the two body weight categories (every other week regimen for body weight at or above 30 kg or every 3 week regimen for body weight less than 30 kg) during a dosing interval at steady state. The t1/2 of tocilizumab intravenous in pediatric patients with SJIA is up to 16 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg and 12 mg/kg for body weight below 30 kg every other week) during a dosing interval at steady-state. Following subcutaneous administration, the effective t1/2 of tocilizumab subcutaneous in SJIA patients is up to 14 days for both the body weight categories (162 mg every week for body weight at or above 30 kg and 162 mg every two weeks for body weight below 30 kg) during a dosing interval at steady state. Reference ID: 5489050 30 Specific Populations Population pharmacokinetic analyses in adult rheumatoid arthritis patients and GCA patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. In RA patients, the body weight-based dose (8 mg per kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg. There was an inverse relationship between tocilizumab exposure and body weight for flat dose subcutaneous regimens. In GCA patients treated with tocilizumab-SC, higher exposure was observed in patients with lower body weight. For the 162 mg every week subcutaneous dosing regimen, the steady-state Cmean was 51% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. For the 162 mg every other week subcutaneous regimen, the steady-state Cmean was 129% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. There is limited data for patients above 100 kg (n=7). Patients with Hepatic Impairment No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted. Patients with Renal Impairment No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted. Most of the RA and GCA patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance less than 80 mL per min and at or above 50 mL per min based on Cockcroft-Gault formula) did not impact the pharmacokinetics of tocilizumab. Approximately one-third of the patients in the tocilizumab-SC GCA clinical trial had moderate renal impairment at baseline (estimated creatinine clearance of 30-59 mL/min). No impact on tocilizumab exposure was noted in these patients. No dose adjustment is required in patients with mild or moderate renal impairment. Drug Interaction Studies In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of TYENNE, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when TYENNE is coadministered with drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives (CYP3A4 substrates) [see Drug Interactions (7.2)]. Simvastatin Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with tocilizumab, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of tocilizumab (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of tocilizumab in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of TYENNE (due to normalization of CYP3A4) or higher exposures after discontinuation of TYENNE. Reference ID: 5489050 31 Omeprazole Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after tocilizumab infusion (8 mg per kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects. Dextromethorphan Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of tocilizumab (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after tocilizumab infusion. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab products. Literature indicates that the IL-6 pathway can mediate anti-tumor responses by promoting increased immune cell surveillance of the tumor microenvironment. However, available published evidence also supports that IL-6 signaling through the IL-6 receptor may be involved in pathways that lead to tumorigenesis. The malignancy risk in humans from an antibody that disrupts signaling through the IL-6 receptor, such as tocilizumab, is presently unknown. Fertility and reproductive performance were unaffected in male and female mice that received a murine analogue of tocilizumab administered by the intravenous route at a dose of 50 mg/kg every three days. 14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis – Intravenous Administration The efficacy and safety of intravenously administered tocilizumab was assessed in five randomized, double-blind, multicenter studies in patients greater than 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. Tocilizumab was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V). Study I (NCT00109408) evaluated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 24 weeks prior to randomization, or who had not discontinued previous methotrexate treatment as a result of clinically important toxic effects or lack of response. In this study, 67% of patients were MTX-naïve, and over 40% of patients had rheumatoid arthritis less than 2 years. Patients received tocilizumab 8 mg per kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly). The primary endpoint was the proportion of tocilizumab patients who achieved an ACR 20 response at Week 24. Study II (NCT00106535) was a 104-week study with an optional 156-week extension phase that evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). Upon completion of 52-weeks, patients received open-label treatment with tocilizumab 8 mg per kg through 104 weeks or they had the option to continue their double-blind treatment if they maintained a greater than 70% improvement in swollen/tender joint count. Two pre-specified interim analyses at week 24 and week 52 were conducted. The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At weeks 52 and 104, the primary endpoints were change from baseline in modified total Sharp-Genant score and the area under the curve (AUC) of the change from baseline in HAQ-DI score. Reference ID: 5489050 32 Study III (NCT00106548) evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Study IV (NCT00106574) evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received tocilizumab 8 mg per kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Study V (NCT00106522) evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomization. Patients received tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Clinical Response The percentages of intravenous tocilizumab-treated patients achieving ACR 20, 50 and 70 responses are shown in Table 3. In all intravenous studies, patients treated with 8 mg per kg tocilizumab had higher ACR 20, ACR 50, and ACR 70 response rates versus MTX- or placebo-treated patients at week 24. During the 24 week controlled portions of Studies I to V, patients treated with tocilizumab at a dose of 4 mg per kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with tocilizumab 8 mg per kg. Reference ID: 5489050 33 Table 3 Clinical Response at Weeks 24 and 52 in Active and Placebo Controlled Trials of Intravenous Tocilizumab (Percent of Patients) Percent of Patients Study I Study II Study III Study IV Study V Response Rate Tocilizumab MTX 8 mg per kg N=284 N=286 (95% CI)a Tocilizumab Tocilizumab Placebo + 4 mg per kg 8 mg per kg MTX + MTX + MTX N=393 N=399 N=398 (95% CI)a (95% CI)a Tocilizumab Tocilizumab Placebo + 4 mg per kg 8 mg per kg MTX + MTX + MTX N=204 N=213 N=205 (95% CI)a (95% CI)a Tocilizumab Placebo + 8 mg per kg DMARDs + DMARDs N=413 N=803 (95% CI)a Tocilizumab Tocilizumab Placebo + 4 mg per kg 8 mg per kg MTX + MTX + MTX N=158 N=161 N=170 (95% CI)a (95% CI)a ACR 20 Week 24 53% 70% 27% 51% 56% 27% 48% 59% 24% 61% 10% 30% 50% (0.11, 0.27) (0.17, 0.29) (0.23, 0.35) (0.15, 0.32) (0.23, 0.41) (0.30, 0.40) (0.15, 0.36) (0.36, 0.56) Week 52 N/A N/A 25% 47% 56% N/A N/A N/A N/A N/A N/A N/A N/A ACR 50 (0.15, 0.28) (0.25, 0.38) Week 24 34% 44% 10% 25% 32% 11% 32% 44% 9% 38% 4% 17% 29% (0.04, 0.20) (0.09, 0.20) (0.16, 0.28) (0.13, 0.29) (0.25, 0.41) (0.23, 0.33) (0.05, 0.25) (0.21, 0.41) Week 52 N/A N/A 10% 29% 36% N/A N/A N/A N/A N/A N/A N/A N/A ACR 70 (0.14, 0.25) (0.21, 0.32) Week 24 15% 28% 2% 11% 13% 2% 12% 22% 3% 21% 1% 5% 12% (0.07, 0.22) (0.03, 0.13) (0.05, 0.15) (0.04, 0.18) (0.12, 0.27) (0.13, 0.21) (-0.06, 0.14) (0.03, 0.22) Week 52 N/A N/A 4% 16% 20% N/A N/A N/A N/A N/A N/A N/A N/A Major Clinical Responses b (0.08, 0.17) (0.12, 0.21) Week 52 N/A N/A 1% 4% 7% N/A N/A N/A N/A N/A N/A N/A N/A (0.01, 0.06) (0.03, 0.09) a CI: 95% confidence interval of the weighted difference to placebo adjusted for site (and disease duration for Study I only) b Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week period Reference ID: 5489050 34 In study II, a greater proportion of patients treated with 4 mg per kg and 8 mg per kg tocilizumab + MTX achieved a low level of disease activity as measured by a DAS 28-ESR less than 2.6 compared with placebo+ MTX treated patients at week 52. The proportion of tocilizumab-treated patients achieving DAS 28-ESR less than 2.6, and the number of residual active joints in these responders in Study II are shown in Table 4. Table 4 Proportion of Patients with DAS28-ESR Less Than 2.6 with Number of Residual Active Joints in Trials of Intravenous Tocilizumab Study II Placebo + MTX N = 393 Tocilizumab 4 mg per kg + MTX N = 399 Tocilizumab 8 mg per kg + MTX N = 398 DAS28-ESR less than 2.6 Proportion of responders at week 52 (n) 95% confidence interval 3% (12) 18% (70) 0.10, 0.19 32% (127) 0.24, 0.34 Of responders, proportion with 0 active joints (n) 33% (4) 27% (19) 21% (27) Of responders, proportion with 1 active joint (n) 8% (1) 19% (13) 13% (16) Of responders, proportion with 2 active joints (n) 25% (3) 13% (9) 20% (25) Of responders, proportion with 3 or more active joints (n) 33% (4) 41% (29) 47% (59) *n denotes numerator of all the percentage. Denominator is the intent-to-treat population. Not all patients received DAS28 assessments at Week 52. The results of the components of the ACR response criteria for Studies III and V are shown in Table 5. Similar results to Study III were observed in Studies I, II and IV. Table 5 Components of ACR Response at Week 24 in Trials of Intravenous Tocilizumab Study III Study V Tocilizumab 4 mg per kg + MTX N=213 Tocilizumab 8 mg per kg + MTX N=205 Placebo + MTX N=204 Tocilizumab 4 mg per kg + MTX N=161 Tocilizumab 8 mg per kg + MTX N=170 Placebo + MTX N=158 Component (mean) Baseline Week 24a Baseline Week 24 a Baseline Week 24 Baseline Week 24 a Baseline Week 24 a Baseline Week 24 Number of tender joints (0-68) 33 19 -7.0 (-10.0, -4.1) 32 14.5 -9.6 (-12.6, -6.7) 33 25 31 21 -10.8 (-14.6, -7.1) 32 17 -15.1 (-18.8, -11.4) 30 30 Number of swollen joints (0-66) 20 10 -4.2 (-6.1, -2.3) 19.5 8 -6.2 (-8.1, -4.2) 21 15 19.5 13 -6.2 (-9.0, -3.5) 19 11 -7.2 (-9.9, -4.5) 19 18 Painb 61 33 -11.0 (-17.0, -5.0) 60 30 -15.8 (-21.7, -9.9) 57 43 63.5 43 -12.4 (-22.1, -2.1) 65 33 -23.9 (-33.7, -14.1) 64 48 Patient global b assessment 66 34 -10.9 (-17.1, -4.8) 65 31 -14.9 (-20.9, -8.9) 64 45 70 46 -10.0 (-20.3, 0.3) 70 36 -17.4 (-27.8, -7.0) 71 51 Physician global b assessment 64 26 -5.6 (-10.5, -0.8) 64 23 -9.0 (-13.8, -4.2) 64 32 66.5 39 -10.5 (-18.6, -2.5) 66 28 -18.2 (-26.3, -10.0) 67.5 43 Disability index (HAQ)c 1.64 1.01 -0.18 (-0.34, -0.02) 1.55 0.96 -0.21 (-0.37, -0.05) 1.55 1.21 1.67 1.39 -0.25 (-0.42, -0.09) 1.75 1.34 -0.34 (-0.51, -0.17) 1.70 1.58 CRP (mg per dL) 2.79 1.17 -1.30 (-2.0, -0.59) 2.61 0.25 -2.156 (-2.86, -1.46) 2.36 1.89 3.11 1.77 -1.34 (-2.5, -0.15) 2.80 0.28 -2.52 (-3.72, -1.32) 3.705 3.06 a Data shown is mean at week 24, difference in adjusted mean change from baseline compared with placebo + MTX at week 24 and 95% confidence interval for that difference b Visual analog scale: 0 = best, 100 = worst c Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities The percent of ACR 20 responders by visit for Study III is shown in Figure 1. Similar response curves were observed in studies I, II, IV, and V. Reference ID: 5489050 35 100 95 90 B5 80 75 70 Ii] ~ 65 ! i 60 i Q. 55 • CIC 2 50 II: .., <( - 45 Q l CJ co I § 35 ., ... 30 25 20 15 10 5 0 \'It<:'! Wt<4 M((I • • • • • • D □ □ Figure 1 Percent of ACR 20 Responders by Visit for Study III (Inadequate Response to MTX)* Placebo + MTX Tocilizumab 8 mg/kg + MTX Tocilizumab 4 mg/kg + MTX Treatment Group (N=204) (N=205) (N=213) *The same patients may not have responded at each timepoint. Radiographic Response In Study II, structural joint damage was assessed radiographically and expressed as change in total Sharp-Genant score and its components, the erosion score and joint space narrowing score. Radiographs of hands/wrists and forefeet were obtained at baseline, 24 weeks, 52 weeks, and 104 weeks and scored by readers unaware of treatments group and visit number. The results from baseline to week 52 are shown in Table 6. Tocilizumab 4 mg per kg slowed (less than 75% inhibition compared to the control group) and tocilizumab 8 mg per kg inhibited (at least 75% inhibition compared to the control group) the progression of structural damage compared to placebo plus MTX at week 52. Reference ID: 5489050 36 Table 6 Mean Radiographic Change from Baseline to Week 52 in Study II Placebo + MTX N=294 Tocilizumab 4 mg per kg + MTX N=343 Tocilizumab 8 mg per kg + MTX N=353 Week 52* Total Sharp-Genant Score, Mean (SD) 1.17 (3.14) 0.33 (1.30) 0.25 (0.98) Adjusted Mean difference** (95%CI) -0.83 (-1.13, -0.52) -0.90 (-1.20, -0.59) Erosion Score, Mean (SD) 0.76 (2.14) 0.20 (0.83) 0.15 (0.77) Adjusted Mean difference** (95%CI) -0.55 (-0.76, -0.34) -0.60 (-0.80, -0.39) Joint Space Narrowing Score, Mean (SD) 0.41 (1.71) 0.13 (0.72) 0.10 (0.49) Adjusted Mean difference** (95%CI) -0.28 (-0.44, -0.11) -0.30 (-0.46, -0.14) * Week 52 analysis employs linearly extrapolated data for patients after escape, withdrawal, or loss to follow up. ** Difference between the adjusted means (tocilizumab + MTX – Placebo + MTX) SD = standard deviation The mean change from baseline to week 104 in Total Sharp-Genant Score for the tocilizumab 4 mg per kg groups was 0.47 (SD = 1.47) and for the 8 mg per kg groups was 0.34 (SD = 1.24). By the week 104, most patients in the control (placebo + MTX) group had crossed over to active treatment, and results are therefore not included for comparison. Patients in the active groups may have crossed over to the alternate active dose group, and results are reported per original randomized dose group. In the placebo group, 66% of patients experienced no radiographic progression (Total Sharp-Genant Score change ≤ 0) at week 52 compared to 78% and 83% in the tocilizumab 4 mg per kg and 8 mg per kg, respectively. Following 104 weeks of treatment, 75% and 83% of patients initially randomized to tocilizumab 4 mg per kg and 8 mg per kg, respectively, experienced no progression of structural damage compared to 66% of placebo treated patients. Health Related Outcomes In Study II, physical function and disability were assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI). Both dosing groups of tocilizumab demonstrated a greater improvement compared to the placebo group in the AUC of change from baseline in the HAQ-DI through week 52. The mean change from baseline to week 52 in HAQ-DI was 0.6, 0.5, and 0.4 for tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, and placebo treatment groups, respectively. Sixty-three percent (63%) and sixty percent (60%) of patients in the tocilizumab 8 mg per kg and tocilizumab 4 mg per kg treatment groups, respectively, achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) at week 52 compared to 53% in the placebo treatment group. Other Health-Related Outcomes General health status was assessed by the Short Form Health Survey (SF-36) in Studies I – V. Patients receiving tocilizumab demonstrated greater improvement from baseline compared to placebo in the Physical Component Summary (PCS), Mental Component Summary (MCS), and in all 8 domains of the SF-36. Cardiovascular Outcomes Reference ID: 5489050 37 Study WA25204 (NCT01331837) was a randomized, open-label (sponsor-blinded), 2-arm parallel-group, multicenter, non-inferiority, cardiovascular (CV) outcomes trial in patients with a diagnosis of moderate to severe RA. This CV safety study was designed to exclude a moderate increase in CV risk in patients treated with tocilizumab compared with a TNF inhibitor standard of care (etanercept). The study included 3,080 seropositive RA patients with active disease and an inadequate response to non- biologic disease-modifying anti-rheumatic drugs, who were aged ≥50 years with at least one additional CV risk factor beyond RA. Patients were randomized 1:1 to IV tocilizumab 8 mg/kg Q4W or SC etanercept 50 mg QW and followed for an average of 3.2 years. The primary endpoint was the comparison of the time-to-first occurrence of any component of a composite of major adverse CV events (MACE; non-fatal myocardial infarction, non-fatal stroke, or CV death), with the final intent-to-treat analysis based on a total of 161 confirmed CV events (83/1538 [5.4%] for tocilizumab; 78/1542 [5.1%] for etanercept) reviewed by an independent and blinded adjudication committee. Non-inferiority of tocilizumab to etanercept for cardiovascular risk was determined by excluding >80% relative increase in the risk of MACE. The estimated hazard ratio (HR) for the risk of MACE comparing tocilizumab to etanercept was 1.05; 95% CI (0.77, 1.43). 14.2 Rheumatoid Arthritis – Subcutaneous Administration The efficacy and safety of subcutaneously administered tocilizumab was assessed in two double-blind, controlled, multicenter studies in patients with active RA. One study, SC-I (NCT01194414), was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously to 8 mg per kg intravenously every four weeks. The second study, SC-II (NCT01232569), was a placebo-controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week subcutaneously to placebo. Both SC-I and SC-II required patients to be >18 years of age with moderate to severe active rheumatoid arthritis diagnosed according to ACR criteria who had at least 4 tender and 4 swollen joints at baseline (SC-I) or at least 8 tender and 6 swollen joints at baseline (SC-II), and an inadequate response to their existing DMARD therapy, where approximately 20% also had a history of inadequate response to at least one TNF inhibitor. All patients in both SC studies received background non-biologic DMARD(s). In SC-I, 1262 patients were randomized 1:1 to receive tocilizumab-SC 162 mg every week or intravenous tocilizumab 8 mg/kg every four weeks in combination with DMARD(s). In SC-II, 656 patients were randomized 2:1 to tocilizumab-SC 162 mg every other week or placebo, in combination with DMARD(s). The primary endpoint in both studies was the proportion of patients who achieved an ACR20 response at Week 24. The clinical response to 24 weeks of tocilizumab-SC therapy is shown in Table 7. In SC-I, the primary outcome measure was ACR20 at Week 24. The pre-specified non-inferiority margin was a treatment difference of 12%. The study demonstrated non-inferiority of tocilizumab with respect to ACR20 at Week 24; ACR50, ACR70, and DAS28 responses are also shown in Table 7. In SC-II, a greater portion of patients treated with tocilizumab 162 mg subcutaneously every other week achieved ACR20, ACR50, and ACR70 responses compared to placebo-treated patients (Table 7). Further, a greater proportion of patients treated with tocilizumab 162 mg subcutaneously every other week achieved a low level of disease activity as measured by a DAS28-ESR less than 2.6 at Week 24 compared to those treated with placebo (Table 7). Reference ID: 5489050 38 Table 6 Clinical Response at Week 24 in Trials of Subcutaneous Tocilizumab (Percent of Patients) SC-Ia SC-IIb TCZ SC 162 mg every week + DMARD TCZ IV 8mg/kg + DMARD TCZ SC 162 mg every other week + DMARD Placebo + DMARD N=558 N=537 N=437 N=219 ACR20 Week 24 69% 73.4% 61% 32% Weighted difference (95% CI) -4% (-9.2, 1.2) 30% (22.0, 37.0) ACR50 Week 24 47% 49% 40% 12% Weighted difference (95% CI) -2% (-7.5, 4.0) 28% (21.5, 34.4) ACR70 Week 24 24% 28% 20% 5% Weighted difference (95% CI) -4% (-9.0, 1.3) 15% (9.8, 19.9) Change in DAS28 [Adjusted mean] Week 24 -3.5 -3.5 -3.1 -1.7 Adjusted mean difference (95% CI) 0 (-0.2, 0.1) -1.4 (-1.7; -1.1) DAS28 < 2.6 Week 24 38.4% 36.9% 32.0% 4.0% Weighted difference (95% CI) 0.9 (-5.0, 6.8) 28.6 (22.0, 35.2) TCZ = tocilizumab a Per Protocol Population b Intent To Treat Population The results of the components of the ACR response criteria and the percent of ACR20 responders by visit for tocilizumab-SC in Studies SC-I and SC-II were consistent with those observed for tocilizumab-IV. Radiographic Response In study SC-II, the progression of structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde modified total Sharp score (mTSS). At week 24, significantly less radiographic progression was observed in patients receiving tocilizumab-SC every other week plus DMARD(s) compared to placebo plus DMARD(s); mean change from baseline in mTSS of 0.62 vs. 1.23, respectively, with an adjusted mean difference of -0.60 (-1.1, -0.1). These results are consistent with those observed in patients treated with intravenous tocilizumab. Health Related Outcomes In studies SC-I and SC-II, the mean decrease from baseline to week 24 in HAQ-DI was 0.6, 0.6, 0.4 and 0.3, and the proportion of patients who achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) was 65%, 67%, 58% and 47%, for the subcutaneous every week, intravenous 8 mg/kg, subcutaneous every other week, and placebo treatment groups, respectively. Other Health-Related Outcomes General health status was assessed by the SF-36 in Studies SC-I and SC-II. In Study SC-II, patients receiving tocilizumab every other week demonstrated greater improvement from baseline compared to placebo in the PCS, MCS, and in all 8 domains of the SF-36. In Study SC-I, improvements in these scores were similar between tocilizumab-SC every week and tocilizumab-IV 8 mg/kg. 14.3 Giant Cell Arteritis – Subcutaneous Administration The efficacy and safety of subcutaneously administered tocilizumab was assessed in a single, randomized, double- blind, multicenter study in patients with active GCA. In Study WA28119 (NCT01791153), 251 screened patients with new-onset or relapsing GCA were randomized to one of four treatment arms. Two subcutaneous doses of tocilizumab (162 mg every week and 162 mg every other week) were compared to two different placebo control groups (pre-specified prednisone-taper regimen over 26 weeks and 52 weeks) randomized 2:1:1:1. The study consisted of a 52-week blinded period, followed by a 104-week open-label extension. Reference ID: 5489050 39 All patients received background glucocorticoid (prednisone) therapy. Each of the tocilizumab-treated groups and one of the placebo-treated groups followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 26 weeks, while the second placebo-treated group followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 52 weeks designed to be more in keeping with standard practice. The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Sustained remission was defined by a patient attaining a sustained (1) absence of GCA signs and symptoms from Week 12 through Week 52, (2) normalization of erythrocyte sedimentation rate (ESR) (to < 30 mm/hr without an elevation to ≥ 30 mm/hr attributable to GCA) from Week 12 through Week 52, (3) normalization of C-reactive protein (CRP) (to < 1 mg/dL, with an absence of successive elevations to ≥ 1mg/dL) from Week 12 through Week 52, and (4) successful adherence to the prednisone taper defined by not more than 100 mg of excess prednisone from Week 12 through Week 52. Tocilizumab 162 mg weekly and 162 mg every other week + 26 weeks prednisone taper both showed superiority in achieving sustained remission from Week 12 through Week 52 compared with placebo + 26 weeks prednisone taper (Table 8). Both tocilizumab treatment arms also showed superiority compared to the placebo + 52 weeks prednisone taper (Table 8). Table 7 Efficacy Results from Study WA28119 PBO + 26 weeks prednisone taper N=50 PBO + 52 weeks prednisone taper N=51 TCZ 162mg SC QW + 26 weeks prednisone taper N=100 TCZ 162 mg SC Q2W + 26 weeks prednisone taper N=49 Sustained remission a Responders, n (%) 7 (14.0%) 9 (17.6%) 56 (56.0%) 26 (53.1%) Unadjusted difference in proportions vs PBO + 26 weeks taper (99.5% CI) N/A N/A 42.0% (18.0, 66.0) 39.1% (12.5 , 65.7) Unadjusted difference in proportions vs PBO + 52 weeks taper (99.5% CI) N/A N/A 38.4% (14.4, 62.3) 35.4% (8.6, 62.2) Components of Sustained Remission Sustained absence of GCA signs and symptomsb, n (%) Sustained ESR<30 mm/hrc, n (%) Sustained CRP normalizationd, n (%) Successful prednisone taperinge, n (%) 20 (40.0%) 20 (40.0%) 17 (34.0%) 10 (20.0%) 23 (45.1%) 22 (43.1%) 13 (25.5%) 20 (39.2%) 69 (69.0%) 83 (83.0%) 72 (72.0%) 60 (60.0%) 28 (57.1%) 37 (75.5%) 34 (69.4%) 28 (57.1%) a Sustained remission was achieved by a patient meeting all of the following components: absence of GCA signs and symptomsb, normalization of ESRc, normalization of CRPd and adherence to the prednisone taper regimene. B Patients who did not have any signs or symptoms of GCA recorded from Week 12 up to Week 52. C Patients who did not have an elevated ESR ≥30 mm/hr which was classified as attributed to GCA from Week 12 up to Week 52. D Patients who did not have two or more consecutive CRP records of ≥ 1mg/dL from Week 12 up to Week 52. E Patients who did not enter escape therapy and received ≤ 100mg of additional concomitant prednisone from Week 12 up to Week 52. Patients not completing the study to week 52 were classified as non-responders in the primary and key secondary analysis: PBO+26: 6 (12.0%), PBO+52: 5 (9.8%), TCZ QW: 15 (15.0%), TCZ Q2W: 9 (18.4%). CRP = C-reactive protein ESR = erythrocyte sedimentation rate PBO = placebo Q2W = every other week dose QW = every week dose TCZ = tocilizumab The estimated annual cumulative prednisone dose was lower in the two tocilizumab dose groups (medians of 1887 mg and 2207 mg on tocilizumab QW and Q2W, respectively) relative to the placebo arms (medians of 3804 mg Reference ID: 5489050 40 and 3902 mg on placebo + 26 weeks prednisone and placebo + 52 weeks prednisone taper, respectively). 14.4 Giant Cell Arteritis – Intravenous Administration Intravenously administered tocilizumab in patients with GCA was assessed in WP41152 (NCT03923738), an open-label PK-PD and safety study to determine the appropriate intravenous dose of tocilizumab that achieved comparable PK-PD profiles to the tocilizumab-SC regimen. At enrollment, all patients (n=24) were in remission on tocilizumab-IV. In Period 1, all patients received open label tocilizumab-IV 7 mg/kg every 4 weeks for 20 weeks. Patients who completed Period 1 and remained in remission (n=22) were eligible to enter Period 2, and received open-label tocilizumab-IV 6 mg/kg every 4 weeks for 20 weeks. The efficacy of intravenous tocilizumab 6 mg/kg in adult patients with GCA is based on pharmacokinetic exposure and extrapolation to the efficacy established for subcutaneous tocilizumab in patients with GCA [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. 14.5 Polyarticular Juvenile Idiopathic Arthritis – Intravenous Administration The efficacy of tocilizumab was assessed in a three-part study, WA19977 (NCT00988221), including an open- label extension in children 2 to 17 years of age with active polyarticular juvenile idiopathic arthritis (PJIA), who had an inadequate response to methotrexate or inability to tolerate methotrexate. Patients had at least 6 months of active disease (mean disease duration of 4.2 ± 3.7 years), with at least five joints with active arthritis (swollen or limitation of movement accompanied by pain and/or tenderness) and/or at least 3 active joints having limitation of motion (mean, 20 ± 14 active joints). The patients treated had subtypes of JIA that at disease onset included Rheumatoid Factor Positive or Negative Polyarticular JIA, or Extended Oligoarticular JIA. Treatment with a stable dose of methotrexate was permitted but was not required during the study. Concurrent use of disease modifying antirheumatic drugs (DMARDs), other than methotrexate, or other biologics (e.g., TNF antagonists or T cell costimulation modulator) were not permitted in the study. Part I consisted of a 16-week active tocilizumab treatment lead-in period (n=188) followed by Part II, a 24-week randomized double-blind placebo-controlled withdrawal period, followed by Part III, a 64-week open-label period. Eligible patients weighing at or above 30 kg received tocilizumab at 8 mg/kg intravenously once every four weeks. Patients weighing less than 30 kg were randomized 1:1 to receive either tocilizumab 8 mg/kg or 10 mg/kg intravenously every four weeks. At the conclusion of the open-label Part I, 91% of patients taking background MTX in addition to tocilizumab and 83% of patients on tocilizumab monotherapy achieved an ACR 30 response at week 16 compared to baseline and entered the blinded withdrawal period (Part II) of the study. The proportions of patients with JIA ACR 50/70 responses in Part I were 84.0%, and 64%, respectively for patients taking background MTX in addition to tocilizumab and 80% and 55% respectively for patients on tocilizumab monotherapy. In Part II, patients (ITT, n=163) were randomized to tocilizumab (same dose received in Part I) or placebo in a 1:1 ratio that was stratified by concurrent methotrexate use and concurrent corticosteroid use. Each patient continued in Part II of the study until Week 40 or until the patient satisfied JIA ACR 30 flare criteria (relative to Week 16) and qualified for escape. The primary endpoint was the proportion of patients with a JIA ACR 30 flare at week 40 relative to week 16. JIA ACR 30 flare was defined as 3 or more of the 6 core outcome variables worsening by at least 30% with no more than 1 of the remaining variables improving by more than 30% relative to Week 16. Tocilizumab treated patients experienced significantly fewer disease flares compared to placebo-treated patients (26% [21/82] versus 48% [39/81]; adjusted difference in proportions -21%, 95% CI: -35%, -8%). During the withdrawal phase (Part II), more patients treated with tocilizumab showed JIA ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo. Reference ID: 5489050 41 14.6 Polyarticular Juvenile Idiopathic Arthritis – Subcutaneous Administration Subcutaneously administered tocilizumab in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA) was assessed in WA28117 (NCT01904279), a 52-week, open-label, multicenter, PK-PD and safety study to determine the appropriate subcutaneous dose of tocilizumab that achieved comparable PK/PD profiles to the tocilizumab-IV regimen. PJIA patients aged 1 to 17 years with an inadequate response or inability to tolerate MTX, including patients with well-controlled disease on treatment with tocilizumab-IV and tocilizumab-naïve patients with active disease, were treated with subcutaneous tocilizumab based on body weight. Patients weighing at or above 30 kg (n = 25) were treated with 162 mg of tocilizumab-SC every 2 weeks and patients weighing less than 30 kg (n = 27) received 162 mg of tocilizumab-SC every 3 weeks for 52 weeks. Of these 52 patients, 37 (71%) were naïve to tocilizumab and 15 (29%) had been receiving tocilizumab-IV and switched to tocilizumab-SC at baseline. The efficacy of subcutaneous tocilizumab in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of intravenous tocilizumab in polyarticular JIA patients and subcutaneous tocilizumab in patients with RA [see Clinical Pharmacology (12.3) and Clinical Studies (14.2 and 14.6)]. 14.7 Systemic Juvenile Idiopathic Arthritis - Intravenous Administration The efficacy of tocilizumab for the treatment of active SJIA was assessed in WA18221 (NCT00642460), a 12-week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients treated with or without MTX, were randomized (tocilizumab:placebo = 2:1) to one of two treatment groups: 75 patients received tocilizumab infusions every two weeks at either 8 mg per kg for patients at or above 30 kg or 12 mg per kg for patients less than 30 kg and 37 were randomized to receive placebo infusions every two weeks. Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR 70 response. After 12 weeks or at the time of escape, due to disease worsening, patients were treated with tocilizumab in the open-label extension phase at weight appropriate dosing. The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set (JIA ACR 30 response) at Week 12 and absence of fever (no temperature at or above 37.5°C in the preceding 7 days). JIA ACR (American College of Rheumatology) responses are defined as the percentage improvement (e.g., 30%, 50%, 70%) in 3 of any 6 core outcome variables compared to baseline, with worsening in no more than 1 of the remaining variables by 30% or more. Core outcome variables consist of physician global assessment, parent per patient global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability (childhood health assessment questionnaire-CHAQ). Primary endpoint result and JIA ACR response rates at Week 12 are shown in Table 9. Reference ID: 5489050 42 Table 8 Efficacy Findings at Week 12 Tocilizumab N=75 Placebo N=37 Primary Endpoint: JIA ACR 30 response + absence of fever Responders 85% 24% Weighted difference (95% CI) 62 (45, 78) - JIA ACR Response Rates at Week 12 JIA ACR 30 Responders Weighted differencea (95% CI)b 91% 67 (51, 83) 24% - JIA ACR 50 Responders Weighted differencea (95% CI) b 85% 74 (58, 90) 11% - JIA ACR 70 Responders Weighted differencea (95% CI) b 71% 63 (46, 80) 8% - aThe weighted difference is the difference between the tocilizumab and Placebo response rates, adjusted for the stratification factors (weight, disease duration, background oral corticosteroid dose and background methotrexate use). b CI: confidence interval of the weighted difference. The treatment effect of tocilizumab was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks). Systemic Features Of patients with fever or rash at baseline, those treated with tocilizumab had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to 5 out of 24 (21%) of placebo-treated patients, and 14 out of 22 (64%) became free of rash compared to 2 out of 18 (11%) of placebo-treated patients. Responses were consistent in the open label extension (data available through 44 weeks). Corticosteroid Tapering Of the patients receiving oral corticosteroids at baseline, 8 out of 31 (26%) placebo and 48 out of 70 (69%), tocilizumab patients achieved a JIA ACR 70 response at week 6 or 8 enabling corticosteroid dose reduction. Seventeen (24%) tocilizumab patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR 30 flare or occurrence of systemic symptoms to week 12. In the open label portion of the study, by week 44, there were 44 out of 103 (43%) tocilizumab patients off oral corticosteroids. Of these 44 patients 50% were off corticosteroids 18 weeks or more. Health Related Outcomes Physical function and disability were assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). Seventy-seven percent (58 out of 75) of patients in the tocilizumab treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of ≥ 0.13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group. 14.8 Systemic Juvenile Idiopathic Arthritis - Subcutaneous Administration Subcutaneously administered tocilizumab in pediatric patients with systemic juvenile idiopathic arthritis (SJIA) was assessed in WA28118 (NCT01904292), a 52-week, open-label, multicenter, PK-PD and safety study to determine the appropriate subcutaneous dose of tocilizumab that achieved comparable PK/PD profiles to the tocilizumab-IV regimen. Reference ID: 5489050 43 Eligible patients received tocilizumab subcutaneously dosed according to body weight, with patients weighing at or above 30 kg (n = 26) dosed with 162 mg of tocilizumab every week and patients weighing below 30 kg (n = 25) dosed with 162 mg of tocilizumab every 10 days (n=8) or every 2 weeks (n=17) for 52 weeks. Of these 51 patients, 26 (51%) were naïve to subcutaneous tocilizumab and 25 (49%) had been receiving tocilizumab intravenously and switched to subcutaneous tocilizumab at baseline. The efficacy of subcutaneous tocilizumab in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of intravenous tocilizumab in systemic JIA patients [see Clinical Pharmacology (12.3) and Clinical Studies (14.8)]. 16 HOW SUPPLIED/STORAGE AND HANDLING TYENNE (tocilizumab-aazg) injection is a preservative-free, sterile clear and colorless to pale yellow solution. The following packaging configurations are available: For Intravenous Infusion TYENNE Single-Dose Vial Each TYENNE carton contains one vial. Each vial is supplied as 80 mg/4 mL (20 mg/mL) (NDC 65219-590-04), 200 mg/10 mL (20 mg/mL) (NDC 65219-592-10), and 400 mg/20 mL (20 mg/mL) (NDC 65219-594-20) TYENNE solution for further dilution prior to intravenous infusion. The vial stopper is not made with natural rubber latex. For Subcutaneous Injection TYENNE Prefilled Syringe Each TYENNE carton contains a single-dose prefilled syringe delivering 162 mg/0.9 mL of TYENNE. The syringe plunger stopper and needle cover are not made with natural rubber latex. The NDC number is 65219-586-04. TYENNE Autoinjector Each TYENNE carton contains a single-dose autoinjector delivering 162 mg/0.9 mL of TYENNE. The syringe plunger stopper and needle cover are not made with natural rubber latex. The NDC number is 65219-584-01. Storage and Handling: Do not use beyond expiration date on the container, package, prefilled syringe, or autoinjector. TYENNE must be refrigerated at 36°F to 46°F (2ºC to 8ºC). Do not freeze. A single prefilled syringe (or autoinjector) may be stored at room temperature at or below 77°F (25°C) for a single period of up to 14 days. Protect the vials, syringes and autoinjectors from light by storage in the original package until time of use, and keep syringes and autoinjectors dry. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). • Serious Infections Inform patients that TYENNE may lower their resistance to infections [see Warnings and Precautions (5.1)]. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment. • Gastrointestinal Perforation Inform patients that some patients who have been treated with TYENNE have had serious side effects in the stomach and intestines [see Warnings and Precautions (5.2)]. Instruct the patient of the importance of contacting their doctor immediately when symptoms of severe, persistent abdominal pain appear to assure rapid evaluation and appropriate treatment. • Hypersensitivity and Serious Allergic Reactions Reference ID: 5489050 44 Inform patients that some patients who have been treated with TYENNE have developed serious allergic reactions, including anaphylaxis and serious skin reactions [see Warnings and Precautions (5.6)]. Advise patients to stop taking TYENNE and seek immediate medical attention if they experience any symptom of serious allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing). Instruction on Injection Technique Assess patient suitability for home use for subcutaneous injection. Perform the first injection under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer subcutaneous TYENNE, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous TYENNE and the suitability for home use [See Instructions for Use]. Prior to use, remove the prefilled syringe (PFS) or autoinjector from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes (PFS) or 45 minutes (autoinjector), out of the reach of children. Do not warm TYENNE in any other way. Advise patients to consult their healthcare provider if the full dose is not received. A puncture-resistant container for disposal of needles, syringes and autoinjectors should be used and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper needle, syringe and autoinjector disposal, and caution against reuse of these items. Pregnancy Inform female patients of reproductive potential that TYENNE may cause fetal harm and to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)]. TYENNE (tocilizumab-aazg) Manufactured by: Fresenius Kabi USA, LLC Lake Zurich, IL 60047, U.S.A. U.S. License Number: 2146 Reference ID: 5489050 45 Medication Guide TYENNE® (tye en’) (tocilizumab-aazg) injection for intravenous use TYENNE® (tye en’) (tocilizumab-aazg) injection for subcutaneous use What is the most important information I should know about TYENNE? TYENNE can cause serious side effects including: 1. Serious Infections. TYENNE is a medicine that affects your immune system. TYENNE can lower the ability of your immune system to fight infections. Some people have serious infections while taking TYENNE, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections. Your healthcare provider should assess you for TB before starting TYENNE Your healthcare provider should monitor you closely for signs and symptoms of TB during treatment with TYENNE. • You should not start taking TYENNE if you have any kind of infection unless your healthcare provider says it is okay. Before starting TYENNE, tell your healthcare provider if you: • think you have an infection or have symptoms of an infection, with or without a fever, such as: o sweating or chills o feel very tired o cough o shortness of breath o muscle aches o weight loss o warm, red, or painful skin or o blood in phlegm o burning when you urinate or sores on your body o diarrhea or stomach urinating more often than pain normal • are being treated for an infection. • get a lot of infections or have infections that keep coming back. • have diabetes, HIV, or a weak immune system. People with these conditions have a higher chance for infections. • have TB or have been in close contact with someone with TB. • live or have lived or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections (histoplasmosis, coccidiomycosis, or blastomycosis). These infections may happen or become more severe if you use TYENNE. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common. • have or have had hepatitis B. After starting TYENNE, call your healthcare provider right away if you have any symptoms of an infection. TYENNE can make you more likely to get infections or make worse any infection that you have. 2. Tears (perforation) of the stomach or intestines. • Tell your healthcare provider if you have had diverticulitis (inflammation in parts of the large intestine) or ulcers in your stomach or intestines. Some people taking TYENNE get tears in their stomach or intestine. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. • Tell your healthcare provider right away if you have fever and stomach-area pain that does not go away, and a change in your bowel habits. 3. Liver problems (Hepatotoxicity): Some people have experienced serious life-threatening liver problems, which required a liver transplant or led to death. Your healthcare provider may tell you to stop taking TYENNE if you develop new or worse liver problems during treatment with TYENNE. Tell your healthcare provider right away if you have any of the following symptoms: o feeling tired (fatigue) o weakness o lack of appetite for several days or longer o nausea and vomiting (anorexia) Reference ID: 5489050 o yellowing of your skin or the whites of your eyes o confusion (jaundice) o abdominal swelling and pain on the right side of o dark “tea-colored” urine your stomach-area o light colored stools 4. Changes in certain laboratory test results. Your healthcare provider should do blood tests before you start receiving TYENNE. If you have rheumatoid arthritis (RA) or giant cell arteritis (GCA) your healthcare provider should do blood tests every 4 to 8 weeks after you start receiving TYENNE for the first 6 months and then every 3 months after that. If you have polyarticular juvenile idiopathic arthritis (PJIA) you will have blood tests done every 4 to 8 weeks during treatment. If you have systemic juvenile idiopathic arthritis (SJIA) you will have blood tests done every 2 to 4 weeks during treatment. These blood tests are to check for the following side effects of TYENNE: • low neutrophil count. Neutrophils are white blood cells that help the body fight off bacterial infections. • low platelet count. Platelets are blood cells that help with blood clotting and stop bleeding. • increase in certain liver function tests. • increase in blood cholesterol levels. You may also have changes in other laboratory tests, such as your blood cholesterol levels. Your healthcare provider should do blood tests to check your cholesterol levels 4 to 8 weeks after you start receiving TYENNE. Your healthcare provider will determine how often you will have follow-up blood tests. Make sure you get all your follow-up blood tests done as ordered by your healthcare provider. You should not receive TYENNE if your neutrophil or platelet counts are too low, or your liver function tests are too high. Your healthcare provider may stop your TYENNE treatment for a period of time or change your dose of medicine if needed because of changes in these blood test results. 5. Cancer. TYENNE may increase your risk of certain cancers by changing the way your immune system works. Tell your healthcare provider if you have ever had any type of cancer. See “What are the possible side effects with TYENNE?” for more information about side effects. What is TYENNE? TYENNE is a prescription medicine called an Interleukin-6 (IL-6) receptor antagonist. TYENNE is used: • To treat adults with moderately to severely active rheumatoid arthritis (RA), after at least one other medicine called a Disease-Modifying Anti-Rheumatic Drug (DMARD) has been used and did not work well. • To treat adults with giant cell arteritis (GCA). • To treat people with active PJIA ages 2 and above. • To treat people with active SJIA ages 2 and above. It is not known if TYENNE is safe and effective in children with PJIA or SJIA under 2 years of age or in children with conditions other than PJIA or SJIA. Do not take TYENNE: if you are allergic to tocilizumab products, or any of the ingredients in TYENNE. See the end of this Medication Guide for a complete list of ingredients in TYENNE. Before you receive TYENNE, tell your healthcare provider about all of your medical conditions, including if you: • have an infection. See “What is the most important information I should know about TYENNE?” • have liver problems. • have any stomach-area (abdominal) pain or been diagnosed with diverticulitis or ulcers in your stomach or intestines. • have had a reaction to tocilizumab or any of the ingredients in TYENNE before. • have or had a condition that affects your nervous system, such as multiple sclerosis. • have recently received or are scheduled to receive a vaccine: o All vaccines should be brought up-to-date before starting TYENNE, unless urgent treatment initiation is required. o People who take TYENNE should not receive live vaccines. o People taking TYENNE can receive non-live vaccines. • plan to have surgery or a medical procedure. • are pregnant or plan to become pregnant or are pregnant. TYENNE may harm your unborn baby. Tell your Reference ID: 5489050 healthcare provider if you become pregnant or think you may be pregnant during treatment with TYENNE. • are breastfeeding or plan to breastfeed. It is not known if TYENNE passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take TYENNE. Tell your healthcare provider about all of the medicines you take, including prescription, over-the-counter medicines, vitamins, and herbal supplements. TYENNE and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take: • any other medicines to treat your RA. You should not take etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade), rituximab (Rituxan), abatacept (Orencia), anakinra (Kineret), certolizumab (Cimzia), or golimumab (Simponi) while you are taking TYENNE. Taking TYENNE with these medicines may increase your risk of infection. • medicines that affect the way certain liver enzymes work. Ask your healthcare provider if you are not sure if your medicine is one of these. Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. How will I receive TYENNE? Into a vein (IV or intravenous infusion) for Rheumatoid Arthritis, Giant Cell Arteritis, PJIA or SJIA: • If your healthcare provider prescribes TYENNE as an IV infusion, you will receive TYENNE from a healthcare provider through a needle placed in a vein in your arm. The infusion will take about 1 hour to give you the full dose of medicine. • For rheumatoid arthritis, giant cell arteritis or PJIA you will receive a dose of TYENNE about every 4 weeks. • For SJIA you will receive a dose of TYENNE about every 2 weeks. • While taking TYENNE, you may continue to use other medicines that help treat your rheumatoid arthritis, PJIA, or SJIA such as methotrexate, non-steroidal anti-inflammatory drugs (NSAIDs) and prescription steroids, as instructed by your healthcare provider. • Keep all of your follow-up appointments and get your blood tests as ordered by your healthcare provider. Under the skin (SC or subcutaneous injection) for Rheumatoid Arthritis, Giant Cell Arteritis, PJIA or SJIA: • See the Instructions for Use at the end of this Medication Guide for instructions about the right way to prepare and give your TYENNE injections at home. • TYENNE is available as a single-dose prefilled syringe or single-dose prefilled autoinjector. • You may also receive TYENNE as an injection under your skin (subcutaneous). If your healthcare provider decides that you or a caregiver can give your injections of TYENNE at home, you or your caregiver should receive training on the right way to prepare and inject TYENNE. Do not try to inject TYENNE until you have been shown the right way to give the injections by your healthcare provider. • For PJIA or SJIA, you may self-inject with the prefilled syringe or prefilled autoinjector, or your caregiver can give you TYENNE, if both your healthcare provider and parent/legal guardian find it appropriate. • Your healthcare provider will tell you how much TYENNE to use and when to use it. What are the possible side effects with TYENNE? TYENNE can cause serious side effects, including: • See “What is the most important information I should know about TYENNE?” • Hepatitis B infection in people who carry the virus in their blood. If you are a carrier of the hepatitis B virus (a virus that affects the liver), the virus may become active while you use TYENNE. Your healthcare provider may do blood tests before you start treatment with TYENNE and while you are using TYENNE. Tell your healthcare provider if you have any of the following symptoms of a possible hepatitis B infection: o feel very tired o skin or eyes look yellow o little or no appetite o vomiting o clay-colored bowel movements o fevers o chills o stomach discomfort o muscle aches o dark urine o skin rash • Serious Allergic Reactions. Serious allergic reactions, including death, can happen with TYENNE. These reactions can happen with any infusion or injection of TYENNE, even if they did not occur with an earlier infusion or injection. Stop taking TYENNE, contact your healthcare provider, and get emergency help right away if you have any of the following signs of a serious allergic reaction: o trouble breathing o swelling of your mouth, lips, tongue, or face o wheezing Reference ID: 5489050 o severe itching o skin rash, hives, redness, or swelling outside of the injection site area o dizziness or fainting o fast heartbeat or pounding in your chest (tachycardia) o sweating • Nervous system problems. While rare, Multiple Sclerosis has been diagnosed in people who take TYENNE. It is not known what effect TYENNE may have on some nervous system disorders. The most common side effects of TYENNE include: • upper respiratory tract infections (common cold, sinus infections) • headache • increased blood pressure (hypertension) • injection site reactions Tell your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of TYENNE. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Fresenius Kabi USA, LLC at 1-800-551-7176. General information about the safe and effective use of TYENNE. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not give TYENNE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TYENNE that is written for health professionals. For more information go to www.TYENNE.com or you can enroll in a patient support program by calling 1-833-522-4227 or visiting the patient support program website: www.kabicare.com. What are the ingredients in TYENNE? Active ingredient: tocilizumab-aazg. Inactive ingredients of Intravenous and Subcutaneous TYENNE: arginine, histidine, hydrochloric acid, lactic acid, polysorbate 80, sodium chloride, sodium hydroxide and Water for Injection. TYENNE is a registered trademark of Fresenius Kabi Manufactured by: Fresenius Kabi USA LLC, Lake Zurich, IL 60047, U.S.A U.S License Number 2146 This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 12/2024 Reference ID: 5489050
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NDA 209241/S-028 Page 3 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov CARTON LABELS NDA 209241/S-028 Page 4 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov NDA 209241/S-028 Page 5 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov NDA 209241/S-028 Page 6 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov NDA 209241/S-028 Page 7 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov NDA 209241/S-028 Page 8 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov CONTAINER LABELS Gurpreet Gill Sangha Digitally signed by Gurpreet Gill Sangha Date: 12/04/2024 09:02:23PM GUID: 5135f2ad000117842392c50c36c7f28a (
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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NOREPINEPHRINE IN SODIUM CHLORIDE INJECTION safely and effectively. See full prescribing information for NOREPINEPHRINE IN SODIUM CHLORIDE INJECTION. NOREPINEPHRINE IN SODIUM CHLORIDE INJECTION, for intravenous use Initial U.S. Approval: 1950 __________________ INDICATIONS AND USAGE _________________ Norepinephrine in Sodium Chloride Injection is a catecholamine indicated for restoration of blood pressure in adult patients with acute hypotensive states. (1) _______________ DOSAGE AND ADMINISTRATION ______________ • No further dilution prior to infusion is required (2.1) • Initial intravenous infusion rate of 8 to 12 mcg per minute, adjust the rate of flow to establish and maintain a low to normal blood pressure (usually 80 to 100 mm Hg) sufficient to maintain the circulation of vital organs (2.2) • The average maintenance dose ranges from 2 to 4 mcg per minute. (2.2) ______________ DOSAGE FORMS AND STRENGTHS _____________ • Injection: in a single dose infusion bags with − 4 mg/250 mL (16 mcg/mL) of norepinephrine in 0.9% Sodium Chloride − 8 mg/250 mL (32 mcg/mL) of norepinephrine in 0.9% Sodium Chloride − 16 mg/250 mL (64 mcg/mL) of norepinephrine in 0.9% Sodium Chloride ___________________ CONTRAINDICATIONS____________________ • None. (4) _______________ WARNINGS AND PRECAUTIONS _______________ • Tissue Ischemia: Avoid extravasation into tissues, which can cause local necrosis (5.1) • Hypotension After Abrupt Discontinuation: Sudden cessation of the infusion rate may result in marked hypotension. Reduce the Norepinephrine in Sodium Chloride Injection infusion rate gradually. (5.2) • Cardiac Arrhythmias: Norepinephrine in Sodium Chloride Injection may cause arrhythmias. Monitor cardiac function in patients with underlying heart disease. (5.3) ____________________ ADVERSE REACTIONS ____________________ Most common adverse reactions are ischemic injury, bradycardia, anxiety, transient headache, respiratory difficulty, and extravasation necrosis at injection site. (6) To report SUSPECTED ADVERSE REACTIONS, contact Long Grove Pharmaceuticals LLC at 1-855-642-2594 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ____________________ DRUG INTERACTIONS ____________________ • Monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types may result in hypertension. (7.1) • Cyclopropane and halothane anesthetics increase cardiac autonomic irritability. (7.4) _______________ USE IN SPECIFIC POPULATIONS _______________ • Elderly patients may be at greater risk of developing adverse reactions. (8.5) See 17 for PATIENT COUNSELING INFORMATION Revised: 10/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions 2.2 Dosage 2.3 Drug Incompatibilities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Tissue Ischemia 5.2 Hypotension after Abrupt Discontinuation 5.3 Cardiac Arrhythmias 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 MAO-Inhibiting Drugs 7.2 Tricyclic Antidepressants 7.3 Antidiabetics 7.4 Halogenated Anesthetics 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Norepinephrine in Sodium Chloride Injection is indicated to raise blood pressure in adult patients with severe, acute hypotension. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions Correct Hypovolemia Address hypovolemia before initiation of Norepinephrine in Sodium Chloride Injection therapy. If the patient does not respond to therapy, suspect occult hypovolemia [see Warnings and Precautions (5.1)]. Administration Infuse Norepinephrine in Sodium Chloride Injection into a large vein. Avoid infusions into the veins of the leg in the elderly or in patients with occlusive vascular disease of the legs [see Warnings and Precautions (5.1)]. Avoid using a catheter-tie-in technique. Inspect parenteral drug products for particulate matter and discoloration prior to use, whenever solution and container permit. Do not open the aluminum foil pouch until time of use. The premixed, ready-to-use infusion bag has a single port for insertion of the infusion set only. Do not use this port to remove content from the bag or add another medication. Once the infusion bag has been connected to the infusion set, it is stable for 24 hours for intermittent or continuous use, as long as the bag stays connected to the infusion set. Discontinuation When discontinuing the infusion, reduce the flow rate gradually. Avoid abrupt withdrawal. Single dose only. Discard unused portion. 2.2 Dosage After an initial dose of 8 to 12 mcg per minute via intravenous infusion, assess patient response and adjust dosage to maintain desired hemodynamic effect. Monitor blood pressure every two minutes or continuously until the desired hemodynamic effect is achieved, and then monitor blood pressure every five minutes for the duration of the infusion. Recommended Average Maintenance Dosage: Typical maintenance intravenous dosage is 2 to 4 mcg per minute. 2.3 Drug Incompatibilities Avoid contact with iron salts and alkalizing and oxidizing agents. 3 Whole blood or plasma, if indicated to increase blood volume, should be administered separately. 3 DOSAGE FORMS AND STRENGTHS Injection: Norepinephrine is a clear, colorless sterile solution in the premixed, ready-to-use single dose intravenous infusion bags available as: • 4 mg/250 mL (16 mcg/mL) of norepinephrine in 0.9% Sodium Chloride • 8 mg/250 mL (32 mcg/mL) of norepinephrine in 0.9% Sodium Chloride • 16 mg/250 mL (64 mcg/mL) of norepinephrine in 0.9% Sodium Chloride 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Tissue Ischemia Administration of Norepinephrine in Sodium Chloride Injection to patients who are hypotensive from hypovolemia can result in severe peripheral and visceral vasoconstriction, decreased renal perfusion and reduced urine output, tissue hypoxia, lactic acidosis, and reduced systemic blood flow despite “normal” blood pressure. Address hypovolemia prior to initiating Norepinephrine in Sodium Chloride Injection [see Dosage and Administration (2.1)]. Avoid Norepinephrine in Sodium Chloride Injection in patients with mesenteric or peripheral vascular thrombosis, as this may increase ischemia and extend the area of infarction. Gangrene of the extremities has occurred in patients with occlusive or thrombotic vascular disease or who received prolonged or high dose infusions. Monitor for changes to the skin of the extremities in susceptible patients. Extravasation of Norepinephrine in Sodium Chloride Injection may cause necrosis and sloughing of surrounding tissue. To reduce the risk of extravasation, infuse into a large vein, check the infusion site frequently for free flow, and monitor for signs of extravasation [see Dosage and Administration (2.1)]. Emergency Treatment of Extravasation To prevent sloughing and necrosis in areas in which extravasation has occurred, infiltrate the ischemic area as soon as possible, using a syringe with a fine hypodermic needle with 5 to 10 mg of phentolamine mesylate in 10 mL to 15 mL of 0.9% Sodium Chloride Injection in adults. Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours. 4 5.2 Hypotension after Abrupt Discontinuation Sudden cessation of the infusion rate may result in marked hypotension. When discontinuing the infusion, gradually reduce the Norepinephrine in Sodium Chloride Injection infusion rate while expanding blood volume with intravenous fluids. 5.3 Cardiac Arrhythmias Norepinephrine in Sodium Chloride Injection elevates intracellular calcium concentrations and may cause arrhythmias, particularly in the setting of hypoxia or hypercarbia. Perform continuous cardiac monitoring of patients with arrhythmias. 6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: • Tissue Ischemia [see Warnings and Precautions (5.1)] • Hypotension [see Warnings and Precautions (5.2)] • Cardiac Arrhythmias [see Warnings and Precautions (5.3)] The most common adverse reactions are hypertension and bradycardia. The following adverse reactions can occur: Nervous system disorders: Anxiety, headache Respiratory disorders: Respiratory difficulty, pulmonary edema 7 DRUG INTERACTIONS 7.1 MAO-Inhibiting Drugs Co-administration of Norepinephrine in Sodium Chloride Injection with monoamine oxidase (MAO) inhibitors or other drugs with MAO-inhibiting properties (e.g., linezolid) can cause severe, prolonged hypertension. If administration of Norepinephrine in Sodium Chloride Injection cannot be avoided in patients who recently have received any of these drugs and in whom, after discontinuation, MAO activity has not yet sufficiently recovered, monitor for hypertension. 7.2 Tricyclic Antidepressants Co-administration of Norepinephrine in Sodium Chloride Injection with tricyclic antidepressants (including amitriptyline, nortriptyline, protriptyline, clomipramine, desipramine, imipramine) can cause severe, prolonged hypertension. If administration of Norepinephrine in Sodium Chloride Injection cannot be avoided in these patients, monitor for hypertension. 5 7.3 Antidiabetics Norepinephrine in Sodium Chloride Injection can decrease insulin sensitivity and raise blood glucose. Monitor glucose and consider dosage adjustment of antidiabetic drugs. 7.4 Halogenated Anesthetics Concomitant use of Norepinephrine in Sodium Chloride Injection with halogenated anesthetics (e.g., cyclopropane, desflurane, enflurane, isoflurane, and sevoflurane) may lead to ventricular tachycardia or ventricular fibrillation. Monitor cardiac rhythm in patients receiving concomitant halogenated anesthetics. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data consisting of a small number of case reports and multiple small trials involving the use of norepinephrine in pregnant women at the time of delivery have not identified an increased risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus from hypotension associated with septic shock, myocardial infarction and stroke which are medical emergencies in pregnancy and can be fatal if left untreated (see Clinical Considerations). In animal reproduction studies, using high doses of intravenous norepinephrine resulted in lowered maternal placental blood flow. Clinical relevance to changes in the human fetus is unknown since the average maintenance dose is ten times lower (see Data). Increased fetal reabsorptions were observed in pregnant hamsters after receiving daily injections at approximately 2 times the maximum recommended dose on a mg/m2 basis for four days during organogenesis (see Data). The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypotension associated with septic shock, myocardial infarction, and stroke are medical emergencies in pregnancy which can be fatal if left untreated. Delaying treatment in pregnant women with hypotension associated with septic shock, myocardial infarction and stroke may increase the risk of maternal and fetal morbidity and mortality. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of norepinephrine on the fetus. 6 Data Animal Data A study in pregnant sheep receiving high doses of intravenous norepinephrine (40 mcg/min, at approximately 10 times the average maintenance dose of 2-4 mcg/min in human, on a mg/kg basis) exhibited a significant decrease in maternal placental blood flow. Decreases in fetal oxygenation, urine and lung liquid flow were also observed. Norepinephrine administration to pregnant rats on Gestation Day 16 or 17 resulted in cataract production in rat fetuses. In hamsters, an increased number of resorptions (29.1% in study group vs. 3.4% in control group), fetal microscopic liver abnormalities and delayed skeletal ossification were observed at approximately 2 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day from Gestation Day 7-10). 8.2 Lactation Risk Summary There are no data on the presence of norepinephrine in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Clinically relevant exposure to the infant is not expected based on the short half-life and poor oral bioavailability of norepinephrine. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of Norepinephrine in Sodium Chloride Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Avoid administration of Norepinephrine in Sodium Chloride Injection into the veins in the leg in elderly patients [see Warnings and Precautions (5.1)]. 10 OVERDOSAGE Overdosage with Norepinephrine in Sodium Chloride Injection may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance, and decreased cardiac output. In case of accidental overdosage, discontinue Norepinephrine in Sodium Chloride Injection until the condition of the patient stabilizes. 7 11 DESCRIPTION Norepinephrine (sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine) is a catecholamine which differs from epinephrine by the absence of a methyl group on the nitrogen atom. Chemically, Norepinephrine Bitartrate is (-)-α-(aminomethyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate (molecular weight 337.3 g/mol) and has the following structural formula: Norepinephrine in Sodium Chloride Injection is a clear, colorless, single dose sterile solution supplied as a ready-to-use intravenous infusion bag for intravenous use and does not require further dilution. Each mL contains the equivalent of 16 or 32 or 64 micrograms of norepinephrine base supplied as 31.90 or 63.80 or 127.6 micrograms per mL of norepinephrine bitartrate monohydrate. In addition, each mL of solution contains 0.01 mg edetate disodium dihydrate as a metal chelator and 9.0 mg sodium chloride for isotonicity. It has a pH of 3.5 to 4.5. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Norepinephrine is a peripheral vasoconstrictor (alpha-adrenergic action) and an inotropic stimulator of the heart and dilator of coronary arteries (beta-adrenergic action). 12.2 Pharmacodynamics The primary pharmacodynamic effects of norepinephrine are cardiac stimulation and vasoconstriction. Cardiac output is generally unaffected, although it can be decreased, and total peripheral resistance is also elevated. The elevation in resistance and pressure result in reflex vagal activity, which slows the heart rate and increases stroke volume. The elevation in vascular tone or resistance reduces blood flow to the major abdominal organs as well as to skeletal muscle. Coronary blood flow is substantially increased secondary to the indirect effects of alpha stimulation. After intravenous administration, a pressor response occurs rapidly and reaches steady state within 5 minutes. The pharmacologic actions of norepinephrine are terminated 8 primarily by uptake and metabolism in sympathetic nerve endings. The pressor action stops within 1-2 minutes after the infusion is discontinued. 12.3 Pharmacokinetics Absorption Following intravenous administration, the steady state plasma concentration is achieved in 5 min. Distribution Plasma protein binding of norepinephrine is approximately 25%. It is mainly bound to plasma albumin and to a smaller extent to prealbumin and alpha 1-acid glycoprotein. The volume of distribution is 8.8 L. Norepinephrine localizes mainly in sympathetic nervous tissue. It crosses the placenta but not the blood-brain barrier. Elimination The mean half-life of norepinephrine is approximately 2.4 min. The average metabolic clearance is 3.1 L/min. Metabolism Norepinephrine is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and MAO. The major metabolites are normetanephrine and 3-methoxy-4-hydroxy mandelic acid (vanillylmandelic acid, VMA), both of which are inactive. Other inactive metabolites include 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxymandelic acid, and 3,4-dihydroxyphenylglycol. Excretion Noradrenaline metabolites are excreted in urine primarily as sulphate conjugates and, to a lesser extent, as glucuronide conjugates. Only small quantities of norepinephrine are excreted unchanged. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis, mutagenesis, and fertility studies have not been performed. 16 HOW SUPPLIED/STORAGE AND HANDLING Norepinephrine in Sodium Chloride Injection (norepinephrine bitartrate) is supplied as a clear, colorless sterile solution in a 250 mL non-PVC infusion bag with single function connector system consisting of a port and cap, packaged individually in an aluminum foil pouch with an oxygen scavenger. Supplied as: 9 Unit of Sale Concentration Package Size NDC 81298-9659-3 4 mg/250 mL (16 mcg/mL) 10 bags NDC 81298-9655-3 8 mg/250 mL (32 mcg/mL) 10 bags NDC 81298-9658-3 16 mg/250 mL (64 mcg/mL) 10 bags Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Protect from light. Once the overwrap is removed, the bag can be stored at room temperature for up to 45 days. 17 PATIENT COUNSELING INFORMATION Risk of Tissue Damage Advise the patient, family, or caregiver to report signs of extravasation urgently [see Warnings and Precautions (5.1)]. Manufactured for: Long Grove Pharmaceuticals, LLC Rosemont, IL 60018 Rev. 10/2024 076273002 R00 NDA 214628/S-004 Page 4 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov NDA 214628/S-004 Page 5 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov NDA 214628/S-004 Page 6 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov NDA 214628/S-004 Page 7 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov NDA 214628/S-004 Page 8 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov NDA 214628/S-004 Page 9 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov NDA 214628/S-004 Page 10 U.S. Food & Drug Administration Silver Spring, MD 20993 www.fda.gov Gurpreet Gill Sangha Digitally signed by Gurpreet Gill Sangha Date: 12/05/2024 04:18:44PM GUID: 5135f2ad000117842392c50c36c7f28a
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2025-02-12T15:47:32.624202
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I I HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TOFIDENCE safely and effectively. See full prescribing information for TOFIDENCE. TOFIDENCE™ (tocilizumab-bavi) injection, for intravenous use Initial U.S. Approval: 2023 TOFIDENCE (tocilizumab-bavi) is biosimilar* to ACTEMRA (tocilizumab). WARNING: RISK OF SERIOUS INFECTIONS See full prescribing information for complete boxed warning. • Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections have occurred in patients receiving tocilizumab products. (5.1) • If a serious infection develops, interrupt TOFIDENCE until the infection is controlled. (5.1) • Perform test for latent TB (except patients with COVID-19); if positive, start treatment for TB prior to starting TOFIDENCE. (5.1) • Monitor all patients for active TB during treatment, even if initial latent TB test is negative. (5.1) -------------------------- RECENT MAJOR CHANGES --------------------------­ Indications and Usage (1.2, 1.5) 7/2024 Dosage and Administration (2.1, 2.3, 2.6) 7/2024 Warnings and Precautions (5.6) 12/2024 --------------------------- INDICATIONS AND USAGE --------------------------­ TOFIDENCE™ (tocilizumab-bavi) is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of: Rheumatoid Arthritis (RA) (1.1) • Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). Giant Cell Arteritis (GCA) (1.2) • Adult Patients with giant cell arteritis.. Polyarticular Juvenile Idiopathic Arthritis (PJIA) (1.3) • Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis. Systemic Juvenile Idiopathic Arthritis (SJIA) (1.4) • Patients 2 years of age and older with active systemic juvenile idiopathic arthritis. Coronavirus Disease 2019 (COVID-19) (1.5) • Hospitalized adult patients with coronavirus disease 2019 (COVID-19) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). ----------------------- DOSAGE AND ADMINISTRATION ---------------------­ For RA, pJIA and sJIA, TOFIDENCE may be used alone or in combination with methotrexate; and in RA, other DMARDs may be used. (2) General Administration and Dosing Information (2.1) • RA, GCA, PJIA and SJIA - It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or ALT or AST above 1.5 times the upper limit of normal (ULN). (5.3, 5.4) • COVID-19 - It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm3 , platelet count below 50,000 mm3 , or ALT or AST above 10 times ULN (5.3, 5.4). • In RA or COVID-19 patients, TOFIDENCE doses exceeding 800 mg per infusion are not recommended. (2.2, 12.3) • In GCA patients, TOFIDENCE doses exceeding 600 mg per infusion are not recommended. (2.3, 12.3) Rheumatoid Arthritis (2.2) Recommended Adult Intravenous Dosage: When used in combination with DMARDs or as monotherapy the recommended starting dose is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response. Giant Cell Arteritis (2.3) Recommended Adult Intravenous Dosage: The recommended dose is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids. TOFIDENCE can be used alone following discontinuation of glucocorticoids. Polyarticular Juvenile Idiopathic Arthritis (2.4) Recommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg Systemic Juvenile Idiopathic Arthritis (2.5) Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Coronavirus Disease 2019 (2.6) The recommended dosage of TOFIDENCE for adult patients with COVID-19 is 8 mg per kg administered by a 60-minute intravenous infusion. Administration of Intravenous Formulation (2.7) • For patients with RA, GCA, COVID-19, PJIA and SJIA patients at or above 30 kg, dilute to 100 mL in 0.9% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique. • For PJIA and SJIA patients less than 30 kg, dilute to 50 mL in 0.9% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique. • Administer as a single intravenous drip infusion over 1 hour; do not administer as bolus or push. Dose Modifications (2.8) • Recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia. --------------------- DOSAGE FORMS AND STRENGTHS---------------------­ Intravenous Infusion Injection: 80 mg/4 mL (20 mg/mL), 200 mg/10 mL (20 mg/mL), 400 mg/20 mL (20 mg/mL) in single-dose vials for further dilution prior to intravenous infusion (3) ------------------------------ CONTRAINDICATIONS ----------------------------­ • Known hypersensitivity to tocilizumab products. (4) ----------------------- WARNINGS AND PRECAUTIONS ----------------------­ • Serious Infections – do not administer TOFIDENCE during an active infection, including localized infections. If a serious infection develops, interrupt TOFIDENCE until the infection is controlled. (5.1) • Gastrointestinal (GI) perforation—use with caution in patients who may be at increased risk. (5.2) • Hepatotoxicity- Monitor patients for signs and symptoms of hepatic injury. Modify or discontinue TOFIDENCE if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (2.8, 5.3) • Laboratory monitoring—recommended due to potential consequences of treatment-related changes in neutrophils, platelets, lipids, and liver function tests. (2.8, 5.4) • Hypersensitivity reactions, including anaphylaxis and death and serious cutaneous reactions including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) – discontinue TOFIDENCE, treat promptly, and monitor until reaction resolves (5.6) • Live vaccines—Avoid use with TOFIDENCE. (5.9, 7.3) ------------------------------ ADVERSE REACTIONS -----------------------------­ Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT. (6) To report SUSPECTED ADVERSE REACTIONS, contact Biogen MA Inc. at 1-877-422-8360 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ----------------------- USE IN SPECIFIC POPULATIONS ---------------------­ • Pregnancy: Based on animal data, may cause fetal harm. (8.1) • Lactation: Discontinue drug or nursing taking into consideration importance of drug to mother. (8.2) Page 1 Reference ID: 5489159 See 17 for PATIENT COUNSELING INFORMATION and Medication Biosimilarity of TOFIDENCE has been demonstrated for the condition(s) of Guide use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, Revised: 12/2024 known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Page 2 Reference ID: 5489159 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS INFECTIONS 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis (RA) 1.2 Giant Cell Arteritis (GCA) 1.3 Polyarticular Juvenile Idiopathic Arthritis (PJIA) 1.4 Systemic Juvenile Idiopathic Arthritis (SJIA) 1.5 Coronavirus Disease 2019 (COVID-19) 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations for Administration 2.2 Recommended Dosage for Rheumatoid Arthritis 2.3 Recommended Dosage for Giant Cell Arteritis 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis 2.5 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis 2.6 Coronavirus Disease 2019 (COVID-19) 2.7 Preparation and Administration Instructions for Intravenous Infusion 2.8 Dosage Modifications due to Serious Infections or Laboratory Abnormalities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections 5.2 Gastrointestinal Perforations 5.3 Hepatotoxicity 5.4 Changes in Laboratory Parameters 5.5 Immunosuppression 5.6 Hypersensitivity Reactions, Including Anaphylaxis 5.7 Demyelinating Disorders 5.8 Active Hepatic Disease and Hepatic Impairment 5.9 Vaccinations 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) 6.2 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) 6.3 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) 6.4 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) 6.5 Clinical Trials Experience in COVID-19 Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) 6.6 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Drugs for Treatment of Adult Indications 7.2 Interactions with CYP450 Substrates 7.3 Live Vaccines 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 9 DRUG ABUSE AND DEPENDENCE 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis – Intravenous Administration 14.2 Giant Cell Arteritis – Intravenous Administration 14.3 Polyarticular Juvenile Idiopathic Arthritis – Intravenous Administration 14.4 Systemic Juvenile Idiopathic Arthritis – Intravenous Administration 14.5 COVID-19 – Intravenous Administration 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Page 3 Reference ID: 5489159 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS INFECTIONS Patients treated with tocilizumab products including TOFIDENCE are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt TOFIDENCE until the infection is controlled. Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients, except those with COVID-19, should be tested for latent tuberculosis before TOFIDENCE use and during therapy. Treatment for latent infection should be initiated prior to TOFIDENCE use. • Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. • Bacterial, viral and other infections due to opportunistic pathogens. The risks and benefits of treatment with TOFIDENCE should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with TOFIDENCE, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis (RA) TOFIDENCE (tocilizumab-bavi) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). 1.2 Giant Cell Arteritis (GCA) TOFIDENCE™ (tocilizumab-bavi) is indicated for the treatment of giant cell arteritis (GCA) in adult patients. 1.3 Polyarticular Juvenile Idiopathic Arthritis (PJIA) Page 4 Reference ID: 5489159 TOFIDENCE™ (tocilizumab-bavi) is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. 1.4 Systemic Juvenile Idiopathic Arthritis (SJIA) TOFIDENCE™ (tocilizumab-bavi) is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older. 1.5 Coronavirus Disease 2019 (COVID-19) TOFIDENCE™ (tocilizumab-bavi) is indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adult patients who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations for Administration Not Recommended for Concomitant Use with Biological DMARDs Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co- stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection. Avoid using TOFIDENCE with biological DMARDs. Baseline Laboratory Evaluation Prior to Treatment Obtain and assess baseline complete blood count (CBC) and liver function tests prior to treatment. • RA, GCA, PJIA and SJIA – It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or ALT or AST above 1.5 times the upper limit of normal (ULN) [see Warnings and Precautions (5.3, 5.4)]. • COVID-19 - It is recommended that TOFIDENCE not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm3 , platelet count below 50,000 mm3 , or ALT or AST above 10 times ULN [see Warnings and Precautions (5.3, 5.4)] 2.2 Recommended Dosage for Rheumatoid Arthritis TOFIDENCE may be used as monotherapy or concomitantly with methotrexate or other non- biologic DMARDs as an intravenous infusion. Recommended Intravenous Dosage Regimen: The recommended dosage of TOFIDENCE for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response. Page 5 Reference ID: 5489159 • Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.1)]. • Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology (12.3)]. When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dose is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8) and Warnings and Precautions (5.3, 5.4). 2.3 Recommended Dosage for Giant Cell Arteritis Recommended Intravenous Dosage Regimen: The recommended dosage of TOFIDENCE for adult patients given as a 60-minute single intravenous drip infusion is 6 mg per kg every 4 weeks in combination with tapering course of glucocorticoids. TOFIDENCE can be used alone following discontinuation of glucocorticoids. • Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)]. • Doses exceeding 600 mg per infusion are not recommended in GCA patients [see Clinical Pharmacology (12.3)]. When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose. 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis TOFIDENCE may be used as an intravenous infusion alone or in combination with methotrexate. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. Recommended Intravenous Dosage Regimen: Page 6 Reference ID: 5489159 I I I I The recommended dosage of TOFIDENCE for PJIA patients given once every 4 weeks as a 60­ minute single intravenous drip infusion is: Recommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)]. 2.5 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis TOFIDENCE may be used as an intravenous infusion or in combination with methotrexate. Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate. Recommended Intravenous Dosage Regimen: The recommended dose of TOFIDENCE for SJIA patients given once every 2 weeks as a 60­ minute single intravenous drip infusion is: Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg When transitioning from intravenous therapy with TOFIDENCE to subcutaneous therapy with another tocilizumab product, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)]. 2.6 Coronavirus Disease 2019 (COVID-19) Administer TOFIDENCE by intravenous infusion only. The recommended dosage of TOFIDENCE for treatment of adult patients with COVID-19 is 8 mg per kg administered as a single 60-minute intravenous infusion. If clinical signs or symptoms Page 7 Reference ID: 5489159 worsen or do not improve after the first dose, one additional infusion of TOFIDENCE may be administered at least 8 hours after the initial infusion. • Doses exceeding 800 mg per infusion are not recommended in patients with COVID-19. 2.7 Preparation and Administration Instructions for Intravenous Infusion TOFIDENCE for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows: • Use a sterile needle and syringe to prepare TOFIDENCE. • Patients less than 30 kg: use a 50 mL infusion bag or bottle of 0.9% Sodium Chloride Injection, USP, and then follow steps 1 and 2 below. • Patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps 1 and 2 below. • Step 1. Withdraw a volume of 0.9% Sodium Chloride Injection, USP, equal to the volume of the TOFIDENCE injection required for the patient’s dose from the infusion bag or bottle [see Dosage and Administration (2.2, 2.4, 2.5)]. For Intravenous Use: Volume of TOFIDENCE Injection per kg of Body Weight Dosage Indication Volume of TOFIDENCE injection per kg of body weight 4 mg/kg Adult RA 0.2 mL/kg 6 mg/kg Adult GCA 0.3 mL/kg 8 mg/kg Adult RA Adult COVID-19 SJIA and PJIA (greater than or equal to 30 kg of body weight) 0.4 mL/kg 10 mg/kg PJIA (less than 30 kg of body weight) 0.5 mL/kg 12 mg/kg SJIA (less than 30 kg of body weight) 0.6 mL/kg • Step 2. Withdraw the amount of TOFIDENCE for intravenous infusion from the vial(s) and add slowly into the 0.9% Sodium Chloride Injection, USP infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming. • The fully diluted TOFIDENCE solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored refrigerated at 36°F to 46°F (2°C to 8°C) for up to 24 hours or room temperature at 68°F to 77°F (20°C to 25°C) for up to 12 hours and should be protected from light. • TOFIDENCE solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used. • Allow the fully diluted TOFIDENCE solution to reach room temperature prior to infusion. • The infusion should be administered over 60 minutes, and must be administered with an infusion set. Do not administer as an intravenous push or bolus. • TOFIDENCE should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of TOFIDENCE with other drugs. Page 8 Reference ID: 5489159 • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used. • Fully diluted TOFIDENCE solutions are compatible with infusion bags and/or infusion sets with the following materials: polypropylene, polyethylene, polyolefin, polyvinyl chloride, polyethersulfone, polyurethane, nylon and stainless steel. 2.8 Dosage Modifications due to Serious Infections or Laboratory Abnormalities Serious Infections Hold TOFIDENCE treatment if a patient develops a serious infection until the infection is controlled. Laboratory Abnormalities Rheumatoid Arthritis and Giant Cell Arteritis Liver Enzyme Abnormalities [see Warnings and Precautions (5.3, 5.4)] Lab Value Recommendation for RA Recommendation for GCA Greater than 1 to 3x ULN Dose modify concomitant DMARDs if appropriate. For persistent increases in this range: • For patients receiving intravenous TOFIDENCE, reduce dose to 4 mg per kg or hold TOFIDENCE until ALT or AST have normalized. Dose modify immunomodulatory agents if appropriate For persistent increases in this range: • For patients receiving intravenous TOFIDENCE, hold TOFIDENCE until ALT or AST have normalized. Greater than 3 to 5x ULN (confirmed by repeat testing) Hold TOFIDENCE dosing until less than 3x ULN and follow recommendations above for greater than 1 to 3x ULN. For persistent increases greater than 3x ULN, discontinue TOFIDENCE. Hold TOFIDENCE dosing until less than 3x ULN and follow recommendations above for greater than 1 to 3x ULN. For persistent increases greater than 3x ULN, discontinue TOFIDENCE. Greater than 5x ULN Discontinue TOFIDENCE. Discontinue TOFIDENCE. Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5.4)] Lab Value (cells per mm3) Recommendation for RA Recommendation for GCA ANC greater than 1000 Maintain dose. Maintain dose. ANC 500 to 1000 Hold TOFIDENCE dosing. When ANC greater than 1000 cells per mm3: • For patients receiving intravenous TOFIDENCE, resume TOFIDENCE at 4 mg per kg and increase to 8 mg per kg as clinically appropriate. Hold TOFIDENCE dosing. When ANC greater than 1000 cells per mm3: • For patients receiving intravenous TOFIDENCE, resume TOFIDENCE at 6 mg per kg. ANC less than 500 Discontinue TOFIDENCE. Discontinue TOFIDENCE. Page 9 Reference ID: 5489159 Low Platelet Count [see Warnings and Precautions (5.4)] Lab Value (cells per mm3) Recommendation for RA Recommendation for GCA 50,000 to 100,000 Hold TOFIDENCE dosing. When platelet count is greater than 100,000 cells per mm3: • For patients receiving intravenous TOFIDENCE, resume TOFIDENCE at 4 mg per kg and increase to 8 mg per kg as clinically appropriate. Hold TOFIDENCE dosing When platelet count is greater than 100,000 cells per mm3: • For patients receiving intravenous TOFIDENCE, resume TOFIDENCE at 6 mg per kg. Less than 50,000 Discontinue TOFIDENCE. Discontinue TOFIDENCE. Polyarticular and Systemic Juvenile Idiopathic Arthritis Dose reduction of tocilizumab products has not been studied in the PJIA and SJIA populations. Dose interruptions of TOFIDENCE are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined above for patients with RA and GCA. If appropriate, dose modify or stop concomitant methotrexate and/or other medications and hold TOFIDENCE dosing until the clinical situation has been evaluated. In PJIA and SJIA the decision to discontinue TOFIDENCE for a laboratory abnormality should be based upon the medical assessment of the individual patient. 3 DOSAGE FORMS AND STRENGTHS Intravenous Infusion Injection: 80 mg/4 mL, 200 mg/10 mL, 400 mg/20 mL as a clear to opalescent, colorless to light yellow solution in 20 mg/mL single-dose vials for further dilution prior to intravenous infusion. 4 CONTRAINDICATIONS TOFIDENCE is contraindicated in patients with known hypersensitivity to tocilizumab products [see Warnings and Precautions (5.6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including tocilizumab products. The most common serious infections Page 10 Reference ID: 5489159 included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with tocilizumab products. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections. Do not administer TOFIDENCE in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating TOFIDENCE in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of serious or an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with TOFIDENCE, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.1), Adverse Reactions (6.1), and Patient Counseling Information (17)]. Hold TOFIDENCE if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with TOFIDENCE should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient. COVID-19 In patients with COVID-19, monitor for signs and symptoms of new infections during and after treatment with TOFIDENCE. There is limited information regarding the use of tocilizumab products in patients with COVID-19 and concomitant active serious infections. The risks and benefits of treatment with TOFIDENCE in COVID-19 patients with other concurrent infections should be considered. Tuberculosis Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating TOFIDENCE. In patients with COVID-19, testing for latent infection is not necessary prior to initiating treatment with TOFIDENCE. Consider anti-tuberculosis therapy prior to initiation of TOFIDENCE in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of Page 11 Reference ID: 5489159 tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating TOFIDENCE. Viral Reactivation Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with tocilizumab. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded. 5.2 Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with tocilizumab. Use TOFIDENCE with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)]. 5.3 Hepatotoxicity Serious cases of hepatic injury have been observed in patients taking intravenous tocilizumab products. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from months to years after treatment initiation with tocilizumab products. While most cases presented with marked elevations of transaminases (> 5 times ULN), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases. During randomized controlled studies, treatment with tocilizumab was associated with a higher incidence of transaminase elevations [see Adverse Reactions (6.1, 6.3, 6.4)]. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with tocilizumab. For RA and GCA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating TOFIDENCE, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter. It is not recommended to initiate TOFIDENCE treatment in RA or GCA patients with elevated transaminases ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than 5x ULN, discontinue TOFIDENCE. For recommended modifications based upon increase in transaminases [see Dosage and Administration (2.8)]. Page 12 Reference ID: 5489159 Patients hospitalized with COVID-19 may have elevated ALT or AST levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19. The decision to administer TOFIDENCE should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with TOFIDENCE. It is not recommended to initiate TOFIDENCE treatment in COVID-19 patients with elevated ALT or AST above 10 x ULN. Monitor ALT and AST during treatment. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (e.g., ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range), TOFIDENCE treatment should be interrupted and investigation done to establish the probable cause. TOFIDENCE should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests. A similar pattern of liver enzyme elevation is noted with tocilizumab products treatment in the PJIA and SJIA populations. Monitor liver test panel at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. 5.4 Changes in Laboratory Parameters Patients with Rheumatoid Arthritis, Giant Cell Arteritis and Coronavirus Disease 2019 Neutropenia Treatment with tocilizumab products was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience. – It is not recommended to initiate TOFIDENCE treatment in RA and GCA patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm3. In patients who develop an absolute neutrophil count less than 500 per mm3 treatment is not recommended. – Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter [see Clinical Pharmacology (12.2)]. For recommended modifications based on ANC results see Dosage and Administration (2.8). – It is not recommended to initiate TOFIDENCE treatment in COVID-19 patients with an ANC less than 1000 per mm3 . Neutrophils should be monitored. Thrombocytopenia Treatment with tocilizumab products was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials [see Adverse Reactions (6.1)]. Page 13 Reference ID: 5489159 – It is not recommended to initiate TOFIDENCE treatment in RA and GCA patients with a platelet count below 100,000 per mm3. In patients who develop a platelet count less than 50,000 per mm3 treatment is not recommended. – Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts see Dosage and Administration (2.8). – In COVID-19 patients with a platelet count less than 50,000 per mm3 , treatment is not recommended. Platelets should be monitored. Elevated Liver Enzymes Refer to 5.3 Hepatotoxicity. For recommended modifications see Dosage and Administration (2.8). Lipid Abnormalities Treatment with tocilizumab products was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol [see Adverse Reactions (6.1)]. – Assess lipid parameters approximately 4 to 8 weeks following initiation of TOFIDENCE therapy. – Subsequently, manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia. Patients with Polyarticular and Systemic Juvenile Idiopathic Arthritis A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with tocilizumab products treatment in the PJIA and SJIA populations. Monitor neutrophils, platelets, ALT and AST at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Monitor lipids as above for approved adult indications [see Dosage and Administration (2.8)]. 5.5 Immunosuppression The impact of treatment with tocilizumab products on the development of malignancies is not known but malignancies were observed in clinical studies [see Adverse Reactions (6.1)]. TOFIDENCE is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies. 5.6 Hypersensitivity Reactions, Including Anaphylaxis Page 14 Reference ID: 5489159 Hypersensitivity reactions, including anaphylaxis, have been reported in association with tocilizumab products [see Adverse Reactions (6)] and anaphylactic events with a fatal outcome have been reported with intravenous infusion of tocilizumab products. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous tocilizumab and 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population. In the SJIA controlled trial with intravenous tocilizumab, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous tocilizumab 0 out of 188 patients (0%) in the tocilizumab all-exposure population experienced hypersensitivity reactions that required treatment discontinuation. Reactions that required treatment discontinuation included generalized erythema, rash, and urticaria. In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous tocilizumab products, with or without concomitant therapies. Events have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of tocilizumab products. In addition, serious cutaneous reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported in patients with autoinflammatory conditions treated with tocilizumab products. TOFIDENCE for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. If a hypersensitivity reaction occurs immediately discontinue TOFIDENCE; treat promptly and monitor until signs and symptoms resolve. 5.7 Demyelinating Disorders The impact of treatment with tocilizumab products on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of TOFIDENCE in patients with preexisting or recent onset demyelinating disorders. 5.8 Active Hepatic Disease and Hepatic Impairment Treatment with TOFIDENCE is not recommended in patients with active hepatic disease or hepatic impairment [see Adverse Reactions (6.1), Use in Specific Populations (8.6)]. 5.9 Vaccinations Avoid use of live vaccines concurrently with TOFIDENCE as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab products. Page 15 Reference ID: 5489159 No data are available on the effectiveness of vaccination in patients receiving tocilizumab products. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly pediatric or elderly patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating TOFIDENCE therapy. The interval between live vaccinations and initiation of TOFIDENCE therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: • Serious Infections [see Warnings and Precautions (5.1)] • Gastrointestinal Perforations [see Warnings and Precautions (5.2)] • Laboratory Parameters [see Warnings and Precautions (5.4)] • Immunosuppression [see Warnings and Precautions (5.5)] • Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.6)] • Demyelinating Disorders [see Warnings and Precautions (5.7)] • Active Hepatic Disease and Hepatic Impairment [see Warnings and Precautions (5.8)] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. 6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The tocilizumab-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of tocilizumab-IV 8 mg per kg monotherapy (288 patients), tocilizumab-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or tocilizumab-IV 4 mg per kg in combination with methotrexate (774 patients). The all exposure population includes all patients in registration studies who received at least one dose of tocilizumab-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years. All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian. Page 16 Reference ID: 5489159 The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1)]. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with tocilizumab-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT. The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking tocilizumab-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of tocilizumab-IV were increased hepatic transaminase values (per protocol requirement) and serious infections. Overall Infections In the 24 week, controlled clinical studies, the rate of infections in the tocilizumab-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis. The overall rate of infections with tocilizumab-IV in the all exposure population remained consistent with rates in the controlled periods of the studies. Serious Infections In the 24 week, controlled clinical studies, the rate of serious infections in the tocilizumab-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group. In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported [see Warnings and Precautions (5.1)]. In the cardiovascular outcomes Study WA25204, the rate of serious infections in the tocilizumab 8 mg/kg IV every 4 weeks group, with or without DMARD, was 4.5 per 100 patient-years, and the rate in the etanercept 50 mg weekly SC group, with or without DMARD, was 3.2 per 100 patient-years [see Clinical Studies (14.1)]. Gastrointestinal Perforations Page 17 Reference ID: 5489159 During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with tocilizumab-IV therapy. In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate [see Warnings and Precautions (5.2)]. The relative contribution of these concomitant medications versus tocilizumab-IV to the development of GI perforations is not known. Infusion Reactions In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting. Anaphylaxis Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with tocilizumab-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of tocilizumab-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction [see Warnings and Precautions (5.6)]. Laboratory Abnormalities Neutropenia In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm3 occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm3 occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm3 and the occurrence of serious infections. Page 18 Reference ID: 5489159 In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.4)]. Thrombocytopenia In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm3 occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events. In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.4)]. Elevated Liver Enzymes Liver enzyme abnormalities are summarized in Table 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tocilizumab-IV, or reduction in tocilizumab-IV dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration (2.8)]. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency [see Warnings and Precautions (5.3, 5.4)]. Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V* Tocilizumab 8 mg per kg MONOTHER APY N = 288 (%) Methotrexate N = 284 (%) Tocilizumab 4 mg per kg + DMARDs N = 774 (%) Tocilizumab 8 mg per kg + DMARDs N = 1582 (%) Placebo + DMARDs N = 1170 (%) AST (U/L) > ULN to 3× ULN 22 26 34 41 17 > 3× ULN to 5× ULN 0.3 2 1 2 0.3 > 5× ULN 0.7 0.4 0.1 0.2 < 0.1 ALT (U/L) > ULN to 3× ULN 36 33 45 48 23 > 3× ULN to 5× ULN 1 4 5 5 1 > 5× ULN 0.7 1 1.3 1.5 0.3 ULN = Upper Limit of Normal *For a description of these studies, see Section 14, Clinical Studies. In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials. In Study WA25204, of the 1538 patients with moderate to severe RA [see Clinical Studies (14.1)] and treated with tocilizumab, elevations in ALT or AST >3 x ULN occurred in 5.3% and Page 19 Reference ID: 5489159 2.2% patients, respectively. One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with tocilizumab. Lipids Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of tocilizumab-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below: – Mean LDL increased by 13 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 20 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 25 mg per dL in tocilizumab 8 mg per kg monotherapy. – Mean HDL increased by 3 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 5 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 4 mg per dL in tocilizumab 8 mg per kg monotherapy. – Mean LDL/HDL ratio increased by an average of 0.14 in the tocilizumab 4 mg per kg+DMARD arm, 0.15 in the tocilizumab 8 mg per kg+DMARD, and 0.26 in tocilizumab 8 mg per kg monotherapy. – ApoB/ApoA1 ratios were essentially unchanged in tocilizumab-treated patients. Elevated lipids responded to lipid lowering agents. In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials. Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of tocilizumab or of other tocilizumab products. In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti­ tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies. Malignancies During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving tocilizumab-IV, compared to 8 malignancies in patients in the control groups. Page 20 Reference ID: 5489159 Exposure-adjusted incidence was similar in the tocilizumab-IV groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years). In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period [see Warnings and Precautions (5.5)]. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg tocilizumab-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2. Table 2 Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per kg Tocilizumab plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD 24 Week Phase 3 Controlled Study Population Preferred Term Tocilizumab 8 mg per kg MONOTHERAPY N = 288 (%) Methotrexate N = 284 (%) Tocilizumab 4 mg per kg + DMARDs N = 774 (%) Tocilizumab 8 mg per kg + DMARDs N = 1582 (%) Placebo + DMARDs N =1170 (%) Upper Respiratory Tract Infection 7 5 6 8 6 Nasopharyngitis 7 6 4 6 4 Headache 7 2 6 5 3 Hypertension 6 2 4 4 3 ALT increased 6 4 3 3 1 Dizziness 3 1 2 3 2 Bronchitis 3 2 4 3 3 Rash 2 1 4 3 1 Mouth Ulceration 2 2 1 2 1 Abdominal Pain Upper 2 2 3 3 2 Gastritis 1 2 1 2 1 Transaminase increased 1 5 2 2 1 Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with tocilizumab-IV in controlled trials were: Infections and Infestations: oral herpes simplex Gastrointestinal disorders: stomatitis, gastric ulcer Investigations: weight increased, total bilirubin increased Blood and lymphatic system disorders: leukopenia General disorders and administration site conditions: edema peripheral Respiratory, thoracic, and mediastinal disorders: dyspnea, cough Page 21 Reference ID: 5489159 Eye disorders: conjunctivitis Renal disorders: nephrolithiasis Endocrine disorders: hypothyroidism 6.2 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab-IV was studied in an open label PK-PD and safety study in 24 patients with GCA who were in remission on tocilizumab-IV at time of enrollment. Patients received tocilizumab 7 mg/kg every 4 weeks for 20 weeks, followed by 6 mg/kg every 4 weeks for 20 weeks. The total patient years exposure to treatment was 17.5 years. The safety of tocilizumab by another route of administration has been studied in one Phase III study with 251 GCA patients. The total patient years duration was 138.5 patient years during the 12-month double blind, placebo-controlled phase of the study. The overall safety profile observed was generally consistent with the known safety profile of tocilizumab. There was an overall higher incidence of infections in GCA patients relative to RA patients. The overall safety profile observed for tocilizumab administered intravenously in GCA patients was consistent with the known safety profile of tocilizumab. 6.3 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the tocilizumab-IV all exposure population (defined as patients who received at least one dose of tocilizumab-IV) was 184.4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients [see Adverse Reactions (6.1 and 6.4)]. Infections The rate of infections in the tocilizumab-IV all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%). Infusion Reactions Page 22 Reference ID: 5489159 In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the tocilizumab-IV all exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and SJIA patients [see Adverse Reactions (6.1 and 6.4)]. No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported. Immunogenicity One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study. Laboratory Abnormalities Neutropenia During routine laboratory monitoring in the tocilizumab-IV all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 3.7% of patients. There was no clear relationship between decreases in neutrophils below 1 x 109 per L and the occurrence of serious infections. Thrombocytopenia During routine laboratory monitoring in the tocilizumab-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50,000 per mm3 without associated bleeding events. Elevated Liver Enzymes During routine laboratory monitoring in the tocilizumab-IV all exposure population, elevation in ALT or AST at or greater than 3 x ULN occurred in 4% and less than 1% of patients, respectively. Lipids During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol greater than 1.5-2 x ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 x ULN occurred in one patient (0.5%). 6.4 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) Page 23 Reference ID: 5489159 The data described below reflect exposure to tocilizumab-IV in one randomized, double-blind, placebo-controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy. At baseline, approximately half of the patients were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension. In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with tocilizumab-IV (8 or 12 mg per kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated with tocilizumab-IV in the open-label extension phase. The most common adverse events (at least 5%) seen in tocilizumab-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea. Infections In the 12 week controlled phase, the rate of all infections in the tocilizumab-IV group was 345 per 100 patient-years and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years. In the 12 week controlled phase, the rate of serious infections in the tocilizumab-IV group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media. Macrophage Activation Syndrome In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with tocilizumab-IV. One patient in the placebo group escaped to tocilizumab-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had tocilizumab-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the tocilizumab-IV SJIA clinical development experience; however no definitive conclusions can be made. Infusion Reactions Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA. Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of tocilizumab-IV and 0% of placebo treated patients experienced events occurring during infusion. Page 24 Reference ID: 5489159 One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment. Within 24 hours after infusion, 16% of patients in the tocilizumab-IV treatment group and 5% of patients in the placebo group experienced an event. In the tocilizumab-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious. Anaphylaxis Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with tocilizumab-IV during the controlled and open label extension study [see Warnings and Precautions (5.6)]. Immunogenicity All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study. Laboratory Abnormalities Neutropenia During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 × 109 per L occurred in 7% of patients in the tocilizumab-IV group, and in no patients in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the tocilizumab-IV group. There was no clear relationship between decrease in neutrophils below 1 x 109 per L and the occurrence of serious infections. Thrombocytopenia During routine monitoring in the 12 week controlled phase, 1% of patients in the tocilizumab-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100,000 per mm3. In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the tocilizumab-IV group, with no associated bleeding. Elevated Liver Enzymes During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3x ULN occurred in 5% and 3% of patients, respectively in the tocilizumab-IV group and in 0% of placebo patients. Page 25 Reference ID: 5489159 In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3x ULN occurred in 13% and 5% of tocilizumab-IV treated patients, respectively. Lipids During routine laboratory monitoring in the 12 week controlled phase, elevation in total cholesterol greater than 1.5x ULN – 2x ULN occurred in 1.5% of the tocilizumab-IV group and in 0% of placebo patients. Elevation in LDL greater than 1.5x ULN – 2x ULN occurred in 1.9% of patients in the tocilizumab-IV group and 0% of the placebo group. In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data. 6.5 Clinical Trials Experience in COVID-19 Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab in hospitalized COVID-19 patients was evaluated in a pooled safety population that includes patients enrolled in EMPACTA, COVACTA, AND REMDACTA. The analysis of adverse reactions included a total of 974 patients exposed to tocilizumab. Patients received a single, 60-minute infusion of intravenous tocilizumab 8 mg/kg (maximum dose of 800 mg). If clinical signs or symptoms worsened or did not improve, one additional dose of tocilizumab 8 mg/kg could be administered between 8- 24 hours after the initial dose. Adverse reactions summarized in Table 3 occurred in at least 3% of tocilizumab -treated patients and more commonly than in patients on placebo in the pooled safety population. Table 3 Adverse Reactions1 Identified From the Pooled COVID-19 Safety Population Adverse Reaction Tocilizumab 8mg per kg N = 974 (%) Placebo N = 483 (%) Hepatic Transaminases increased 10% 8% Constipation 9% 8% Urinary tract infection 5% 4% Hypertension 4% 1% Hypokalaemia 4% 3% Anxiety 4% 2% Diarrhea 4% 2% Insomnia 4% 3% Nausea 3% 2% 1 Patients are counted once for each category regardless of the number of reactions Page 26 Reference ID: 5489159 In the pooled safety population, the rates of infection/serious infection events were 30%/19% in patients receiving tocilizumab versus 32%/23% receiving placebo. Laboratory Abnormalities In the pooled safety population of EMPACTA, COVACTA, and REMDACTA, neutrophil counts <1000 cells/mcl occurred in 3.4% of patients who received tocilizumab and 0.5% of patients who received placebo. Platelet counts <50,000 cells/mcl occurred in 3.2% of patients who received tocilizumab and 1.5% of patients who received placebo. ALT or AST at or above 5x ULN occurred in 11.7% of patients who received tocilizumab and 9.9% of patients who received placebo. 6.6 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tocilizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Hypersensitivity Reactions: Fatal anaphylaxis, Stevens-Johnson Syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)] • Pancreatitis • Drug-induced liver injury, Hepatitis, Hepatic failure, Jaundice [see Warnings and Precautions (5.3)] 7 DRUG INTERACTIONS 7.1 Concomitant Drugs for Treatment of Adult Indications In RA patients, population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. Concomitant administration of a single intravenous dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration (2.2)]. In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed. 7.2 Interactions with CYP450 Substrates Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab products may restore CYP450 activities to higher levels than those in the absence of tocilizumab products leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP Page 27 Reference ID: 5489159 enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effect on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of tocilizumab, respectively. The effect of tocilizumab products on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of TOFIDENCE, in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise caution when coadministering TOFIDENCE with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab products on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12.3)]. 7.3 Live Vaccines Avoid use of live vaccines concurrently with TOFIDENCE [see Warnings and Precautions (5.9)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The limited available data with tocilizumab products in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as tocilizumab products, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant [see Clinical Considerations]. In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition [see Data]. Based on the animal data, there may be a potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Page 28 Reference ID: 5489159 Clinical Considerations Fetal/Neonatal adverse reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to TOFIDENCE in utero [see Warnings and Precautions (5.9)]. Data Animal Data An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre­ and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring. Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery. 8.2 Lactation Risk Summary No information is available on the presence of tocilizumab products in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab products are transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab products are unknown. The lack of clinical data during lactation precludes clear determination of the risk of tocilizumab products to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TOFIDENCE and the potential adverse effects on the breastfed child from Tofidence or from the underlying maternal condition. Page 29 Reference ID: 5489159 8.4 Pediatric Use TOFIDENCE by intravenous use is indicated for the treatment of pediatric patients with: • Active systemic juvenile idiopathic arthritis in patients 2 years of age and older • Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older The safety and effectiveness of TOFIDENCE in pediatric patients with conditions other than PJIA or SJIA have not been established. The safety and effectiveness in pediatric patients below the age of 2 have not been established in PJIA or SJIA. Systemic Juvenile Idiopathic Arthritis – Intravenous Use A multicenter, open-label, single arm study to evaluate the PK, safety and exploratory PD and efficacy of tocilizumab over 12-weeks in SJIA patients (N=11) under 2 years of age was conducted. Patients received intravenous tocilizumab 12 mg/kg every two weeks. Concurrent use of stable background treatment with corticosteroids, MTX, and/or non-steroidal anti- inflammatory drugs was permitted. Patients who completed the 12-week period could continue to the optional extension period (a total of 52-weeks or until the age of 2 years, whichever was longer). The primary PK endpoints (Cmax, Ctrough and AUC2weeks) of tocilizumab at steady-state in this study were within the ranges of these parameters observed in patients with SJIA aged 2 to 17 years. The safety and immunogenicity of tocilizumab for patients with SJIA under 2 years of age was assessed descriptively. SAEs, AEs leading to discontinuation, and infectious AEs were reported by 27.3%, 36.4%, and 81.8% of patients. Six patients (54.5%) experienced hypersensitivity reactions, defined as all adverse events occurring during or within 24 hours after an infusion considered related to tocilizumab. Three of these patients experienced serious hypersensitivity reactions and were withdrawn from the study. Three patients with hypersensitivity reactions (two with serious hypersensitivity reactions) developed treatment induced anti-tocilizumab antibodies after the event. There were no cases of MAS based on the protocol-specified criteria, but 2 cases of suspected MAS based on Ravelli criteria1. 8.5 Geriatric Use Of the 2644 patients who received tocilizumab in Studies I to V [see Clinical Studies (14)], a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. The frequency of serious infection among tocilizumab treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly. 1 Ravelli A, Minoia F, Davì S on behalf of the Paediatric Rheumatology International Trials Organisation, the Childhood Arthritis and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis. Annals of the Rheumatic Diseases 2016;75:481-489. Page 30 Reference ID: 5489159 In the EMPACTA, COVACTA, and REMDACTA studies, of the 974 COVID-19 patients in the tocilizumab arm, 375 (39%) were 65 years of age or older. No overall differences in safety or effectiveness of tocilizumab were observed between patients 65 years of age and older and those under the age of 65 years of age in these studies [see Adverse Reactions (6.5) and Clinical Studies (14.5)]. In the RECOVERY study, of the 2022 COVID-19 patients in the tocilizumab arm, 930 (46%) were 65 years of age or older. No overall differences in effectiveness of tocilizumab were observed between patients 65 years of age and older and those under the age 65 years of age in this study [see Clinical Studies (14.5)]. 8.6 Hepatic Impairment The safety and efficacy of tocilizumab products have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology [see Warnings and Precautions (5.8)]. 8.7 Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. Tocilizumab products have not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. 9 DRUG ABUSE AND DEPENDENCE No studies on the potential for tocilizumab products to cause dependence have been performed. However, there is no evidence from the available data that tocilizumab products treatment results in dependence. 10 OVERDOSAGE There are limited data available on overdoses with tocilizumab products. One case of accidental overdose was reported with intravenous tocilizumab in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment. Page 31 Reference ID: 5489159 11 DESCRIPTION Tocilizumab-bavi is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H2L2 polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. Tocilizumab-bavi has a molecular weight of approximately 148 kDa. The antibody is produced in mammalian (Chinese hamster ovary) cells. Intravenous Infusion TOFIDENCE (tocilizumab-bavi) injection is a sterile, clear to opalescent, colorless to light yellow, preservative-free solution for further dilution prior to intravenous infusion with a pH of approximately 6.2. Each single-dose vial, formulated in an aqueous solution, is available at a concentration of 20 mg/mL containing 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL of TOFIDENCE. Each mL of solution contains arginine hydrochloride (10.53 mg), histidine (0.81 mg), L-histidine hydrochloride monohydrate (1.01 mg), polysorbate 80 (0.5 mg), sucrose (20 mg), and water for injection. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tocilizumab products bind to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B- cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis. 12.2 Pharmacodynamics In clinical studies in RA patients with the 4 mg per kg and 8 mg per kg intravenous doses decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen and increases in hemoglobin) with doses, however the greatest improvements were observed with 8 mg per kg tocilizumab. Pharmacodynamic changes were also observed to occur after tocilizumab administration in GCA, PJIA, and SJIA patients (decreases in CRP, ESR, and increases in hemoglobin). The relationship between these pharmacodynamic findings and clinical efficacy is not known. Page 32 Reference ID: 5489159 In healthy subjects administered tocilizumab in doses from 2 to 28 mg per kg intravenously, absolute neutrophil counts decreased to the nadir 3 to 5 days following tocilizumab administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis and GCA patients demonstrated a similar pattern of absolute neutrophil counts following tocilizumab administration [see Warnings and Precautions (5.4)]. 12.3 Pharmacokinetics PK of tocilizumab is characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of tocilizumab elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies. Rheumatoid Arthritis - Intravenous Administration The pharmacokinetics in healthy subjects and RA patients suggest that PK is similar between the two populations. The population PK model was developed from an analysis dataset composed of an IV dataset of 1793 patients from Study I, Study III, Study IV, and Study V. Cmean is included in place of AUCtau, since for dosing regimens with different inter-dose intervals, the mean concentration over the dosing period characterizes the comparative exposure better than AUCtau. At high serum concentrations, when total clearance of tocilizumab is dominated by linear clearance, a terminal half-life of approximately 21.5 days was derived from the population parameter estimates. For doses of 4 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab at steady state were 86.1 (44.8–202) mcg/mL, 0.1 (0.0–14.6) mcg/mL, and 18.0 (8.9–50.7) mcg/mL, respectively. For doses of 8 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 176 (75.4–557) mcg/mL, 13.4 (0.1–154) mcg/mL, and 54.0 (17–260) mcg/mL, respectively. Cmax increased dose-proportionally between doses of 4 and 8 mg/kg IV every 4 weeks, while a greater than dose-proportional increase was observed in Cmean and Ctrough. At steady-state, Cmean and Ctrough were 3.0 and 134 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively. The accumulation ratios for AUC and Cmax after multiple doses of 4 and 8 mg/kg IV Q4W are low, while the accumulation ratios for Ctrough are higher (2.62 and 2.47, respectively). For Cmax, greater than 90% of the steady-state value was reached after the 1st IV infusion. For AUCtau and Cmean, 90% of the steady-state value was reached after the 1st and 3rd infusion for 4 mg/kg and 8 Page 33 Reference ID: 5489159 mg/kg IV, while for Ctrough, approximately 90% of the steady-state value was reached after the 4th IV infusion after both doses. Population PK analysis identified body weight as a significant covariate impacting the pharmacokinetics of tocilizumab. When given IV on a mg/kg basis, individuals with body weight ≥ 100 kg are predicted to have mean steady-state exposures higher than mean values for the patient population. Therefore, tocilizumab doses exceeding 800 mg per infusion are not recommended in patients with RA [see Dosage and Administration (2.1)]. Giant Cell Arteritis – Intravenous Administration The pharmacokinetics of tocilizumab IV in GCA patients was characterized by a non- compartmental pharmacokinetic analysis which included 22 patients treated with 6 mg/kg intravenously every 4 weeks for 20 weeks. The median (range) Cmax, Ctrough and Cmean of tocilizumab at steady state were 178 (115-320) mcg/mL, 22.7 (3.38-54.5) mcg/mL and 57.5 (32.9-110) mcg/mL, respectively. Steady state trough concentrations were within the range observed in GCA patients treated with tocilizumab by another route of administration. Based on pharmacokinetic exposure and extrapolation between RA and GCA patients, when given IV on a mg/kg basis, tocilizumab doses exceeding 600 mg per infusion are not recommended in patients with GCA [see Dosage and Administration (2.3)]. Polyarticular Juvenile Idiopathic Arthritis – Intravenous Administration The pharmacokinetics of tocilizumab (TCZ) in PJIA patients was characterized by a population pharmacokinetic analysis which included 188 patients who were treated with TCZ IV. For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab at steady state were 181 (114–331) mcg/mL, 3.28 (0.02–35.4) mcg/mL, and 38.6 (22.2–83.8) mcg/mL, respectively. For doses of 10 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 167 (125–220) mcg/mL, 0.35 (0–11.8) mcg/mL, and 30.8 (16.0–48.0) mcg/mL, respectively. The accumulation ratios were 1.05 and 1.16 for AUC4weeks, and 1.43 and 2.22 for Ctrough for 10 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. No accumulation for Cmax was observed. Following 10 mg/kg and 8 mg/kg TCZ IV every 4 weeks doses in PJIA patients (aged 2 to 17 years), steady state concentrations (trough and average) were within the range of exposures in adult RA patients following 4 mg/kg and 8 mg/kg every 4 weeks, and steady state peak concentrations in PJIA patients were comparable to those following 8 mg/kg every 4 weeks in adult RA patients. Systemic Juvenile Idiopathic Arthritis—Intravenous Administration Page 34 Reference ID: 5489159 The pharmacokinetics of tocilizumab (TCZ) in SJIA patients was characterized by a population pharmacokinetic analysis which included 89 patients who were treated with TCZ IV. For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 253 (120–404) mcg/mL, 70.7 (5.26–127) mcg/mL, and 117 (37.6–199) mcg/mL, respectively. For doses of 12 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 274 (149–444) mcg/mL, 65.9 (19.0–135) mcg/mL, and 124 (60–194) mcg/mL, respectively. The accumulation ratios were 1.95 and 2.01 for AUC4weeks, and 3.41 and 3.20 for Ctrough for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. Accumulation data for Cmax were 1.37 and 1.42 for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. Following every other week dosing with tocilizumab IV, steady state was reached by 8 weeks for both body weight groups. Mean estimated tocilizumab exposure parameters were similar between the two dose groups defined by body weight. COVID-19 -Intravenous Administration The pharmacokinetics of tocilizumab in COVID-19 patients was characterized by a population pharmacokinetic analysis of a dataset composed of 380 adult patients treated with tocilizumab 8mg/kg intravenously (IV) in the COVACTA study [see Clinical Studies (14.5)] and another clinical study. For one dose of 8 mg/kg tocilizumab IV, the estimated median (range) Cmax and Cday28 of tocilizumab were 151 (77.5-319) mcg/mL and 0.229 (0.00119-19.4) mcg/mL, respectively. For two doses of 8 mg/kg tocilizumab IV separated by at least 8 hours, the estimated median (range) Cmax and Cday28 of tocilizumab was 290 (152-604) mcg/mL and 7.04 (0.00474-54.8) mcg/mL, respectively. The weight-tiered dosing used in RECOVERY study, 800 mg for patients >90 kg, 600 mg for patients >65 and ≤90 kg, 400 mg for patients >40 and ≤65 kg, and 8mg/kg for patients ≤40 kg, is comparable to 8 mg/kg dosing and is expected to have similar exposure. Distribution Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L. In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution was 3.37 L resulting in a volume of distribution at steady state of 7.46 L. In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L. Page 35 Reference ID: 5489159 In pediatric patients with SJIA, the central volume of distribution was 1.87 L, the peripheral volume of distribution was 2.14 L resulting in a volume of distribution at steady state of 4.01 L. In COVID-19 patients treated with one or two infusions of tocilizumab 8 mg/kg intravenously separated by 8 hours, the estimated central volume of distribution was 4.52 L, and the estimated peripheral volume of distribution was 4.23 L, resulting in a volume of distribution of 8.75 L. Elimination Tocilizumab is eliminated by a combination of linear clearance and nonlinear elimination. The concentration-dependent nonlinear elimination plays a major role at low tocilizumab concentrations. Once the nonlinear pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance. The saturation of the nonlinear elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies. The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA patients, 6.7 mL per h in GCA patients, 5.8 mL per h in pediatric patients with PJIA, and 5.7 mL per h in pediatric patients with SJIA. In COVID-19 patients, serum concentrations were below the limit of quantification after 35 days on average following one infusion of tocilizumab 8 mg/kg intravenously. The average linear clearance in the population pharmacokinetic analysis was estimated to be 17.6 mL per hour in patients with baseline ordinal scale category 3 (OS 3, patients requiring supplemental oxygen), 22.5 mL per hour in patients with baseline OS 4 (patients requiring high-flow oxygen or non-invasive ventilation), 29 mL per hour in patients with baseline OS 5 (patients requiring mechanical ventilation), and 35.4 mL per hour in patients with baseline OS 6 (patients requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support). Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. For intravenous administration in RA patients, the concentration-dependent apparent t1/2 is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For intravenous administration in GCA patients, the TCZ concentration-dependent apparent t1/2 was 13.2 days following 6 mg/kg every 4 weeks. The t1/2 of tocilizumab in children with PJIA is up to 17 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg or 10 mg/kg for body weight below 30 kg) during a dosing interval at steady state. Page 36 Reference ID: 5489159 The t1/2 of tocilizumab intravenous in pediatric patients with SJIA is up to 16 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg and 12 mg/kg for body weight below 30 kg every other week) during a dosing interval at steady-state. Specific Populations Population pharmacokinetic analyses in adult rheumatoid arthritis patients and GCA patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. In RA patients, the body weight-based dose (8 mg per kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg. In COVID-19 patients, exposure following body-weight-based intravenous dosing (8 mg per kg tocilizumab up to 100 kg body weight with a maximum dose of 800 mg) was dependent on body weight and disease severity assessed by an ordinal scale (OS). Within an OS category, compared to patients with a mean body weight of 80 kg, exposure was 20% lower in patients weighing less than 60 kg. Exposure in patients weighing more than 100 kg was in the same range as exposure in patients with a mean body weight of 80 kg. For an 80 kg patient, exposure decreases as OS category increases; for each category increase, exposure decreases by 13%. Patients with Hepatic Impairment No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted. Patients with Renal Impairment No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted. Most of the RA and GCA patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance less than 80 mL per min and at or above 50 mL per min based on Cockcroft-Gault formula) did not impact the pharmacokinetics of tocilizumab. No dose adjustment is required in patients with mild or moderate renal impairment. Drug Interaction Studies In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P­ gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of TOFIDENCE , in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., Page 37 Reference ID: 5489159 warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when TOFIDENCE is coadministered with drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives (CYP3A4 substrates) [see Drug Interactions (7.2)]. Simvastatin Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with tocilizumab, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of tocilizumab (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of tocilizumab in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of TOFIDENCE, (due to normalization of CYP3A4) or higher exposures after discontinuation of TOFIDENCE. Omeprazole Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after tocilizumab infusion (8 mg per kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects. Dextromethorphan Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of tocilizumab (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after tocilizumab infusion. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab products. Literature indicates that the IL-6 pathway can mediate anti-tumor responses by promoting increased immune cell surveillance of the tumor microenvironment. However, available published evidence also supports that IL-6 signaling through the IL-6 receptor may be involved in pathways that lead to tumorigenesis. The malignancy risk in humans from an antibody that disrupts signaling through the IL-6 receptor, such as tocilizumab, is presently unknown. Page 38 Reference ID: 5489159 Fertility and reproductive performance were unaffected in male and female mice that received a murine analogue of tocilizumab administered by the intravenous route at a dose of 50 mg/kg every three days. 14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis—Intravenous Administration The efficacy and safety of intravenously administered tocilizumab was assessed in five randomized, double-blind, multicenter studies in patients greater than 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. Tocilizumab was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V). Study I (NCT00109408) evaluated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 24 weeks prior to randomization, or who had not discontinued previous methotrexate treatment as a result of clinically important toxic effects or lack of response. In this study, 67% of patients were MTX-naïve, and over 40% of patients had rheumatoid arthritis less than 2 years. Patients received tocilizumab 8 mg per kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly). The primary endpoint was the proportion of tocilizumab patients who achieved an ACR 20 response at Week 24. Study II (NCT00106535) was a 104-week study with an optional 156-week extension phase that evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). Upon completion of 52-weeks, patients received open-label treatment with tocilizumab 8 mg per kg through 104 weeks or they had the option to continue their double-blind treatment if they maintained a greater than 70% improvement in swollen/tender joint count. Two pre-specified interim analyses at week 24 and week 52 were conducted. The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At weeks 52 and 104, the primary endpoints were change from baseline in modified total Sharp-Genant score and the area under the curve (AUC) of the change from baseline in HAQ-DI score. Study III (NCT00106548) evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Page 39 Reference ID: 5489159 Study IV (NCT00106574) evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received tocilizumab 8 mg per kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Study V (NCT00106522) evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomization. Patients received tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Clinical Response The percentages of intravenous tocilizumab-treated patients achieving ACR 20, 50 and 70 responses are shown in Table 4. In all intravenous studies, patients treated with 8 mg per kg tocilizumab had higher ACR 20, ACR 50, and ACR 70 response rates versus MTX- or placebo- treated patients at week 24. During the 24 week controlled portions of Studies I to V, patients treated with tocilizumab at a dose of 4 mg per kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with tocilizumab 8 mg per kg. Page 40 Reference ID: 5489159 Table 4 Clinical Response at Weeks 24 and 52 in Active and Placebo Controlled Trials of Intravenous Tocilizumab (Percent of Patients) Percent of Patients Response Rate Study I Study II Study III Study IV Study V MTX Tocilizum ab 8 mg per kg Place bo + MTX Tocilizum ab 4 mg per kg + MTX Tocilizum ab 8 mg per kg + MTX Place bo + MTX Tocilizum ab 4 mg per kg + MTX Tocilizum ab 8 mg per kg + MTX Placebo + DMAR Ds Tocilizum ab 8 mg per kg + DMARDs Place bo + MTX Tocilizuma b4 mg per kg + MTX Tocilizum ab 8 mg per kg + MTX N=28 4 N=286 N=393 N=399 N=398 N=204 N=213 N=205 N=413 N=803 N=158 N=161 N=170 (95% CI)a ( 95% CI)a ( 95% CI)a ( 95% CI)a ( 95% CI)a ( 95% CI)a ( 95% CI)a ( 95% CI)a ( 95% CI)a ACR 20 Week 24 53% 70% (0.11, 0.27) 27% 51% (0.17, 0.29) 56% (0.23, 0.35) 27% 48% (0.15, 0.32) 59% (0.23, 0.41) 24% 61% (0.30, 0.40) 10% 30% (0.15, 0.36) 50% (0.36, 0.56) Week 52 N/A N/A 25% 47% (0.15, 0.28) 56% (0.25, 0.38) N/A N/A N/A N/A N/A N/A N/A N/A ACR 50 Week 24 34% 44% (0.04, 0.20) 10% 25% (0.09, 0.20) 32% (0.16, 0.28) 11% 32% (0.13, 0.29) 44% (0.25, 0.41) 9% 38% (0.23, 0.33) 4% 17% (0.05, 0.25) 29% (0.21, 0.41) Week 52 N/A N/A 10% 29% (0.14, 0.25) 36% (0.21, 0.32) N/A N/A N/A N/A N/A N/A N/A N/A ACR 70 Week 24 15% 28% (0.07, 0.22) 2% 11% (0.03, 0.13) 13% (0.05, 0.15) 2% 12% (0.04, 0.18) 22% (0.12, 0.27) 3% 21% (0.13, 0.21) 1% 5% (-0.06, 0.14) 12% (0.03, 0.22) Week 52 N/A N/A 4% 16% (0.08, 0.17) 20% (0.12, 0.21) N/A N/A N/A N/A N/A N/A N/A N/A Major Clinical Response sb Week 52 N/A N/A 1% 4% (0.01, 0.06) 7% (0.03, 0.09) N/A N/A N/A N/A N/A N/A N/A N/A a CI: 95% confidence interval of the weighted difference to placebo adjusted for site (and disease duration for Study I only) b Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week period Reference ID: 5489159 Page 41 In study II, a greater proportion of patients treated with 4 mg per kg and 8 mg per kg tocilizumab + MTX achieved a low level of disease activity as measured by a DAS 28-ESR less than 2.6 compared with placebo +MTX treated patients at week 52. The proportion of tocilizumab-treated patients achieving DAS 28-ESR less than 2.6, and the number of residual active joints in these responders in Study II are shown in Table 5. Table 5 Proportion of Patients with DAS28-ESR Less Than 2.6 with Number of Residual Active Joints in Trials of Intravenous Tocilizumab Study II Placebo + MTX N = 393 Tocilizumab 4 mg per kg + MTX N = 399 Tocilizumab 8 mg per kg + MTX N = 398 DAS28-ESR less than 2.6 Proportion of responders at week 52 (n) 95% confidence interval 3% (12) 18% (70) 0.10, 0.19 32% (127) 0.24, 0.34 Of responders, proportion with 0 active joints (n) 33% (4) 27% (19) 21% (27) Of responders, proportion with 1 active joint (n) 8% (1) 19% (13) 13% (16) Of responders, proportion with 2 active joints (n) 25% (3) 13% (9) 20% (25) Of responders, proportion with 3 or more active joints (n) 33% (4) 41% (29) 47% (59) *n denotes numerator of all the percentage. Denominator is the intent-to-treat population. Not all patients received DAS28 assessments at Week 52. The results of the components of the ACR response criteria for Studies III and V are shown in Table 6. Similar results to Study III were observed in Studies I, II and IV. Page 42 Reference ID: 5489159 Table 6 Components of ACR Response at Week 24 in Trials of Intravenous Tocilizumab Study III Study V Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX Placebo + MTX N=213 N=205 N=204 N=161 N=170 N=158 Component (mean) Baseline Week 24a Baseline Week 24a Baseline Week 24 Baseline Week 24a Baseline Week 24a Baseline Week 24 Number of tender joints (0-68) 33 19 -7.0 (-10.0, ­ 4.1) 32 14.5 -9.6 (-12.6, ­ 6.7) 33 25 31 21 -10.8 (-14.6, ­ 7.1) 32 17 -15.1 (-18.8, ­ 11.4) 30 30 Number of swollen joints (0-66) 20 10 -4.2 (-6.1, ­ 2.3) 19.5 8 -6.2 (-8.1, ­ 4.2) 21 15 19.5 13 -6.2 (-9.0, ­ 3.5) 19 11 -7.2 (-9.9, ­ 4.5) 19 18 Painb 61 33 -11.0 (-17.0, ­ 5.0) 60 30 -15.8 (-21.7, ­ 9.9) 57 43 63.5 43 -12.4 (-22.1, ­ 2.1) 65 33 -23.9 (-33.7, ­ 14.1) 64 48 Patient global assessmentb 66 34 -10.9 (-17.1, ­ 4.8) 65 31 -14.9 (-20.9, ­ 8.9) 64 45 70 46 -10.0 (-20.3, 0.3) 70 36 -17.4 (-27.8, ­ 7.0) 71 51 Physician global assessmentb 64 26 -5.6 (-10.5, ­ 0.8) 64 23 -9.0 (-13.8, ­ 4.2) 64 32 66.5 39 -10.5 (-18.6, ­ 2.5) 66 28 -18.2 (-26.3, ­ 10.0) 67.5 43 Disability index (HAQ) c 1.64 1.01 -0.18 (-0.34, ­ 0.02) 1.55 0.96 -0.21 (-0.37, ­ 0.05) 1.55 1.21 1.67 1.39 -0.25 (-0.42, ­ 0.09) 1.75 1.34 -0.34 (-0.51, ­ 0.17) 1.70 1.58 CRP (mg per dL) 2.79 1.17 -1.30 (-2.0, ­ 0.59) 2.61 0.25 -2.156 (-2.86, ­ 1.46) 2.36 1.89 3.11 1.77 -1.34 (-2.5, ­ 0.15) 2.80 0.28 -2.52 (-3.72, ­ 1.32) 3.705 3.06 a Data shown is mean at week 24, difference in adjusted mean change from baseline compared with placebo + MTX at week 24 and 95% confidence interval for that difference b Visual analog scale: 0 = best, 100 = worst c Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities Page 43 Reference ID: 5489159 100 95 to ., 80 n ,0 .. 55 i t 00 :;5 "' I 50 ◄ .; ., l i 40 ! 35 a. 30 i, 10 15 10 0 WKH ffl<24 a • • Platft:Mt + l\tTX (N-2fM) _,_ ... _..,_ i.t>cUf-Iu.iblb. n•&ll& + MTX (N-2&.5) 8 0 □ todlinn1i&b4 1ualq + MTX(N- JU) The percent of ACR 20 responders by visit for Study III is shown in Figure 1. Similar response curves were observed in studies I, II, IV, and V. Figure 1 Percent of ACR 20 Responders by Visit for Study III (Inadequate Response to MTX)* *The same patients may not have responded at each timepoint. Radiographic Response In Study II, structural joint damage was assessed radiographically and expressed as change in total Sharp-Genant score and its components, the erosion score and joint space narrowing score. Radiographs of hands/wrists and forefeet were obtained at baseline, 24 weeks, 52 weeks, and 104 weeks and scored by readers unaware of treatments group and visit number. The results from baseline to week 52 are shown in Table 7. tocilizumab 4 mg per kg slowed (less than 75% inhibition compared to the control group) and tocilizumab 8 mg per kg inhibited (at least 75% inhibition compared to the control group) the progression of structural damage compared to placebo plus MTX at week 52. Page 44 Reference ID: 5489159 Table 7 Mean Radiographic Change from Baseline to Week 52 in Study II Placebo + MTX Tocilizumab 4 mg per kg + MTX Tocilizumab 8 mg per kg + MTX N=294 N=343 N=353 Week 52* Total Sharp-Genant Score, Mean (SD) 1.17 (3.14) 0.33 (1.30) 0.25 (0.98) Adjusted Mean difference** (95%CI) -0.83 (-1.13, -0.52) -0.90 (-1.20, -0.59) Erosion Score, Mean (SD) 0.76 (2.14) 0.20 (0.83) 0.15 (0.77) Adjusted Mean difference** (95%CI) -0.55 (-0.76, -0.34) -0.60 (-0.80, -0.39) Joint Space Narrowing Score, Mean (SD) 0.41 (1.71) 0.13 (0.72) 0.10 (0.49) Adjusted Mean difference** (95%CI) -0.28 (-0.44, -0.11) -0.30 (-0.46, -0.14) * Week 52 analysis employs linearly extrapolated data for patients after escape, withdrawal, or loss to follow up. ** Difference between the adjusted means (tocilizumab + MTX - Placebo + MTX) SD = standard deviation The mean change from baseline to week 104 in Total Sharp-Genant Score for the tocilizumab 4 mg per kg groups was 0.47 (SD = 1.47) and for the 8 mg per kg groups was 0.34 (SD = 1.24). By the week 104, most patients in the control (placebo + MTX) group had crossed over to active treatment, and results are therefore not included for comparison. Patients in the active groups may have crossed over to the alternate active dose group, and results are reported per original randomized dose group. In the placebo group, 66% of patients experienced no radiographic progression (Total Sharp- Genant Score change ≤ 0) at week 52 compared to 78% and 83% in the tocilizumab 4 mg per kg and 8 mg per kg, respectively. Following 104 weeks of treatment, 75% and 83% of patients initially randomized to tocilizumab 4 mg per kg and 8 mg per kg, respectively, experienced no progression of structural damage compared to 66% of placebo treated patients. Health Related Outcomes In Study II, physical function and disability were assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI). Both dosing groups of tocilizumab demonstrated a greater improvement compared to the placebo group in the AUC of change from baseline in the HAQ-DI through week 52. The mean change from baseline to week 52 in HAQ-DI was 0.6, 0.5, and 0.4 for tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, and placebo treatment groups, respectively. Sixty-three percent (63%) and sixty percent (60%) of patients in the tocilizumab 8 Page 45 Reference ID: 5489159 mg per kg and tocilizumab 4 mg per kg treatment groups, respectively, achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) at week 52 compared to 53% in the placebo treatment group. Other Health-Related Outcomes General health status was assessed by the Short Form Health Survey (SF-36) in Studies I – V. Patients receiving tocilizumab demonstrated greater improvement from baseline compared to placebo in the Physical Component Summary (PCS), Mental Component Summary (MCS), and in all 8 domains of the SF-36. Cardiovascular Outcomes Study WA25204 (NCT01331837) was a randomized, open-label (sponsor-blinded), 2-arm parallel-group, multi-center, non-inferiority, cardiovascular (CV) outcomes trial in patients with a diagnosis of moderate to severe RA. This CV safety study was designed to exclude a moderate increase in CV risk in patients treated with tocilizumab compared with a TNF inhibitor standard of care (etanercept). The study included 3,080 seropositive RA patients with active disease and an inadequate response to non-biologic disease-modifying anti-rheumatic drugs, who were aged ≥50 years with at least one additional CV risk factor beyond RA. Patients were randomized 1:1 to IV tocilizumab 8 mg/kg Q4W or SC etanercept 50 mg QW and followed for an average of 3.2 years. The primary endpoint was the comparison of the time-to-first occurrence of any component of a composite of major adverse CV events (MACE; non-fatal myocardial infarction, non-fatal stroke, or CV death), with the final intent-to-treat analysis based on a total of 161 confirmed CV events (83/1538 [5.4%] for tocilizumab; 78/1542 [5.1%] for etanercept) reviewed by an independent and blinded adjudication committee. Non-inferiority of tocilizumab to etanercept for cardiovascular risk was determined by excluding >80% relative increase in the risk of MACE. The estimated hazard ratio (HR) for the risk of MACE comparing tocilizumab to etanercept was 1.05; 95% CI (0.77, 1.43). 14.2 Giant Cell Arteritis - Intravenous Administration Intravenously administered tocilizumab in patients with GCA was assessed in WP41152 (NCT03923738), an open-label PK-PD and safety study to determine the appropriate intravenous dose of tocilizumab that achieved comparable PK-PD profiles to tocilizumab by another route of administration. At enrollment, all patients (n=24) were in remission on tocilizumab IV. In Period 1, all patients received open-label tocilizumab IV 7 mg/kg every 4 weeks for 20 weeks. Patients who completed Period 1 and remained in remission (n=22) were eligible to enter Period 2, and received open-label tocilizumab IV 6 mg/kg every 4 weeks for 20 weeks. Page 46 Reference ID: 5489159 The efficacy of intravenous tocilizumab 6 mg/kg in adult patients with GCA is based on pharmacokinetic exposure and extrapolation to the efficacy established for tocilizumab by another route of administration in patients with GCA. 14.3 Polyarticular Juvenile Idiopathic Arthritis—Intravenous Administration The efficacy of tocilizumab was assessed in a three-part study, WA19977 (NCT00988221), including an open-label extension in children 2 to 17 years of age with active polyarticular juvenile idiopathic arthritis (PJIA), who had an inadequate response to methotrexate or inability to tolerate methotrexate. Patients had at least 6 months of active disease (mean disease duration of 4.2 ± 3.7 years), with at least five joints with active arthritis (swollen or limitation of movement accompanied by pain and/or tenderness) and/or at least 3 active joints having limitation of motion (mean, 20 ± 14 active joints). The patients treated had subtypes of JIA that at disease onset included Rheumatoid Factor Positive or Negative Polyarticular JIA, or Extended Oligoarticular JIA. Treatment with a stable dose of methotrexate was permitted but was not required during the study. Concurrent use of disease modifying antirheumatic drugs (DMARDs), other than methotrexate, or other biologics (e.g., TNF antagonists or T cell costimulation modulator) were not permitted in the study. Part I consisted of a 16-week active tocilizumab treatment lead-in period (n=188) followed by Part II, a 24-week randomized double-blind placebo-controlled withdrawal period, followed by Part III, a 64-week open-label period. Eligible patients weighing at or above 30 kg received tocilizumab at 8 mg/kg intravenously once every four weeks. Patients weighing less than 30 kg were randomized 1:1 to receive either tocilizumab 8 mg/kg or 10 mg/kg intravenously every four weeks. At the conclusion of the open-label Part I, 91% of patients taking background MTX in addition to tocilizumab and 83% of patients on tocilizumab monotherapy achieved an ACR 30 response at week 16 compared to baseline and entered the blinded withdrawal period (Part II) of the study. The proportions of patients with JIA ACR 50/70 responses in Part I were 84.0%, and 64%, respectively for patients taking background MTX in addition to tocilizumab and 80% and 55% respectively for patients on tocilizumab monotherapy. In Part II, patients (ITT, n=163) were randomized to tocilizumab (same dose received in Part I) or placebo in a 1:1 ratio that was stratified by concurrent methotrexate use and concurrent corticosteroid use. Each patient continued in Part II of the study until Week 40 or until the patient satisfied JIA ACR 30 flare criteria (relative to Week 16) and qualified for escape. The primary endpoint was the proportion of patients with a JIA ACR 30 flare at week 40 relative to week 16. JIA ACR 30 flare was defined as 3 or more of the 6 core outcome variables worsening by at least 30% with no more than 1 of the remaining variables improving by more than 30% relative to Week 16. Tocilizumab treated patients experienced significantly fewer disease flares compared to placebo- treated patients (26% [21/82] versus 48% [39/81]; adjusted difference in proportions -21%, 95% CI: -35%, -8%). During the withdrawal phase (Part II), more patients treated with tocilizumab showed JIA ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo. Page 47 Reference ID: 5489159 I I 14.4 Systemic Juvenile Idiopathic Arthritis—Intravenous Administration The efficacy of tocilizumab for the treatment of active SJIA was assessed in WA18221 (NCT00642460), a 12-week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients treated with or without MTX, were randomized (tocilizumab:placebo = 2:1) to one of two treatment groups: 75 patients received tocilizumab infusions every two weeks at either 8 mg per kg for patients at or above 30 kg or 12 mg per kg for patients less than 30 kg and 37 were randomized to receive placebo infusions every two weeks. Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR 70 response. After 12 weeks or at the time of escape, due to disease worsening, patients were treated with tocilizumab in the open- label extension phase at weight appropriate dosing. The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set (JIA ACR 30 response) at Week 12 and absence of fever (no temperature at or above 37.5°C in the preceding 7 days). JIA ACR (American College of Rheumatology) responses are defined as the percentage improvement (e.g., 30%, 50%, 70%) in 3 of any 6 core outcome variables compared to baseline, with worsening in no more than 1 of the remaining variables by 30% or more. Core outcome variables consist of physician global assessment, parent per patient global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability (childhood health assessment questionnaire-CHAQ). Primary endpoint result and JIA ACR response rates at Week 12 are shown in Table 8. Table 8 Efficacy Findings at Week 12 Tocilizumab N=75 Placebo N=37 Primary Endpoint: JIA ACR 30 response + absence of fever Responders 85% 24% Weighted difference (95% CI) 62 (45, 78) - JIA ACR Response Rates at Week 12 JIA ACR 30 Responders Weighted differencea (95% CI)b 91% 67 (51, 83) 24% - JIA ACR 50 Responders Weighted differencea (95% CI)b 85% 74 (58, 90) 11% - JIA ACR 70 Responders 71% 8% Page 48 Reference ID: 5489159 Weighted differencea 63 - (95% CI)b (46, 80) a The weighted difference is the difference between the tocilizumab and Placebo response rates, adjusted for the stratification factors (weight, disease duration, background oral corticosteroid dose and background methotrexate use). b CI: confidence interval of the weighted difference. The treatment effect of tocilizumab was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks). Systemic Features Of patients with fever or rash at baseline, those treated with tocilizumab had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to 5 out of 24 (21%) of placebo-treated patients, and 14 out of 22 (64%) became free of rash compared to 2 out of 18 (11%) of placebo-treated patients. Responses were consistent in the open label extension (data available through 44 weeks). Corticosteroid Tapering Of the patients receiving oral corticosteroids at baseline, 8 out of 31 (26%) placebo and 48 out of 70 (69%), tocilizumab patients achieved a JIA ACR 70 response at week 6 or 8 enabling corticosteroid dose reduction. Seventeen (24%) tocilizumab patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR 30 flare or occurrence of systemic symptoms to week 12. In the open label portion of the study, by week 44, there were 44 out of 103 (43%) tocilizumab patients off oral corticosteroids. Of these 44 patients 50% were off corticosteroids 18 weeks or more. Health Related Outcomes Physical function and disability were assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). Seventy-seven percent (58 out of 75) of patients in the tocilizumab treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of ≥ 0.13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group. 14.5 COVID-19 - Intravenous Administration The efficacy of tocilizumab for the treatment of COVID-19 was based on RECOVERY (NCT04381936), a randomized, controlled, open-label, platform study, and supported by the results from EMPACTA (NCT04372186), a randomized, double-blind, placebo-controlled study. Results of two other randomized, double-blind, placebo-controlled studies, COVACTA (NCT04320615) and REMDACTA (NCT04409262), which evaluated the efficacy of tocilizumab for the treatment of COVID-19 are also summarized. Page 49 Reference ID: 5489159 RECOVERY (Randomised Evaluation of COVID-19 Therapy) Collaborative Group Study in Hospitalized Adults Diagnosed with COVID-19 RECOVERY was a randomized, controlled, open-label, multicenter platform study conducted in the United Kingdom to evaluate the efficacy and safety of potential treatments in hospitalized adult patients with severe COVID-19 pneumonia. Eligible patients for the tocilizumab portion of the study had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical contraindications to any of the treatments and had clinical evidence of progressive COVID-19 (defined as oxygen saturation <92% on room air or receiving oxygen therapy, and CRP ≥75 mg/L). Patients were then randomized to receive either standard of care (SoC) or intravenous tocilizumab at a weight-tiered dosing comparable to the recommended dosage [see Clinical Pharmacology (12.3)] in addition to SoC. Efficacy analyses were performed in the intent-to-treat (ITT) population comprising 4116 adult patients who were randomized to the tocilizumab + SoC arm (n=2022) or to the SoC arm (n=2094). The mean age of participants was 64 years (range: 20 to 101), and patients were 67% male, 76% White, 11% Asian, 3% Black or African American, and 1% mixed race. At baseline, 0.2% of patients were not on supplemental oxygen, 45% of patients required low flow oxygen, 41% of patients required non-invasive ventilation or high-flow oxygen, and 14% of patients required invasive mechanical ventilation; 82% of patients were reported to be receiving systemic corticosteroids. The primary efficacy endpoint was time to death through Day 28. The results for the overall population and the subgroups of patients who were or were not receiving systemic corticosteroids at time of randomization are summarized in Table 9. Table 9 Mortality through Day 28 in RECOVERY tocilizumab + SoC N=2022 n (%)1 SoC N=2094 n (%)1 Hazard Ratio (95% CI) Risk Difference (95% CI) Mortality 621 (30.7%) 729 (34.9%) 0.85 (0.76, 0.94) p= 0.00281 -4.1% (-7.0, -1.3) By baseline receipt of corticosteroid use Mortality for patients receiving systemic corticosteroids at randomization2 482/1664 (29.0%) 600/1721 (34.9%) 0.79 (0.70, 0.89) -5.9% (-9.1, -2.8) Mortality for patients not receiving systemic corticosteroids at randomization2 139/357 (39.0%) 127/367 (34.6%) 1.16 (0.91, 1.48) 4.4% (-2.6, 11.5) 1 P-value reflects that the RECOVERY trial primary analysis results were statistically significant at the two-sided significance level of α = 0.05. 2 Probabilities of dying by Day 28 were estimated by the Kaplan-Meier method. Page 50 Reference ID: 5489159 EMPACTA EMPACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous tocilizumab 8 mg/kg in combination with SoC in hospitalized, non-ventilated adult patients with COVID-19 pneumonia. Eligible patients were at least 18 years of age, had confirmed SARS-CoV-2 infection by a positive reverse-transcriptase polymerase chain reaction (RT-PCR) result, had pneumonia confirmed by radiography, and had SpO2 < 94% on ambient air. Of the 389 patients randomized, efficacy analyses were performed in the modified intent-to-treat (mITT) population comprising 377 patients who were randomized and received study medication (249 in the tocilizumab arm; 128 in the placebo arm). The mean age of participants was 56 years (range: 20 to 95); 59% of patients were male, 56% were of Hispanic or Latino ethnicity, 53% were White, 20% were American Indian/Alaska Native, 15% were Black/African American and 2% were Asian. At baseline, 9% patients were not on supplemental oxygen, 64% patients required low flow oxygen, 27% patients required high-flow oxygen, and 73% were on corticosteroids. The primary efficacy endpoint evaluated time to progression to mechanical ventilation or death through Day 28. The hazard ratio comparing tocilizumab to placebo was 0.56 (95% CI, 0.33 to 0.97), a statistically significant result (log-rank, p-value = 0.036). The cumulative proportion of patients who required mechanical ventilation or died by Day 28 was 12.0% (95% CI, 8.5% to 16.9%) in the tocilizumab arm and 19.3% (95% CI, 13.3% to 27.4%) in the placebo arm. Mortality at Day 28 was 10.4% in the tocilizumab arm versus 8.6% in the placebo arm (weighted difference (tocilizumab arm - placebo arm): 2.0% [95% CI, -5.2% to 7.8%]). COVACTA COVACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous tocilizumab 8 mg/kg in combination with SoC for the treatment of adult patients hospitalized with severe COVID-19 pneumonia. The study randomized 452 patients who were at least 18 years of age with confirmed SARS-CoV-2 infection by a positive RT-PCR result, had pneumonia confirmed by radiography, and had oxygen saturation of 93% or lower on ambient air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mmHg or less. At baseline, 3% of patients were not on supplemental oxygen, 28% were on low flow oxygen, 30% were on non-invasive ventilation or high flow oxygen, 38% were on invasive mechanical ventilation, and 22% were on corticosteroids. The primary efficacy endpoint was clinical status on Day 28 assessed on a 7-category ordinal scale that ranged from “discharged” to “death.” There were no statistically significant differences observed in the distributions of clinical status on the 7-category ordinal scale at Day 28 when comparing the tocilizumab arm to the placebo arm. Page 51 Reference ID: 5489159 Mortality at Day 28 was 19.7% in the tocilizumab arm versus 19.4% in the placebo arm (weighted difference (tocilizumab arm - placebo arm): 0.3% [95% CI, -7.6 to 8.2]). REMDACTA REMDACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous tocilizumab 8 mg/kg in combination with intravenous remdesivir (RDV) 200 mg on Day 1 followed by 100 mg once daily for a total of 10 days in hospitalized patients with severe COVID-19 pneumonia. The study randomized 649 adult patients with SARS-CoV-2 infection confirmed by a positive polymerase chain reaction (PCR) result, pneumonia confirmed by radiography, and who required supplemental oxygen > 6 L/min to maintain SpO2 >93%. At baseline, 7% of patients were on low flow oxygen, 80% were on non-invasive ventilation or high flow oxygen, 14% were on invasive mechanical ventilation, and 84% were on corticosteroids. The primary efficacy endpoint was time from randomization to hospital discharge or ‘ready for discharge’ up to Day 28. There was no statistically significant difference between the treatment arms with respect to time to hospital discharge or “ready for discharge” through Day 28. Mortality at Day 28 was 18.1% in the tocilizumab + RDV arm versus 19.5% in the placebo +RDV arm (weighted difference (tocilizumab arm - placebo arm): -1.3% [95% CI, -7.8% to 5.2%]). Mortality Across Studies in Patients Receiving Baseline Corticosteroids A study-level meta-analysis was conducted on EMPACTA, COVACTA, REMDACTA and RECOVERY studies. For each of the four studies, the risk difference through Day 28 was estimated by the Kaplan-Meier method in the subgroup of patients receiving baseline corticosteroids, summarized in Figure 2. Patients from the RECOVERY trial represent 78.8% of the total sample size in this meta-analysis. The combined risk difference showed that tocilizumab treatment (n=2261) resulted in a 4.61% absolute reduction in the risk of death at Day 28 (risk difference=-4.6%; 95% CI: -7.3% to -1.9%) compared to SoC (n=2034). Page 52 Reference ID: 5489159 soc toc.ilizumab + SOC Favors Risk Study Total Deaths(•/•) Deaths(•/•) toc.ilizumab + SOC soc C Difference (9s•;, C l) <XN,CTA 97 41 12 (33,5• ) 58 U (2ll5 ... ) •4.1124.7. 16.6) EMP,CTA 27• 91 10(11 . ... ) 183 23 (13 3 ... ) 181 66. 102) REMCIIICTA 539 181 39 (21,S...) 358 619(195 ... ) -2.31 -9.6. 5.0J RECOYERY 3385 in1 600 (34.e...J 16'4 482 (290' I --- 591-91. 281 OJerall - -46 (-73,•l9) ,200 -10.0 00 100 20.0 R 0.!Mftru (95"" Ch Figure 2 Risk Differences Through Day 28 for Baseline Corticosteroid Use Subpopulation in RECOVERY, EMPACTA, COVACTA and REMDACTA studies 16 HOW SUPPLIED/STORAGE AND HANDLING TOFIDENCE (tocilizumab-bavi) injection is a preservative-free, sterile, clear to opalescent, colorless to light yellow solution. TOFIDENCE is supplied as 80 mg/4 mL (NDC 64406-024­ 01), 200 mg/10 mL (NDC 64406-022-01), and 400 mg/20 mL (NDC 64406-023-01) individually packaged 20 mg/mL single-dose vials for further dilution prior to intravenous infusion. Storage and Handling: Do not use beyond expiration date on the container or package. TOFIDENCE must be refrigerated at 36°F to 46°F (2ºC to 8ºC). Do not freeze. Protect the vials from light by storage in the original package until time of use. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). • Serious Infections Inform patients that TOFIDENCE may lower their resistance to infections [see Warnings and Precautions (5.1)]. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment. • Gastrointestinal Perforation Inform patients that some patients who have been treated with TOFIDENCE have had serious side effects in the stomach and intestines [see Warnings and Precautions (5.2)]. Instruct the patient of the importance of contacting their doctor immediately when symptoms of severe, persistent abdominal pain appear to assure rapid evaluation and appropriate treatment. • Hypersensitivity and Serious Allergic Reactions Inform patients that some patients who have been treated with TOFIDENCE have developed serious allergic reactions, including anaphylaxis and serious skin reactions [see Warnings and Precautions (5.6)]. Advise patients to stop taking TOFIDENCE and seek immediate medical Page 53 Reference ID: 5489159 attention if they experience any symptom of serious allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing). Pregnancy Inform female patients of reproductive potential that TOFIDENCE may cause fetal harm and to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)]. TOFIDENCE (tocilizumab-bavi) Manufactured by: Biogen MA Inc. Cambridge, MA 02142 U.S. License No.: 2344 TOFIDENCE is a trademark of Biogen MA Inc. © 2024 Biogen MA Inc. All rights reserved. Page 54 Reference ID: 5489159 Medication Guide TOFIDENCE™ (TOE-FIH-DENCE) (tocilizumab-bavi) injection for intravenous use What is the most important information I should know about TOFIDENCE? TOFIDENCE can cause serious side effects including: 1. Serious Infections. TOFIDENCE is a medicine that affects your immune system. TOFIDENCE can lower the ability of your immune system to fight infections. Some people have serious infections while taking TOFIDENCE, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections. Your healthcare provider should assess you for TB before starting TOFIDENCE (except if you have COVID-19). If you have COVID-19, your healthcare provider should monitor you for signs and symptoms of new infections during and after treatment with TOFIDENCE. Your healthcare provider should monitor you closely for signs and symptoms of TB during treatment with TOFIDENCE. • You should not start taking TOFIDENCE if you have any kind of infection unless your healthcare provider says it is okay. Before starting TOFIDENCE, tell your healthcare provider if you: • think you have an infection or have symptoms of an infection, with or without a fever, such as: o sweating or chills o feel very tired o cough o shortness of breath o muscle aches o weight loss o warm, red, or painful skin or o blood in phlegm o burning when you urinate or urinating sores on your body o diarrhea or stomach pain more often than normal • are being treated for an infection. • get a lot of infections or have infections that keep coming back. • have diabetes, HIV, or a weak immune system. People with these conditions have a higher chance for infections. • have TB, or have been in close contact with someone with TB. • live or have lived, or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections (histoplasmosis, coccidiomycosis, or blastomycosis). These infections may happen or become more severe if you use TOFIDENCE. Ask your healthcare provider, if you do not know if you have lived in an area where these infections are common. • have or have had hepatitis B. After starting TOFIDENCE, call your healthcare provider right away if you have any symptoms of an infection. TOFIDENCE can make you more likely to get infections or make worse any infection that you have. If you have COVID-19, your healthcare provider should monitor you for signs and symptoms of new infections during and after treatment with TOFIDENCE. 2. Tears (perforation) of the stomach or intestines. • Tell your healthcare provider if you have had diverticulitis (inflammation in parts of the large intestine) or ulcers in your stomach or intestines. Some people taking TOFIDENCE get tears in their stomach or intestine. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. • Tell your healthcare provider right away if you have fever and stomach-area pain that does not go away, and a change in your bowel habits. 3. Liver problems (Hepatotoxicity): Some people have experienced serious life-threatening liver problems, which required a liver transplant or led to death. Your healthcare provider may tell you to stop taking TOFIDENCE if you develop new or worse liver problems during treatment with TOFIDENCE. Tell your healthcare provider right away if you have any of the following symptoms: • feeling tired (fatigue) • weakness • lack of appetite for several days or longer • nausea and vomiting (anorexia) • yellowing of your skin or the whites of your • confusion eyes (jaundice) Reference ID: 5489159 • abdominal swelling and pain on the right side • dark “tea-colored” urine of your stomach-area • light colored stools 4. Changes in certain laboratory test results. Your healthcare provider should do blood tests before you start receiving TOFIDENCE. If you have rheumatoid arthritis (RA) or giant cell arteritis (GCA) your healthcare provider should do blood tests every 4 to 8 weeks after you start receiving TOFIDENCE for the first 6 months and then every 3 months after that. If you have polyarticular juvenile idiopathic arthritis (PJIA) you will have blood tests done every 4 to 8 weeks during treatment. If you have systemic juvenile idiopathic arthritis (SJIA) you will have blood tests done every 2 to 4 weeks during treatment. These blood tests are to check for the following side effects of TOFIDENCE: • low neutrophil count. Neutrophils are white blood cells that help the body fight off bacterial infections. • low platelet count. Platelets are blood cells that help with blood clotting and stop bleeding. • increase in certain liver function tests. • increase in blood cholesterol levels. You may also have changes in other laboratory tests, such as your blood cholesterol levels. Your healthcare provider should do blood tests to check your cholesterol levels 4 to 8 weeks after you start receiving TOFIDENCE. Your healthcare provider will determine how often you will have follow-up blood tests. Make sure you get all your follow-up blood tests done as ordered by your healthcare provider. You should not receive TOFIDENCE if your neutrophil or platelet counts are too low or your liver function tests are too high. Your healthcare provider may stop your TOFIDENCE treatment for a period of time or change your dose of medicine if needed because of changes in these blood test results. 5. Cancer. TOFIDENCE may increase your risk of certain cancers by changing the way your immune system works. Tell your healthcare provider if you have ever had any type of cancer. See “What are the possible side effects with TOFIDENCE?” for more information about side effects. What is TOFIDENCE? TOFIDENCE is a prescription medicine called an Interleukin-6 (IL-6) receptor antagonist. TOFIDENCE is used: • To treat adults with moderately to severely active rheumatoid arthritis (RA), after at least one other medicine called a Disease-Modifying Anti-Rheumatic Drug (DMARD) has been used and did not work well. • To treat adults with giant cell arteritis (GCA). • To treat people with active PJIA ages 2 and above. • To treat people with active SJIA ages 2 and above. • To treat hospitalized adults with coronavirus disease 2019 (COVID-19) receiving systemic corticosteroids and requiring supplemental oxygen or mechanical ventilation. It is not known if TOFIDENCE is safe and effective in children with PJIA or SJIA under 2 years of age or in children with conditions other than PJIA or SJIA. Do not take TOFIDENCE: if you are allergic to tocilizumab products, or any of the ingredients in TOFIDENCE. See the end of this Medication Guide for a complete list of ingredients in TOFIDENCE. Before you receive TOFIDENCE, tell your healthcare provider about all of your medical conditions, including if you: • have an infection. See “What is the most important information I should know about TOFIDENCE?” • have liver problems. • have any stomach-area (abdominal) pain or been diagnosed with diverticulitis or ulcers in your stomach or intestines. • have had a reaction to tocilizumab products or any of the ingredients in TOFIDENCE before. • have or had a condition that affects your nervous system, such as multiple sclerosis. • have recently received or are scheduled to receive a vaccine: o All vaccines should be brought up-to-date before starting TOFIDENCE, unless urgent treatment initiation is required. o People who take TOFIDENCE should not receive live vaccines. o People taking TOFIDENCE can receive non-live vaccines. • plan to have surgery or a medical procedure. • are pregnant or plan to become pregnant or are pregnant. TOFIDENCE may harm your unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with TOFIDENCE. Reference ID: 5489159 • are breastfeeding or plan to breastfeed. It is not known if TOFIDENCE passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take TOFIDENCE. Tell your healthcare provider about all of the medicines you take, including prescription, over-the-counter medicines, vitamins and herbal supplements. TOFIDENCE and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take: • any other medicines to treat your RA. You should not take etanercept (Enbrel®), adalimumab (Humira®), infliximab (Remicade®), rituximab (Rituxan®), abatacept (Orencia®), anakinra (Kineret®), certolizumab (Cimzia®), or golimumab (Simponi®), while you are taking TOFIDENCE. Taking TOFIDENCE with these medicines may increase your risk of infection. • medicines that affect the way certain liver enzymes work. Ask your healthcare provider if you are not sure if your medicine is one of these. Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. How will I receive TOFIDENCE? Into a vein (IV or intravenous infusion) for Rheumatoid Arthritis, Giant Cell Arteritis, PJIA, SJIA, or COVID-19: • If your healthcare provider prescribes TOFIDENCE as an IV infusion, you will receive TOFIDENCE from a healthcare provider through a needle placed in a vein in your arm. The infusion will take about 1 hour to give you the full dose of medicine. • For rheumatoid arthritis, giant cell arteritis or PJIA you will receive a dose of TOFIDENCE about every 4 weeks. • For SJIA you will receive a dose of TOFIDENCE about every 2 weeks. • For COVID-19, you will receive a single dose of TOFIDENCE, and if needed one additional dose. • While taking TOFIDENCE, you may continue to use other medicines that help treat your rheumatoid arthritis, PJIA, SJIA, or COVID-19 such as methotrexate, non-steroidal anti-inflammatory drugs (NSAIDs) and prescription steroids, as instructed by your healthcare provider. • Keep all of your follow-up appointments and get your blood tests as ordered by your healthcare provider. What are the possible side effects with TOFIDENCE? TOFIDENCE can cause serious side effects, including: • See “What is the most important information I should know about TOFIDENCE?” • Hepatitis B infection in people who carry the virus in their blood. If you are a carrier of the hepatitis B virus (a virus that affects the liver), the virus may become active while you use TOFIDENCE. Your healthcare provider may do blood tests before you start treatment with TOFIDENCE and while you are using TOFIDENCE. Tell your healthcare provider if you have any of the following symptoms of a possible hepatitis B infection: o feel very tired o skin or eyes look yellow o little or no appetite o vomiting o clay-colored bowel movements o fevers o chills o stomach discomfort o muscle aches o dark urine o skin rash • Serious Allergic Reactions. Serious allergic reactions, including death, can happen with TOFIDENCE. These reactions can happen with any infusion of TOFIDENCE, even if they did not occur with an earlier infusion. Stop taking TOFIDENCE, contact healthcare provider, and get emergency help right away if you have any of the following signs of a serious allergic reaction: o trouble breathing o swelling of your mouth, lips, tongue, or face o wheezing o severe itching o skin rash, hives, redness, or swelling outside of the injection site area o dizziness or fainting o fast heartbeat or pounding in your chest (tachycardia), o sweating • Nervous system problems. While rare, Multiple Sclerosis has been diagnosed in people who take TOFIDENCE. It is not known what effect TOFIDENCE may have on some nervous system disorders. The most common side effects of TOFIDENCE include: • upper respiratory tract infections (common cold, sinus infections) • headache • increased blood pressure (hypertension) Tell your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of TOFIDENCE. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Biogen MA Inc. at 1-877-422-8360. . General information about the safe and effective use of TOFIDENCE. Reference ID: 5489159 Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not give TOFIDENCE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TOFIDENCE that is written for health professionals. What are the ingredients in TOFIDENCE? Active ingredient: tocilizumab-bavi. Inactive ingredients of Intravenous TOFIDENCE: arginine hydrochloride, histidine, L-histidine hydrochloride monohydrate,polysorbate 80, sucrose, and water for Injection. TOFIDENCE is a trademark of Biogen MA Inc. Manufactured by: Biogen MA Inc., Cambridge, MA 02142, U.S. License No.: 2344 © 2024 Biogen MA Inc. All rights reserved. For more information, go to www.tofidence.com or call 1-877-422-8360 . Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 12/2024 Reference ID: 5489159
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2025-02-12T15:47:32.735417
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IC-GREEN safely and effectively. See full prescribing information for IC-GREEN. IC-GREEN® (indocyanine green for injection), for intravenous or interstitial use Initial U.S. Approval: 1959 -----------------------------RECENT MAJOR CHANGES---------------------------­ Indications and Usage, For determining Cardiac Output, 12/2024 Hepatic Function, and Liver Blood Flow (1.1) Removed Indications and Usage (1.1, 1.2, 1.3) 12/2024 Dosage and Administration, Indicator-Dilution Studies 12/2024 and Hepatic Function Studies (2.1, 2.2) Removed Dosage and Administration (2.1, 2.2, 2.3, 2.5) 12/2024 -----------------------------INDICATIONS AND USAGE----------------------------­ IC-GREEN is an optical imaging agent indicated for: • Fluorescence imaging of vessels (micro- and macro-vasculature), blood flow and tissue perfusion before, during and after vascular, gastrointestinal, organ transplant, plastic, micro- and reconstructive surgeries, including general minimally invasive surgical procedures, in adults and pediatric patients aged 1 month and older (1.1) • Fluorescence imaging of extrahepatic biliary ducts in adults and pediatric patients aged 12 years and older (1.2) • Fluorescence imaging of lymph nodes and lymphatic vessels during lymphatic mapping in adults with cervical and uterine cancer (1.3) • Ophthalmic angiography in adults and pediatric patients (1.4) ------------------------DOSAGE AND ADMINISTRATION------------------------­ • Visualization of vessels, blood flow and tissue perfusion (2.5 mg/mL solution) o 1.25 mg to 5 mg by intravenous injection is recommended for a surgical procedure in adults and pediatric patients aged 1 month and older. o 3.75 mg to 10 mg by intravenous injection is recommended for visualization of perfusion in extremities through the skin for plastic, micro- and reconstructive surgeries in adults. o Additional doses may be administered. Do not exceed a total dose of 2 mg/kg. (2.1) • Visualization of extrahepatic biliary ducts in adults and pediatric patients aged 12 years and older (2.5 mg/mL solution) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Visualization of Vessels, Blood Flow and Tissue Perfusion 1.2 Visualization of Extrahepatic Biliary Ducts 1.3 Lymphatic Mapping of Cervical and Uterine Cancer 1.4 Ophthalmic Angiography 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose, Administration and Imaging for Visualization of Vessels, Blood Flow and Tissue Perfusion 2.2 Recommended Dose, Administration and Imaging for Visualization of Extrahepatic Biliary Ducts 2.3 Recommended Dose, Administration and Imaging for Lymphatic Mapping of Cervical and Uterine Cancer 2.4 Recommended Dose and Administration for Ophthalmic Angiography 2.5 Reconstitution Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity reactions 5.2 Interference with Thyroid Radioactive Iodine Uptake Studies o 2.5 mg by intravenous injection at least 45 minutes prior to surgery. o Additional doses may be administered. Do not exceed a total dose of 2 mg/kg. (2.2) • Lymphatic mapping of cervical and uterine cancer in adults (1.25 mg/mL solution) o 5 mg interstitially as four 1 mL injections. o See Full Prescribing Information for injection techniques. (2.3) • Ophthalmic Angiography o Doses up to 40 mg in 2 ml of Sterile Water for Injection by intravenous injection. (2.4) • See Full Prescribing Information for reconstitution instructions. (2.5). ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ For injection: 25 mg of indocyanine green as a lyophilized, green powder for reconstitution in a single-patient-use vial (3) -------------------------------CONTRAINDICATIONS----------------------------------­ Hypersensitivity to indocyanine green (4) ------------------------WARNINGS AND PRECAUTIONS-------------------------­ Hypersensitivity reactions: Hypersensitivity reactions including anaphylaxis and urticaria have occurred. Always have cardiopulmonary resuscitation personnel and equipment readily available and monitor patients. (5.1) ------------------------------ADVERSE REACTIONS---------------------------------­ The most common adverse reactions reported are anaphylaxis and urticaria. (6) To report SUSPECTED ADVERSE REACTIONS, contact Diagnostic Green LLC at 1-844-424-3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS----------------------------------­ Interference with Thyroid Radioactive Iodine Uptake Studies: Do not perform radioactive iodine uptake studies for at least one week following the use of IC-GREEN. (7) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/2024 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Lymphatic Mapping of Cervical and Uterine Cancer 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5489561 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Visualization of Vessels, Blood Flow and Tissue Perfusion IC-GREEN is indicated for fluorescence imaging of vessels (micro- and macro­ vasculature), blood flow and tissue perfusion before, during and after vascular, gastrointestinal, organ transplant, plastic, micro- and reconstructive surgeries, including general minimally invasive surgical procedures in adults and pediatric patients aged 1 month and older. 1.2 Visualization of Extrahepatic Biliary Ducts IC-GREEN is indicated for fluorescence imaging of extrahepatic biliary ducts in adults and pediatric patients aged 12 years and older. 1.3 Lymphatic Mapping of Cervical and Uterine Cancer IC-GREEN is indicated for fluorescence imaging of lymph nodes and delineation of lymphatic vessels during lymphatic mapping in adults with cervical and uterine cancer for which this procedure is a component of intraoperative management. 1.4 Ophthalmic Angiography IC-GREEN is indicated for use in ophthalmic angiography in adults and pediatric patients. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose, Administration and Imaging for Visualization of Vessels, Blood Flow and Tissue Perfusion Dosing Adults: The recommended dose of IC-GREEN for a single image sequence for visualization of vessels, blood flow and tissue perfusion in adults is 1.25 mg to 5 mg administered intravenously as 0.5 mL to 2 mL of a 2.5 mg/mL solution. For visualization of perfusion in extremities through the skin in adults, the recommended dose is 3.75 mg to 10 mg administered intravenously as 1.5 mL to 4 mL of a 2.5 mg/mL solution. Immediately flush with a 10 mL bolus of 0.9% Sodium Chloride Injection. Pediatric patients aged 1 month and older: The recommended dose of IC-GREEN for a single image sequence for visualization of vessels, blood flow and tissue perfusion in pediatric patients aged 1 month and older is 1.25 mg to 5 mg administered intravenously as 0.5 mL to 2 mL of a 2.5 mg/mL solution. Lower doses may be administered in younger patients and in those with lower body weight. Adjust the amount and type of flush to avoid volume and/or sodium overload. Reference ID: 5489561 In both adults and pediatric patients aged 1 month and older, additional doses may be administered to obtain imaging sequences during the procedure. Do not exceed the maximum total dose of 2 mg/kg. Administration Prior to the imaging procedure, draw up the desired dose of IC-GREEN solution into appropriate syringes and prepare a 10 mL syringe of 0.9% Sodium Chloride Injection. Administer via a central or peripheral venous line using a three-way stopcock attached to an injection port on the infusion line. Inject the prepared IC-GREEN into the line as a tight bolus. Immediately switch the access on the stopcock and inject the prepared flush. Imaging Instructions IC-GREEN may be used with an FDA-authorized imaging device that is intended to be used with indocyanine green for fluorescence imaging of vessels, blood flow and tissue perfusion. A fluorescence response should be visible in blood vessels within 5 seconds to 15 seconds after injection. 2.2 Recommended Dose, Administration and Imaging for Visualization of Extrahepatic Biliary Ducts Dosing and Administration The recommended dose of IC-GREEN for visualization of extrahepatic biliary ducts in adults and pediatric patients aged 12 years and older is 2.5 mg administered intravenously as 1 mL of a 2.5 mg/mL solution at least 45 minutes prior to surgery. Additional doses may be administered to obtain imaging sequences during the procedure. Do not exceed a total dose of 2 mg/kg. Imaging Instructions IC-GREEN may be used with an FDA-authorized imaging device that is intended to be used with indocyanine green for fluorescence imaging of extrahepatic biliary ducts. Fluorescence is visible in the biliary tree within 45 minutes after injection. 2.3 Recommended Dose, Administration and Imaging for Lymphatic Mapping of Cervical and Uterine Cancer Dosing and Administration The recommended dose of IC-GREEN for lymphatic mapping of cervical and uterine cancer in adults is 5 mg administered interstitially as four 1 mL injections of a 1.25 mg/mL solution into the cervix, at the 3 o’ clock and the 9 o’clock positions with a superficial (1 mm to 3 mm) and a deep (1 cm to 3 cm) injection at each position. Reference ID: 5489561 Imaging Instructions IC-GREEN may be used with an FDA-authorized imaging device that is intended to be used with indocyanine green for fluorescence imaging of lymph nodes and delineation of lymphatic vessels during lymphatic mapping of cervical and uterine cancer. Fluorescent lymphatic vessels and lymph nodes should begin to be visible within 1 minute after injection. 2.4 Recommended Dose and Administration for Ophthalmic Angiography Dosing and Administration Doses up to 40 mg IC-GREEN in 2 mL of Sterile Water for Injection depending on the imaging equipment and technique used should be administered intravenously and immediately followed by a 5 mL bolus of 0.9% Sodium Chloride Injection. The antecubital vein can be used for IC-GREEN administration. 2.5 Reconstitution Instructions General • Prepare IC-GREEN using aseptic techniques prior to procedure. • Inspect the reconstituted solution for particulate matter. The reconstituted solution should be a clear, green solution. • Use the prepared solution within 6 hours. • Discard any unused product. Visualization of Vessels, Blood Flow, Tissue Perfusion and Extrahepatic Biliary Ducts Dissolve 25 mg of IC-GREEN with 10 mL Sterile Water for Injection to form a concentration of 2.5 mg/mL indocyanine green. Lymphatic Mapping of Cervical and Uterine Cancer Dissolve 25 mg of IC-GREEN with 20 mL Sterile Water for Injection to form a concentration of 1.25 mg/mL indocyanine green. Ophthalmic Angiography Dissolve doses up to 40 mg of IC-GREEN with 2 mL Sterile Water for Injection. 3 DOSAGE FORMS AND STRENGTHS For injection: 25 mg of indocyanine green as a sterile, lyophilized, green powder for reconstitution provided in a 25 mL single-patient-use vial. 4 CONTRAINDICATIONS IC-GREEN is contraindicated in patients with a history of hypersensitivity to indocyanine green. Reactions have included anaphylaxis [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Reference ID: 5489561 Hypersensitivity reactions including anaphylaxis, urticaria and deaths due to anaphylaxis have been reported following intravenous administration of IC-GREEN [see Adverse Reactions (6)]. IC-GREEN is contraindicated in patients with a history of hypersensitivity to indocyanine green [see Contraindications (4)]. Always have cardiopulmonary resuscitation personnel and equipment readily available and monitor all patients for hypersensitivity reactions. 5.2 Interference with Thyroid Radioactive Iodine Uptake Studies Because IC-GREEN contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration [see Drug Interactions (7)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.1)]. The following adverse reactions have been identified during post-approval use of IC­ GREEN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: Anaphylaxis, urticaria 7 DRUG INTERACTIONS Interference with Thyroid Radioactive Iodine Uptake Studies Because IC-GREEN contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of IC­ GREEN. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of IC-GREEN in pregnant women. Available data from a very small number of scientific literature studies with indocyanine green use in pregnant women over several decades have not reported any drug associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Data from one small study in which indocyanine green was administered intravenously to pregnant women during labor suggest there is no placental transfer of the drug. Animal reproduction studies have not been conducted with indocyanine green. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, Reference ID: 5489561 respectively. 8.2 Lactation Risk Summary Seventeen cases of indocyanine green use in lactating women have been reported in the scientific literature with no adverse events observed in the breastfed infant. However, there are no data on the presence of indocyanine green in human milk or the effects on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for IC-GREEN and any potential adverse effects on the breastfed infant from IC-GREEN or from the underlying maternal condition. 8.4 Pediatric Use Use of IC-GREEN for visualization of vessels, blood flow and tissue perfusion has been established in pediatric patients aged 1 month and older. Pediatric use is supported by published data in 49 pediatric patients who received indocyanine green for assessment of blood flow and tissue perfusion in cardiovascular, vascular, and plastic, micro- and reconstructive surgical procedures, and by clinical trials in adults. No overall differences in safety or effectiveness have been observed between pediatric patients and adults. The dose range was similar to the effective dose range in adults [see Dosage and Administration (2.1)]. The use of IC-GREEN for visualization of vessels, blood flow and tissue perfusion has not been established in pediatric patients aged less than 1 month. Use of IC-GREEN for visualization of extrahepatic biliary ducts has been established in pediatric patients aged 12 years and older. Pediatric use is supported by clinical trials in adults in addition to clinical use in pediatric patients. No overall differences in safety or effectiveness have been observed between pediatric patients and adults. The dose range was similar to the effective dose range in adults [see Dosage and Administration (2.2)]. The use of IC-GREEN for visualization of extrahepatic biliary ducts has not been established in pediatric patients aged less than 12 years. Use of IC-GREEN for visualization of lymph nodes and lymphatic vessels during lymphatic mapping for cervical and uterine cancer have not been established in pediatric patients. Use of IC-GREEN for ophthalmic angiography has been established in pediatric patients. Pediatric use is supported by evidence from the published literature. 8.5 Geriatric Use Of the total number of patients in clinical studies of indocyanine green for injection for visualization of vessels, blood flow and tissue perfusion, 7% were 65 and over, while 1% were 75 and over. Of the total number of patients in clinical studies of indocyanine green for injection for visualization of lymph nodes and lymphatic vessels during lymphatic mapping of cervical and uterine cancer, 9% were 65 and over, while 2% were 75 and over. Clinical studies of indocyanine green for injection for visualization of Reference ID: 5489561 extrahepatic biliary ducts did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. 11 DESCRIPTION IC-GREEN (indocyanine green for injection) is an optical imaging agent for intravenous or interstitial use. Each vial contains 25 mg of indocyanine green with not more than 5% sodium iodide as a sterile, lyophilized, green powder. IC-GREEN has a pH of 5.5-7.5 when reconstituted with Sterile Water for Injection, USP. The chemical name for Indocyanine Green is 1 HBenz[e]indolium, 2-[7-[1,3-dihydro-1,1­ dimethyl-3-(4- sulfobutyl)-2H-benz[e]indol-2-ylidene]-1,3,5-heptatrienyl]-1,1-dimethyl-3­ (4-sulfobutyl)-, hydroxide, inner salt, sodium salt. Molecular Formula: C43H47N2NaO6S2; Molecular Mass: 774.96 g/mol, with the following structural formula: Indocyanine green has a peak spectral absorption at 805 nm in blood. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action When bound to proteins in plasma or in lymph fluid, indocyanine green absorbs light in the near-infrared region with peak absorption at 805 nm and emits fluorescence (light) at a slightly longer wavelength, with peak emission at 830 nm. Fluorescence imaging devices provide external energy as near infrared light for indocyanine green to absorb, resulting in excitation of the indocyanine green, and the emitted light (fluorescence) is transferred from the field of view to an image on a monitor. These optical properties of indocyanine green are utilized in fluorescence imaging of the micro- and macro­ vasculature, blood flow and tissue perfusion, the extrahepatic biliary ducts, and for lymphatic mapping of lymph nodes and lymphatic vessels. 12.2 Pharmacodynamics Reference ID: 5489561 There are no pharmacodynamic data. 12.3 Pharmacokinetics Distribution Following intravenous injection, indocyanine green binds to plasma proteins (98%) and is largely confined to the intravascular compartment. Indocyanine green undergoes no significant extrahepatic or enterohepatic circulation; simultaneous arterial and venous blood estimations have shown negligible renal, peripheral, lung or cerebro-spinal uptake of the dye. After biliary obstruction, the dye appears in the hepatic lymph, independently of the bile, suggesting that the biliary mucosa is sufficiently intact to prevent diffusion of the dye, though allowing diffusion of bilirubin. Following interstitial injection, indocyanine green binds to proteins in lymph fluid and the interstitial space, is taken up by the lymphatic vessels, and drains to the lymph nodes. Since excessive dye extravasation does not take place in the highly fenestrated choroidal vasculature, IC-GREEN is useful in both absorption and fluorescence infrared angiography of the choroidal vasculature when using appropriate filters and film in a fundus camera. Elimination Indocyanine green is taken up from the plasma almost exclusively by the hepatic parenchymal cells and is secreted entirely into the bile. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been performed to evaluate the potential for carcinogenicity, mutagenicity, or impairment of fertility by indocyanine green. 14 CLINICAL STUDIES 14.1 Lymphatic Mapping of Cervical and Uterine Cancer The effectiveness of IC-GREEN for fluorescence imaging of lymph nodes and delineation of lymphatic vessels during lymphatic mapping in adults with cervical and uterine cancer has been established based on a study of another formulation of indocyanine green for injection. Below is a description of the FILM Study (NCT 02209532). The study was a randomized, prospective, multi-center, open-label study in patients with early stage uterine or cervical cancer and no known regional nodal or metastatic disease by standard clinical evaluation. Indocyanine green and a blue dye comparator were injected into the cervix of patients at the beginning of the operative procedure. A total of 176 patients were randomized to receive either indocyanine green followed by blue dye or blue dye followed by indocyanine green. A total of four 1 mL Reference ID: 5489561 injections of a 1.25 mg/ml solution of indocyanine green for a total dose of 5 mg were administered interstitially into the cervix at the 3 o'clock and 9 o'clock positions with a superficial (1 mm to 3 mm) and a deep (1 cm to 3 cm) injection at each position. Lymphatic mapping was performed intraoperatively using a fluorescence imaging device and standard light, followed by excision of tissues identified by indocyanine green, blue dye, or the surgeon's visual and palpation examination. The resected tissues were evaluated by histopathology to confirm presence of lymph nodes. The efficacy of indocyanine green in the detection of lymphatic vessels and lymph nodes during lymphatic mapping procedures was determined by the number of histology- confirmed lymph nodes detected by indocyanine green and/or the blue dye comparator. The mean age of the 176 patients was 63 years (range: 31 to 88 years); distribution by race and ethnicity was 79% White, 4% Black or African American, 3% Asian, 13% Hispanic/Latino and 1% other. Table 1 shows the distribution of resected, confirmed lymph nodes detected by indocyanine green or blue dye in the modified intent-to-treat population (mlTT). Among the confirmed lymph nodes identified, 93% were identified using indocyanine green, and 43% were identified using blue dye, a difference of 50% [95% confidence interval 39% to 60%]. Table 1: Distribution of Resected, Confirmed Lymph Nodes Detected by Indocyanine Green or Blue Dye (BD) Analysis Population Nodes (n) All Lymph Nodes Detected with Indocyanine Green All Lymph Nodes Detected with BD Lymph Nodes Detected with Indocyanine Green Only Lymph Nodes Detected with BD Only Lymph Nodes Detected with Neither mlTT 513 (476/513) 93% (220/513) 43% (262/513) 51% (6/513) 1% (31/513) 6% Table 2 shows the number of patients with at least one resected, confirmed lymph node and the number of patients with at least one bilateral lymph node pair detected by indocyanine green or blue dye. With indocyanine green, approximately 97% of patients had at least one resected, confirmed lymph node detected and 73% had at least one bilateral lymph node pair detected, compared with 68% and 28%, respectively, with blue dye (p-values for each analysis <0.0001). Table 2: Distribution of Patients with at Least One Confirmed Unilateral Lymph Node/ Bilateral Pair Detected by Indocyanine Green or Blue Dye (BD) Analysis Population Patients (n) Patients with All Lymph Nodes Detected with Patients with All Lymph Nodes Detected with Patients with Lymph Nodes Detected Patients with Lymph Nodes Detected Patients with Lymph Nodes Detected Reference ID: 5489561 Indocyanine Green BD with Indocyanine Green only with BD only with Neither mlTT Unilateral* 172 (167/172) 97% (118/172) 68% (51/172) 30% (2/172) 1% (3/172) 3% mlTT Bilateral** (126/172) 73% (49/172) 28% (79/172) 46% (2/172) 1% (44/172) 26% *: patients with at least one resected confirmed lymph node detected unilaterally **: patients with at least one resected confirmed lymph node detected bilaterally 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied IC-GREEN (indocyanine green for injection) is supplied as a kit (NDC 70100-725­ 02) containing the following: • Six 25 mL single-patient-use vials of IC-GREEN (25 mg each) as a sterile, lyophilized green powder for reconstitution NDC 70100-725-01 • Six single-dose vials of Sterile Water for Injection (10 mL each) NDC 63323­ 185-10 or NDC 0409-4887-17 Storage and Handling Store at 20°C to 25°C (68°F to 77°F). 17 PATIENT COUNSELING INFORMATION Hypersensitivity Reactions Advise patients to seek medical attention for reactions following injection of IC-GREEN such as difficulty breathing, swollen tongue or throat, skin reactions including hives, itching and flushed or pale skin, low blood pressure, a weak and rapid pulse and other symptoms or signs of an anaphylactic reaction [see Warnings and Precautions (5.1)]. Manufactured by: Patheon Italia S.p.A. 20900 Monza (MB), ITALY Distributed by: Diagnostic Green LLC Farmington Hills, Ml 48331 Sterile Water for injection, USP is manufactured by: Fresenius Kabi USA, LLC Grand Island, NY 14072 or Hospira, Inc. Rocky Mount, NC 27804 XXXXXXX Reference ID: 5489561
custom-source
2025-02-12T15:47:32.876375
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ISOVUE safely and effectively. See full prescribing information for ISOVUE. ISOVUE® (iopamidol) injection, for intra-arterial or intravenous use Initial U.S. Approval: 1985 WARNING: RISKS ASSOCIATED WITH INTRATHECAL ADMINISTRATION Intrathecal administration, even if inadvertent, can cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. ISOVUE is for intra-arterial or intravenous use only. (5.1) ----------------------------INDICATIONS AND USAGE--------------------------­ ISOVUE is a radiographic contrast agent indicated for: Intra-arterial Procedures† (1.1) • Cerebral arteriography in adults • Peripheral arteriography in adults • Selective visceral arteriography and aortography in adults • Coronary arteriography and cardiac ventriculography in adults • Angiocardiography in pediatric patients Intravenous Procedures† (1.2) • Excretory urography in adults and pediatric patients • Computed tomography (CT) of head and body in adults and pediatric patients • Peripheral venography in adults †Specific concentrations are recommended for each type of imaging procedure. (2.2, 2.3, 2.4) ------------------------DOSAGE AND ADMINISTRATION---------------------­ • Individualize the volume and concentration according to the specific dosing tables accounting for factors such as age, body weight, size of the vessel, and the rate of blood flow within the vessel. (2.2, 2.3, 2.4) • See full prescribing information for important dosage and administration information. (2.1) -------------------------DOSAGE FORMS AND STRENGTHS-----------------­ Injection: 200 mg Iodine/mL, 250 mg Iodine/mL, 300 mg Iodine/mL, and 370 mg Iodine/mL in single-dose vials or bottles (3) ---------------------------------CONTRAINDICATIONS---------------------------­ None (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ • Hypersensitivity Reactions: Life-threatening or fatal reactions can occur. Always have emergency resuscitation equipment and trained personnel available. (5.2) • Acute Kidney Injury: Acute injury including renal failure can occur. Use the lowest dose and maintain adequate hydration to minimize risk. (5.3) • Cardiovascular Adverse Reactions: Hemodynamic disturbances including shock and cardiac arrest may occur during or after ISOVUE administration. (5.4) • Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age: Individualize thyroid function monitoring based on risk factors such as prematurity. (5.8) ------------------------------ADVERSE REACTIONS------------------------------­ Most common adverse reactions (incidence >1%) are pain, hot flashes, burning sensation, nausea, and warmth. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------USE IN SPECIFIC POPULATIONS-----------------------­ Lactation: A lactating woman may pump and discard breast milk for 10 hours after ISOVUE administration. (8.2) See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISKS ASSOCIATED WITH INTRATHECAL ADMINISTRATION 1 INDICATIONS AND USAGE 1.1 Intra-arterial Procedures 1.2 Intravenous Procedures 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosing and Administration Information 2.2 Recommended Dosage for Intra-arterial Procedures in Adults 2.3 Recommended Dosage for Intravenous Procedures in Adults 2.4 Recommended Dosage in Pediatric Patients 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risks Associated with Intrathecal Administration 5.2 Hypersensitivity Reactions 5.3 Acute Kidney Injury 5.4 Cardiovascular Adverse Reactions 5.5 Thromboembolic Events 5.6 Extravasation and Injection Site Reactions 5.7 Thyroid Storm in Patients with Hyperthyroidism 5.8 Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age 5.9 Hypertensive Crisis in Patients with Pheochromocytoma 5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease 5.11 Severe Cutaneous Adverse Reactions 5.12 Interference with Laboratory Tests 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions 7.2 Drug-Laboratory Test Interactions 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed 1 of 13 Reference ID: 5491290 FULL PRESCRIBING INFORMATION WARNING: RISKS ASSOCIATED WITH INTRATHECAL ADMINISTRATION Intrathecal administration, even if inadvertent, can cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema [see Warnings and Precautions (5.1)]. ISOVUE is for intra-arterial or intravenous use only [see Dosage and Administration (2.1)]. 1 INDICATIONS AND USAGE 1.1 Intra-arterial Procedures† ISOVUE is indicated for: • Cerebral arteriography in adults • Peripheral arteriography in adults • Selective visceral arteriography and aortography in adults • Coronary arteriography and cardiac ventriculography in adults • Angiocardiography in pediatric patients 1.2 Intravenous Procedures† ISOVUE is indicated for: • Excretory urography in adults and pediatric patients • Computerized tomography (CT) of the head and body in adults and pediatric patients • Peripheral venography in adults †Specific concentrations of ISOVUE are recommended for each type of imaging procedure [see Dosage and Administration (2.2, 2.3, 2.4)]. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosing and Administration Information • ISOVUE is for intra-arterial or intravenous use only and must not be administered intrathecally [see Warnings and Precautions (5.1)]. • Specific concentrations of ISOVUE are recommended for each type of imaging procedure [see Dosage and Administration (2.2, 2.3, 2.4)]. • Individualize the volume, concentration, and injection rate of ISOVUE according to the specific dosing tables [see Dosage and Administration (2.2, 2.3, 2.4)]. Consider factors such as: age, body weight, blood vessel size and blood flow rate, anticipated pathology and degree and extent of opacification required, structures or area to be examined, concomitant medical conditions, imaging equipment, and technique to be employed. • Hydrate patients before and after ISOVUE administration [see Warnings and Precautions (5.3)]. • Use aseptic technique for all handling and administration of ISOVUE. • ISOVUE may be administered at either body temperature (37°C, 98.6°F) or room temperature (20°C to 25°C, 68°F to 77°F). • Visually inspect ISOVUE for particulate matter or discoloration before administration. Do not administer ISOVUE if particulate matter or discolorations are observed. • Do not mix ISOVUE with other drugs or inject in intravenous lines containing other drugs or total nutritional admixtures. • ISOVUE single-dose containers are intended for one procedure only. Discard any unused portion. 2 of 13 Reference ID: 5491290 2.2 Recommended Dosage for Intra-arterial Procedures in Adults The recommended doses for intra-arterial procedures in adults are shown in Table 1. Table 1: Recommended Concentrations and Volumes of ISOVUE for Intra-arterial Procedures in Adults Imaging Procedure Concentration (mg Iodine/mL) Volume to Administer per Single Injection for Selected Injection Sites Maximum Cumulative Total Dose Cerebral Arteriography 300 8 mL to 12 mL by carotid puncture or transfemoral catheterization 90 mL Peripheral Arteriography 300 • 5 mL to 40 mL into the femoral artery or subclavian artery • 25 mL to 50 mL into the aorta for a distal runoff 250 mL Selective Visceral Arteriography and Aortography 370 • Up to 10 mL for the renal arteries • Up to 50 mL into the larger vessels such as the aorta or celiac artery 225 mL Coronary Arteriography and Cardiac Ventriculography 370 • 2 mL to 10 mL for selective coronary artery injection • 25 mL to 50 mL for cardiac ventriculography or for nonselective opacification of multiple coronary arteries following injection at the aortic root 200 mL 2.3 Recommended Dosage for Intravenous Procedures in Adults The recommended doses for intra-arterial procedures in adults are shown in Table 2. Table 2: Recommended Concentrations and Volumes of ISOVUE for Intravenous Procedures in Adults Imaging Procedure Concentration (mg Iodine/mL) Volume to Administer Excretory Urography 250 50 mL to 100 mL by rapid injection 300 50 mL by rapid injection 370 40 mL by rapid injection CT of the Head 250 130 mL to 240 mL 300 100 mL to 200 mL 3 of 13 Reference ID: 5491290 CT of the Body 250 130 mL to 240 mL by rapid infusion or bolus injection 300 100 mL to 200 mL by rapid infusion or bolus injection 370 80 mL to 160 mL by rapid infusion or bolus injection Peripheral Venography 200 25 mL to 150 mL per lower extremity; the maximum total dose is 350 mL 2.4 Recommended Dosage in Pediatric Patients The recommended doses in pediatric patients are shown in Table 3. Table 3: Recommended Concentrations and Volumes per Body Weight of ISOVUE for Intra- arterial and Intravenous Procedures in Pediatric Patients Imaging Procedure Concentration (mg Iodine/mL) Volume per Body Weight to Administer Maximum Dose Intra-arterial Procedures Angiocardiography 370 0.5 mL/kg to 2 mL/kg per single injection Maximum Cumulative Dose by Weight • Neonates: 5 mL/kg • Aged 4 weeks and older: 8 mL/kg • Do not exceed maximum cumulative doses by age below. Maximum Cumulative Dose by Age • <2 years 40 mL • 2 years to 4 years 50 mL • 5 years to 9 years 100 mL • 10 years to 18 years 125 mL Intravenous Procedures Excretory Urography 250 1.2 mL/kg to 3.6 mL/kg 120 mL 300 1 mL/kg to 3 mL/kg 100 mL CT of the Head and Body 250 1.2 mL/kg to 3.6 mL/kg 120 mL 300 1 mL/kg to 3 mL/kg 100 mL 4 of 13 Reference ID: 5491290 3 DOSAGE FORMS AND STRENGTHS Injection: Clear, colorless to pale yellow solution available in the following concentrations of iodine: Concentration (mg Iodine/mL) Package Size Package Type 200 200 mL Single-Dose Bottle 250 100 mL Single-Dose Bottle 300 30 mL and 50 mL Single-Dose Vial 100 mL and 150 mL Single-Dose Bottle 370 50 mL Single-Dose Vial 75 mL, 100 mL, 125 mL, and 150 mL Single-Dose Bottle 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Risks Associated with Intrathecal Administration Intrathecal administration, even if inadvertent, can cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. ISOVUE is for intra-arterial or intravenous use only and must not be administered intrathecally [see Dosage and Administration (2.1)]. 5.2 Hypersensitivity Reactions ISOVUE can cause life-threatening or fatal hypersensitivity reactions including anaphylaxis. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock [see Adverse Reactions (6.2)]. Most severe reactions develop shortly after the start of injection (e.g., within 1 to 3 minutes), but delayed reactions can also occur. There is increased risk of hypersensitivity reactions in patients with a history of previous reactions to contrast agents, and allergic disorders (i.e., bronchial asthma, allergic rhinitis, and food allergies) or other hypersensitivities. Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions does not prevent serious life-threatening reactions but may reduce both their incidence and severity. Obtain a history of allergy, hypersensitivity, or hypersensitivity reactions to iodinated contrast agents and always have emergency resuscitation equipment and trained personnel available prior to ISOVUE administration. Monitor all patients for hypersensitivity reactions. 5.3 Acute Kidney Injury Acute kidney injury, including renal failure, may occur after ISOVUE administration. Risk factors include: pre-existing renal insufficiency, dehydration, diabetes mellitus, congestive heart failure, advanced vascular disease, elderly age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma or other paraproteinemias, and repetitive or large doses of ISOVUE. Use the lowest necessary dose of ISOVUE in patients with renal impairment. Adequately hydrate patients prior to and following ISOVUE administration. Do not use laxatives, diuretics, or preparatory dehydration prior to ISOVUE administration. 5.4 Cardiovascular Adverse Reactions ISOVUE increases the circulatory osmotic load and may induce acute or delayed hemodynamic disturbances in patients with congestive heart failure, severely impaired renal function, combined renal 5 of 13 Reference ID: 5491290 and hepatic disease, and combined renal and cardiac disease, particularly when repetitive or large doses are administered. Fatal cardiovascular reactions have occurred mostly within 10 minutes of ISOVUE injection; the main feature was cardiac arrest with cardiovascular disease as the main underlying factor. Hypotensive collapse and shock have occurred. Cardiac decompensation, serious arrhythmias, and myocardial ischemia or infarction can occur during coronary arteriography and ventriculography. The administration of ISOVUE may cause pulmonary edema in patients with heart failure. Based upon published reports, deaths associated with the administration of iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Use the lowest necessary dose of ISOVUE in patients with congestive heart failure and always have emergency resuscitation equipment and trained personnel available. Monitor all patients for severe cardiovascular reactions. 5.5 Thromboembolic Events Serious, in some cases fatal, thromboembolic events, including myocardial infarction and stroke, can occur during angiographic procedures. During these procedures, increased thrombosis and activation of the complement system occurs. Risk factors for developing thromboembolic events include: length of procedure, catheter and syringe material, underlying disease state, and concomitant medications. To minimize thromboembolic events, use meticulous angiographic techniques and minimize the length of the procedure. Avoid blood remaining in contact with syringes containing iodinated contrast agents, which increases risk of clotting. Avoid angiocardiography in patients with homocystinuria because of the risk of inducing thrombosis and embolism. 5.6 Extravasation and Injection Site Reactions Extravasation can occur with ISOVUE administration, particularly in patients with severe arterial or venous disease. Inflammation, blistering, skin necrosis, and compartment syndrome have been reported following extravasation. In addition, injection site reactions such as pain and swelling at the injection site can also occur [see Adverse Reactions (6.2)]. Ensure intravascular placement of catheters prior to injection. Monitor patients for extravasation and advise patients to seek medical care for progression of symptoms. 5.7 Thyroid Storm in Patients with Hyperthyroidism Thyroid storm has occurred after the intravascular use of iodinated agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of ISOVUE. 5.8 Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age Thyroid dysfunction characterized by hypothyroidism or transient thyroid suppression has been reported after both single exposure and multiple exposures to iodinated contrast agents in pediatric patients 0 years to 3 years of age. Younger age, very low birth weight, prematurity, underlying medical conditions affecting thyroid function, admission to neonatal or pediatric intensive care units, and congenital cardiac conditions are associated with an increased risk of hypothyroidism after iodinated contrast agent exposure. Pediatric patients with congenital cardiac conditions may be at greatest risk given that they often require high doses of contrast during invasive cardiac procedures. An underactive thyroid during early life may be harmful for cognitive and neurological development and may require thyroid hormone replacement therapy. After exposure to iodinated contrast agents, individualize thyroid function monitoring based on underlying risk factors, especially in term and preterm neonates. 5.9 Hypertensive Crisis in Patients with Pheochromocytoma Hypertensive crisis in patients with pheochromocytoma has occurred with iodinated contrast agents. Closely monitor patients when administering ISOVUE if pheochromocytoma or catecholamine-secreting 6 of 13 Reference ID: 5491290 paragangliomas are suspected. Inject the minimum amount of ISOVUE necessary and have measures for treatment of hypertensive crisis readily available. 5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease Iodinated contrast agents can promote sickling in individuals who are homozygous for sickle cell disease. Hydrate patients prior to and following ISOVUE administration and use only if the necessary imaging information cannot be obtained with alternative imaging modalities. 5.11 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR) may develop from 1 hour to several weeks after intravascular contrast agent administration. These reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). Reaction severity may increase and time to onset may decrease with repeat administration of a contrast agent; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering ISOVUE to patients with a history of a severe cutaneous adverse reaction to ISOVUE. 5.12 Interference with Laboratory Tests ISOVUE can interfere with protein-bound iodine test [see Drug Interactions (7.2)]. 6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: • Risks Associated with Intrathecal Administration [see Warnings and Precautions (5.1)] • Hypersensitivity Reactions [see Warnings and Precautions (5.2)] • Acute Kidney Injury [see Warnings and Precautions (5.3)] • Cardiovascular Adverse Reactions [see Warnings and Precautions (5.4)] • Thromboembolic Events [see Warnings and Precautions (5.5)] • Extravasation and Injection Site Reactions [see Warnings and Precautions (5.6)] • Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age [see Warnings and Precautions (5.8)] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adults The safety of ISOVUE was evaluated in 2,246 adult patients receiving ISOVUE by intra-arterial or intravenous route in clinical studies. Table 4 shows the common adverse reactions (>1%). Table 4: Adverse Reactions Reported in >1% of Patients Receiving Intra-arterial or Intravenous Injection of ISOVUE in Clinical Studies Adverse Reaction ISOVUE (N=2,246) % Pain 2.8 Hot flashes 1.5 Burning sensation 1.4 Nausea 1.2 Warmth 1.1 7 of 13 Reference ID: 5491290 The following adverse reactions occurred in ≤ 1% of patients receiving intra-arterial or intravenous injection of ISOVUE: Cardiovascular disorders: tachycardia, hypotension, hypertension, myocardial ischemia, circulatory collapse, S-T segment depression, bigeminy, extrasystoles, ventricular fibrillation, angina pectoris, bradycardia, transient ischemic attack, thrombophlebitis Gastrointestinal disorders: vomiting, anorexia General disorders: headache, fever, chills, excessive sweating, back spasm Nervous system disorders: vasovagal reaction, tingling in arms, grimace, faintness Renal and urinary disorders: urinary retention Respiratory: throat constriction, dyspnea, pulmonary edema Skin and subcutaneous tissues: rash, urticaria, pruritus, flushing Special senses: taste alterations, nasal congestion, visual disturbances Adverse Reactions in Pediatric Patients In a clinical trial with 76 pediatric patients undergoing angiocardiography, two adverse reactions (2.6%) were reported: worsening cyanosis and worsening peripheral perfusion. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ISOVUE. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. Blood and lymphatic system disorders: thrombocytopenia Cardiovascular disorders: cardiopulmonary arrest, cardiac decompensation, arrhythmias, myocardial infarction, shock, electrocardiographic changes (e.g., increased QTc, increased R-R, increased T- wave amplitude), decreased systolic pressure, deep vein thrombosis, arterial spasms, vasodilation, chest pain, pallor Endocrine disorders: hyperthyroidism, hypothyroidism Eye disorders: lacrimation increased, conjunctivitis, eye pruritus, transient blindness, visual disturbance, photophobia Gastrointestinal disorders: retching, abdominal pain, salivary hypersecretion, salivary gland enlargement General disorders and administration site conditions: injection site pain, malaise Immune system disorders: anaphylaxis characterized by cardiovascular, respiratory, and cutaneous manifestations (e.g., chest tightness, laryngeal edema, periorbital edema, facial edema); delayed hypersensitivity reactions including generalized maculopapular rash, erythema, pruritus, localized blistering, skin peeling Musculoskeletal disorders: compartment syndrome following extravasation, muscle spasm, musculoskeletal pain, muscular weakness Nervous system disorders: coma, seizure, tremors, syncope, depressed level of consciousness or loss of consciousness, encephalopathy Psychiatric disorders: confusional state Respiratory system disorders: respiratory arrest, respiratory failure, acute respiratory distress syndrome, respiratory distress, apnea, asthma, sneezing, choking, laryngeal edema, bronchospasm, rhinitis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), erythema multiforme and drug reaction with eosinophilia and systemic symptoms (DRESS), skin necrosis, face edema 7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions Metformin In patients with renal impairment, metformin can cause lactic acidosis. Iodinated contrast agents appear to increase the risk of metformin-induced lactic acidosis, possibly as a result of worsening renal function. 8 of 13 Reference ID: 5491290 Stop metformin at the time of, or prior to, ISOVUE administration in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast agents. Re-evaluate eGFR 48 hours after the imaging procedure and reinstitute metformin use only after renal function is stable. Radioactive Iodine Administration of ISOVUE may interfere with thyroid uptake of radioactive iodine (I-131 and I-123) and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post ISOVUE. 7.2 Drug-Laboratory Test Interactions Protein-Bound Iodine Test Iodinated contrast agents, including ISOVUE, will temporarily increase protein-bound iodine in blood. Avoid protein-bound iodine test for at least 16 days following administration of ISOVUE. However, thyroid function tests that do not depend on iodine estimations, e.g., triiodothyronine (T3) resin uptake and total or free thyroxine (T4) assays, are not affected. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published literature and postmarketing cases from decades of use with iopamidol during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Iopamidol crosses the placenta and reaches fetal tissues in small amounts (see Data). In animal reproduction studies, no adverse developmental outcomes were observed with intravenous administration of iopamidol to pregnant rats and rabbits during organogenesis at doses up to 2.7 and 1.4 times, respectively, the maximum recommended human dose (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Literature reports show that intravenously administered iopamidol crosses the placenta and is visualized in the digestive tract of exposed infants after birth. Animal Data Iopamidol did not affect fetal development and did not induce teratogenic changes in the offspring in either rats or rabbits at the following dose levels tested: 600 mg, 1,500 mg, or 4,000 mg iodine/kg in rats, administered intravenously once a day during days 6 through 15 of pregnancy; 300 mg, 800 mg, or 2,000 mg iodine/kg in rabbits, administered intravenously once a day during days 6 through 18 of pregnancy. 8.2 Lactation Risk Summary There are no data on the presence of iopamidol in human milk, the effects on the breastfed infant, or the effects on milk production. Iodinated contrast agents are present unchanged in human milk in very low amounts, with poor absorption from the gastrointestinal tract of a breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ISOVUE and any potential adverse effects on the breastfed infant from ISOVUE or from the underlying maternal condition. 9 of 13 Reference ID: 5491290 Clinical Considerations Interruption of breastfeeding after exposure to iodinated contrast agents is not necessary because the potential exposure of the breastfed infant to iodine is small. However, a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 10 hours (approximately 5 half- lives) after ISOVUE administration in order to minimize drug exposure to a breastfed infant. 8.4 Pediatric Use The safety and effectiveness of ISOVUE have been established in pediatric patients for angiocardiography, excretory urography, and contrast computed tomography (head and body). Pediatric patients at higher risk of experiencing adverse reactions during and after contrast medium administration may include those having asthma, sensitivity to medication or allergens, cyanotic heart disease, congestive heart failure, or serum creatinine greater than 1.5 mg/dL, or those less than 12 months of age. Thyroid function tests indicative of thyroid dysfunction, characterized by hypothyroidism or transient thyroid suppression have been reported following iodinated contrast media administration in pediatric patients, including term and preterm neonates; some patients were treated for hypothyroidism. After exposure to iodinated contrast media, individualize thyroid function monitoring in pediatric patients 0 years to 3 years of age based on underlying risk factors, especially in term and preterm neonates [see Warning and Precautions (5.8) and Adverse Reactions (6.2)]. The safety and effectiveness of ISOVUE for cerebral, peripheral, and selective visceral arteriography, aortography, coronary arteriography, cardiac ventriculography, and peripheral venography have not been established in pediatric patients. 8.5 Geriatric Use Iopamidol is excreted by the kidney, and the risk of adverse reactions to ISOVUE may be greater in patients with renal impairment. Because patients 65 years of age and older are more likely to have renal impairment, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions (5.3) and Use in Specific Populations [8.6]). 8.6 Renal Impairment The clearance of iopamidol decreases with increasing degree of renal impairment and results in delayed opacification of the urinary system. In addition, preexisting renal impairment increases the risk for acute kidney injury [see Warnings and Precautions (5.3)]. Iopamidol can be removed by dialysis. 10 OVERDOSAGE The manifestations of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems. Treatment of an overdose is directed toward support of all vital functions and the prompt institution of symptomatic therapy. Iopamidol can be removed by dialysis. 11 DESCRIPTION ISOVUE (iopamidol) injection is a radiographic contrast agent for intra-arterial or intravenous use. Iopamidol is designated chemically as (S)-N,N’-bis[2-hydroxy-1-(hydroxymethyl)-ethyl]-2,4,6-triiodo-5­ lactamidoisophthalamide with a molecular weight of 777.09, an empirical formula of C17H22I3N3O8, and the following structural formula: 10 of 13 Reference ID: 5491290 ISOVUE is a sterile, clear, colorless to pale yellow solution available in four concentrations of iodine: • ISOVUE 200 mg iodine/mL: Each mL contains 408 mg iopamidol (providing 200 mg organically bound iodine) and the following inactive ingredients: 0.26 mg edetate calcium disodium (providing 0.029 mg (0.001 mEq) sodium) and 1 mg tromethamine. • ISOVUE 250 mg iodine/mL: Each mL contains 510 mg iopamidol (providing 250 mg organically bound iodine) and the following inactive ingredients: 0.33 mg edetate calcium disodium (providing 0.036 mg (0.002 mEq) sodium) and 1 mg tromethamine. • ISOVUE 300 mg iodine/mL: Each mL contains 612 mg iopamidol (providing 300 mg organically bound iodine) and the following inactive ingredients: 0.39 mg edetate calcium disodium (providing 0.043 mg (0.002 mEq) sodium) and 1 mg tromethamine. • ISOVUE 370 mg iodine/mL: Each mL contains 755 mg iopamidol (providing 370 mg organically bound iodine) and the following inactive ingredients: 0.48 mg edetate calcium disodium (providing 0.053 mg (0.002 mEq) sodium) and 1 mg tromethamine. The pH of ISOVUE has been adjusted to 6.5 to 7.5 with hydrochloric acid and/or sodium hydroxide. Physicochemical characteristics are shown in Table 5. ISOVUE is hypertonic as compared to plasma and cerebrospinal fluid (approximately 285 and 301 mOsm/kg water, respectively). Table 5: Physicochemical Characteristics of ISOVUE Concentration (mg Iodine/mL) 200 250 300 370 Osmolality @ 37°C (mOsm/kg water) 413 524 616 796 Viscosity (cP) @ 37°C 2.0 3.0 4.7 9.4 Viscosity (cP) @ 20°C 3.3 5.1 8.8 20.9 Specific Gravity @ 37°C 1.227 1.281 1.339 1.405 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Intravascular injection of iopamidol opacifies those vessels where the contrast agent is present, permitting radiographic visualization through attenuation of photons. In imaging of the body, iodinated contrast agents diffuse from the vessels into the extravascular space. In normal brain with an intact blood-brain barrier, contrast does not diffuse into the extravascular space. In patients with a disrupted blood-brain barrier, contrast agent accumulates in the extravascular space in the region of disruption. 11 of 13 Reference ID: 5491290 12.2 Pharmacodynamics Following administration of ISOVUE, the degree of enhancement is related to the iodine concentration in the tissue of interest. However, the exposure-response relationships and time course of pharmacodynamic response of iopamidol have not been fully characterized. 12.3 Pharmacokinetics Distribution Plasma concentrations of iodine fall within 5 to 10 minutes due to distribution into the vascular and extracellular fluid compartments. Equilibration with the extracellular compartments is reached in about 10 minutes. The apparent volume of distribution suggests that iopamidol is distributed evenly between blood and extracellular fluid. Iopamidol may be visualized in the renal parenchyma within 30 to 60 seconds following rapid intravenous administration. Iopamidol did not bind to serum or plasma proteins at 1 hour after administration. Elimination The plasma half-life is approximately 2 hours; the half-life is not dose dependent. Metabolism Iopamidol does not undergo significant metabolism, deiodination, or biotransformation. Excretion Iopamidol is excreted primarily through the kidneys. In patients with normal renal function, the cumulative urinary excretion for iopamidol, expressed as a percentage of administered intravenous dose, is approximately 35% to 40% at 60 minutes, 80% to 90% at 8 hours, and 90% or greater in the 72- to 96­ hour period after administration. In patients with normal renal function, approximately 1% or less of the administered dose appears in cumulative 72- to 96-hour fecal samples. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed with iopamidol to evaluate carcinogenic potential. No evidence of genetic toxicity was obtained in in vitro tests. In animal reproduction studies performed on rats, intravenously administered iopamidol did not induce adverse effects on fertility or general reproductive performance. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ISOVUE (iopamidol) injection is a clear, colorless to pale yellow solution available in the following presentations: Concentration (mg Iodine/mL) Package Size Package Type Sale Unit NDC 200 200 mL Single-Dose Bottle Carton of 10 0270-1314-15 250 100 mL Single-Dose Bottle Carton of 10 0270-1317-02 30 mL Single-Dose Vial Carton of 10 0270-1315-25 300 50 mL Single-Dose Vial Carton of 10 0270-1315-30 100 mL Single-Dose Bottle Carton of 10 0270-1315-35 150 mL Single-Dose Bottle Carton of 10 0270-1315-50 370 50 mL Single-Dose Vial Carton of 10 0270-1316-30 12 of 13 Reference ID: 5491290 75 mL Single-Dose Bottle Carton of 10 0270-1316-52 100 mL Single-Dose Bottle Carton of 10 0270-1316-35 125 mL Single-Dose Bottle Carton of 10 0270-1316-04 150 mL Single-Dose Bottle Carton of 10 0270-1316-37 Storage and Handling Store at 20°C to 25°C (68°F to 77°F) [See USP controlled room temperature]. Protect from light. 17 PATIENT COUNSELING INFORMATION Hypersensitivity Reactions Advise the patient concerning the risk of hypersensitivity reactions that can occur both during and after ISOVUE administration. Advise the patient to report any signs or symptoms of hypersensitivity reactions during the procedure and to seek immediate medical attention for any signs or symptoms experienced after discharge [see Warnings and Precautions (5.2)]. Advise patients to inform their physician if they develop a rash after receiving ISOVUE [see Warnings and Precautions (5.11)]. Acute Kidney Injury Advise the patient concerning appropriate hydration to decrease the risk of contrast induced kidney injury [see Warnings and Precautions (5.3)]. Extravasation If extravasation occurs during injection, advise patients to seek medical care for progression of symptoms [see Warnings and Precautions (5.6)]. Thyroid Dysfunction Advise parents/caregivers about the risk of developing thyroid dysfunction after ISOVUE administration. Advise parents/caregivers about when to seek medical care for their child to monitor for thyroid function [see Warnings and Precautions (5.8)]. Lactation Advise a lactating woman that interruption of breastfeeding is not necessary, however, to minimize exposure to a breastfed infant, a lactating woman may consider pumping and discarding breast milk for 10 hours after ISOVUE administration [see Use in Specific Populations (8.2)]. Manufactured for: Bracco Diagnostic Inc. Monroe Township, NJ 08831 Manufactured by: BIPSO GmbH 78224 Singen (Germany) ISOVUE is a registered trademark of Bracco Diagnostics Inc. 13 of 13 Reference ID: 5491290
custom-source
2025-02-12T15:47:33.839157
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use REYATAZ safely and effectively. See full prescribing information for REYATAZ. REYATAZ (atazanavir) capsules, for oral use REYATAZ (atazanavir) oral powder Initial U.S. Approval: 2003 ---------------------------RECENT MAJOR CHANGES--------------------------­ Contraindications (4) 12/2024 --------------------------INDICATIONS AND USAGE---------------------------­ REYATAZ is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg. (1) ------------------------DOSAGE AND ADMINISTRATION---------------------­ • Pretreatment testing: Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Hepatic testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ. (2.2) • Treatment-naive adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food or REYATAZ 400 mg once daily with food. (2.3) • Treatment-experienced adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food. (2.3) • Pediatric patients: REYATAZ capsule dosage is based on body weight not to exceed the adult dose and must be taken with food. (2.4) • REYATAZ oral powder: Must be taken with ritonavir and food and should not be used in pediatric patients who weigh less than 5 kg. (2.5) • Pregnancy: REYATAZ 300 mg with ritonavir 100 mg once daily with food, with dosing modifications for some concomitant medications. (2.6) • Dosing modifications: may be required for concomitant therapy (2.3, 2.4, 2.5, 2.6), renal impairment (2.7), and hepatic impairment. (2.8) ----------------------DOSAGE FORMS AND STRENGTHS--------------------­ • Capsules: 200 mg, 300 mg. (3, 16) • Oral powder: 50 mg packet. (3, 16) ------------------------------CONTRAINDICATIONS------------------------------­ • In patients with previously demonstrated hypersensitivity (eg, Stevens- Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ. (4) • Coadministration with drugs that are strong inducers of CYP3A, due to the potential for loss of therapeutic effect and development of resistance. (4) • Coadministration with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events. (4) --------------------------WARNINGS AND PRECAUTIONS-------------------­ • Cardiac conduction abnormalities: PR interval prolongation may occur in some patients. ECG monitoring should be considered in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval. (5.1, 7.3, 12.2, 17) • Severe Skin Reactions: Discontinue if severe rash develops. (5.2, 17) • Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. Do not dose reduce. If a concomitant transaminase increase occurs, evaluate for alternative etiologies. (5.8) • Phenylketonuria: REYATAZ oral powder contains phenylalanine which can be harmful to patients with phenylketonuria. (5.3) • Hepatotoxicity: Patients with hepatitis B or C virus are at risk of increased transaminases or hepatic decompensation. Monitor hepatic laboratory tests prior to therapy and during treatment. (2.8, 5.4, 8.8) • Chronic kidney disease has been reported during postmarketing surveillance in patients with HIV-1 treated with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Monitor renal laboratory tests prior to therapy and during treatment. Consider discontinuation of REYATAZ in patients with progressive renal disease. (5.5) • Nephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. (5.6) • The concomitant use of REYATAZ with ritonavir and certain other medications may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.7, 7.3) • Patients receiving REYATAZ may develop new onset or exacerbations of diabetes mellitus/hyperglycemia (5.9), immune reconstitution syndrome (5.10), and redistribution/accumulation of body fat. (5.11) • Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. (5.12) -------------------------------ADVERSE REACTIONS-----------------------------­ Most common adverse reactions (≥2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------------------DRUG INTERACTIONS----------------------------- Coadministration of REYATAZ can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir. The potential drug-drug interactions must be considered prior to and during therapy. (4, 7, 12.3) ------------------------USE IN SPECIFIC POPULATIONS----------------------­ • Pregnancy: Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. (8.1) • Hepatitis B or C co-infection: Monitor liver enzymes. (5.4, 6.1) • Renal impairment: REYATAZ is not recommended for use in treatment- experienced patients with end-stage renal disease managed with hemodialysis. (2.7, 8.7) • Hepatic impairment: REYATAZ is not recommended in patients with severe hepatic impairment. REYATAZ with ritonavir is not recommended in patients with any degree of hepatic impairment. (2.8, 8.8) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 12/2024 1 Reference ID: 5490094 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Overview 2.2 Testing Prior to Initiation and During Treatment with REYATAZ 2.3 Dosage of REYATAZ in Adult Patients 2.4 Dosage of REYATAZ Capsules in Pediatric Patients 2.5 Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients 2.6 Dosage Adjustments in Pregnant Patients 2.7 Dosage in Patients with Renal Impairment 2.8 Dosage Adjustments in Patients with Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiac Conduction Abnormalities 5.2 Severe Skin Reactions 5.3 Patients with Phenylketonuria 5.4 Hepatotoxicity 5.5 Chronic Kidney Disease 5.6 Nephrolithiasis and Cholelithiasis 5.7 Risk of Serious Adverse Reactions Due to Drug Interactions 5.8 Hyperbilirubinemia 5.9 Diabetes Mellitus/Hyperglycemia 5.10 Immune Reconstitution Syndrome 5.11 Fat Redistribution 5.12 Hemophilia 5.13 Resistance/Cross-Resistance 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Potential for REYATAZ to Affect Other Drugs 7.2 Potential for Other Drugs to Affect REYATAZ 7.3 Established and Other Potentially Significant Drug Interactions 7.4 Drugs with No Observed Interactions with REYATAZ 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Age/Gender 8.7 Impaired Renal Function 8.8 Impaired Hepatic Function 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Adult Participants without Prior Antiretroviral Therapy 14.2 Adult Participants with Prior Antiretroviral Therapy 14.3 Pediatric Participants 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed 2 Reference ID: 5490094 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE REYATAZ is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg. Limitations of Use: • REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Use in Specific Populations (8.4)]. • Use of REYATAZ with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12.4)]. 2 DOSAGE AND ADMINISTRATION 2.1 Overview • REYATAZ capsules and oral powder must be taken with food. • Do not open the capsules. • The recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.3, 2.4, 2.5, and 2.6) and Drug Interactions (7)]. • REYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14)]. • REYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than 5 kg [see Dosage and Administration (2.5)]. • Efficacy and safety of REYATAZ with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir. 2.2 Testing Prior to Initiation and During Treatment with REYATAZ Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Renal laboratory testing should include serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination [see Warnings and Precautions (5.5, 5.6)]. Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ [see Warnings and Precautions (5.4)]. 2.3 Dosage of REYATAZ in Adult Patients Table 1 displays the recommended dosage of REYATAZ capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of REYATAZ and 3 Reference ID: 5490094 ritonavir when given concomitantly with other antiretroviral drugs and H2-receptor antagonists (H2RA). Ritonavir is required with several REYATAZ dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended. Table 1: Recommended REYATAZ and Ritonavir Dosage in Adultsa,b REYATAZ Once Daily Ritonavir Once Daily Dosage Dosage Treatment-Naive Adult Patients recommended regimen 300 mg 100 mg unable to tolerate ritonavir 400 mg N/A in combination with efavirenz 400 mg 100 mg Treatment-Experienced Adult Patients recommended regimen 300 mg 100 mg in combination with both H2RA and tenofovir DF 400 mg 100 mg a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b For adult patients who cannot swallow the capsules, REYATAZ oral powder is taken once daily with food at the same recommended adult dosage as the capsules along with ritonavir. 2.4 Dosage of REYATAZ Capsules in Pediatric Patients The recommended daily dosage of REYATAZ capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2). Table 2: Recommended Dosage of REYATAZ Capsules and Ritonavir in Pediatric Patients (6 to less than 18 years of age)a,b Body weight REYATAZ Daily Dosage Ritonavir Daily Dosage Treatment-Naive and Treatment-Experiencedc Less than 15 kg Capsules not recommended N/A At least 15 kg to less than 35 kg 200 mg 100 mg At least 35 kg 300 mg 100 mg Treatment-Naive, at least 13 years old and cannot tolerate ritonavir At least 40 kg 400 mg N/A a Administer REYATAZ capsules and ritonavir simultaneously with food. b The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid­ 4 Reference ID: 5490094 reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). c In treatment-experienced patients, REYATAZ capsules must be administered with ritonavir. When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation. 2.5 Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients REYATAZ oral powder is for use in treatment-naive or treatment-experienced pediatric patients who are at least 3 months of age and weighing at least 5 kg. REYATAZ oral powder must be mixed with food or a beverage for administration and ritonavir must be given immediately afterwards. Table 3 displays the recommended dosage of REYATAZ oral powder and ritonavir. Table 3: Recommended Dosage of REYATAZ Oral Powder and Ritonavir in Pediatric Patients (at least 3 months of age and weighing at least 5 kg)a,b Body Weight Daily Dosage of REYATAZ Oral Powder Daily Dosage of Ritonavir Oral Solution 5 kg to less than 15 kg 200 mg (4 packets)c,d 80 mg 15 kg to less than 25 kg 250 mg (5 packets)d 80 mg a The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid- reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b For pediatric patients at least 25 kg who cannot swallow REYATAZ capsules, 300 mg (6 packets) REYATAZ oral powder is taken once daily with food along with 100 mg ritonavir. c Only patients weighing 5 to less than 10 kg who do not tolerate the 200 mg (4 packets) dose of REYATAZ oral powder and have not previously taken an HIV protease inhibitor, may take 150 mg (3 packets) REYATAZ oral powder with close HIV viral load monitoring. d Each packet contains 50 mg of REYATAZ. When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation. Instructions for Mixing REYATAZ Oral Powder [see FDA-approved Instructions for Use] • Determine the number of packets (3, 4, 5 or 6 packets) that are needed. • Prior to mixing, tap the packet to settle the powder. • It is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with a beverage (milk, infant formula, or water) may be used for infants who can drink from a cup. For young infants (less than 6 months) who cannot eat solid 5 Reference ID: 5490094 food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered. • Use a clean pair of scissors to cut each packet along the dotted line. • Mixing with food: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture. • Mixing with a beverage such as milk or water in a small drinking cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time. • Mixing with liquid infant formula using an oral dosing syringe and a small medicine cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant. • Administer ritonavir immediately following REYATAZ powder administration. • Administer the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation [may leave the mixture at a temperature of 68°F to 86°F (20°C to 30°C) for up to one hour]. Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture. 2.6 Dosage Adjustments in Pregnant Patients Table 4 includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults) [see Use in Specific Populations (8.1)]. Table 4: Recommended Dosage of REYATAZ and Ritonavir in Pregnant Patientsa REYATAZ Ritonavir Once Daily Once Daily Dosage Dosage Treatment-Naive and Treatment-Experienced Recommended Regimen 300 mg 100 mg Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovir DFb In combination with EITHER 400 mg 100 mg H2RA OR tenofovir DF 6 Reference ID: 5490094 a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b REYATAZ is not recommended for treatment-experienced pregnant patients during the second and third trimester taking REYATAZ with BOTH tenofovir DF and H2RA. 2.7 Dosage in Patients with Renal Impairment For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end-stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ is not recommended in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis [see Use in Specific Populations (8.7)]. 2.8 Dosage Adjustments in Patients with Hepatic Impairment Table 5 displays the recommended REYATAZ dosage in treatment-naive patients with hepatic impairment. The use of REYATAZ in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of REYATAZ with ritonavir in patients with any degree of hepatic impairment is not recommended. Table 5: Recommended Dosage of REYATAZ Capsules in Treatment-Naive Adults with Hepatic Impairment REYATAZ Once Daily Dosage Mild hepatic impairment (Child-Pugh Class A) 400 mg Moderate hepatic impairment (Child-Pugh Class B) 300 mg Severe hepatic impairment (Child-Pugh Class C) REYATAZ with or without ritonavir is not recommended 3 DOSAGE FORMS AND STRENGTHS REYATAZ Capsules: • 200 mg capsule with blue cap and blue body, printed with white ink “BMS 200 mg” on the cap and with white ink “3631” on the body. • 300 mg capsule with red cap and blue body, printed with white ink “BMS 300 mg” on the cap and with white ink “3622” on the body. REYATAZ Oral Powder: • 50 mg of atazanavir as an oral powder in a packet. 4 CONTRAINDICATIONS REYATAZ is contraindicated: 7 Reference ID: 5490094 • in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens- Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder [see Warnings and Precautions (5.2)]. • when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6). • when coadministered with drugs that are strong inducers of CYP3A due to the potential for loss of therapeutic effect and development of resistance. Coadministration is contraindicated with, but not limited to, the following drugs listed in Table 6: Table 6: Drugs Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Drug Class Drugs within class that are contraindicated with REYATAZ Alpha 1-adrenoreceptor antagonist Antiarrhythmics Anticonvulsants Antimycobacterials Antineoplastics Antipsychotics Benzodiazepines Ergot Derivatives GI Motility Agent Hepatitis C Direct-Acting Antivirals Herbal Products Lipid-Modifying Agents: Phosphodiesterase-5 (PDE-5) Inhibitor Protease Inhibitors Non-nucleoside Reverse Transcriptase Inhibitors Alfuzosin Amiodarone (with ritonavir), quinidine (with ritonavir) Carbamazepine, phenobarbital, phenytoin Rifampin Apalutamide, encorafenib, irinotecan, ivosidenib Lurasidone (with ritonavir), pimozide Orally administered midazolama, triazolam Dihydroergotamine, ergonovine, ergotamine, methylergonovine Cisapride Elbasvir/grazoprevir; glecaprevir/pibrentasvir St. John’s wort (Hypericum perforatum) Lomitapide, lovastatin, simvastatin Sildenafilb when dosed as REVATIO® for the treatment of pulmonary arterial hypertension Indinavir Nevirapine a See Drug Interactions, Table 16 (7) for parenterally administered midazolam. b See Drug Interactions, Table 16 (7) for sildenafil when dosed as VIAGRA® for erectile dysfunction. 8 Reference ID: 5490094 5 WARNINGS AND PRECAUTIONS 5.1 Cardiac Conduction Abnormalities REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some study participants. In healthy participants and in participants with HIV-1 treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions (6.2) and Overdosage (10)]. In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir­ treated participants (n=920), 5.2% of lopinavir/ritonavir-treated participants (n=252), 10.4% of nelfinavir-treated participants (n=48), and 3.0% of efavirenz-treated participants (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir with ritonavir-treated participants and 5% (6/116) of lopinavir/ritonavir-treated participants who had on-study electrocardiogram measurements. Because of limited clinical experience in those with preexisting conduction system disease (eg, marked first-degree AV block or second- or third- degree AV block), ECG monitoring should be considered in these patients [see Clinical Pharmacology (12.2)]. 5.2 Severe Skin Reactions In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of participants with HIV-1 treated with REYATAZ. The median time to onset of rash in clinical studies was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies [see Adverse Reactions (6.1)]. Dosing with REYATAZ was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients receiving REYATAZ [see Contraindications (4) and Adverse Reactions (6.1)]. REYATAZ should be discontinued if severe rash develops. 5.3 Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). Each packet of REYATAZ oral powder contains 35 mg of phenylalanine. REYATAZ capsules do not contain phenylalanine. 5.4 Hepatotoxicity Patients with underlying hepatitis B or C virus or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with REYATAZ and during treatment [see Dosage and Administration (2.2), Adverse Reactions (6.1), and Use in Specific Populations (8.8)]. 9 Reference ID: 5490094 5.5 Chronic Kidney Disease Chronic kidney disease in patients with HIV-1 treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to REYATAZ in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with REYATAZ and continued during treatment with REYATAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking REYATAZ. In patients with progressive kidney disease, discontinuation of REYATAZ may be considered [see Dosage and Administration (2.2 and 2.7) and Adverse Reactions (6.2)]. 5.6 Nephrolithiasis and Cholelithiasis Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 receiving REYATAZ therapy. Some patients required hospitalization for additional management, and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered [see Adverse Reactions (6.2)]. 5.7 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of REYATAZ with ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving REYATAZ with ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of REYATAZ with ritonavir, respectively. These interactions may lead to: • clinically significant adverse reactions potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications. • clinically significant adverse reactions from greater exposures of REYATAZ with ritonavir. • loss of therapeutic effect (virologic response) of REYATAZ with ritonavir and possible development of resistance. See Table 16 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during therapy containing REYATAZ with ritonavir; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7)]. 5.8 Hyperbilirubinemia Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is 10 Reference ID: 5490094 reversible upon discontinuation of REYATAZ. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established [see Adverse Reactions (6.1)]. 5.9 Diabetes Mellitus/Hyperglycemia New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in patients with HIV-1 receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established [see Adverse Reactions (6.2)]. 5.10 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium, cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.11 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.12 Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established. 11 Reference ID: 5490094 5.13 Resistance/Cross-Resistance Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors [see Microbiology (12.4)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • cardiac conduction abnormalities [see Warnings and Precautions (5.1)] • rash [see Warnings and Precautions (5.2)] • hyperbilirubinemia [see Warnings and Precautions (5.8)] • chronic kidney disease [see Warnings and Precautions (5.5)] • nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.6)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Treatment-Naive Adult Participants The safety profile of REYATAZ in treatment-naive adults is based on 1625 participants with HIV­ 1 in clinical trials. 536 participants received REYATAZ 300 mg with ritonavir 100 mg and 1089 participants received REYATAZ 400 mg or higher (without ritonavir). The most common adverse reactions were nausea, jaundice/scleral icterus, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment- naive participants receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively. Table 7: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV- 1,b Study AI424-138 96 weeksc 96 weeksc REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabined (n=441) lopinavir/ritonavird 400 mg/ 100 mg (twice daily) and tenofovir DF/emtricitabinee (n=437) Digestive System Nausea 4% 8% Jaundice/scleral icterus 5% * Diarrhea 2% 12% 12 Reference ID: 5490094 Table 7: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV- 1,b Study AI424-138 Skin and Appendages Rash 3% 2% * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d Administered as a fixed-dose. e As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. Table 8: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV- 1,b Studies AI424-034, AI424-007, and AI424-008 Study AI424-034 Studies AI424-007, -008 64 weeksc REYATAZ 400 mg (once daily) with lamivudine/ zidovudinee (n=404) 64 weeksc efavirenz 600 mg (once daily) with lamivudine/ zidovudinee (n=401) 120 weeksc,d REYATAZ 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279) 73 weeksc,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine (n=191) Body as a Whole Headache 6% 6% 1% 2% Digestive System Nausea 14% 12% 6% 4% Jaundice/scleral icterus 7% * 7% * Vomiting 4% 7% 3% 3% Abdominal pain 4% 4% 4% 2% Diarrhea 1% 2% 3% 16% Nervous System Insomnia 3% 3% <1% * Dizziness 2% 7% <1% * Peripheral neurologic <1% 1% 4% 3% symptoms Skin and Appendages 13 Reference ID: 5490094 Table 8: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV- 1,b Studies AI424-034, AI424-007, and AI424-008 Study AI424-034 Studies AI424-007, -008 64 weeksc REYATAZ 400 mg (once daily) with lamivudine/ zidovudinee (n=404) 64 weeksc efavirenz 600 mg (once daily) with lamivudine/ zidovudinee (n=401) 120 weeksc,d REYATAZ 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279) 73 weeksc,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine (n=191) Rash 7% 10% 5% 1% * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on regimens containing REYATAZ. c Median time on therapy. d Includes long-term follow-up. e As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. Adverse Reactions in Treatment-Experienced Adult Participants The safety profile of REYATAZ in treatment-experienced adults with HIV-1 is based on 119 participants with HIV-1 in clinical trials. The most common adverse reactions are jaundice/scleral icterus and myalgia. Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment- experienced participants receiving REYATAZ with ritonavir are presented in Table 9. Table 9: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1,b Study AI424-045 48 weeksc 48 weeksc REYATAZ with ritonavir lopinavir/ritonavir 400/100 mg 300/100 mg (once daily) and tenofovir DF and (twice dailyd) and tenofovir DF and NRTI NRTI (n=119) (n=118) Body as a Whole Fever 2% * Digestive System 14 Reference ID: 5490094 Table 9: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1,b Study AI424-045 48 weeksc REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) 48 weeksc lopinavir/ritonavir 400/100 mg (twice dailyd) and tenofovir DF and NRTI (n=118) Jaundice/scleral icterus 9% * Diarrhea 3% 11% Nausea 3% 2% Nervous System Depression 2% <1% Musculoskeletal System Myalgia 4% * * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d As a fixed-dose product. Laboratory Abnormalities in Treatment-Naive Participants The percentages of adult treatment-naive participants with HIV-1 treated with combination therapy, including REYATAZ 300 mg with ritonavir 100 mg or REYATAZ 400 mg (without ritonavir) with Grade 3–4 laboratory abnormalities, are presented in Tables 10 and 11, respectively. Table 10: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1,a Study AI424-138 Variable Chemistry SGOT/AST Limite High ≥5.1 × ULN 96 weeksb REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabinec (n=441) 3% 96 weeksb lopinavir/ritonavir 400 mg/100 mgc (twice daily) and tenofovir DF/emtricitabined (n=437) 1% 15 Reference ID: 5490094 Table 10: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1,a Study AI424-138 96 weeksb 96 weeksb REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabinec lopinavir/ritonavir 400 mg/100 mgc (twice daily) and tenofovir DF/emtricitabined Variable Limite (n=441) (n=437) SGPT/ALT ≥5.1 × ULN 3% 2% Total Bilirubin ≥2.6 × ULN 44% <1% Lipase ≥2.1 × ULN 2% 2% Creatine Kinase ≥5.1 × ULN 8% 7% Total Cholesterol ≥240 mg/dL 11% 25% Hematology Neutrophils Low <750 cells/mm3 5% 2% a Based on the regimen containing REYATAZ. b Median time on therapy. c Administered as a fixed-dose product. d As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. e ULN=upper limit of normal. Table 11: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1,a Studies AI424-034, AI424­ 007, and AI424-008 Variable Limitd Study AI424-034 64 weeksb 64 weeksb REYATAZ efavirenz 400 mg 600 mg once daily once daily and and lamivudine/ lamivudine/ zidovudinee zidovudinee (n=404) (n=401) Studies AI424-007, -008 120 weeksb,c 73 weeksb,c REYATAZ nelfinavir 400 mg 750 mg TID or once daily 1250 mg BID with stavudine with stavudine and and lamivudine or lamivudine or with stavudine with stavudine and didanosine and didanosine (n=279) (n=191) Chemistry SGOT/AST High ≥5.1 × ULN 2% 2% 7% 5% 16 Reference ID: 5490094 Table 11: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1,a Studies AI424-034, AI424­ 007, and AI424-008 Study AI424-034 Studies AI424-007, -008 64 weeksb 64 weeksb 120 weeksb,c 73 weeksb,c REYATAZ 400 mg once daily and lamivudine/ zidovudinee efavirenz 600 mg once daily and lamivudine/ zidovudinee REYATAZ 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosine Variable Limitd (n=404) (n=401) (n=279) (n=191) SGPT/ALT ≥5.1 × ULN 4% 3% 9% 7% Total Bilirubin ≥2.6 × ULN 35% <1% 47% 3% Amylase ≥2.1 × ULN * * 14% 10% Lipase ≥2.1 × ULN <1% 1% 4% 5% Creatine Kinase ≥5.1 × ULN 6% 6% 11% 9% Total Cholesterol ≥240 mg/dL 6% 24% 19% 48% Triglycerides ≥751 mg/dL <1% 3% 4% 2% Hematology Low Hemoglobin <8.0 g/dL 5% 3% <1% 4% Neutrophils <750 cells/mm3 7% 9% 3% 7% * None reported in this treatment arm. a Based on regimen(s) containing REYATAZ. b Median time on therapy. c Includes long-term follow-up. d ULN = upper limit of normal. e As a fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. Change in Lipids from Baseline in Treatment-Naive Participants with HIV-1 For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL- cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively. 17 Reference ID: 5490094 Table 12: Lipid Values, Mean Change from Baseline, Study AI424-138 REYATAZ with ritonavira,b lopinavir/ritonavirb,c Baseline Week 48 Week 96 Baseline Week 48 Week 96 mg/dL mg/dL Changed mg/dL Changed mg/dL mg/dL Changed mg/dL Changed (n=428e) (n=372e) (n=372e) (n=342e) (n=342e) (n=424e) (n=335e) (n=335e) (n=291e) (n=291e) LDL- Cholesterolf 92 105 +14% 105 +14% 93 111 +19% 110 +17% HDL- Cholesterolf 37 46 +29% 44 +21% 36 48 +37% 46 +29% Total Cholesterolf 149 169 +13% 169 +13% 150 187 +25% 186 +25% Triglyceridesf 126 145 +15% 140 +13% 129 194 +52% 184 +50% a REYATAZ 300 mg with ritonavir 100 mg once daily with the fixed-dose product: 300 mg tenofovir DF/ 200 mg emtricitabine once daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and 1% in the REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ with ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ with ritonavir arm. c Lopinavir/ritonavir (400 mg/100 mg) twice daily with the fixed-dose product 300 mg tenofovir DF/200 mg emtricitabine once daily. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values, respectively. e Number of participants with LDL-cholesterol measured. f Fasting. Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034 REYATAZa,b efavirenzb,c LDL-Cholesterolf Baseline mg/dL (n=383e) 98 Week 48 mg/dL (n=283e) 98 Week 48 Changed (n=272e) +1% Baseline mg/dL (n=378e) 98 Week 48 mg/dL (n=264e) 114 Week 48 Changed (n=253e) +18% HDL-Cholesterol 39 43 +13% 38 46 +24% Total Cholesterol 164 168 +2% 162 195 +21% Triglyceridesf 138 124 −9% 129 168 +23% a REYATAZ 400 mg once daily with the fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. 18 Reference ID: 5490094 b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and <1% in the REYATAZ arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the REYATAZ arm. c Efavirenz 600 mg once daily with the fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of participants with LDL-cholesterol measured. f Fasting. Laboratory Abnormalities in Treatment-Experienced Participants with HIV-1 The percentages of adult treatment-experienced participants with HIV-1 treated with combination therapy, including REYATAZ with ritonavir having Grade 3–4 laboratory abnormalities, are presented in Table 14. Table 14: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1, Study AI424-045a 48 weeksb 48 weeksb REYATAZ with ritonavir 300/100 mg (once daily) and lopinavir/ritonavir 400/100 mg (twice dailyd) tenofovir DF and NRTI and tenofovir DF and NRTI Variable Limitc (n=119) (n=118) Chemistry High SGOT/AST ≥5.1 × ULN 3% 3% SGPT/ALT ≥5.1 × ULN 4% 3% Total Bilirubin ≥2.6 × ULN 49% <1% Lipase ≥2.1 × ULN 5% 6% Creatine Kinase ≥5.1 × ULN 8% 8% Total Cholesterol ≥240 mg/dL 25% 26% Triglycerides ≥751 mg/dL 8% 12% Glucose ≥251 mg/dL 5% <1% Hematology Low Platelets <50,000 cells/mm3 2% 3% Neutrophils <750 cells/mm3 7% 8% a Based on regimen(s) containing REYATAZ. b Median time on therapy. c ULN = upper limit of normal. 19 Reference ID: 5490094 d As a fixed-dose product. Change in Lipids from Baseline in Treatment-Experienced Participants with HIV-1 For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with REYATAZ with ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated. Table 15: Lipid Values, Mean Change from Baseline, Study AI424-045 REYATAZ with ritonavira,b Lopinavir/ritonavirb,c Baseline mg/dL Week 48 mg/dL Week 48 Changed Baseline mg/dL Week 48 mg/dL Week 48 Changed (n=111e) (n=75e) (n=74e) (n=108e) (n=76e) (n=73e) LDL-Cholesterolf 108 98 −10% 104 103 +1% HDL-Cholesterol 40 39 −7% 39 41 +2% Total Cholesterol 188 170 −8% 181 187 +6% Triglyceridesf 215 161 −4% 196 224 +30% a REYATAZ 300 mg once daily with ritonavir and tenofovir DF, and 1 NRTI. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 4% in the lopinavir/ritonavir treatment arm and 4% in the REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the REYATAZ with ritonavir arm. c Lopinavir/ritonavir (400/100 mg), as a fixed dose regimen, BID with tenofovir DF and 1 NRTI. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of participants with LDL-cholesterol measured. f Fasting. Adverse Reactions in Pediatric Participants with HIV-1: REYATAZ Capsules The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric participants with HIV-1, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A. The safety profile of REYATAZ in pediatric participants with HIV-1 (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 adverse events (≥5%, regardless of causality) reported in pediatric participants were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in <2% of participants. The most 20 Reference ID: 5490094 common Grade 3–4 laboratory abnormalities occurring in pediatric participants taking the capsule formulation were elevation of total bilirubin (≥3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%. Adverse Reactions in Pediatric Participants with HIV-1: REYATAZ Oral Powder The data described below reflect exposure to REYATAZ oral powder in 155 participants weighing at least 5 kg to less than 35 kg, including 134 participants exposed for 48 weeks. These data are from two pooled, open-label, multi-center clinical trials in treatment-naive and treatment- experienced pediatric participants with HIV-1 (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from 3 months to 10 years of age. In these studies, 51% were female and 49% were male. All participants received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs). The safety profile of REYATAZ in pediatric participants taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric participants taking REYATAZ capsules. The most common Grade 3–4 laboratory abnormalities occurring in pediatric participants weighing 5 kg to less than 35 kg taking REYATAZ oral powder were increased amylase (33%), neutropenia (9%), increased SGPT/ALT (9%), elevation of total bilirubin (≥2.6 times ULN, 16%), and increased lipase (8%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%. Adverse Reactions in Participants with HIV-1 and Hepatitis B and/or Hepatitis C Virus In Study AI424-138, 60 participants administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 51 participants treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed-dose tenofovir DF/emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the participants administered REYATAZ with ritonavir and 8% (4/50) of the participants treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the participants administered REYATAZ with ritonavir and none (0/50) of the participants treated with lopinavir/ritonavir. In Study AI424-045, 20 participants administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 18 participants treated with lopinavir/ritonavir 400 mg/100 mg twice daily (as fixed- dose product), were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the participants administered REYATAZ with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir treated. AST levels >5 times ULN developed in 10% (2/20) of the participants administered REYATAZ with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir. In Studies AI424-008 and AI424-034, 74 participants treated with REYATAZ 400 mg once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 15% of the participants treated with REYATAZ, 14% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir. AST levels >5 times ULN developed in 9% of the participants treated with 21 Reference ID: 5490094 REYATAZ, 5% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative participants [see Warnings and Precautions (5.8)]. 6.2 Postmarketing Experience The following events have been identified during postmarketing use of REYATAZ. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: edema Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation [see Warnings and Precautions (5.1)] Gastrointestinal System: pancreatitis Hepatic System: hepatic function abnormalities Hepatobiliary Disorders: cholelithiasis [see Warnings and Precautions (5.6)], cholecystitis, cholestasis Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see Warnings and Precautions (5.9)] Musculoskeletal System: arthralgia Renal System: nephrolithiasis [see Warnings and Precautions (5.6)], interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease [see Warnings and Precautions (5.5)] Skin and Appendages: alopecia, maculopapular rash [see Contraindications (4) and Warnings and Precautions (5.2)], pruritus, angioedema 7 DRUG INTERACTIONS 7.1 Potential for REYATAZ to Affect Other Drugs Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. Atazanavir is a weak inhibitor of CYP2C8. Use of REYATAZ without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected [see Clinical Pharmacology, Table 22 (12.3)]. The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. 22 Reference ID: 5490094 7.2 Potential for Other Drugs to Affect REYATAZ Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect (see Table 16). Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered with REYATAZ [see Dosage and Administration (2.3, 2.4, 2.5 and 2.6)]. 7.3 Established and Other Potentially Significant Drug Interactions Table 16 provides dosing recommendations in adults as a result of drug interactions with REYATAZ. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment HIV Antiviral Agents Nucleoside Reverse ↓ atazanavir It is recommended that REYATAZ be given (with food) 2 h before or 1 h Transcriptase Inhibitors (NRTIs): ↓ didanosine after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine didanosine buffered formulations exposure. Thus, REYATAZ and didanosine EC should be administered at different times. enteric coated (EC) capsules Nucleotide Reverse ↓ atazanavir When coadministered with tenofovir DF in adults, it is recommended that Transcriptase Inhibitors: tenofovir disoproxil fumarate ↑ tenofovir REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is (DF) unknown. Higher tenofovir concentrations could potentiate tenofovir­ associated adverse reactions, including renal disorders. Patients receiving REYATAZ and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking REYATAZ with ritonavir and tenofovir DF, see Dosage and Administration (2.6). Non-nucleoside Reverse ↓ atazanavir In HIV-treatment-naive adult patients: Transcriptase Inhibitors (NNRTIs): efavirenz If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with efavirenz is not recommended. nevirapine ↓ atazanavir ↑ nevirapine Coadministration of REYATAZ with nevirapine is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions [see Contraindications (4)]. 23 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment Protease Inhibitors: saquinavir (soft gelatin capsules) ↑ saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2)]. indinavir Coadministration of REYATAZ with indinavir is contraindicated. Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4)]. ritonavir ↑ atazanavir If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. Others ↑ other protease inhibitor Coadministration with other protease inhibitors is not recommended. Hepatitis C Antiviral Agents elbasvir/grazoprevir ↑ grazoprevir Coadministration of REYATAZ with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4)]. glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of REYATAZ with glecaprevir/pibrentasvir is contraindicated due to the potential for increased the risk of ALT elevations [see Contraindications (4)]. voxilaprevir/sofosbuvir/ velpatasvir ↑ voxilaprevir Coadministration with REYATAZ is not recommended. Other Agents Alpha 1-Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Coadministration of REYATAZ with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4)]. Antacids and buffered medications: ↓ atazanavir REYATAZ should be administered 2 hours before or 1 hour after antacids and buffered medications. Antiarrhythmics: amiodarone, quinidine amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Concomitant use of REYATAZ with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life- threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. Coadministration with REYATAZ without ritonavir has the potential to produce serious and/or life-threatening adverse events but has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ without ritonavir. Anticoagulants: warfarin ↑ warfarin Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that International Normalized Ratio (INR) be monitored. Direct-Acting Oral Anticoagulants: betrixaban, dabigatran, edoxaban ↑ betrixaban ↑ dabigatran ↑ edoxaban Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors. 24 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment rivaroxaban REYATAZ with ritonavir Coadministration of REYATAZ with ritonavir, a strong CYP3A4/P-gp ↑ rivaroxaban inhibitor, and rivaroxaban is not recommended, as it may result in an increased risk of bleeding. REYATAZ Coadministration of REYATAZ, a CYP3A4 inhibitor, and rivaroxaban may ↑ rivaroxaban result in an increased risk of bleeding. Close monitoring is recommended when REYATAZ is coadministered with rivaroxaban. apixaban REYATAZ with ritonavir Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp ↑ apixaban inhibitor, may result in an increased risk of bleeding. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in the apixaban prescribing information. REYATAZ Concomitant use of REYATAZ, a CYP3A4 inhibitor, and apixaban may ↑ apixaban result in an increased risk of bleeding. Close monitoring is recommended when apixaban is coadministered with REYATAZ. Antidepressants: tricyclic ↑ tricyclic Coadministration with REYATAZ has the potential to produce serious and/or antidepressants antidepressants life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ. trazodone ↑ trazodone Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered. Antiepileptics: ↓ atazanavir Coadministration of REYATAZ (with or without ritonavir) with carbamazepine ↑ carbamazepine carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)]. phenytoin, phenobarbital ↓ atazanavir ↓ phenytoin ↓ phenobarbital Coadministration of REYATAZ (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)]. lamotrigine ↓ lamotrigine Coadministration of lamotrigine and REYATAZ with ritonavir may require dosage adjustment of lamotrigine. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir. Antifungals: REYATAZ with Coadministration of ketoconazole has only been studied with REYATAZ ketoconazole, itraconazole ritonavir: ↑ ketoconazole ↑ itraconazole without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously when administering REYATAZ with ritonavir. 25 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment voriconazole REYATAZ with ritonavir in participants with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir REYATAZ with ritonavir in participants without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir The use of voriconazole in patients receiving REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ with ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available. Antigout: colchicine ↑ colchicine The coadministration of REYATAZ with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult dosage of colchicine when administered with REYATAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimycobacterials: rifampin ↓ atazanavir Coadministration of REYATAZ with rifampin is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)]. rifabutin ↑ rifabutin A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin­ associated adverse reactions including neutropenia is warranted. Antineoplastics: irinotecan ↑ irinotecan Coadministration of REYATAZ with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications (4)]. 26 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment apalutamide ↓ atazanavir Coadministration of REYATAZ (with or without ritonavir) and apalutamide is contraindicated due to the potential for subsequent loss of virologic response and possible resistance to the class of protease inhibitors [see Contraindications (4)]. ivosidenib ↓ atazanavir ↑ ivosidenib Coadministration of ivosidenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for loss of virologic response and risk of serious adverse events such as QT interval prolongation. encorafenib ↓ atazanavir ↑ encorafenib Coadministration of encorafenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for the loss of virologic response and risk of serious adverse events such as QT interval prolongation. Antiplatelets ticagrelor ↑ ticagrelor Coadministration with ticagrelor is not recommended due to potential increase in the risk of dyspnea, bleeding and other adverse events associated with ticagrelor. clopidogrel ↓ clopidogrel active metabolite Coadministration of REYATAZ (with or without ritonavir) and clopidogrel is not recommended. This is due to the potential reduction of the antiplatelet activity of clopidogrel. Antipsychotics: pimozide ↑ pimozide Coadministration of REYATAZ with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. lurasidone REYATAZ with ritonavir ↑ lurasidone REYATAZ ↑ lurasidone REYATAZ with ritonavir Coadministration of lurasidone with REYATAZ with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications (4)]. REYATAZ without ritonavir If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. quetiapine ↑ quetiapine Initiation of REYATAZ with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking REYATAZ with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Benzodiazepines: ↑ midazolam Coadministration of REYATAZ with either orally administered midazolam or midazolam (oral) triazolam ↑ triazolam triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with REYATAZ can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4)]. 27 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment parenterally administered ↑ midazolam Coadministration with parenteral midazolam should be done in a setting midazolamb which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Calcium channel blockers: diltiazem ↑ diltiazem and desacetyl-diltiazem Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of diltiazem and REYATAZ with ritonavir has not been studied. felodipine, nifedipine, nicardipine, and verapamil ↑ calcium channel blocker Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. Corticosteroids: ↓ atazanavir Coadministration with dexamethasone or other corticosteroids that induce dexamethasone and other corticosteroids (all routes of administration) ↑ corticosteroids CYP3A may result in loss of therapeutic effect of REYATAZ and development of resistance to atazanavir and/or ritonavir. Alternative corticosteroids should be considered. Coadministration with corticosteroids (all routes of administration) that are metabolized by CYP3A, particularly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. For coadministration of cutaneously administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for additional information. Endothelin receptor REYATAZ Coadministration of bosentan and REYATAZ without ritonavir is not antagonists: ↓ atazanavir recommended. bosentan REYATAZ with ritonavir ↑ bosentan For adult patients who have been receiving REYATAZ with ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. For adult patients who have been receiving bosentan, discontinue bosentan at least 36 hours before starting REYATAZ with ritonavir. At least 10 days after starting REYATAZ with ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine ↑ ergot derivatives Coadministration of REYATAZ with ergot derivatives is contraindicated. This is due to the potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4)]. GI Motility Agents: cisapride ↑ cisapride Coadministration of REYATAZ with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. Gonadotropin-releasing ↓ atazanavir Coadministration of elagolix and REYATAZ with or without ritonavir is not hormone Receptor (GnRH) Antagonists: ↑ elagolix recommended due to the potential of loss of virologic response and the potential risk of adverse events such as bone loss and hepatic transaminase elagolix elevations associated with elagolix. In the event coadministration is necessary, limit concomitant use of elagolix 200mg twice daily with REYATAZ with or without ritonavir for up to 1 month or limit concomitant use of elagolix 150 mg once daily with REYATAZ (with or without ritonavir) for up to 6 months and monitor virologic response. 28 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment Herbal Products: St. John’s wort (Hypericum perforatum) ↓ atazanavir Coadministration of products containing St. John’s wort with REYATAZ is contraindicated. This may result in loss of therapeutic effect of REYATAZ and the development of resistance [see Contraindications (4)]. Kinase inhibitors: fostamatinib ↑ R406 (active metabolite of fostamatinib) When coadministering fostamatinib with REYATAZ (with or without ritonavir), monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Coadministration of REYATAZ with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4)]. atorvastatin, rosuvastatin ↑ atorvastatin ↑ rosuvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs. Other Lipid Modifying Agents: lomitapide ↑ lomitapide Coadministration of REYATAZ with lomitapide is contraindicated. This is due to the potential for risk of markedly increased transaminase levels and hepatotoxicity associated with increased plasma concentrations of lomitapide. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir [see Contraindications (4)]. 29 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment H2-Receptor antagonists ↓ atazanavir Coadministration may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist (H2RA). An H2RA dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment- naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2RA. No single dose of the H2RA should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. The use of REYATAZ without ritonavir in pregnant patients is not recommended. In treatment-experienced adult patients: Whenever an H2RA is given to a patient receiving REYATAZ with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ with ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA. • REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA. • REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA. • REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with either tenofovir DF or an H2RA for pregnant patients during the second and third trimester. REYATAZ is not recommended for pregnant patients during the second and third trimester taking REYATAZ with both tenofovir DF and an H2RA. 30 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment Hormonal contraceptives: ↓ ethinyl estradiol Use caution if considering coadministration of oral contraceptives with ethinyl estradiol and norgestimate or norethindrone ↑ norgestimatec ↑ ethinyl estradiol ↑ norethindroned REYATAZ or REYATAZ with ritonavir. If REYATAZ with ritonavir is coadministered with an oral contraceptive, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ with ritonavir and other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. Immunosuppressants: cyclosporine, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with REYATAZ. Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/nasal steroid: REYATAZ Concomitant use of fluticasone propionate and REYATAZ without ritonavir fluticasone ↑ fluticasone should be used with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. REYATAZ with ritonavir ↑ fluticasone With concomitant use of fluticasone propionate and REYATAZ with ritonavir systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ with ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1)]. Macrolide antibiotics: ↑ clarithromycin Increased concentrations of clarithromycin may cause QTc prolongations; clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ with ritonavir and clarithromycin has not been studied. 31 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment Opioids: buprenorphine REYATAZ or REYATAZ with ritonavir ↑ buprenorphine ↑ norbuprenorphine REYATAZ ↓ atazanavir Coadministration of REYATAZ with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. The coadministration of REYATAZ and buprenorphine without ritonavir is not recommended. PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of REYATAZ with REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated [see Contraindications (4)]. The following dose adjustments are recommended for the use of ADCIRCA® (tadalafil) with REYATAZ: Coadministration of ADCIRCA® in patients on REYATAZ (with or without ritonavir): • For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA®: • Avoid the use of ADCIRCA® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use CIALIS® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. REYATAZ with ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. REYATAZ: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions. 32 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment Proton-pump inhibitors: omeprazole ↓ atazanavir Coadministration of REYATAZ with or without ritonavir and omeprazole may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: The proton-pump inhibitor (PPI) dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with PPIs is not recommended. a For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3). b See Contraindications (4), Table 6 for orally administered midazolam. c In combination with atazanavir 300 mg with ritonavir 100 mg once daily. d In combination with atazanavir 400 mg once daily. 7.4 Drugs with No Observed Interactions with REYATAZ No clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see Clinical Pharmacology, Tables 21 and 22 (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2­ 4% and 15-20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to 33 Reference ID: 5490094 rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed [see Data]. Clinical Considerations Dose Adjustments during Pregnancy and the Postpartum Period • REYATAZ must be administered with ritonavir in pregnant patients. • For pregnant patients, no dosage adjustment is required for REYATAZ with the following exceptions: • For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir DF, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antagonist and tenofovir DF in treatment-experienced pregnant patients. • No dosage adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)]. Maternal Adverse Reactions Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take REYATAZ [see Warnings and Precautions (5.8)], including those who are pregnant [see Data]. Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia. Fetal/Neonatal Adverse Reactions All infants, including neonates exposed to REYATAZ in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life [see Data]. Data Human Data In Study AI424-182, REYATAZ with ritonavir (300/100 mg or 400/100 mg) coadministered with lamivudine/zidovudine (150 mg/ 300 mg, as fixed-dose product) was administered to 41 pregnant women with HIV-1, during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV-1 RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ with ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ with ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182. Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 pregnant women with HIV-1, all had 34 Reference ID: 5490094 test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life. Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy). Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis. Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir, and overall birth defects compared with the background birth defect rate. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies is 2-4%. Animal Data In animal reproduction studies, there was no evidence of mortality or teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused neonatal growth retardation during lactation that reversed after weaning. Maternal drug exposure at this dose was 1.3 times the human exposure at the recommended clinical exposure. Minimal maternal toxicity occurred at this exposure level. 8.2 Lactation Risk Summary Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Atazanavir was present in the milk of lactating rats and was associated with neonatal growth retardation that reversed after weaning. Potential risks of breastfeeding include: (1) HIV-1 transmission (in infants without HIV-1), (2) developing viral resistance (in infants with HIV-1), and (3) adverse reactions in a breastfed infant similar to those seen in adults. 35 Reference ID: 5490094 8.4 Pediatric Use REYATAZ is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1, 3 months of age and older weighing at least 5 kg. REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Indications and Usage (1)]. All REYATAZ contraindications, warnings, and precautions apply to pediatric patients [see Contraindications (4) and Warnings and Precautions (5)]. The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 5 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397 [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. The safety profile in pediatric patients was generally similar to that observed in adults [see Adverse Reactions (6.1)]. See Dosage and Administration (2.4, 2.5) for dosing recommendations for the use of REYATAZ capsules and REYATAZ oral powder in pediatric patients. 8.5 Geriatric Use Clinical studies of REYATAZ did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Based on a comparison of mean single-dose pharmacokinetic values for Cmax and AUC, a dose adjustment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring of REYATAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Age/Gender A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18-40 years) and elderly (n=30; ≥65 years) healthy participants. There were no clinically significant pharmacokinetic differences observed due to age or gender. 8.7 Impaired Renal Function REYATAZ is not recommended for use in treatment-experienced patients with HIV-1, who have end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)]. 8.8 Impaired Hepatic Function REYATAZ is not recommended for use in patients with severe hepatic impairment. REYATAZ with ritonavir is not recommended in patients with any degree of hepatic impairment [see Dosage and Administration (2.8) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg (three times the 400 mg maximum recommended dose) have been taken by healthy participants without symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ in a patient with HIV-1 (73 times the 400-mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved 36 Reference ID: 5490094 spontaneously. At REYATAZ doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed [see Warnings and Precautions (5.1, 5.8) and Clinical Pharmacology (12.2)]. Treatment of overdosage with REYATAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with REYATAZ. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine. 11 DESCRIPTION The active ingredient in REYATAZ capsules and oral powder is atazanavir sulfate, which is an HIV-1 protease inhibitor. The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8­ hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13­ pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C38H52N6O7•H2SO4, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula: Atazanavir sulfate is a white to pale-yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3°C. REYATAZ Capsules are available for oral administration in strengths of 200 mg or 300 mg of atazanavir, which are equivalent to 227.8 mg or 341.69 mg of atazanavir sulfate, respectively. The capsules also contain the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue No. 2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue No. 2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol. 37 Reference ID: 5490094 REYATAZ oral powder comes in a packet containing 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 g of powder. The powder is off-white to pale yellow and contains the following inactive ingredients: aspartame, sucrose, and orange-vanilla flavor. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Atazanavir is an HIV-1 antiretroviral drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics Cardiac Electrophysiology Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy participants receiving atazanavir. In placebo-controlled Study AI424-076, the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram [see Warnings and Precautions (5.1)]. Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy participants. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 participants with HIV-1, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy participant or participant with HIV-1 in clinical trials had a QTc interval >500 msec [see Warnings and Precautions (5.1)]. 12.3 Pharmacokinetics The pharmacokinetics of atazanavir were evaluated in adult participants who either were healthy, or with HIV-1, after administration of REYATAZ 400 mg once daily and after administration of REYATAZ 300 mg with ritonavir 100 mg once daily (see Table 17). 38 Reference ID: 5490094 Table 17: Steady-State Pharmacokinetics of Atazanavir in Healthy Participants or Participants with HIV-1 in the Fed State 300 mg with ritonavir 400 mg once daily 100 mg once daily Healthy Participants Healthy Participants Participants with HIV-1 Participants with HIV-1 Parameter (n=14) (n=13) (n=28) (n=10) Cmax (ng/mL) Geometric mean (CV%) 5199 (26) 2298 (71) 6129 (31) 4422 (58) Mean (SD) 5358 (1371) 3152 (2231) 6450 (2031) 5233 (3033) Tmax (h) Median 2.5 2.0 2.7 3.0 AUC (ng•h/mL) Geometric mean (CV%) 28132 (28) 14874 (91) 57039 (37) 46073 (66) Mean (SD) 29303 (8263) 22262 (20159) 61435 (22911) 53761 (35294) T-half (h) Mean (SD) 7.9 (2.9) 6.5 (2.6) 18.1 (6.2)a 8.6 (2.3) Cmin (ng/mL) Geometric mean (CV%) 159 (88) 120 (109) 1227 (53) 636 (97) Mean (SD) 218 (191) 273 (298)b 1441 (757) 862 (838) a n=26. b n=12. Figure 1 displays the mean plasma concentrations of atazanavir at steady state after REYATAZ 400 mg once daily (as two 200-mg capsules) with a light meal and after REYATAZ 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in adult participants with HIV-1. 39 Reference ID: 5490094 10000 100 ~ ATV.ctO0mg 10 Median wild-type ECro=14 ng/ml - ATVIRTV300/100 mg - EC,, 0 2 4 • • 10 12 14 16 19 20 22 21 Time {h) Figure 1: Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10) for Adult Participants with HIV-1 Absorption Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold. Food Effect Administration of REYATAZ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of REYATAZ with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400-mg dose of REYATAZ with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of REYATAZ with either a light meal or high- fat meal decreased the coefficient of variation of AUC and Cmax by approximately one-half compared to the fasting state. Coadministration of a single 300-mg dose of REYATAZ and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Coadministration of 40 Reference ID: 5490094 REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state. Distribution Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in participants with HIV-1 dosed with REYATAZ 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42. Metabolism Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A. Elimination Following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half- life of atazanavir in healthy participants (n=214) and adult participants with HIV-1 (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal. Specific Populations Renal Impairment In healthy participants, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. REYATAZ has been studied in adult participants with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir Cmax was 9% lower, AUC was 19% higher, and Cmin was 96% higher in participants with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched participants with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for Cmax, AUC, and Cmin were approximately 25% to 43% lower compared to participants with normal renal function. The mechanism of this decrease is unknown. REYATAZ is not recommended for use in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7)]. 41 Reference ID: 5490094 Hepatic Impairment REYATAZ has been studied in adult participants with moderate-to-severe hepatic impairment (14 with Child-Pugh B and 2 with Child-Pugh C) after a single 400-mg dose. The mean AUC(0-∞) was 42% greater in participants with impaired hepatic function than in healthy participants. The mean half-life of atazanavir in hepatically impaired participants was 12.1 hours compared to 6.4 hours in healthy participants. A dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of atazanavir are expected. REYATAZ is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of REYATAZ in combination with ritonavir has not been studied in participants with hepatic impairment; thus, coadministration of REYATAZ with ritonavir is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.8)]. Pediatrics The pharmacokinetic parameters for atazanavir at steady state in pediatric participants taking the powder formulation are summarized in Table 18 by weight ranges [see Dosage and Administration (2.5)]. Table 18: Steady-State Pharmacokinetics of Atazanavir (powder formulation) with Ritonavir in Pediatric Participants with HIV-1 Body Weight (range in kg) [n] atazanavir with ritonavir Dose (mg) Cmax ng/mL Geometric Mean (CV%) AUC ng•h/mL Geometric Mean (CV%) Cmin ng/mL Geometric Mean (CV%) 5 to <10 [20] 150/80 4131 (55%) 32503 (61%) 336 (76%) 5 to <10 [10] 200/80 4466 (59%) 39519 (54%) 550 (60%) 10 to <15 [18] 200/80 5197 (53%) 50305 (67%) 572 (111%) 15 to <25 [32] 250/80 5394 (46%) 55687 (45%) 686 (68%) 25 to <35 [8] 300/100 4209 (52%) 44329 (63%) 468 (104%) The pharmacokinetic parameters for atazanavir at steady state in pediatric participants taking the capsule formulation were predicted by a population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses [see Dosage and Administration (2.4)]. 42 Reference ID: 5490094 Table 19: Predicted Steady-State Pharmacokinetics of Atazanavir (capsule formulation) with Ritonavir in Pediatric Participants with HIV-1 Body Weight (range in kg) atazanavir with ritonavir Dose (mg) Cmax ng/mL Geometric Mean (CV%) AUC ng•h/mL Geometric Mean (CV%) Cmin ng/mL Geometric Mean (CV%) 15 to <35 200/100 3303 (86%) 37235 (84%) 538 (99%) ≥35 300/100 2980 (82%) 37643 (83%) 653 (89%) Pregnancy The pharmacokinetic data from pregnant women with HIV-1 receiving REYATAZ Capsules with ritonavir are presented in Table 20. Table 20: Steady-State Pharmacokinetics of Atazanavir with Ritonavir in Pregnant Women with HIV-1 in the Fed State Atazanavir 300 mg with ritonavir 100 mg 2nd Trimester 3rd Trimester Postpartumb (n=20) Pharmacokinetic Parameter (n=5a) (n=34) 3078.85 3291.46 5721.21 Cmax ng/mL (50) (48) (31) Geometric mean (CV%) AUC ng•h/mL 27657.1 34251.5 61990.4 Geometric mean (CV%) (43) (43) (32) 538.70 668.48 1462.59 Cmin ng/mLc (46) (50) (45) Geometric mean (CV%) a Available data during the 2nd trimester are limited. b Atazanavir peak concentrations and AUCs were found to be approximately 28% to 43% higher during the postpartum period (4-12 weeks) than those observed historically in, non-pregnant patients with HIV-1. Atazanavir plasma trough concentrations were approximately 2.2-fold higher during the postpartum period when compared to those observed historically in non-pregnant patients with HIV-1. c Cmin is concentration 24 hours post-dose. Drug Interaction Data Atazanavir is a metabolism-dependent CYP3A inhibitor, with a Kinact value of 0.05 to 0.06 min−1 and Ki value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (Ki=1.9 µM) and CYP2C8 (Ki=2.1 µM). Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, REYATAZ decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced. 43 Reference ID: 5490094 Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for information on other potential drug interactions with ritonavir. Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, Cmax, and Cmin are summarized in Tables 21 and 22. Neither didanosine EC nor diltiazem had a significant effect on atazanavir exposures (see Table 22 for effect of atazanavir on didanosine EC or diltiazem exposures). REYATAZ did not have a significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see Drug Interactions (7). Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 Cmax AUC Cmin atenolol 50 mg QD, d 7–11 (n=19) and d 19–23 400 mg QD, d 1–11 (n=19) 1.00 (0.89, 1.12) 0.93 (0.85, 1.01) 0.74 (0.65, 0.86) clarithromycin 500 mg BID, d 7–10 (n=29) and d 18–21 400 mg QD, d 1–10 (n=29) 1.06 (0.93, 1.20) 1.28 (1.16, 1.43) 1.91 (1.66, 2.21) didanosine (ddI) (buffered tablets) and stavudine (d4T)b ddI: 200 mg × 1 dose, d4T: 40 mg × 1 dose (n=31) 400 mg × 1 dose simultaneously with ddI and d4T (n=31) 0.11 (0.06, 0.18) 0.13 (0.08, 0.21) 0.16 (0.10, 0.27) ddI: 200 mg × 1 dose, d4T: 40 mg × 1 dose (n=32) 400 mg × 1 dose 1 h after ddI + d4T (n=32) 1.12 (0.67, 1.18) 1.03 (0.64, 1.67) 1.03 (0.61, 1.73) efavirenz 600 mg QD, d 7–20 (n=27) 400 mg QD, d 1–20 (n=27) 0.41 (0.33, 0.51) 0.26 (0.22, 0.32) 0.07 (0.05, 0.10) 600 mg QD, d 7–20 400 mg QD, d 1–6 1.14 1.39 1.48 (n=13) (n=23) then 300 mg with ritonavir 100 mg QD, 2 h (0.83, 1.58) (1.02, 1.88) (1.24, 1.76) before efavirenz, d 7–20 (n=13) 44 Reference ID: 5490094 Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 Cmax AUC Cmin 600 mg QD, 300 mg QD with 1.17 1.00 0.58 d 11–24 (pm) (n=14) ritonavir 100 mg QD, d 1–10 (pm) (n=22), then 400 mg QD with (1.08, 1.27) (0.91, 1.10) (0.49, 0.69) ritonavir 100 mg QD, d 11–24 (pm), (simultaneously with efavirenz) (n=14) famotidine 40 mg BID, d 7–12 (n=15) 400 mg QD, d 1–6 (n=45), d 7–12 (simultaneous administration) (n=15) 0.53 (0.34, 0.82) 0.59 (0.40, 0.87) 0.58 (0.37, 0.89) 40 mg BID, d 7–12 400 mg QD (pm), d 1–6 1.08 0.95 0.79 (n=14) (n=14), d 7–12 (10 h after, 2 h before famotidine) (n=14) (0.82, 1.41) (0.74, 1.21) (0.60, 1.04) 40 mg BID, d 11–20 300 mg QD with 0.86 0.82 0.72 (n=14)c ritonavir 100 mg QD, d 1–10 (n=46), d 11–20d (0.79, 0.94) (0.75, 0.89) (0.64, 0.81) (simultaneous administration) (n=14) 20 mg BID, d 11–17 300 mg QD with 0.91 0.90 0.81 (n=18) ritonavir 100 mg QD and tenofovir DF 300 mg (0.84, 0.99) (0.82, 0.98) (0.69, 0.94) QD, d 1–10 (am) (n=39), d 11–17 (am) (simultaneous administration with am famotidine) (n=18)d,e 40 mg QD (pm), 300 mg QD with 0.89 0.88 0.77 d 18–24 (n=20) ritonavir 100 mg QD and tenofovir DF 300 mg QD, d 1–10 (am) (n=39), (0.81, 0.97) (0.80, 0.96) (0.63, 0.93) d 18–24 (am) (12 h after pm famotidine) (n=20)e 40 mg BID, d 18–24 300 mg QD with 0.74 0.79 0.72 (n=18) ritonavir 100 mg QD and tenofovir DF 300 mg (0.66, 0.84) (0.70, 0.88) (0.63, 0.83) QD, d 1–10 (am) (n=39), d 18–24 (am) (10 h after pm famotidine and 2 h before am famotidine) (n=18)e 45 Reference ID: 5490094 Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 Cmax AUC Cmin 40 mg BID, d 11–20 (n=15) 300 mg QD with ritonavir 100 mg QD, d 1–10 (am) (n=46), then 400 mg QD with ritonavir 100 mg QD, d 11–20 (am) (n=15) 1.02 (0.87, 1.18) 1.03 (0.86, 1.22) 0.86 (0.68, 1.08) grazoprevir/ elbasvir grazoprevir 200 mg QD d 1–35 (n = 11) 300 mg QD with ritonavir 100 mg QD, d 1–35 (n = 11) 1.12 (1.01, 1.24) 1.43 (1.30, 1.57) 1.23 (1.13, 1.34) elbasvir 50 mg QD d 1–35 (n = 8) 300 mg QD with ritonavir 100 mg QD, d 1–35 (n = 8) 1.02 (0.96, 1.08) 1.07 (0.98,1.17) 1.15 (1.02, 1.29) ketoconazole 200 mg QD, d 7–13 (n=14) 400 mg QD, d 1–13 (n=14) 0.99 (0.77, 1.28) 1.10 (0.89, 1.37) 1.03 (0.53, 2.01) nevirapinef,g 200 mg BID, d 1–23 (n=23) 300 mg QD with ritonavir 100 mg QD, d 4–13, then 400 mg QD with ritonavir 100 mg QD, d 14–23 (n=23)h 0.72 (0.60, 0.86) 1.02 (0.85, 1.24) 0.58 (0.48, 0.71) 0.81 (0.65, 1.02) 0.28 (0.20, 0.40) 0.41 (0.27, 0.60) omeprazole 40 mg QD, d 7–12 (n=16)i 400 mg QD, d 1–6 (n=48), d 7–12 (n=16) 0.04 (0.04, 0.05) 0.06 (0.05, 0.07) 0.05 (0.03, 0.07) 40 mg QD, d 11–20 (n=15)i 300 mg QD with ritonavir 100 mg QD, d 1–20 (n=15) 0.28 (0.24, 0.32) 0.24 (0.21, 0.27) 0.22 (0.19, 0.26) 20 mg QD, d 17–23 (am) (n=13) 300 mg QD with ritonavir 100 mg QD, d 7–16 (pm) (n=27), d 17– 23 (pm) (n=13)j,k 0.61 (0.46, 0.81) 0.58 (0.44, 0.75) 0.54 (0.41, 0.71) 20 mg QD, d 17–23 (am) (n=14) 300 mg QD with ritonavir 100 mg QD, d 7–16 (am) (n=27), then 400 mg QD with ritonavir 100 mg QD, d 17–23 (am) (n=14)l,m 0.69 (0.58, 0.83) 0.70 (0.57, 0.86) 0.69 (0.54, 0.88) pitavastatin 4 mg QD for 5 days 300 mg QD for 5 days 1.13 (0.96, 1.32) 1.06 (0.90, 1.26) NA rifabutin 150 mg QD, d 15–28 (n=7) 400 mg QD, d 1–28 (n=7) 1.34 (1.14, 1.59) 1.15 (0.98, 1.34) 1.13 (0.68, 1.87) 46 Reference ID: 5490094 Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 Cmax AUC Cmin rifampin 600 mg QD, d 17–26 (n=16) 300 mg QD with ritonavir 100 mg QD, d 7–16 (n=48), d 17–26 (n=16) 0.47 (0.41, 0.53) 0.28 (0.25, 0.32) 0.02 (0.02, 0.03) ritonavirn 100 mg QD, d 11–20 (n=28) 300 mg QD, d 1–20 (n=28) 1.86 (1.69, 2.05) 3.38 (3.13, 3.63) 11.89 (10.23, 13.82) tenofovir DFo 300 mg QD, d 9–16 (n=34) 400 mg QD, d 2–16 (n=34) 0.79 (0.73, 0.86) 0.75 (0.70, 0.81) 0.60 (0.52, 0.68) 300 mg QD, d 15–42 (n=10) 300 mg with ritonavir 100 mg QD, d 1–42 (n=10) 0.72p (0.50, 1.05) 0.75p (0.58, 0.97) 0.77p (0.54, 1.10) voriconazole (Participants with at least one functional CYP2C19 allele) 200 mg BID, d 2–3, 22–30; 400 mg BID, d 1, 21 (n=20) 300 mg with ritonavir 100 mg QD, d 11–30 (n=20) 0.87 (0.80, 0.96) 0.88 (0.82, 0.95) 0.80 (0.72, 0.90) voriconazole (Participants without a functional CYP2C19 allele) 50 mg BID, d 2–3, 22–30; 100 mg BID, d 1, 21 (n=8) 300 mg with ritonavir 100 mg QD, d 11–30 (n=8) 0.81 (0.66, 1.00) 0.80 (0.65, 0.97) 0.69 (0.54, 0.87) a Data provided are under fed conditions unless otherwise noted. b All drugs were given under fasted conditions. c REYATAZ 300 mg with ritonavir 100 mg once daily coadministered with famotidine 40 mg twice daily resulted in atazanavir geometric mean Cmax that was similar and AUC and Cmin values that were 1.79- and 4.46-fold higher relative to REYATAZ 400 mg once daily alone. d Similar results were noted when famotidine 20 mg BID was administered 2 hours after and 10 hours before atazanavir 300 mg with ritonavir 100 mg and tenofovir DF 300 mg. e Coadministration of atazanavir with ritonavir and tenofovir DF was administered after a light meal. f Study was conducted in participants with HIV-1. g Compared with atazanavir 400 mg historical data without nevirapine (n=13), the ratio of geometric means (90% confidence intervals) for Cmax, AUC, and Cmin were 1.42 (0.98, 2.05), 1.64 (1.11, 2.42), and 1.25 (0.66, 2.36), respectively, for atazanavir with ritonavir 300/100 mg; and 2.02 (1.42, 2.87), 2.28 (1.54, 3.38), and 1.80 (0.94, 3.45), respectively, for atazanavir with ritonavir 400/100 mg. h Parallel group design; n=23 for atazanavir with ritonavir and nevirapine, n=22 for atazanavir 300 mg/ritonavir 100 mg without nevirapine. Participants were treated with nevirapine prior to study entry. i Omeprazole 40 mg was administered on an empty stomach 2 hours before REYATAZ. 47 Reference ID: 5490094 j Omeprazole 20 mg was administered 30 minutes prior to a light meal in the morning and REYATAZ 300 mg with ritonavir 100 mg in the evening after a light meal, separated by 12 hours from omeprazole. k REYATAZ 300 mg with ritonavir 100 mg once daily separated by 12 hours from omeprazole 20 mg daily resulted in increases in atazanavir geometric mean AUC (10%) and Cmin (2.4-fold), with a decrease in Cmax (29%) relative to REYATAZ 400 mg once daily in the absence of omeprazole (study days 1–6). l Omeprazole 20 mg was given 30 minutes prior to a light meal in the morning and REYATAZ 400 mg with ritonavir 100 mg once daily after a light meal, 1 hour after omeprazole. Effects on atazanavir concentrations were similar when REYATAZ 400 mg with ritonavir 100 mg was separated from omeprazole 20 mg by 12 hours. m REYATAZ 400 mg with ritonavir 100 mg once daily administered with omeprazole 20 mg once daily resulted in increases in atazanavir geometric mean AUC (32%) and Cmin (3.3-fold), with a decrease in Cmax (26%) relative to REYATAZ 400 mg once daily in the absence of omeprazole (study days 1–6). n Compared with atazanavir 400 mg QD historical data, administration of atazanavir with ritonavir 300/100 mg QD increased the atazanavir geometric mean values of Cmax, AUC, and Cmin by 18%, 103%, and 671%, respectively. o Note that similar results were observed in studies where administration of tenofovir DF and REYATAZ was separated by 12 hours. p Ratio of atazanavir with ritonavir and tenofovir DF to atazanavir with ritonavir. Atazanavir 300 mg with ritonavir 100 mg results in higher atazanavir exposure than atazanavir 400 mg (see footnote o). The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir and tenofovir DF were: Cmax = 3190 ng/mL, AUC = 34459 ng•h/mL, and Cmin = 491 ng/mL. Study was conducted in participants with HIV-1. NA = not available. Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without REYATAZ; No Effect = 1.00 Cmax AUC Cmin acetaminophen 1 g BID, d 1–20 (n=10) 300 mg QD with ritonavir 100 mg QD, d 11–20 (n=10) 0.87 (0.77, 0.99) 0.97 (0.91, 1.03) 1.26 (1.08, 1.46) atenolol 50 mg QD, d 7–11 (n=19) and d 19–23 400 mg QD, d 1–11 (n=19) 1.34 (1.26, 1.42) 1.25 (1.16, 1.34) 1.02 (0.88, 1.19) clarithromycin 500 mg BID, d 7–10 (n=21) and d 18–21 400 mg QD, d 1–10 (n=21) 1.50 (1.32, 1.71) OH-clarithromycin: 0.28 (0.24, 0.33) 1.94 (1.75, 2.16) OH-clarithromycin: 0.30 (0.26, 0.34) 2.60 (2.35, 2.88) OH-clarithromycin: 0.38 (0.34, 0.42) ddI (enteric­ coated [EC] capsules)b 400 mg d 1 (fasted), d 8 (fed) (n=34) 400 mg QD, d 2–8 (n=34) 0.64 (0.55, 0.74) 0.66 (0.60, 0.74) 1.13 (0.91, 1.41) 400 mg d 1 (fasted), d 19 (fed) (n=31) 300 mg QD with ritonavir 100 mg QD, d 9–19 (n=31) 0.62 (0.52, 0.74) 0.66 (0.59, 0.73) 1.25 (0.92, 1.69) 48 Reference ID: 5490094 Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without REYATAZ; No Effect = 1.00 Cmax AUC Cmin diltiazem 180 mg QD, d 7–11 (n=28) and d 19–23 400 mg QD, d 1–11 (n=28) 1.98 (1.78, 2.19) desacetyl-diltiazem: 2.72 (2.44, 3.03) 2.25 (2.09, 2.16) desacetyl-diltiazem: 2.65 (2.45, 2.87) 2.42 (2.14, 2.73) desacetyl-diltiazem: 2.21 (2.02, 2.42) ethinyl estradiol Ortho-Novum 400 mg QD, ethinyl estradiol: 1.15 ethinyl estradiol: 1.48 ethinyl estradiol: 1.91 & norethindronec 7/7/7 QD, d 16–29 (0.99, 1.32) (1.31, 1.68) (1.57, 2.33) d 1–29 (n=19) norethindrone: 1.67 norethindrone: 2.10 norethindrone: 3.62 (n=19) (1.42, 1.96) (1.68, 2.62) (2.57, 5.09) ethinyl estradiol Ortho Tri-Cyclen 300 mg QD with ethinyl estradiol: ethinyl estradiol: ethinyl estradiol: & norgestimated QD, d 1–28 (n=18), then Ortho Tri- Cyclen® LO QD, d 29–42e (n=14) ritonavir 100 mg QD, d 29–42 (n=14) 0.84 (0.74, 0.95) 17-deacetyl norgestimate:f 1.68 (1.51, 1.88) 0.81 (0.75, 0.87) 17-deacetyl norgestimate:f 1.85 (1.67, 2.05) 0.63 (0.55, 0.71) 17-deacetyl norgestimate:f 2.02 (1.77, 2.31) glecaprevir/ pibrentasvir 300 mg glecaprevir (n=12) 300 mg QD with ritonavir 100 mg QD (n=12) ≥4.06g (3.15, 5.23) ≥6.53g (5.24, 8.14) ≥14.3g (9.85, 20.7) 120 mg pibrentasvir (n=12) 300 mg QD with ritonavir 100 mg QD (n=12) ≥1.29g (1.15, 1.45) ≥1.64g (1.48, 1.82) ≥2.29g (1.95, 2.68) grazoprevir/ elbasvir grazoprevir 200 mg QD d 1– 35 (n=12) 300 mg QD with ritonavir 100 mg QD d 1–35 (n=12) 6.24 (4.42, 8.81) 10.58 (7.78, 14.39) 11.64 (7.96, 17.02) elbasvir 50 mg QD d 1–35 (n=10) 300 mg QD with ritonavir 100 mg QD d 1–35 (n=10) 4.15 (3.46, 4.97) 4.76 (4.07, 5.56) 6.45 (5.51, 7.54) methadone Stable maintenance dose, d 1–15 (n=16) 400 mg QD, d 2–15 (n=16) (R)-methadoneh 0.91 (0.84, 1.0) total: 0.85 (0.78, 0.93) (R)-methadoneh 1.03 (0.95, 1.10) total: 0.94 (0.87, 1.02) (R)-methadoneh 1.11 (1.02, 1.20) total: 1.02 (0.93, 1.12) nevirapinei,j 200 mg BID, 300 mg QD with 1.17 1.25 1.32 d 1–23 ritonavir 100 mg (1.09, 1.25) (1.17, 1.34) (1.22, 1.43) (n=23) QD, d 4–13, then 1.21 1.26 1.35 400 mg QD with (1.11, 1.32) (1.17, 1.36) (1.25, 1.47) ritonavir 100 mg QD, d 14–23 (n=23) 49 Reference ID: 5490094 Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without REYATAZ; No Effect = 1.00 Cmax AUC Cmin omeprazolek 40 mg single dose, d 7 and d 20 (n=16) 400 mg QD, d 1–12 (n=16) 1.24 (1.04, 1.47) 1.45 (1.20, 1.76) NA rifabutin 300 mg QD, d 1–10 then 150 mg QD, d 11–20 (n=3) 600 mg QD,l d 11–20 (n=3) 1.18 (0.94, 1.48) 25-O-desacetyl­ rifabutin: 8.20 (5.90, 11.40) 2.10 (1.57, 2.79) 25-O-desacetyl­ rifabutin: 22.01 (15.97, 30.34) 3.43 (1.98, 5.96) 25-O-desacetyl­ rifabutin: 75.6 (30.1, 190.0) 150 mg twice weekly, d 1–15 (n=7) 300 mg QD with ritonavir 100 mg QD, d 1–17 (n=7) 2.49m (2.03, 3.06) 25-O-desacetyl­ rifabutin: 7.77 (6.13, 9.83) 1.48m (1.19, 1.84) 25-O-desacetyl­ rifabutin: 10.90 (8.14, 14.61) 1.40m (1.05, 1.87) 25-O-desacetyl­ rifabutin: 11.45 (8.15, 16.10) pitavastatin 4 mg QD for 5 days 300 mg QD for 5 days 1.60 (1.39, 1.85) 1.31 (1.23, 1.39) NA rosiglitazonen 4 mg single dose, d 1, 7, 17 (n=14) 400 mg QD, d 2–7, then 300 mg QD with ritonavir 100 mg QD, d 8–17 (n=14) 1.08 (1.03, 1.13) 0.97 (0.91, 1.04) 1.35 (1.26, 1.44) 0.83 (0.77, 0.89) NA NA rosuvastatin 10 mg single dose 300 mg QD with ritonavir 100 mg QD for 7 days ↑ 7-foldo ↑ 3-foldo NA saquinavirp (soft gelatin capsules) 1200 mg QD, d 1–13 (n=7) 400 mg QD, d 7–13 (n=7) 4.39 (3.24, 5.95) 5.49 (4.04, 7.47) 6.86 (5.29, 8.91) sofosbuvir/ velpatasvir/ voxilaprevir 400 mg sofosbuvir single dose (n=15) 300 mg with100 mg ritonavir single dose (n=15) 1.29 (1.09, 1.52) sofosbuvir metabolite GS-331007 1.05 (0.99, 1.12) 1.40 (1.25, 1.57) sofosbuvir metabolite GS-331007 1.25 (1.16, 1.36) NA 100 mg velpatasvir single dose (n=15) 300 mg with 100 mg ritonavir single dose (n=15) 1.29 (1.07, 1.56) 1.93 (1.58, 2.36) NA 100 mg voxilaprevir single dose (n=15) 300 mg with 100 mg ritonavir single dose (n=15) 4.42 (3.65, 5.35) 4.31 (3.76, 4.93) NA tenofovir DFq 300 mg QD, d 9–16 (n=33) and d 24–30 (n=33) 400 mg QD, d 2–16 (n=33) 1.14 (1.08, 1.20) 1.24 (1.21, 1.28) 1.22 (1.15, 1.30) 50 Reference ID: 5490094 Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without REYATAZ; No Effect = 1.00 Cmax AUC Cmin 300 mg QD, d 1–7 (pm) (n=14) d 25–34 (pm) (n=12) 300 mg QD with ritonavir 100 mg QD, d 25–34 (am) (n=12)r 1.34 (1.20, 1.51) 1.37 (1.30, 1.45) 1.29 (1.21, 1.36) voriconazole (Participants with at least one functional CYP2C19 allele) 200 mg BID, d 2–3, 22–30; 400 mg BID, d 1, 21 (n=20) 300 mg with ritonavir 100 mg QD, d 11–30 (n=20) 0.90 (0.78, 1.04) 0.67 (0.58, 0.78) 0.61 (0.51, 0.72) voriconazole (Participants without a functional CYP2C19 allele) 50 mg BID, d 2–3, 22–30; 100 mg BID, d 1, 21 (n=8) 300 mg with ritonavir 100 mg QD, d 11–30 (n=8) 4.38 (3.55, 5.39) 5.61 (4.51, 6.99) 7.65 (5.71, 10.2) lamivudine and zidovudine 150 mg lamivudine and 300 mg zidovudine BID, d 1–12 (n=19) 400 mg QD, d 7–12 (n=19) lamivudine: 1.04 (0.92, 1.16) zidovudine: 1.05 (0.88, 1.24) zidovudine glucuronide: 0.95 (0.88, 1.02) lamivudine: 1.03 (0.98, 1.08) zidovudine: 1.05 (0.96, 1.14) zidovudine glucuronide: 1.00 (0.97, 1.03) lamivudine: 1.12 (1.04, 1.21) zidovudine: 0.69 (0.57, 0.84) zidovudine glucuronide: 0.82 (0.62, 1.08) a Data provided are under fed conditions unless otherwise noted. b 400 mg ddI EC and REYATAZ were administered together with food on Days 8 and 19. c d Upon further dose normalization of ethinyl estradiol 25 mcg with atazanavir relative to ethinyl estradiol 35 mcg without atazanavir, the ratio of geometric means (90% confidence intervals) for Cmax, AUC, and Cmin were 0.82 (0.73, 0.92), 1.06 (0.95, 1.17), and 1.35 (1.11, 1.63), respectively. Upon further dose normalization of ethinyl estradiol 35 mcg with atazanavir with ritonavir relative to ethinyl estradiol 25 mcg without atazanavir with ritonavir, the ratio of geometric means (90% confidence intervals) for Cmax, AUC, and Cmin were 1.17 (1.03, 1.34), 1.13 (1.05, 1.22), and 0.88 (0.77, 1.00), respectively. e f All participants were on a 28-day lead-in period; one full cycle of Ortho Tri-Cyclen® . Ortho Tri-Cyclen® contains 35 mcg of ethinyl estradiol. Ortho Tri-Cyclen® LO contains 25 mcg of ethinyl estradiol. Results were dose normalized to an ethinyl estradiol dose of 35 mcg. 17-deacetyl norgestimate is the active component of norgestimate. g Effect of atazanavir with ritonavir on the first dose of glecaprevir and pibrentasvir is reported. h (R)-methadone is the active isomer of methadone. i Study was conducted in participants with HIV-1. 51 Reference ID: 5490094 j Participants were treated with nevirapine prior to study entry. k Omeprazole was used as a metabolic probe for CYP2C19. Omeprazole was given 2 hours after REYATAZ on Day 7; and was given alone 2 hours after a light meal on Day 20. l Not the recommended therapeutic dose of atazanavir. m When compared to rifabutin 150 mg QD alone d1–10 (n=14). Total of rifabutin and 25-O-desacetyl-rifabutin: AUC 2.19 (1.78, 2.69). n Rosiglitazone used as a probe substrate for CYP2C8. o Mean ratio (with/without coadministered drug). ↑ indicates an increase in rosuvastatin exposure. p The combination of atazanavir and saquinavir 1200 mg QD produced daily saquinavir exposures similar to the values produced by the standard therapeutic dosing of saquinavir at 1200 mg TID. However, the Cmax is about 79% higher than that for the standard dosing of saquinavir (soft gelatin capsules) alone at 1200 mg TID. q Note that similar results were observed in a study where administration of tenofovir DF and REYATAZ was separated by 12 hours. r Administration of tenofovir DF and REYATAZ was temporally separated by 12 hours. NA = not available. 12.4 Microbiology Mechanism of Action Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1-infected cells, thus preventing formation of mature virions. Antiviral Activity in Cell Culture Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC50 values above the EC50 values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity. Resistance In Cell Culture: HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed 52 Reference ID: 5490094 at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant. Clinical Studies of Treatment-Naive Participants: Comparison of Ritonavir-Boosted REYATAZ vs Unboosted REYATAZ: Study AI424-089 compared REYATAZ 300 mg once daily with ritonavir 100 mg vs REYATAZ 400 mg once daily when administered with lamivudine and extended- release stavudine in treatment-naive participants with HIV-1. A summary of the number of virologic failures and virologic failure isolates with atazanavir resistance in each arm is shown in Table 23. Table 23: Summary of Virologic Failuresa at Week 96 in Study AI424-089: Comparison of Ritonavir Boosted REYATAZ vs Unboosted REYATAZ: Randomized Participants REYATAZ 300 mg REYATAZ 400 mg with ritonavir 100 mg (n=95) (n=105) Virologic Failure (≥50 copies/mL) at Week 96 15 (16%) 34 (32%) Virologic Failure with Genotypes and Phenotypes Data 5 17 Virologic Failure Isolates with atazanavir ­ resistance at Week 96 0/5 (0%)b 4/17 (24%)b Virologic Failure Isolates with I50L Emergence at Week 96c 0/5 (0%)b 2/17 (12%)b Virologic Failure Isolates with Lamivudine Resistance at Week 96 2/5 (40%)b 11/17 (65%)b a Virologic failure includes participants who were never suppressed through Week 96 and on study at Week 96, had virologic rebound or discontinued due to insufficient viral load response. b Percentage of Virologic Failure Isolates with genotypic and phenotypic data. c Mixture of I50I/L emerged in 2 other atazanavir 400 mg-treated participants. Neither isolate was phenotypically resistant to atazanavir. Clinical Studies of Treatment-Naive Participants Receiving REYATAZ 300 mg with Ritonavir 100 mg: In Phase 3 Study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from participants who experienced virologic failure (HIV-1 RNA ≥400 copies/mL) or discontinued before achieving suppression on atazanavir with ritonavir (n=39; 9%) and lopinavir/ritonavir (n=39; 9%) through 96 weeks of treatment. In the atazanavir with ritonavir arm, one of the virologic failure isolates had a 56-fold decrease in atazanavir susceptibility emerge on therapy with the development of PI resistance-associated substitutions 53 Reference ID: 5490094 L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M. The NRTI resistance-associated substitution M184V also emerged on treatment in this isolate conferring emtricitabine resistance. Two atazanavir with ritonavir-virologic failure isolates had baseline phenotypic atazanavir resistance and IAS-defined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with a 17-fold decrease in atazanavir susceptibility from baseline and the other failure isolate with baseline atazanavir resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on atazanavir treatment associated with a 3-fold decrease in atazanavir susceptibility from baseline. Five of the treatment failure isolates in the atazanavir with ritonavir arm developed phenotypic emtricitabine resistance with the emergence of either the M184I (n=1) or the M184V (n=4) substitution on therapy and none developed phenotypic tenofovir disoproxil resistance. In the lopinavir/ritonavir arm, one of the virologic failure participant isolates had a 69-fold decrease in lopinavir susceptibility emerge on therapy with the development of PI substitutions L10V, V11I, I54V, G73S, and V82A in addition to baseline PI substitutions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six lopinavir/ritonavir virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance. Clinical Studies of Treatment-Naive Participants Receiving REYATAZ 400 mg without Ritonavir: atazanavir-resistant clinical isolates from treatment-naive participants who experienced virologic failure on REYATAZ 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of atazanavir therapy), often in combination with an A71V substitution, but also developed one or more other PI substitutions (eg, V32I, L33F, G73S, V82A, I85V, or N88S) with or without the I50L substitution. In treatment-naive participants, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to atazanavir but retained in cell culture susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L substitution on the efficacy of subsequently administered PIs. Clinical Studies of Treatment-Experienced Participants: In studies of treatment-experienced participants treated with atazanavir or atazanavir with ritonavir, most atazanavir-resistant isolates from participants who experienced virologic failure developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions to develop in the viral isolates of participants who failed treatment with atazanavir 300 mg once daily and ritonavir 100 mg once daily (together with tenofovir DF and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T. Other substitutions that developed on atazanavir with ritonavir treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of participant isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the participant at baseline, atazanavir resistance developed through substitutions associated with resistance to other PIs and could include the development of the I50L substitution. The I50L substitution has been detected in treatment-experienced participants experiencing 54 Reference ID: 5490094 virologic failure after long-term treatment. Protease cleavage site changes also emerged on atazanavir treatment, but their presence did not correlate with the level of atazanavir resistance. Clinical Studies of Pediatric Participants in AI424-397 (PRINCE I) and AI424-451 (PRINCE II): Treatment-emergent atazanavir with ritonavir resistance-associated amino acid substitution M36I in the protease was detected in the virus of one participant among treatment failures in AI424-397. In addition, three known resistance-associated substitutions for other PIs arose in the viruses from one participant each (L19I/R, H69K/R, and I72I/V). Reduced susceptibility to atazanavir, ritonavir, or atazanavir with ritonavir was not seen with these viruses. In AI424-451, atazanavir with ritonavir resistance-associated substitutions G16E, V82A/I/T, I84V, and/or L90M arose in the viruses of two participants. The virus population harboring the M46M/V, V82V/I, I84I/V, and L90L/M substitutions acquired phenotypic resistance to ritonavir (ritonavir phenotypic fold- change of 3.5, with a ritonavir cutoff of 2.5-fold change). However, these substitutions did not result in phenotypic resistance to atazanavir (atazanavir phenotypic fold-change of <1.8, with an atazanavir cutoff of 2.2-fold change). Secondary PI resistance-associated amino acid substitutions also arose in the viruses of one participant each, including V11V/I, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61E/G emerged in the viruses of two participants who failed treatment with atazanavir with ritonavir. Viruses from nine participants in the two studies developed NRTI resistance-associated substitutions: K65K/R (n=1), M184V (n=7), and T215I (n=1). Cross-Resistance Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from atazanavir clinical trials of PI-experienced participants showed that isolates cross-resistant to multiple PIs were cross-resistant to atazanavir. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to atazanavir. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to atazanavir, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to atazanavir. Isolates resistant to atazanavir were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced participants, PI-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other PIs. Baseline Genotype/Phenotype and Virologic Outcome Analyses Genotypic and/or phenotypic analysis of baseline virus may aid in determining atazanavir susceptibility before initiation of atazanavir with ritonavir therapy. An association between virologic response at 48 weeks and the number and type of primary PI resistance-associated substitutions detected in baseline HIV-1 isolates from antiretroviral-experienced participants receiving atazanavir with ritonavir once daily or lopinavir / ritonavir (fixed-dose product) twice daily in Study AI424-045 is shown in Table 24. Overall, both the number and type of baseline PI substitutions affected response rates in treatment- experienced participants. In the atazanavir with ritonavir group, participants had lower response 55 Reference ID: 5490094 rates when 3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were present compared to participants with 1–2 PI substitutions, including one of these substitutions. Table 24: HIV-1 RNA Response by Number and Type of Baseline PI Substitution, Antiretroviral-Experienced Participants in Study AI424-045, As-Treated Analysis Virologic Response = HIV RNA <400 copies/mLb Number and Type of Baseline PI atazanavir with ritonavir lopinavir/ritonavirc Substitutionsa (n=110) (n=113) 3 or more primary PI substitutions includingd: D30N 75% (6/8) 50% (3/6) M36I/V 19% (3/16) 33% (6/18) M46I/L/T 24% (4/17) 23% (5/22) I54V/L/T/M/A 31% (5/16) 31% (5/16) A71V/T/I/G 34% (10/29) 39% (12/31) G73S/A/C/T 14% (1/7) 38% (3/8) V77I 47% (7/15) 44% (7/16) V82A/F/T/S/I 29% (6/21) 27% (7/26) I84V/A 11% (1/9) 33% (2/6) N88D 63% (5/8) 67% (4/6) L90M 10% (2/21) 44% (11/25) Number of baseline primary PI substitutionsa All patients, as-treated 58% (64/110) 59% (67/113) 0–2 PI substitutions 75% (50/67) 75% (50/67) 3–4 PI substitutions 41% (14/34) 43% (12/28) 5 or more PI substitutions 0% (0/9) 28% (5/18) a Primary substitutions include any change at D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90. b Results should be interpreted with caution because the subgroups were small. c Administered as a fixed-dose product. d There were insufficient data (n<3) for PI substitutions V32I, I47V, G48V, I50V, and F53L. The response rates of antiretroviral-experienced participants in Study AI424-045 were analyzed by baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The analyses are based on a select population with 62% of participants receiving an NNRTI-based 56 Reference ID: 5490094 regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for REYATAZ. Table 25: Baseline Phenotype by Outcome, Antiretroviral-Experienced Participants in Study AI424-045, As-Treated Analysis Baseline Phenotypea Virologic Response = HIV-1 RNA <400 copies/mLb atazanavir with ritonavir (n=111) lopinavir/ritonavirc (n=111) 0–2 71% (55/78) 70% (56/80) >2–5 53% (8/15) 44% (4/9) >5–10 13% (1/8) 33% (3/9) >10 10% (1/10) 23% (3/13) a Fold change susceptibility in cell culture relative to the wild-type reference. b Results should be interpreted with caution because the subgroups were small. c Administered as a fixed-dose product. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose. Mutagenesis Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay). Impairment of Fertility At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir boosted with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed. 57 Reference ID: 5490094 14 CLINICAL STUDIES 14.1 Adult Participants without Prior Antiretroviral Therapy Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of either REYATAZ or lopinavir/ritonavir, each in combination with fixed-dose tenofovir DF-emtricitabine in treatment-naive participants with HIV-1 infection. Study AI424-138 (NCT00272779) was a 96­ week, open-label, randomized, multicenter study, comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with the fixed-dose product, tenofovir DF/emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive participants. Participants had a mean age of 36 years (range: 19-72), 49% were Caucasian, 18% Black, 9% Asian, 23% Hispanic/Mestizo/mixed race, and 68% were male. The median baseline plasma CD4+ cell count was 204 cells/mm3 (range: 2 to 810 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.94 log10 copies/mL (range: 2.60 to 5.88 log10 copies/mL). Treatment response and outcomes through Week 96 are presented in Table 26. Table 26: Outcomes of Treatment Through Week 96 in Treatment-Naive Adults (Study AI424-138) REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine (once daily)a (n=441) lopinavir/ritonavirb 400 mg/100 mg (twice daily) with tenofovir DF/emtricitabine (once daily)a (n=437) Outcome 96 Weeks 96 Weeks Responderc,d,e 75% 68% Virologic failuref 17% 19% Rebound 8% 10% Never suppressed through Week 96 9% 9% Death 1% 1% Discontinued due to adverse event 3% 5% Discontinued for other reasonsg 4% 7% a As a fixed-dose product: 300 mg tenofovir DF/200 mg emtricitabine once daily. b As a fixed-dose product: 400 mg lopinavir/100 mg ritonavir (twice daily). c Participants achieved HIV-1 RNA <50 copies/mL at Week 96. Roche Amplicor, v1.5 ultra-sensitive assay. d Pre-specified ITT analysis at Week 48 using as-randomized cohort: atazanavir with ritonavir 78% and lopinavir/ritonavir 76% (difference estimate: 1.7% [95% confidence interval: −3.8%, 7.1%]). e Pre-specified ITT analysis at Week 96 using as-randomized cohort: atazanavir with ritonavir 74% and lopinavir/ritonavir 68% (difference estimate: 6.1% [95% confidence interval: 0.3%, 12.0%]). 58 Reference ID: 5490094 f Includes viral rebound and failure to achieve confirmed HIV-1 RNA <50 copies/mL through Week 96. g Includes lost to follow-up, participant’s withdrawal, noncompliance, protocol violation, and other reasons. Through 96 weeks of therapy, the proportion of responders among participants with high viral loads (ie, baseline HIV-1 RNA ≥100,000 copies/mL) was comparable for the REYATAZ with ritonavir (165 of 223 participants, 74%) and lopinavir/ritonavir (148 of 222 participants, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm3 for the REYATAZ with ritonavir arm and 273 cells/mm3 for the lopinavir/ritonavir arm. Study AI424-034: REYATAZ once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine/zidovudine twice daily. Study AI424-034 (NCT00013897) was a randomized, double-blind, multicenter trial comparing REYATAZ (400 mg once daily) to efavirenz (600 mg once daily), each in combination with the fixed-dose product of lamivudine /zidovudine (150 mg/300 mg) given twice daily, in 810 antiretroviral treatment-naive participants. Participants had a mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian, and 65% were male. The mean baseline CD4+ cell count was 321 cells/mm3 (range: 64 to 1424 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.8 log10 copies/mL (range: 2.2 to 5.9 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 27. Table 27: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-034) REYATAZ efavirenz 400 mg once daily 600 mg once daily and lamivudine/ and lamivudine/ zidovudined zidovudined Outcome (n=405) (n=405) Respondera 67% (32%) 62% (37%) Virologic failureb 20% 21% Rebound 17% 16% Never suppressed through Week 48 3% 5% Death – <1% Discontinued due to adverse event 5% 7% Discontinued for other reasonsc 8% 10% a Participants achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor HIV-1 Monitor Assay, test version 1.0 or 1.5 as geographically appropriate. b Includes viral rebound and failure to achieve confirmed HIV-1 RNA <400 copies/mL through Week 48. c Includes lost to follow-up, participant’s withdrawal, noncompliance, protocol violation, and other reasons. d As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. 59 Reference ID: 5490094 Through 48 weeks of therapy, the proportion of responders among participants with high viral loads (ie, baseline HIV-1 RNA ≥100,000 copies/mL) was comparable for the REYATAZ and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm3 for the REYATAZ arm and 160 cells/mm3 for the efavirenz arm. Study AI424-008: REYATAZ 400 mg once daily compared to REYATAZ 600 mg once daily, and compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine twice daily. Study AI424-008 (NCT identifier not available) was a 48-week, randomized, multicenter trial, blinded to dose of REYATAZ, comparing REYATAZ at two dose levels (400 mg and 600 mg once daily) to nelfinavir (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive participants. Participants had a mean age of 35 years (range: 18 to 69), 55% were Caucasian, and 63% were male. The mean baseline CD4+ cell count was 295 cells/mm3 (range: 4 to 1003 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.7 log10 copies/mL (range: 1.8 to 5.9 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 28. Table 28: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-008) REYATAZ nelfinavir 400 mg once daily with lamivudine and stavudine 1250 mg twice daily with lamivudine and stavudine Outcome (n=181) (n=91) Respondera 67% (33%) 59% (38%) Virologic failureb 24% 27% Rebound 14% 14% Never suppressed through Week 48 10% 13% Death <1% – Discontinued due to adverse event 1% 3% Discontinued for other reasonsc 7% 10% a Participants achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor HIV-1 Monitor Assay, test version 1.0 or 1.5 as geographically appropriate. b Includes viral rebound and failure to achieve confirmed HIV-1 RNA <400 copies/mL through Week 48. c Includes lost to follow-up, participant’s withdrawal, noncompliance, protocol violation, and other reasons. Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm3 for the REYATAZ 400-mg arm and 211 cells/mm3 for the nelfinavir arm. 60 Reference ID: 5490094 14.2 Adult Participants with Prior Antiretroviral Therapy Study AI424-045: REYATAZ once daily with ritonavir once daily compared to REYATAZ once daily and saquinavir (soft gelatin capsules) once daily, and compared to lopinavir/ritonavir twice daily, each in combination with tenofovir DF and one NRTI. Study AI424-045 (NCT00035932): was a randomized, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatin capsules (1200 mg once daily), and to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with tenofovir DF and one NRTI, in 347 (of 358 randomized) participants who experienced virologic failure on highly active antiretroviral therapy regimens containing PIs, NNRTIs, and NRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 85 weeks for NNRTIs, and 283 weeks for NRTIs. The mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male. The mean baseline CD4+ cell count was 338 cells/mm3 (range: 14 to 1543 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/mL (range: 2.6 to 5.88 log10 copies/mL). Treatment outcomes through Week 48 for the REYATAZ with ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. REYATAZ with ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV-1 RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that REYATAZ with ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV-1 RNA lower limit of quantification [see Microbiology, Tables 24 and 25 (12.4)]. 61 Reference ID: 5490094 Table 29: Outcomes of Treatment Through Week 48 in Study AI424-045 (Participants with Prior Antiretroviral Experience) REYATAZ 300 mg with ritonavir 100 mg lopinavir/ritonavir Differencea once daily and (400/100 mg) twice (REYATAZ­ tenofovir DF and daily and tenofovir DF 1 NRTI and 1 NRTI lopinavir/ritonavir)b Outcome (n=119) (n=118) (CI) HIV-1 RNA Change from −1.58 −1.70 +0.12c Baseline (log10 copies/mL)c (−0.17, 0.41) CD4+ Change from Baseline 116 123 −7 (cells/mm3)e (−67, 52) Percent of Participants Respondinge 55% 57% −2.2% HIV-1 RNA <400 copies/mLc (−14.8%, 10.5%) 38% 45% HIV-1 RNA <50 copies/mLc −7.1% (−19.6%, 5.4%) a Time-averaged difference through Week 48 for HIV-1 RNA; Week 48 difference in HIV-1 RNA percentages and CD4+ mean changes, REYATAZ with ritonavir vs lopinavir/ritonavir; CI = 97.5% confidence interval for change in HIV-1 RNA; 95% confidence interval otherwise. b Administered as a fixed-dose product. c Roche Amplicor HIV-1 Monitor Assay, test version 1.5. d Protocol-defined primary efficacy outcome measure. e Based on participants with baseline and Week 48 CD4+ cell count measurements (REYATAZ with ritonavir, n=85; lopinavir/ritonavir, n=93). f Participants achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48. No participants in the REYATAZ with ritonavir treatment arm and three participants in the lopinavir/ritonavir treatment arm experienced a new-onset CDC Category C event during the study. In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for REYATAZ 400 mg with saquinavir (n=115) was −1.55 log10 copies/mL, and the time-averaged difference in change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33. The corresponding mean increase in CD4+ cell count was 72 cells/mm3. Through 48 weeks of treatment, the proportion of participants in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%). In this study, coadministration of REYATAZ and saquinavir did not provide adequate efficacy [see Drug Interactions (7)]. 62 Reference ID: 5490094 Study AI424-045 also compared changes from baseline in lipid values. [See Adverse Reactions (6.1).] Study AI424-043 (NCT00028301): Study AI424-043 was a randomized, open-label, multicenter trial comparing REYATAZ (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with two NRTIs, in 300 participants who experienced virologic failure to only one prior PI-containing regimen. Through 48 weeks, the proportion of participants with plasma HIV-1 RNA <400 (<50) copies/mL was 49% (35%) for participants randomized to REYATAZ (n=144) and 69% (53%) for participants randomized to lopinavir/ritonavir (n=146). The mean change from baseline was −1.59 log10 copies/mL in the REYATAZ treatment arm and −2.02 log10 copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, REYATAZ without ritonavir was inferior to lopinavir/ritonavir in PI- experienced participants with prior virologic failure and is not recommended for such patients. 14.3 Pediatric Participants Pediatric Trials with REYATAZ Capsules Study AI424-040; PACTG 1020A (NCT00006604): Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ capsules was based on data from this open-label, multicenter clinical trial which included participants from 6 years to 21 years of age. In this study, 105 participants (43 antiretroviral-naive and 62 antiretroviral-experienced) received once daily REYATAZ capsule formulation, with or without ritonavir, in combination with two NRTIs. One-hundred five (105) participants (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated. Using an intent-to-treat (ITT) analysis, the overall proportions of antiretroviral-naive and -experienced participants with HIV-1 RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced participants with HIV-1 RNA <50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm3 in antiretroviral-naive participants and 220 cells/mm3 in antiretroviral-experienced participants. Pediatric Trials with REYATAZ Oral Powder Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ oral powder was based on data from two open-label, multicenter clinical trials. • AI424-397 (PRINCE I; NCT01099579): In pediatric participants from 3 months to less than 6 years of age • AI424-451 (PRINCE II; NCT01335698): In pediatric participants from 3 months to less than 11 years of age In these studies, 155 participants (59 antiretroviral-naive and 96 antiretroviral-experienced) received once daily REYATAZ oral powder with ritonavir, in combination with two NRTIs. For inclusion in both trials, treatment-naive participants had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced participants had to have documented 63 Reference ID: 5490094 genotypic and phenotypic sensitivity at screening to REYATAZ and at least 2 NRTIs. Participants exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Participants who received REYATAZ or REYATAZ with ritonavir at any time prior to study enrollment or who had a history of treatment failure on two or more protease inhibitors were excluded from the trials. One hundred thirty-four (134) participants from both studies weighing 5 kg to less than 35 kg treated with REYATAZ oral powder with ritonavir were evaluated. Participants 5 kg to less than 10 kg received either 150 mg or 200 mg REYATAZ and 80 mg ritonavir oral solution; participants 10 kg to less than 15 kg received 200 mg REYATAZ and 80 mg ritonavir oral solution; participants 15 kg to less than 25 kg received 250 mg REYATAZ and 80 mg ritonavir oral solution; and participants 25 kg to less than 35 kg received 300 mg REYATAZ and 100 mg ritonavir. Using a modified ITT analysis, the overall proportions of antiretroviral-naive and antiretroviral­ experienced participants with HIV-1 RNA <400 copies/mL at Week 48 were 79% (41/52) and 62% (51/82), respectively in participants who received REYATAZ oral powder with ritonavir. The overall proportions of antiretroviral-naive and antiretroviral-experienced participants with HIV-1 RNA <50 copies/mL at Week 48 were 54% (28/52) and 50% (41/82), respectively, in participants who received REYATAZ oral powder with ritonavir. The median increase from baseline in absolute CD4 count (percent) at 48 weeks of therapy (last observation carried forward) was 215 cells/mm3 (6%) in antiretroviral-naive participants and 133 cells/mm3 (4%) in antiretroviral-experienced participants who received REYATAZ oral powder with ritonavir. 16 HOW SUPPLIED/STORAGE AND HANDLING REYATAZ Capsules REYATAZ (atazanavir) capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures. Product Strength* Capsule Shell Color (cap/body) Markings on Capsule (ink color) Capsules per Bottle NDC Number cap body 200 mg blue/blue BMS 200 mg (white) 3631 (white) 60 0003-3631-12 300 mg red/blue BMS 300 mg (white) 3622 (white) 30 0003-3622-12 * 200 mg atazanavir equivalent to 227.8 mg atazanavir sulfate. 300 mg atazanavir equivalent to 341.69 mg atazanavir sulfate. Keep capsules in a tightly closed container. Store REYATAZ capsules at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 64 Reference ID: 5490094 REYATAZ Oral Powder REYATAZ oral powder is an orange-vanilla flavored powder, packed in child-resistant packets. Each packet contains 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 g of powder. REYATAZ oral powder is supplied in cartons (NDC 0003-3638-10) of 30 packets each. [See Dosage and Administration (2.5)]. Store REYATAZ oral powder at a temperature of 68°F to 86°F (20°C to 30°C). Store REYATAZ oral powder in the original packet. Do not open until ready to use. After REYATAZ oral powder is mixed with food or liquid, it may be kept at a temperature 68°F to 86°F (20°C to 30°C) for up to 1 hour. Take REYATAZ oral powder within 1 hour after mixing with food or liquid. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). REYATAZ is not a cure for HIV-1 infection. Advise patients to remain under the care of a healthcare provider while using REYATAZ. Cardiac Conduction Abnormalities Inform patients that atazanavir may produce changes in the electrocardiogram (eg, PR prolongation). Tell patients to consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness [see Warnings and Precautions (5.1)]. Severe Skin Reaction Inform patients that there have been reports of severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with REYATAZ use. Advise patients that if signs or symptoms of severe skin reactions or hypersensitivity reactions develop, they must discontinue REYATAZ and seek medical evaluation immediately [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Hyperbilirubinemia Inform patients that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns [see Warnings and Precautions (5.8)]. Patients with Phenylketonuria Advise caregivers of patients with phenylketonuria that REYATAZ oral powder contains phenylalanine [see Warnings and Precautions (5.3)]. Chronic Kidney Disease Inform patients that treatment with REYATAZ may lead to the development of chronic kidney disease, and to maintain adequate hydration while taking REYATAZ [see Warnings and Precautions (5.5)]. 65 Reference ID: 5490094 Nephrolithiasis and Cholelithiasis Inform patients that kidney stones and/or gallstones have been reported with REYATAZ use. Some patients with kidney stones and/or gallstones required hospitalization for additional management, and some had complications. Discontinuation of REYATAZ may be necessary as part of the medical management of these adverse events [see Warnings and Precautions (5.6)]. Drug Interactions REYATAZ may lead to significant interaction with some drugs; therefore, advise patients to report the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort, to their healthcare provider prior to use [see Contraindications (4), Warnings and Precautions (5.7)]. Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV-1, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV-1 treatment is started [see Warnings and Precautions (5.10)]. Fat Redistribution Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.11)]. Dosing Instructions Advise patients to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always be used in combination with other antiretroviral drugs. Advise patients that they should not alter the dose or discontinue therapy without consulting with their healthcare provider. Tell patients if a dose of REYATAZ is missed, they should take the dose as soon as possible and then return to their normal schedule; however, if a dose is skipped the patient should not double the next dose. Pregnancy Inform pregnant patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in pregnant patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry [see Use in Specific Populations (8.1)]. Lactation Instruct patients with HIV-1 that the potential risks of breastfeeding include: (1) HIV-1 transmission to infants without HIV-1, (2) developing viral resistance in infants with HIV-1, and (3) adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)]. 66 Reference ID: 5490094 PATIENT INFORMATION REYATAZ® (RAY-ah-taz) REYATAZ® (RAY-ah-taz) (atazanavir) (atazanavir) capsules oral powder Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with REYATAZ. For more information, see “Do not take REYATAZ if you” and “Before taking REYATAZ”. What is REYATAZ? REYATAZ is a prescription medicine that is used to treat human immunodeficiency virus-1 (HIV-1) infection, in combination with other HIV-1 medicines in adults and children 3 months of age and older and who weigh at least 11 pounds (5 kg). HIV-1 is the virus that causes AIDS (Acquired Immunodeficiency Syndrome). REYATAZ should not be used in children younger than 3 months of age. Do not take REYATAZ if you: • are allergic to atazanavir or any of the ingredients in REYATAZ. See the end of this leaflet for a complete list of ingredients in REYATAZ. • are taking any of the following medicines. Taking REYATAZ with these medicines may affect how REYATAZ works. REYATAZ may cause serious or life-threatening side effects, or death when used with these medicines: o alfuzosin o lurasidone (when REYATAZ is used with o amiodarone (when REYATAZ is used with ritonavir) ritonavir) o lomitapide o apalutamide o lovastatin o carbamazepine o midazolam, when taken by mouth for sedation o cisapride o nevirapine o elbasvir and grazoprevir o phenobarbital o encorafenib o phenytoin o ergot medicines including: o pimozide • dihydroergotamine o quinidine (when REYATAZ is used with ritonavir) • ergonovine o rifampin • ergonovine ergotamine o sildenafil, when used for the treatment of • methylergonovine pulmonary arterial hypertension o glecaprevir and pibrentasvir o simvastatin o indinavir o St. John’s wort o irinotecan o triazolam o ivosidenib Before taking REYATAZ, tell your healthcare provider about all of your medical conditions, including if you: • have heart problems • have liver problems, including hepatitis B or C virus • have phenylketonuria (PKU). The artificial sweetener aspartame in REYATAZ oral powder contains phenylalanine, which can be harmful to people with PKU. • have kidney problems • are receiving dialysis treatment • have diabetes • have hemophilia • are pregnant or plan to become pregnant. o REYATAZ must be taken with ritonavir during pregnancy. o Hormonal forms of birth control, such as injections, vaginal rings or implants, contraceptive patch, and some birth control pills may not work during treatment with REYATAZ. Talk to your healthcare provider about forms of birth control that may be used during treatment with REYATAZ. o Pregnancy Exposure Registry. There is a pregnancy exposure registry for people who take REYATAZ during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. 67 Reference ID: 5490094 o After your baby is born, tell your healthcare provider if your baby’s skin or the white part of their eyes turns yellow. • are breastfeeding or plan to breastfeed. REYATAZ can pass into your breast milk. o Talk to your healthcare provider about the following risks of breastfeeding during treatment with REYATAZ: • The HIV-1 virus may pass to your baby if your baby does not have the HIV-1 virus. • The HIV-1 virus may become harder to treat if your baby has the HIV-1 virus. • Your baby may get side effects from REYATAZ. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with REYATAZ. Keep a list of your medicines to show your healthcare provider and pharmacist. • You can ask your healthcare provider or pharmacist for a list of medicines that interact with REYATAZ. • Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take REYATAZ with other medicines. How should I take REYATAZ? • Take REYATAZ exactly as your healthcare provider tells you to. • Do not change your dose or stop taking REYATAZ unless your healthcare provider tells you to. • Stay under the care of your healthcare provider during treatment with REYATAZ. • REYATAZ must be used with other HIV-1 medicines. • Take REYATAZ 1 time each day. • REYATAZ comes as capsules and oral powder. • Take REYATAZ capsules and oral powder with food. • Swallow the capsules whole. Do not open the capsules. • REYATAZ oral powder must be mixed with food or liquid. Your child’s healthcare provider will prescribe the right dose of REYATAZ based on your child’s weight. See the detailed “Instructions for Use” that comes with REYATAZ oral powder for information about the correct way to mix and give a dose of REYATAZ oral powder to your child. • REYATAZ oral powder must be taken with ritonavir. • If you miss a dose of REYATAZ, take it as soon as you remember. Then take the next dose at your regular time. Do not take 2 doses at the same time. • If you take too much REYATAZ, call your healthcare provider or go to the nearest hospital emergency room right away. When your supply of REYATAZ starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of REYATAZ. The amount of HIV-1 in your blood may increase if the medicine is stopped for even a short time. The virus may become resistant to REYATAZ and harder to treat. What are the possible side effects of REYATAZ? REYATAZ can cause serious side effects, including: • A change in the way your heart beats (heart rhythm change). Tell your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of a heart problem. • Skin rash. Skin rash is common with REYATAZ but can sometimes be severe. Severe rash may develop with other symptoms which could be serious. If you develop a severe rash or a rash with any of the following symptoms, stop taking REYATAZ and call your healthcare provider or go to the nearest hospital emergency room right away: o general feeling of discomfort or “flu-like” symptoms o blisters o fever o mouth sores o muscle or joint aches o swelling of your face o red or inflamed eyes, like “pink eye” (conjunctivitis) o painful, warm, or red lump under your skin • Liver problems. If you have liver problems, including hepatitis B or C virus, your liver problems may get worse when you take REYATAZ. Your healthcare provider will do blood tests to check your liver before you start REYATAZ and during treatment. Tell your healthcare provider right away if you get any of the following symptoms: o dark “tea-colored” urine o nausea o your skin or the white part of your eyes turns yellow o itching o light colored stools o stomach-area pain 68 Reference ID: 5490094 • Chronic kidney disease. REYATAZ may affect how well your kidneys work. Your healthcare provider will do blood and urine tests to check your kidneys before you start REYATAZ and during treatment. Drink plenty of fluids during treatment with REYATAZ. • Kidney stones have happened in some people who take REYATAZ, and sometimes may lead to hospitalization. Tell your healthcare provider right away if you get symptoms of kidney stones which may include pain in your low back or low stomach area, blood in your urine, or pain when you urinate. • Gallbladder stones have happened in some people who take REYATAZ, and sometimes may lead to hospitalization. Tell your healthcare provider right away if you get symptoms of a gallbladder problem which may include: o pain in the right or middle upper stomach area o nausea and vomiting o fever o your skin or the white part of your eyes turns yellow • Yellowing of your skin or the white part of your eyes is common with REYATAZ but may be a symptom of a serious problem. These symptoms may be due to increases in bilirubin levels in your blood (bilirubin is made by the liver). Tell your healthcare provider right away if your skin or the white part of your eyes turns yellow. • New or worsening diabetes and high blood sugar (hyperglycemia) have happened in some people who take protease inhibitor medicines like REYATAZ. Some people have had to start taking medicine to treat diabetes or have changes to their dose of their diabetes medicine. Tell your healthcare provider if you notice an increase in thirst or if you start urinating more often while taking REYATAZ. • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider if you start having new symptoms after starting REYATAZ. • Changes in body fat can happen in people taking HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known. • Increased bleeding problems in people with hemophilia have happened when taking protease inhibitors like REYATAZ. The most common side effects of REYATAZ include: • nausea • dizziness • headache • muscle pain • stomach-area pain • diarrhea • vomiting • depression • trouble sleeping • fever • numbness, tingling, or burning of hands or feet Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of REYATAZ. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store REYATAZ? REYATAZ capsules: • Store REYATAZ capsules at room temperature, between 68°F to 77°F (20°C to 25°C). • Keep capsules in a tightly closed container. • The REYATAZ bottle comes with a child-resistant closure. REYATAZ oral powder: • Store REYATAZ oral powder at a temperature of 68°F to 86°F (20°C to 30°C). • Store REYATAZ oral powder in the original packet. Do not open until ready to use. • After REYATAZ oral powder is mixed with food or liquid it may be kept at a temperature of 68°F to 86°F (20°C to 30°C) for up to 1 hour. Take REYATAZ oral powder within 1 hour after mixing with food or liquid. Keep REYATAZ and all medicines out of the reach of children. General information about the safe and effective use of REYATAZ 69 Reference ID: 5490094 Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use REYATAZ for a condition for which it was not prescribed. Do not give REYATAZ to other people, even if they have the o same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about REYATAZ that is written for health professionals. For more information, go to www.reyataz.com or call 1-800-321-1335. What are the ingredients in REYATAZ? Active ingredient: atazanavir sulfate Inactive ingredients: REYATAZ capsules: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain gelatin, FD&C Blue No. 2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue No. 2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol. REYATAZ oral powder: aspartame, sucrose, and orange-vanilla flavor. Distributed by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA. REYATAZ® is a registered trademark of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: December 2024 [print code] 70 Reference ID: 5490094 Instructions for Use REYATAZ (RAY-ah-taz) (atazanavir) oral powder Read this Instructions for Use before you prepare your child’s first dose of REYATAZ oral powder, each time you get a refill, and as needed. There may be new information. This information does not take the place of talking to your child’s healthcare provider about their medical condition or treatment. Ask your child’s healthcare provider or pharmacist if you have questions about how to mix or give a dose of REYATAZ oral powder. Important information: • For more information about REYATAZ oral powder, see the Patient Information leaflet. • REYATAZ oral powder must be mixed with food or liquid. If REYATAZ oral powder is mixed with water, your child must eat food right after taking REYATAZ oral powder. • REYATAZ oral powder must be taken with ritonavir. • Talk with your child’s healthcare provider to help decide the best schedule for giving your child REYATAZ oral powder. Instructions for mixing REYATAZ oral powder: REYATAZ oral powder should be mixed with food such as applesauce or yogurt, instead of a liquid (milk, infant formula, or water) in young children and infants who can take food. • Infants less than 6 months old and who cannot eat solid food or drink from a cup should be given REYATAZ oral powder mixed with infant formula using an oral dosing syringe. • REYATAZ oral powder that is mixed in infant formula or liquid should not be given using a baby bottle. When preparing REYATAZ oral powder with either food or liquid, choose a clean, flat work surface. Place a clean paper towel on the work surface. Place the supplies you will need on the paper towel. Wash and dry your hands before and after preparing REYATAZ oral powder. Preparing a dose of REYATAZ oral powder mixed with food: Before you prepare a dose of REYATAZ oral powder mixed with food, gather the following supplies: • paper towel • tablespoon • small clean container (such as a small cup or bowl) • a food such as applesauce or yogurt • the correct number of packets of REYATAZ oral powder needed for the prescribed dose • a clean pair of scissors 71 Reference ID: 5490094 ~~ ~· ({: : - Step 1. Place at least 1 tablespoon of a food such as applesauce or yogurt in the small container (see Figure A). Figure A Step 2. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure B). Figure B Step 3. Using a clean pair of scissors, cut open the packet on the dotted line (see Figure C). Figure C Step 4. Empty the contents of the packet into the small container onto the food (see Figure D). Figure D 72 Reference ID: 5490094 Repeat Steps 2 through 4 for each packet of REYATAZ oral powder needed for the total prescribed dose. Step 5. Use a tablespoon to gently mix the powder and the food together (see Figure E). Figure E Steps 6 through 8 must be completed within 1 hour of mixing the medicine. Step 6. Use the tablespoon or a small spoon to feed the REYATAZ oral powder and food mixture to your child. Look in your child’s mouth to make sure that all of the mixture is swallowed. Step 7. Add 1 tablespoon more of food to the empty container and gently stir to mix with any contents that may still be in the container. Step 8. Use the tablespoon or a small spoon to feed your child the mixture, making sure your child has swallowed all of the mixture. Step 9. Give your child ritonavir as prescribed right after taking REYATAZ oral powder. Step 10. Wash the container and tablespoon. Allow the container and spoon to dry. Throw away the paper towel and clean the work surface. Preparing a dose of REYATAZ oral powder mixed with liquid in a small drinking cup: Before you prepare a dose of REYATAZ oral powder mixed with liquid in a small drinking cup, gather the following supplies: 73 Reference ID: 5490094 30 mL MEDICINE CUP -30ml -25ml -2omL -15mL • paper towel • spoon • 30 milliliter (mL) medicine cup (ask your pharmacist for this). See Figure F. • small drinking cup • liquid such as milk or water • the correct number of packets of REYATAZ oral powder needed for the prescribed dose • a clean pair of scissors Figure F Step 1. Using the 30 mL medicine cup, pour at least 30 mL of liquid into the small drinking cup (see Figure G). Figure G Step 2. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure H). Figure H Step 3. Using a clean pair of scissors, cut open the packet on the dotted line (see Figure I). Figure I 74 Reference ID: 5490094 Step 4. Empty the contents of the packet into the small drinking cup (see Figure J). Figure J Repeat Steps 2 through 4 for each packet of REYATAZ oral powder needed for the total prescribed dose. Step 5. Hold the small drinking cup with one hand. With your other hand, use the spoon to gently mix the powder and the liquid (see Figure K). Figure K Steps 6 and 7 must be completed within 1 hour of mixing the medicine. Step 6. Have your child drink all of the mixture in the small drinking cup. Step 7. To make sure there is no mixture left in the small drinking cup add 15 mL more liquid to the small drinking cup: • Stir with the spoon. • Repeat Step 6 above. If REYATAZ oral powder is mixed with water, your child must eat food right after taking REYATAZ oral powder. Step 8. Give your child ritonavir as prescribed right after taking REYATAZ oral powder. Step 9. Wash the small drinking cup, medicine cup, and spoon. Allow the small drinking cup, medicine cup, and spoon to dry. Throw away the paper towel and clean the work surface. 75 Reference ID: 5490094 ORAL DOSING SYRINGE _.,­ - 2'- -,o- -,~ ...... -1om1.. Preparing a dose of REYATAZ oral powder mixed with liquid infant formula using an oral dosing syringe and a small medicine cup: Before you prepare a dose of REYATAZ oral powder mixed with infant formula using an oral dosing syringe, gather the following supplies: • paper towel • small spoon • 30 milliliter (mL) medicine cup (ask your pharmacist for this). See Figure L. • 10 mL oral dosing syringe (ask your pharmacist for this). See Figure L. • infant formula • the correct number of packets of REYATAZ oral powder needed for the prescribed dose • a clean pair of scissors Figure L Step 1. Prepare the infant formula according to the directions on the infant formula package. Step 2. Pour 10 mL of infant formula into the medicine cup (see Figure M). Figure M Step 3. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure N). Figure N 76 Reference ID: 5490094 Step 4. Using a clean pair of scissors, cut open the packet on the dotted line (see Figure O). Figure O Step 5. Empty the contents of the packet into the medicine cup (see Figure P). Figure P Repeat Steps 3 through 5 for each packet of REYATAZ oral powder needed for the total prescribed dose. Step 6. Hold the medicine cup with one hand. With your other hand, use the small spoon to gently mix the powder and the infant formula (see Figure Q). Figure Q Steps 7 through 9 must be completed within 1 hour of mixing the medicine. 77 Reference ID: 5490094 Step 7. Draw up the powder and infant formula mixture into the oral dosing syringe as follows: • Check that the plunger is completely pushed into barrel of the syringe (see Figure R). Figure R • Place the tip of the syringe into the powder and infant formula mixture in the medicine cup (see Figure S). Figure S • Slowly pull back on the plunger and draw up 10 mL of the mixture (see Figure T). Figure T Step 8. Place the tip of the oral dosing syringe in your baby’s mouth along the inner cheek on either the right or left side (see Figure U). Slowly push on the plunger to give your baby all of the REYATAZ oral powder and infant formula mixture. • Draw up any remaining mixture with the oral dosing syringe and repeat until all of the mixture has been given to the baby. Figure U 78 Reference ID: 5490094 Step 9. To make sure there is no mixture left in the medicine cup or syringe: • Repeat Step 1 above to add 10 mL more infant formula to the medicine cup. • Stir with a small spoon. • Then repeat Steps 7 through 8 above. To make sure that your baby gets all of the medicine, do not give REYATAZ oral powder in a baby bottle. Step 10. Give your baby ritonavir as prescribed right after taking REYATAZ oral powder. Step 11. Remove the plunger from the oral dosing syringe. Wash the medicine cup, spoon, and oral dosing syringe. Allow the medicine cup, spoon, and oral dosing syringe to dry. Throw away the paper towel and clean the work surface. How should I store REYATAZ oral powder? • Store REYATAZ oral powder at a temperature of 68°F to 86°F (20°C to 30°C). • Store REYATAZ oral powder in the original packet. Do not open until ready to use. • After REYATAZ oral powder is mixed with food or liquid, it may be kept at a temperature of 68°F to 86°F (20°C to 30°C) for up to 1 hour. Take REYATAZ oral powder within 1 hour after mixing with food or liquid. Keep REYATAZ oral powder and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA [print code] Revised: September 2020 79 Reference ID: 5490094
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2025-02-12T15:47:34.136951
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_________________ ______________ _____________ ____________________ ___________________ _______________ _______________ _______________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ONYDATM XR safely and effectively. See full prescribing information for ONYDATM XR. ONYDATM XR (clonidine hydrochloride) extended-release oral suspension Initial U.S. Approval: 1974 __________________ INDICATIONS AND USAGE ONYDA XR is a centrally acting alpha2-adrenergic agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy or as adjunctive therapy to central nervous system (CNS) stimulant medications in pediatric patients 6 years of age and older. (1) _______________ DOSAGE AND ADMINISTRATION • Starting dosage is 0.1 mg of ONYDA XR orally once daily at bedtime with or without food. Dosage may be increased in increments of 0.1 mg per day at weekly intervals. Maximum recommended dosage is 0.4 mg once daily at bedtime. (2.1) • Do not substitute ONYDA XR for other clonidine products on a mg-per­ mg basis because of differing pharmacokinetic profiles. (2.3) • When discontinuing, taper the dose in decrements of no more than 0.1 mg every 3 to 7 days to avoid rebound hypertension. (2.4) ______________ DOSAGE FORMS AND STRENGTHS Extended-release oral suspension: 0.1 mg clonidine hydrochloride per mL (3) CONTRAINDICATIONS History of a hypersensitivity reaction to clonidine. Reactions have included generalized rash, urticaria, angioedema. (4) WARNINGS AND PRECAUTIONS • Hypotension/bradycardia: Titrate slowly and monitor vital signs frequently in patients at risk for hypotension, heart block, bradycardia, syncope, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Avoid concomitant use of drugs with additive effects unless clinically indicated. Advise patients to avoid becoming dehydrated or overheated. (5.1) • Somnolence/Sedation: Has been observed with clonidine. Consider the potential for additive sedative effects with CNS depressant drugs. Caution patients against operating heavy equipment or driving until they know how they respond to ONYDA XR (5.2) • Cardiac Conduction Abnormalities: May worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate slowly and monitor vital signs frequently. (5.5) ____________________ADVERSE REACTIONS____________________ Most common adverse reactions (incidence at least 5% and twice the rate of placebo) as monotherapy in ADHD: somnolence, fatigue, irritability, nightmare, insomnia, constipation, dry mouth. (6.1) Most common adverse reactions (incidence at least 5% and twice the rate of placebo) as adjunct therapy to psychostimulant in ADHD: somnolence, fatigue, decreased appetite, dizziness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Tris Pharma, Inc., at (732) 940-0358 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ____________________DRUG INTERACTIONS____________________ • CNS Depressants: Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. (7) • Tricyclic Antidepressants: May reduce the hypotensive effect of clonidine. (7) • Drugs Known to Affect Sinus Node Function or AV Nodal Conduction: Avoid use of ONYDA XR with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta- blockers) due to a potential for additive effects such as bradycardia and AV block. (7) • Antihypertensive drugs: Use caution when coadministered with ONYDA XR. (7) USE IN SPECIFIC POPULATIONS _______________ Renal Impairment: The dosage of ONYDA XR must be adjusted according to the degree of impairment, and patients should be carefully monitored. (8.6, 12.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 6/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Administration Instructions 2.3 Switching from Other Clonidine Products 2.4 Discontinuation 2.5 Missed Doses 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension/Bradycardia 5.2 Sedation and Somnolence 5.3 Rebound Hypertension 5.4 Allergic Reactions 5.5 Cardiac Conduction Abnormalities 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.6 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Page 1 of 23 Reference ID: 5491889 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE ONYDA XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to central nervous system (CNS) stimulant medications in pediatric patients 6 years of age and older [see Clinical Studies (14)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The starting dosage of ONYDA XR is 0.1 mg orally once daily at bedtime with or without food [see Clinical Pharmacology (12.3)]. Titrate the dose of ONYDA XR in increments of 0.1 mg per day at weekly intervals depending on clinical response up to the maximum recommended dosage of 0.4 mg once daily at bedtime. Doses of ONYDA XR higher than 0.4 mg once daily were not evaluated in clinical trials for ADHD and are not recommended. When ONYDA XR is added to a CNS stimulant, adjust the dose of the CNS stimulant depending on the clinical response to ONYDA XR. 2.2 Administration Instructions Instruct patients to read the “Instructions for Use” for complete administration instructions. • Use the oral dosing dispenser and bottle adapter provided with ONYDA XR. • Ensure that the bottle adapter is firmly inserted into the bottle before first use and keep the adapter in place for the duration of the usage of the bottle. • Gently shake ONYDA XR with a smooth up and down motion (to avoid foaming) for at least 10 seconds before each administration. • Discard any unused ONYDA XR remaining in the bottle after 60 days of first opening the bottle. 2.3 Switching from Other Clonidine Products For patients switching from another clonidine product, discontinue that treatment, and titrate with ONYDA XR using the titration schedule [see Dosage and Administration (2.1)]. Do not substitute for other clonidine products on a milligram-per-milligram basis because of differing pharmacokinetic profiles [see Clinical Pharmacology (12.3)]. 2.4 Discontinuation When discontinuing ONYDA XR, taper the total daily dose in decrements of no more than 0.1 mg every 3 to 7 days to avoid rebound hypertension [see Warnings and Precautions (5.3)]. Page 2 of 23 Reference ID: 5491889 2.5 Missed Doses If a dose of ONYDA XR is missed, skip that dose and take the next dose as scheduled. Do not take more than the prescribed total daily amount of ONYDA XR in any 24-hour period. 3 DOSAGE FORMS AND STRENGTHS Extended-release oral suspension: Light beige to tan viscous suspension containing 0.1 mg clonidine hydrochloride per mL. 4 CONTRAINDICATIONS ONYDA XR is contraindicated in patients with a history of a hypersensitivity reaction to clonidine. Reactions have included generalized rash, urticaria, and angioedema [see Warnings and Precautions (5.4) and Adverse Reactions (6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension/Bradycardia Treatment with ONYDA XR can cause dose-related decreases in blood pressure and heart rate [see Adverse Reactions (6.1)]. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Titrate ONYDA XR slowly in patients with a history of hypotension, and those with underlying conditions that may be worsened by hypotension and bradycardia; e.g., heart block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure. In patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, advise patients to avoid becoming dehydrated or overheated. Monitor blood pressure and heart rate, and adjust dosages accordingly in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope [see Drug Interactions (7)]. 5.2 Sedation and Somnolence Somnolence and sedation were commonly reported adverse reactions in clinical studies with clonidine hydrochloride extended-release tablets. In patients that completed 5 weeks of therapy in a controlled, fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day versus 4% of placebo treated patients reported somnolence as an adverse reaction. In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with clonidine hydrochloride extended-release tablets plus a stimulant versus 7% treated with placebo plus a stimulant reported somnolence. Before using ONYDA XR with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects [see Drug Page 3 of 23 Reference ID: 5491889 Interactions (7)]. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with ONYDA XR. Advise patients to avoid use with alcohol. 5.3 Rebound Hypertension Abrupt discontinuation of ONYDA XR can cause rebound hypertension. In adults with hypertension, sudden cessation of clonidine extended-release formulation treatment in the 0.2 to 0.6 mg per day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety. In adults with hypertension, sudden cessation of treatment with immediate-release clonidine has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. No studies evaluating abrupt discontinuation of clonidine hydrochloride extended-release tablets in pediatric patients with ADHD have been conducted; however, to minimize the risk of rebound hypertension, gradually reduce the dose of ONYDA XR in decrements of no more than 0.1 mg every 3 to 7 days. Patients should be instructed not to discontinue ONYDA XR therapy without consulting their physician due to the potential risk of withdrawal effects. 5.4 Allergic Reactions In patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or use of oral ONYDA XR therapy may be associated with the development of a generalized skin rash. In patients who develop an allergic reaction from clonidine transdermal system, use of ONYDA XR may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema). 5.5 Cardiac Conduction Abnormalities The sympatholytic action of clonidine may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. There have been post- marketing reports of patients with conduction abnormalities and/or taking other sympatholytic drugs who developed severe bradycardia requiring intravenous (IV) atropine, IV isoproterenol, and temporary cardiac pacing while taking clonidine. Titrate ONYDA XR slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs. 6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail elsewhere in labeling: • Hypotension/bradycardia [see Warnings and Precautions (5.1)] • Sedation and somnolence [see Warnings and Precautions (5.2)] • Rebound hypertension [see Warnings and Precautions (5.3)] • Allergic reactions [see Warnings and Precautions (5.4)] • Cardiac Conduction Abnormalities [see Warnings and Precautions (5.5)] Page 4 of 23 Reference ID: 5491889 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ONYDA XR for the treatment of ADHD in pediatric patients 6 years and older is based upon adequate and well-controlled studies of clonidine hydrochloride extended-release tablets (referred to as “clonidine hydrochloride extended-release” in this section). The safety results of these adequate and well-controlled studies of clonidine hydrochloride extended- release tablets are presented below. Two clonidine hydrochloride extended-release ADHD clinical studies (Study 1 and Study 2) evaluated 256 patients in two 8-week placebo-controlled studies. A third clonidine hydrochloride extended-release ADHD clinical study (Study 3) evaluated 135 pediatric patients 6 to 17 years of age in a 40-week placebo-controlled randomized-withdrawal study. Study 1: Fixed-dose clonidine hydrochloride extended-release Monotherapy Study 1 was a short-term, multi-center, randomized, double-blind, placebo-controlled study of two fixed doses (0.2 mg/day or 0.4 mg/day) of clonidine hydrochloride extended-release in pediatric patients 6 to 17 years of age who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. Most Common Adverse Reactions (incidence of ≥ 5% and at least twice the rate of placebo): somnolence, fatigue, irritability, insomnia, nightmare, constipation, dry mouth. Adverse Reactions Leading to Discontinuation of clonidine hydrochloride extended-release: Five patients (7%) in the low dose group (0.2 mg), 15 patients (20%) in the high dose group (0.4 mg), and 1 patient in the placebo group (1%) reported adverse reactions that led to discontinuation. The most common adverse reactions that led to discontinuation were somnolence and fatigue. Commonly observed adverse reactions (incidence of ≥2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 1. Page 5 of 23 Reference ID: 5491889 Table 1: Common Adverse Reactions Occurring in ≥2%of Patients Treated with Clonidine Hydrochloride Extended-Release Tablets and Greater than the Rate of Placebo in the Fixed-Dose Monotherapy Trial -Treatment Period (Study 1) Preferred Term Clonidine hydrochloride extended-release tablets 0.2 mg/day N=76 (%) Clonidine hydrochloride extended-release tablets 0.4 mg/day N=78 (%) Placebo N=76 (%) PSYCHIATRIC DISORDERS Somnolence* 38 31 4 Nightmare 4 9 0 Emotional Disorder 4 4 1 Aggression 3 1 0 Tearfulness 1 3 0 Enuresis 0 4 0 Sleep Terror 3 0 0 Poor Quality Sleep 0 3 1 NERVOUS SYSTEM DISORDERS Headache 20 13 16 Insomnia 5 6 1 Tremor 1 4 0 Abnormal Sleep-Related Event 3 1 0 GASTRO-INTESTINAL DISORDERS Upper Abdominal Pain 15 10 12 Nausea 4 5 3 Constipation 1 6 0 Dry Mouth 0 5 1 GENERAL DISORDERS Fatigue† Irritability 16 9 13 5 1 4 CARDIAC DISORDERS Dizziness Bradycardia 7 0 3 4 5 0 INVESTIGATIONS Increased Heart Rate 0 3 0 Page 6 of 23 Reference ID: 5491889 Preferred Term Clonidine hydrochloride extended-release tablets 0.2 mg/day N=76 (%) Clonidine hydrochloride extended-release tablets 0.4 mg/day N=78 (%) Placebo N=76 (%) METABOLISM AND NUTRITION DISORDERS Decreased Appetite 3 4 4 * Somnolence includes the terms "somnolence" and "sedation". † Fatigue includes the terms "fatigue" and "lethargy". Commonly observed adverse reactions (incidence of ≥2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 2. Table 2: Common Adverse Reactions Occurring in ≥2% of Patients Treated with Clonidine Hydrochloride Extended-Release Tablets and Greater than the Rate of Placebo in the Fixed-Dose Monotherapy Trial -Taper Period* (Study 1) Preferred Term Clonidine hydrochloride extended-release tablets 0.2 mg/day N=76 (%) Clonidine hydrochloride extended-release tablets 0.4 mg/day N=78 (%) Placebo N=76 (%) Abdominal Pain Upper 0 6 3 Headache 5 2 3 Gastrointestinal Viral 0 5 0 Somnolence 2 3 0 Heart Rate Increased 0 3 0 Otitis Media Acute 3 0 0 * Taper Period: 0.2 mg dose, week 8; 0.4 mg dose, weeks 6-8; Placebo dose, weeks 6-8 Study 2: Flexible-dose clonidine hydrochloride extended-release as Adjunctive Therapy to Psychostimulants Study 2 was a short-term, randomized, double-blind, placebo-controlled study of a flexible dose of clonidine hydrochloride extended-release as adjunctive therapy to a psychostimulant in pediatric patients 6 to 17 years of age who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes, during which clonidine hydrochloride extended-release was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Page 7 of 23 Reference ID: 5491889 Most clonidine hydrochloride extended-release treated patients (75.5%) were escalated to the maximum dose of 0.4 mg/day. Most Common Adverse Reactions (incidence of ≥ 5% and at least twice the rate of placebo): somnolence, fatigue, decreased appetite, dizziness. Adverse Reactions Leading to Discontinuation: There was one patient in the clonidine hydrochloride extended-release + stimulant (group (1%) who discontinued because of an adverse event (severe bradyphrenia, with severe fatigue). Commonly observed adverse reactions (incidence of ≥2% in the treatment group and greater than the rate on placebo) during the treatment period are listed in Table 3. Table 3: Common Adverse Reactions Occurring in ≥2% of Patients Treated with Clonidine Hydrochloride Extended-Release Tablets and Greater than the Rate of Placebo in the Flexible-Dose Adjunctive to Stimulant Therapy Trial ­ Treatment Period (Study 2) Preferred Term Clonidine hydrochloride extended-release tablets + Stimulant N=102 (%) PBO+Stimulant N=96 (%) PSYCHIATRIC DISORDERS Somnolence+ Aggression Affect Lability Emotional Disorder 19 2 2 2 7 1 1 0 GENERAL DISORDERS Fatigue† Irritability 14 2 4 7 NERVOUS SYSTEM DISORDERS Headache Insomnia 7 4 12 3 GASTRO-INTESTINAL DISORDERS Upper Abdominal Pain 7 4 RESPIRATORY DISORDERS Nasal Congestion 2 2 METABOLISM AND NUTRITION DISORDERS Decreased Appetite 6 3 Page 8 of 23 Reference ID: 5491889 Preferred Term Clonidine hydrochloride extended-release tablets + Stimulant N=102 (%) PBO+Stimulant N=96 (%) CARDIAC DISORDERS Dizziness 5 1 +Somnolence includes the terms: "somnolence" and "sedation" † Fatigue includes the terms "fatigue" and "lethargy" Commonly observed adverse reactions (incidence of ≥2% in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 4. Table 4: Common Adverse Reactions Occurring in ≥2% of Patients Treated with Clonidine Hydrochloride Extended-Release Tablets and Greater than the Rate of Placebo in the Flexible-Dose Adjunctive to Stimulant Therapy Trial ­ Taper Period+ (Study 2) Preferred Term Clonidine hydrochloride extended-release tablets + Stimulant N=102 (%) Placebo+Stimulant N=96 (%) Nasal Congestion 4 2 Headache 3 1 Irritability 3 2 Throat Pain 3 1 Gastroenteritis Viral 2 0 Rash 2 0 +Taper Period: weeks 6-8 Adverse Reactions Leading to Discontinuation Thirteen percent (13%) of patients receiving clonidine hydrochloride extended-release discontinued from the pediatric monotherapy study due to adverse reactions, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of clonidine hydrochloride extended-release monotherapy treated patients were somnolence/sedation (5%) and fatigue (4%). Effect on Blood Pressure and Heart Rate In patients that completed 5 weeks of treatment in a controlled, fixed-dose monotherapy study in pediatric patients, during the treatment period the maximum placebo-subtracted mean change in systolic blood pressure was -4.0 mmHg on clonidine hydrochloride extended-release 0.2 mg/day Page 9 of 23 Reference ID: 5491889 and -8.8 mmHg on clonidine hydrochloride extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on clonidine hydrochloride extended-release 0.2 mg/day and -7.3 mmHg on clonidine hydrochloride extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on clonidine hydrochloride extended-release 0.2 mg/day and -7.7 beats per minute on clonidine hydrochloride extended-release 0.4 mg/day. During the taper period of the fixed-dose monotherapy study the maximum placebo-subtracted mean change in systolic blood pressure was +3.4 mmHg on clonidine hydrochloride extended-release 0.2 mg/day and -5.6 mmHg on clonidine hydrochloride extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on clonidine hydrochloride extended-release 0.2 mg/day and -5.4 mmHg on clonidine hydrochloride extended-release 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on clonidine hydrochloride extended-release 0.2 mg/day and -3.0 beats per minute on clonidine hydrochloride extended-release 0.4 mg/day. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clonidine hydrochloride extended-release tablets (and excludes those already mentioned in Section 6.1). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Psychiatric: hallucinations Cardiovascular: Q-T prolongation 7 DRUG INTERACTIONS The interactions of ONYDA XR with co-administration of other drugs have not been studied. The drug interaction data provided in this section is based on oral immediate-release clonidine formulations. Table 5 displays clinically important drug interactions with ONYDA XR. Table 5: Clinically Important Drug Interactions with ONYDA XR Antihypertensive drugs Clinical Implication Concomitant use of antihypertensive drugs with clonidine potentiates the hypotensive effects of clonidine. Intervention Monitor blood pressure and heart rate, and adjust dosage of ONYDA XR accordingly in patients treated concomitantly with antihypertensives [see Warnings and Precautions (5.1)]. Page 10 of 23 Reference ID: 5491889 CNS depressants Clinical Implication Concomitant use of CNS depressants with clonidine potentiates the sedating effects [see Warnings and Precautions (5.2)]. Intervention Avoid concomitant use of CNS depressants with ONYDA XR. Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers) Clinical Implication Concomitant use of drugs that affect sinus node function or AV node conduction with clonidine potentiate bradycardia and risk of AV block [see Warnings and Precautions (5.5)]. Intervention Avoid concomitant use of drugs that affect sinus node function or AV node conduction with ONYDA XR. Tricyclic antidepressants Clinical Implication Concomitant use of tricyclic antidepressants with clonidine can increase blood pressure and may counteract the hypotensive effects of clonidine. Intervention Monitor blood pressure and adjust dosage of ONYDA XR as needed. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including ONYDA XR, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/adhd-medications/. Risk Summary Prolonged experience with clonidine in pregnant women over several decades, based on published literature, including controlled trials, a retrospective cohort study and case reports, have not identified a drug associated risk of major birth defects, miscarriage, and adverse maternal or fetal outcomes. In animal embryofetal studies, increased resorptions were seen in rats and mice administered oral clonidine hydrochloride from implantation through organogenesis at 10 and 5 times, respectively, the maximum recommended human dose Page 11 of 23 Reference ID: 5491889 (MRHD) given to adolescents on a mg/m2 basis. No developmental effects were seen in rabbits administered oral clonidine hydrochloride during organogenesis at doses up to 3 times the MRHD (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Oral administration of clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal organogenesis at doses of up to 80 mcg/kg/day (approximately 3 times the oral maximum recommended daily dose [MRHD] of 0.4 mg/day given to adolescents on a mg/m2 basis) produced no developmental effects. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD given to adolescents on a mg/m2 basis) were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating and throughout gestation. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRHD) when treatment of the dams was restricted to gestation days 6-15. Increases in resorptions were observed in both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice, respectively) or higher when the animals were treated on gestation days 1-14; 500 mcg/kg/day was the lowest dose employed in this study. 8.2 Lactation Risk Summary Based on published lactation studies, clonidine hydrochloride is present in human milk at relative infant doses ranging from 4.1% to 8.4% of the maternal weight-adjusted dosage. Although in most cases, there were no reported adverse effects in breastfed infants exposed to clonidine, there is one case report of sedation, hypotonia, and apnea in an infant exposed to clonidine through breast milk. If an infant is exposed to clonidine through breastmilk, monitor for symptoms of hypotension and bradycardia, such as sedation, lethargy, tachypnea and poor feeding (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ONYDA XR and any potential adverse effects on the breastfed child from ONYDA XR or from the underlying maternal condition. Exercise caution when ONYDA XR is administered to a nursing woman. Clinical Considerations Monitor breastfeeding infants exposed to ONYDA XR through breast milk for symptoms of hypotension and/or bradycardia such as sedation, lethargy, tachypnea, and poor feeding. Page 12 of 23 Reference ID: 5491889 8.3 Females and Males of Reproductive Potential Infertility Findings in animal studies revealed that ONYDA XR may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and efficacy of clonidine hydrochloride extended-release in the treatment of ADHD have been established in pediatric patients 6 to 17 years of age. Use of clonidine hydrochloride extended-release in pediatric patients 6 to 17 years of age is supported by three adequate and well-controlled studies; a short-term, placebo-controlled monotherapy trial, a short-term adjunctive therapy trial and a longer-term randomized monotherapy trial [see Clinical Studies (14)]. Safety and efficacy in pediatric patients below the age of 6 years has not been established. Juvenile Animal Data In studies in juvenile rats, clonidine hydrochloride alone or in combination with methylphenidate had an effect on bone growth at clinically relevant doses and produced a slight delay in sexual maturation in males at 3 times the maximum recommended human dose (MRHD) for clonidine and methylphenidate. In a study where juvenile rats were treated orally with clonidine hydrochloride from day 21 of age to adulthood, a slight delay in onset of preputial separation (delayed sexual maturation) was seen in males treated with 300 mcg/kg/day, which is approximately 3 times the MRHD of 0.4 mg/day on a mg/m2 basis. The no-effect dose was 100 mcg/kg/day, which is approximately equal to the MRHD. There was no drug effects on fertility or on other measures of sexual or neurobehavioral development. In a study where juvenile rats were treated with clonidine alone (300 mcg/kg/day) or in combination with methylphenidate (10 mg/kg/day in females and 50/30 mg/kg/day in males; the dose was lowered from 50 to 30 mg/kg/day in males due to self-injurious behavior during the first week of treatment) from day 21 of age to adulthood, decreases in bone mineral density and mineral content were observed in males treated with 300 mcg/kg/day clonidine alone and in combination with 50/30 mg/kg/day methylphenidate and a decrease in femur length was observed in males treated with the combination at the end of the treatment period. These doses are approximately 3 times the MRHD of 0.4 mg/day clonidine and 54 mg/day methylphenidate on a mg/m2 basis. All these effects in male were not reversed at the end of a 4-week recovery period. In addition, similar findings were seen in males treated with a lower dose of clonidine (30 mcg/kg/day) in combination with 50 mg/kg/day of methylphenidate and a decrease in femur length was observed in females treated with clonidine alone at the end of the recovery period. These effects were accompanied by a decrease in body weight gain in treated animals during the treatment period but the effect was reversed at the end of the recovery period. A delay in preputial separation (sexual maturation) was observed in males treated with the combination treatment of 300 mcg/kg/day clonidine and 50/30 mg/kg/day methylphenidate. There was no effect on reproduction or sperm analysis in these males. Page 13 of 23 Reference ID: 5491889 Cl H Q-N=={J Cl H HCI 8.6 Renal Impairment The impact of renal impairment on the pharmacokinetics of clonidine in pediatric patients has not been assessed. The initial dosage of ONYDA XR should be based on degree of impairment. Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental ONYDA XR following dialysis. 10 OVERDOSAGE Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in pediatric patients than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations. 11 DESCRIPTION ONYDA XR contains clonidine hydrochloride, a centrally acting alpha2-adrenergic agonist. Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-[(2,6-dichlorophenyl)imino]imidazolidine hydrochloride. The following is the structural formula: The molecular formula of clonidine hydrochloride is C9H9Cl2N3•HCl and the molecular weight is 266.5. The pKa is 8.05. Clonidine hydrochloride is an odorless, bitter, white to almost white, crystalline powder soluble in water and alcohol. The pH of a 5% solution in water is between 3.5 and 5.5. ONYDA XR is an extended-release suspension for oral administration. Each mL of ONYDA XR contains 0.09 mg clonidine equivalent to 0.1 mg clonidine hydrochloride (0.095 mg clonidine hydrochloride complexed with sodium polystyrene sulfonate and 0.005 mg clonidine hydrochloride). The pH of ONYDA XR is between 2.8 and 4. The inactive ingredients are anhydrous citric acid, edetate disodium, glycerin, modified starch, methylparaben, orange flavor, polyvinyl acetate dispersion 30%, povidone, polysorbate 80, propylparaben, purified water, sucrose, sodium polystyrene sulfonate, triacetin, xanthan gum. Page 14 of 23 Reference ID: 5491889 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Clonidine stimulates alpha2-adrenergic receptors in the brain. Clonidine is not a central nervous system stimulant. The mechanism of action of clonidine in ADHD is not known. 12.2 Pharmacodynamics Clonidine is a known antihypertensive agent. By stimulating alpha2-adrenergic receptors in the brain stem, clonidine reduces sympathetic outflow from the central nervous system and decreases peripheral resistance, renal vascular resistance, heart rate, and blood pressure. 12.3 Pharmacokinetics Immediate-release clonidine hydrochloride, extended-release clonidine hydrochloride tablets, and ONYDA XR have different pharmacokinetic characteristics. Dose substitution on a milligram for milligram basis will result in differences in exposures [see Dosage and Administration (2.3)]. Absorption Following a single 0.2 mg dose of ONYDA XR in 20 healthy adult subjects under fasting conditions in a crossover study, the median (range) time to peak plasma concentrations (Tmax) for clonidine was 7.50 (4 –17) hours after dosing. Peak concentration (Cmax) was 95.6% of the Cmax of clonidine extended-release tablet 0.1 mg administered at 0 and 12 hours under fasting conditions. The relative bioavailability of ONYDA XR compared with an equal dose of clonidine extended-release tablet was 96.1%. After oral administration of 0.2 mg of ONYDA XR once daily over 5 days under fasted conditions in healthy adult subjects, the peak steady state plasma concentration (Cmax.ss) was 107.9%, and steady state relative bioavailability (AUCt, ss) was 97.7% compared with 0.1 mg of clonidine extended-release tablet administered twice daily under fasting conditions. The minimum concentration at steady state (Cmin,ss) of ONYDA XR was about 26% lower than that of the equal dose of clonidine extended-release tablet. Following oral administration of an immediate release formulation in healthy adult subjects, plasma clonidine concentration peaks in approximately 3 to 5 hours. A comparison across studies suggests that the Cmax is 50% lower for clonidine hydrochloride extended-release tablets compared to immediate-release clonidine hydrochloride. Effect of Food Food had no effect on plasma exposures of clonidine after administration of ONYDA XR (see Figure 1). Page 15 of 23 Reference ID: 5491889 1- 0-•-0>•~ ....... Figure 1: Mean Clonidine Concentration-Time Profiles After Single Dose Administration Clonidine Plasma Concentration (pg/mL) 400 300 200 100 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (h) ONYDA XR-fed 0.2 mg at 0 hour ONYDA XR-fasted 0.2 mg at 0 hour Clonidine HCl extended-release tablets, 0.1 mg fasted at 0 and 12 hours Elimination The plasma half-life of immediate-release clonidine ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Metabolism About 50% of the absorbed dose is metabolized in the liver. Excretion Following oral administration about 40% to 60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. Although studies of the effect of renal impairment and studies of clonidine excretion have not been performed with ONYDA XR, results are expected to be similar to those of the immediate-release formulation. Specific Populations Pediatric patients Page 16 of 23 Reference ID: 5491889 Plasma clonidine concentrations in pediatric patients 6 to 17 years (0.1 mg twice daily and 0.2 mg twice daily of clonidine hydrochloride extended-release tablets) with ADHD are greater than those of adults with hypertension, with pediatric patients 6 to 17 years receiving higher doses on a mg/kg basis. Body weight normalized clearance (CL/F) in pediatric patients aged 6 to 17 years was higher than CL/F observed in adults with hypertension. Clonidine concentrations in plasma increased with increases in dose over the dose range of 0.2 to 0.4 mg/day. Clonidine CL/F was independent of dose administered over the 0.2 to 0.4 mg/day dose range. Clonidine CL/F appeared to decrease slightly with increases in age over the range of 6 to 17 years, and females had a 23% lower CL/F than males. The incidence of "sedation-like" events (somnolence and fatigue) appeared to be independent of clonidine dose or concentration within the studied dose range in the titration study. Results from the add-on study showed that clonidine CL/F was 11% higher in patients who were receiving methylphenidate and 44% lower in those receiving amphetamine compared to subjects not on adjunctive therapy. Drug Interaction Studies Alcohol: In an in vitro alcohol-induced dose dumping study, a significantly faster and more variable ONYDA XR drug release was observed in the presence of 20% alcohol, but not with 5% or 10% alcohol, when compared to 0% alcohol. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility Carcinogenesis Clonidine hydrochloride was not carcinogenic when administered in the diet of rats (for up to 132 weeks) or mice (for up to 78 weeks) at doses of up to 1,620 (male rats), 2,040 (female rats), or 2,500 (mice) mcg/kg/day. These doses are approximately 20, 25, and 15 times, respectively, the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m2 basis. Mutagenesis There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity. Impairment of Fertility In a reproduction study fertility of female rats appeared to be adversely affected at dose levels of 500 and 2,000 mcg/kg/day (10 and 40 times the MRHD on a mg/m2 basis). Lower doses have not been adequately evaluated and a no adverse effect level could not be established. 14 CLINICAL STUDIES The efficacy of ONYDA XR for the treatment of ADHD in pediatric patients 6 years of age and older is based upon adequate and well-controlled studies of clonidine hydrochloride extended- release tablets (referred to as “clonidine hydrochloride extended-release” in this section). The efficacy results of these adequate and well-controlled studies of clonidine hydrochloride extended-release tablets are presented below. Page 17 of 23 Reference ID: 5491889 Efficacy of clonidine hydrochloride extended-release in the treatment of ADHD was established in pediatric patients 6 to 17 years in: • One short-term, placebo-controlled monotherapy trial (Study 1) • One short-term adjunctive therapy to psychostimulants trial (Study 2) • One randomized withdrawal trial as monotherapy (Study 3) Short-term Monotherapy and Adjunctive Therapy to Psychostimulant Studies for ADHD The efficacy of clonidine hydrochloride extended-release in the treatment of ADHD was established in 2 (one monotherapy and one adjunctive therapy) placebo-controlled trials in pediatric patients aged 6 to 17 years, who met DSM-IV criteria of ADHD hyperactive or combined hyperactive/inattentive subtypes. Signs and symptoms of ADHD were evaluated using the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS-IV) total score including hyperactive/impulsivity and inattentive subscales. Study 1 was an 8-week randomized, double-blind, placebo-controlled, fixed dose study of pediatric patients 6 to 17 years (N=236) with a 5-week primary efficacy endpoint. Patients were randomly assigned to one of the following three treatment groups: clonidine hydrochloride extended-release 0.2 mg/day (N=78), clonidine hydrochloride extended-release 0.4 mg/day (N=80), or placebo (N=78). Dosing for the clonidine hydrochloride extended-release groups started at 0.1 mg/day and was titrated in increments of 0.1 mg/week to their respective dose (as divided doses). Patients were maintained at their dose for a minimum of 2 weeks before being gradually tapered down to 0.1 mg/day at the last week of treatment. At both doses, improvements in ADHD symptoms were statistically significantly superior in clonidine hydrochloride extended-release-treated patients compared with placebo-treated patients at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 6). Study 2 was an 8-week randomized, double-blind, placebo-controlled, flexible dose study in pediatric patients 6 to 17 years (N=198) with a 5-week primary efficacy end point. Patients had been treated with a psychostimulant (methylphenidate or amphetamine) for four weeks with inadequate response. Patients were randomly assigned to one of two treatment groups: clonidine hydrochloride extended-release adjunct to a psychostimulant (N=102) or psychostimulant alone (N=96). The clonidine hydrochloride extended-release dose was initiated at 0.1 mg/day and doses were titrated in increments of 0.1 mg/week up to 0.4 mg/day, as divided doses, over a 3-week period based on tolerability and clinical response. The dose was maintained for a minimum of 2 weeks before being gradually tapered to 0.1 mg/day at the last week of treatment. ADHD symptoms were statistically significantly improved in clonidine hydrochloride extended-release plus stimulant group compared with the stimulant alone group at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 6). Page 18 of 23 Reference ID: 5491889 Table 5: Short-Term Trials Study Number Treatment Group Primary Efficacy Measure: ADHDRS-IV Total Score Mean Baseline LS Mean Change Placebo-subtracted Score (SD) from Baseline Differencea (95% CI) (SE) Study 1 Clonidine hydrochloride extended-release tablets 43.8 (7.47) -15.0 (1.38) -8.5 (-12.2, -4.8) (0.2 mg/day) Clonidine hydrochloride extended-release tablets 44.6 (7.73) -15.6 (1.33) -9.1 (-12.8, -5.5) (0.4 mg/day) Placebo 45.0 (8.53) -6.5 (1.35) ---------- Study 2 Clonidine hydrochloride extended-release tablets 38.9 (6.95) -15.8 (1.18) -4.5 (-7.8, -1.1) (0.4 mg/day) + Psychostimulant Psychostimulant alone 39.0 (7.68) -11.3 (1.24) ---------- a Difference (drug minus placebo) in least-squares mean change from baseline. SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. Maintenance Monotherapy for ADHD Study 3 was a double-blind, placebo-controlled, randomized-withdrawal study in pediatric patients 6 to 17 years (n=253) with DSM-IV-TR diagnosis of ADHD. The study consisted of a 10-week, open-label phase (4 weeks of dose optimization and 6 weeks of dose maintenance), a 26-week double-blind phase, and a 4-week taper-down and follow-up phase. All patients were initiated at 0.1 mg/day and increased at weekly intervals in increments of 0.1 mg/day until reaching personalized optimal dose (0.1, 0.2, 0.3 or 0.4 mg/day, as divided doses). Eligible patients had to demonstrate treatment response as defined by ≥ 30% reduction in ADHD-RS-IV total score and a Clinical Global Impression-Improvement score of 1 or 2 during the open label phase. Patients who sustained treatment response (n=135) until the end of the open label phase were randomly assigned to one of the two treatment groups, clonidine hydrochloride extended- release (N=68) and Placebo (N=67), to evaluate the long-term efficacy of maintenance dose of clonidine hydrochloride extended-release in the double-blind phase. The primary efficacy endpoint was the percentage of patients with treatment failure defined as a ≥ 30% increase (worsening) in ADHD-RS-IV total score and ≥ 2 points increase (worsening) in Clinical Global Impression – Severity Scale in 2 consecutive visits or early termination for any reason. A total of 73 patients experienced treatment failure in the double-blind phase: 31 patients (45.6%) in the clonidine hydrochloride extended-release group and 42 patients (62.7%) in the placebo group, with a statistically significant difference in the primary endpoint favoring clonidine (Table 7). Page 19 of 23 Reference ID: 5491889 The cumulative proportion of patients with treatment failure over time during the double-blind phase is displayed in Figure 2. Table 6: Treatment Failure: Double-Blind Full Analysis Set (Study 3) Study 3 Double-Blind Full Analysis Set Clonidine Hydrochloride Extended-Release Tablets Placebo Number of patients 68 67 Number of treatment failures 31 (45.6%) 42 (62.7%) Basis of Treatment Failure Clinical criteriaa,b 11 (16.2%) 9 (13.4%) Lack of efficacyc 1 (1.5%) 3 (4.5%) Withdrawal of informed assent/consent 4 (5.9%) 20 (29.9%) Other early terminations 15 (22.1%) 10 (14.9%) ADHD-RS-IV = Attention Deficit Hyperactivity Disorder-Rating Scale-4th edition; CGI-S = Clinical Global Impression-Severity a a At the same 2 consecutive visits a (1) 30% or greater reduction in ADHD-RS-IV, and (2) 2-point or more increase in CGI-S. bbTwo patients (1 placebo and 1 clonidine hydrochloride extended-release tablets) withdrew consent, but met the clinical criteria for treatment failure. c cThree patients (all placebo) discontinued the study due to treatment failure, but met only the criterion for ADHD-RS-IV. Page 20 of 23 Reference ID: 5491889 1 0 + Censored Q) 0.9 Clonidine Hydrochloride Extended-Release Tablets ... ::::, - Placebo ca LL ... 0 C Q) E ... ca 0.7 Q) ... I- .c .. , . ·- -+tt-+ ... -~ 0 t ' --- VI . ... - - C , .. Q) 0.5 ·,.:; ca . c.. .. - 0 0. r C - 0 .. - ~ .. I 0 I Q, 03 It 0 ... c.. "C 0. Q) ... ca E ·,.:; 0 1 VI w II II 00 ,. 0 20 40 60 80 100 120 a 160 180 200 22 Days from Randomization to Treatment Failure Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Pediatric Patients (6 to 17 Years) with Treatment Failure (Study 3) 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ONYDA XR (clonidine hydrochloride) extended-release oral suspension 0.1 mg/mL is a light beige to tan viscous suspension. ONYDA XR is supplied in 120 mL bottles with a child-resistant closure and is packaged in a carton with two oral dosing dispensers and two press in bottle adapters (NDC 24478-148-02). Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Page 21 of 23 Reference ID: 5491889 Store and dispense ONYDA XR in the original bottle. Dispense with bottle adapter and oral dosing dispenser supplied in the carton. Discard any unused ONYDA XR remaining in the bottle after 60 days of first opening the bottle. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Dosage and Administration Advise patients that ONYDA XR may be taken with or without food. When initiating treatment, provide titration instructions [see Dosage and Administration (2.1)]. Administration Instructions Instruct patients to read the “Instructions for Use” for complete administration instructions [see Dosage and Administration (2.2)]. Advise patients to: • firmly insert the bottle adapter into the bottle and do not remove the bottle adapter once inserted. Use the oral dispenser provided with ONYDA XR. • gently shake ONYDA XR with a smooth up and down motion (to avoid foaming) for at least 10 seconds before each administration. • discard any unused ONYDA XR after 60 days of opening the bottle. Missed Dose If patients miss a dose of ONYDA XR, advise them to skip the dose and take the next dose as scheduled and not to take more than the prescribed total daily amount of ONYDA XR in any 24-hour period [see Dosage and Administration (2.5)]. Hypotension/Bradycardia Advise patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, to avoid becoming dehydrated or overheated [see Warnings and Precautions (5.1)]. Sedation and Somnolence Instruct patients to use caution when driving a car or operating heavy equipment until they know how they will respond to treatment with ONYDA XR. Also advise patients to avoid the use of ONYDA XR with other centrally active depressants and with alcohol [see Warnings and Precautions (5.2)]. Rebound Hypertension Advise patients not to discontinue ONYDA XR abruptly [see Warnings and Precautions (5.3)]. Allergic Reactions Page 22 of 23 Reference ID: 5491889 Advise patients to discontinue ONYDA XR and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur, such as generalized rash, urticaria, or angioedema [see Warnings and Precautions (5.4)]. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ONYDA XR during pregnancy [see Use in Specific Populations (8.1)]. Lactation Advise breastfeeding women using ONYDA XR to monitor infants for excess sedation, decreased muscle tone, and respiratory depression and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)]. Fertility Advise females and males of reproductive potential that ONYDA XR may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. Manufactured by/Distributed by: Tris Pharma, Inc. Monmouth Junction, NJ 08852 www.trispharma.com LB8735 Rev. 01 Page 23 of 23 Reference ID: 5491889 PATIENT INFORMATION ONYDATM XR (oh-nee-dah) (clonidine hydrochloride) extended-release oral suspension What is ONYDA XR? ONYDA XR is a prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) alone or with certain other ADHD medicines in children 6 years of age and older. It is not known if ONYDA XR is safe and effective in children under 6 years of age. Who should not take ONYDA XR? Do not take ONYDA XR if you are allergic to clonidine. See the end of this Patient Information for a complete list of ingredients in ONYDA XR. Before taking ONYDA XR, tell your healthcare provider about all of your medical conditions, including if you: • have kidney problems • have low or high blood pressure • have a history of passing out (syncope) • have heart problems, including slow heart rate or other heart rhythm problems • had a stroke or have stroke symptoms • had an allergic reaction after taking clonidine through your skin in a transdermal system (patch) • are pregnant or plan to become pregnant. It is not known if ONYDA XR will harm the unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. o There is a pregnancy registry for females who are exposed to ADHD medications, including ONYDA XR, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to ONYDA XR and their baby. If you become pregnant during treatment with ONYDA XR, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhdmedications/ • are breastfeeding or plan to breastfeed. ONYDA XR passes into the breast milk. Babies who are breastfed during treatment with ONYDA XR may become very sleepy, develop relaxed or floppy muscles, and develop trouble breathing. Call the baby’s healthcare provider if the baby is breastfed during treatment with ONYDA XR and develops any of these symptoms. Talk to your healthcare provider about the best way to feed your baby if you take ONYDA XR. Tell your healthcare provider about all of the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ONYDA XR and certain other medicines may affect each other causing serious side effects. Especially tell your healthcare provider if you take: • anti-depression medicines • other medicines that contain clonidine • heart or blood pressure medicines • medicines that cause sleepiness (sedation) • other medicines for ADHD Ask your healthcare provider or pharmacist if you are not sure if your medicine is listed above. Know the medicines that you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist when you get a new medicine. How should I take ONYDA XR? • Take ONYDA XR 1 time daily at bedtime with or without food. • Take ONYDA XR exactly as your healthcare provider tells you. • Your healthcare provider may change your dose of ONYDA XR. Do not change your dose of ONYDA XR without talking to your healthcare provider. • If you are taking another clonidine medicine, stop taking it before you start treatment with ONYDA XR. • The dose of ONYDA XR is not the same as other clonidine medicines. Do not change between ONYDA XR and other clonidine medicines unless your healthcare provider tells you. • Do not stop taking ONYDA XR without talking to your healthcare provider. • If you miss a dose of ONYDA XR, skip the missed dose and take the next dose at their regular scheduled time. Do not take more ONYDA XR in a 24-hour period than your healthcare provider prescribed for your daily dose. • Throw away (discard of) any remaining ONYDA XR if you have not used it after 60 days of first opening the bottle. • See the detailed Instructions for Use for information on how to take a dose of ONYDA XR. If you take too much ONYDA XR, call your healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest hospital emergency room right away. Reference ID: 5491889 What should I avoid while taking ONYDA XR? • Do not become dehydrated or too hot (overheated) to decrease your chance of passing out during treatment with ONYDA XR. • Do not drive, operate heavy machinery, or do other dangerous activities until you know how ONYDA XR affects you because ONYDA XR can cause sleepiness and tiredness that could cause slow reaction times. • Do not drink alcohol or take other medicines that make you sleepy or dizzy during treatment with ONYDA XR until you talk with your healthcare provider. Taking ONYDA XR with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse. What are possible side effects of ONYDA XR? ONYDA XR may cause serious side effects, including: • Decreased blood pressure and heart rate. ONYDA XR can decrease your blood pressure and heart rate, which can increase your chance of passing out (syncope). If you have a history of passing out or have other medical problems or take other medicines that increase your risk of passing out, your risk is higher. Your healthcare provider should check your heart rate and blood pressure before starting treatment and regularly during treatment with ONYDA XR. See “What should I avoid while taking ONYDA XR?” • Sleepiness and tiredness that could cause slow reaction times (sedation and somnolence). See “What should I avoid while taking ONYDA XR?” • Rebound high blood pressure (hypertension). Suddenly stopping ONYDA XR can cause high blood pressure to return if you have a history of high blood pressure. Suddenly stopping ONYDA XR may also cause withdrawal symptoms including headache, increased heart rate, nausea, flushing or warm feeling, lightheadedness, tightness in your chest and nervousness or anxiety. Do not suddenly stop ONYDA XR treatment without first talking to your healthcare provider. • Allergic reactions. You may develop an allergic reaction to ONYDA XR if you had an allergic reaction to clonidine taken through your skin in a patch. Stop taking ONYDA XR and call your healthcare provider right away or go to the nearest emergency room if you develop any signs or symptoms of an allergic reaction, including: o skin rash o hives o swelling of the eyes, face, lips, or tongue The most common side effects of ONYDA XR when used alone include: • falling asleep or sleepiness and • nightmare • constipation tiredness that could cause slow • trouble sleeping • dry mouth reaction times • irritability The most common side effects of ONYDA XR when used with other ADHD medicines include: • falling asleep or sleepiness and • decreased appetite • dizziness tiredness that could cause slow reaction times ONYDA XR may cause fertility problems in females and males, which may affect your ability to have a child. Talk to your healthcare provider if this is a concern for you. These are not all of the possible side effects of ONYDA XR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ONYDA XR? • Store ONYDA XR at room temperature between 68°F to 77°F (20°C to 25°C). • Protect from light and keep ONYDA XR in the original container. Tightly close the child-resistant cap. • Throw away (discard of) any remaining ONYDA XR if you have not used it after 60 days of first opening the bottle. Keep ONYDA XR and all medicines out of the reach of children. General information about the safe and effective use of ONYDA XR. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ONYDA XR for a condition for which it was not prescribed. Do not give ONYDA XR to other people, even if they have the same symptoms that you have. It may harm them. You can also ask your pharmacist or healthcare provider for information about ONYDA XR that is written for health professionals. What are the ingredients in ONYDA XR? Active Ingredient: clonidine hydrochloride Inactive Ingredients: anhydrous citric acid, edetate disodium, glycerin, modified starch, methylparaben, orange flavor, polyvinyl acetate dispersion 30%, povidone, polysorbate 80, propylparaben, purified water, sucrose, sodium polystyrene sulfonate, triacetin, and xanthan gum Manufactured by/Distributed by: Tris Pharma, Inc. Monmouth Junction, NJ 08852 www.trispharma.com For more information about ONYDA XR call 1-732-940-0358. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 5/2024 Reference ID: 5491889 Oral dosing syringe -Bottle White end of plunger I Barrel / . Ip Bottle Adapter INSTRUCTIONS FOR USE ONYDATM XR (oh-nee-dah) (clonidine hydrochloride) extended-release oral suspension This Instructions for Use contains information on how to take ONYDA XR. Important Information You Need to Know Before Taking ONYDA XR: • ONYDA XR is for oral use only (taken by mouth). • Take ONYDA XR with or without food. • Use only the oral dosing syringe and bottle adapter that come with ONYDA XR to measure and take a dose of ONYDA XR. • Shake the ONYDA XR bottle gently. • Check the expiration date (EXP) on the carton label. Do not take ONYDA XR after the expiration date has passed. Call your healthcare provider or pharmacist if your medicine is expired. • Throw away (discard of) any remaining ONYDA XR if you have not used it after 60 days of first opening the bottle. Supplies included in the ONYDA XR carton: • 1 bottle of ONYDA XR • 2 oral dosing syringes • 2 bottle adapters Figure A Reference ID: 5491889 bottle neck Step 1: Figure B Preparing to take ONYDA XR: • Wash and dry your hands (see Figure B). • Remove the ONYDA XR bottle, 1 oral dosing syringe, and 1 bottle adapter from the carton. Tell your pharmacist right away if you are missing any supplies from the carton. Step 2: • Place the ONYDA XR bottle on a flat surface like a table or countertop and remove the child resistant cap by pressing down and turning counterclockwise (see Figure C). Insert the bottle adapter (first time use only). • Hold the bottle firmly and insert the ridged end of the bottle adapter into the neck of the bottle. • Firmly push the bottle adapter all the way down with your thumb until the top of the adapter is aligned and flat (flush) with the top of the bottle (See Figure D). • Do not remove the bottle adapter once it has been inserted into the bottle. Figure C Figure D Reference ID: 5491889 shake well £~n ~ ' Step 3: • Put the cap back on the bottle and close it tightly by turning the cap clockwise (see Figure E). Figure E • Shake the bottle gently with a smooth up and down motion to avoid foaming (see Figure F). • Shake the bottle gently for at least 10 seconds before you take each dose. Figure F Step 4: • Place the ONYDA XR bottle upright on the table or countertop. Open the cap again by pressing down and turn counterclockwise to remove the cap (see Figure G). Figure G Reference ID: 5491889 Step 5: • Check the ONYDA XR oral dosing syringe to find the right dose in milliliters (mL) that has been prescribed by the healthcare provider (see Figure H). • Make sure the oral dosing syringe is dry. Figure H Step 6: • Insert the tip of the oral dosing syringe through the adapter into the bottle (see Figure I). • Push the plunger all the way down (see Figure J). Figure I Figure J Reference ID: 5491889 measure to white end 7 of plunger Step 7: Measuring the dose of ONYDA XR: • With the tip of the oral dosing syringe in place in the adapter, hold the ONYDA XR bottle with 1 hand and turn the bottle upside down. Pull the plunger down until the white end of the plunger reaches the number of mL you need for the prescribed dose (see Figure K). • Push and pull the plunger a few times to make sure that there are no air bubbles. • Tap the barrel of the oral dosing syringe if needed to get rid of any air bubbles (see Figure L). Figure K Figure L Step 8: • Turn the bottle over and place it upright on a table or countertop, then remove the oral dosing syringe from the bottle adapter (see Figure M). Figure M Reference ID: 5491889 Step 9: Figure N • Check that the correct dose in mL was pulled up into the oral dosing syringe (see Figure N). • If the dose is not correct: o Insert the oral syringe tip back into the bottle and fully push in the plunger to the bottom of the syringe barrel so that all of the oral suspension flows back into the bottle. o Repeat Steps 6 through 8. Step 10: Figure O Taking the dose of ONYDA XR: • The child should be in a seated position before taking ONYDA XR. • Tilt the head slightly upwards. • Place the oral dosing syringe into the mouth and point it toward the cheek (see Figure O). • Close the mouth tightly around the oral dosing syringe and slowly push the plunger all the way down to give the ONYDA XR dose (see Figure P). • After all the medication has been taken, remove the oral dosing syringe from the mouth. Figure P Reference ID: 5491889 Step 11: Closing the bottle: • Put the ONYDA XR cap back on the bottle and close the cap tightly by turning the cap clockwise (see Figure Q). Figure Q Step 12: Cleaning up: • Clean the oral dosing syringe after each use by rinsing with tap water (see Figure R). • Allow the oral dosing syringe to dry and keep it in a safe place for the next use. • Wash and dry your hands. Figure R Disposing of ONYDA XR: • Throw away any unused or expired ONYDA XR in your household trash. • Throw away any remaining ONYDA XR if you have not used it 60 days after first opening the bottle. Storing ONYDA XR: • Store ONYDA XR at room temperature between 68°F to 77°F (20°C to 25°C). • Protect from light and keep ONYDA XR in the original container. Tightly close the child- resistant cap. Keep ONYDA XR and all medicines out of the reach of children. Manufactured by/Distributed by: Tris Pharma, Inc. Monmouth Junction, NJ 08852 Rev. 00 This Instructions for Use has been approved by the U.S. Food and Drug Administration Approved: 5/2024 Reference ID: 5491889
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FORANE safely and effectively. See full prescribing information for FORANE. FORANE (isoflurane, USP) liquid for inhalation Initial U.S. Approval: 1979 ----------------------------INDICATIONS AND USAGE--------------------------­ FORANE, a general anesthetic, is an inhalation agent indicated for induction and maintenance of general anesthesia. (1) ----------------------DOSAGE AND ADMINISTRATION----------------------­ • FORANE should be administered only by persons trained in the administration of general anesthesia. FORANE should only be delivered using a vaporizer specifically designed and designated for use with isoflurane. (2) • The administration of general anesthesia must be individualized and titrated based on the patient’s age and clinical status. (2) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ Liquid (stable): 100% (3) -------------------------------CONTRAINDICATIONS-----------------------------­ • Patients in whom general anesthesia is contraindicated (4) • Patients with known sensitivity to FORANE or other halogenated agents (4) • Patients with known or suspected genetic susceptibility to malignant hyperthermia (4) • Patients with a history of confirmed hepatitis due to a halogenated inhalational anesthetic or a history of unexplained moderate to severe hepatic dysfunction (e.g., jaundice associated with fever and/or eosinophilia) after anesthesia with FORANE or other halogenated inhalational anesthetics (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ • Malignant Hyperthermia: Malignant hyperthermia may occur, especially in individuals with known or suspected susceptibility based on genetic factors or family history. Discontinue triggering agents, administer intravenous dantrolene sodium, and apply supportive therapies. (5.1) • Perioperative Hyperkalemia: Perioperative hyperkalemia may occur. Patients with latent or overt neuromuscular disease, particularly with Duchenne muscular dystrophy, appear to be most vulnerable. Early, aggressive intervention is recommended. (5.2) • Hepatic Reactions: May cause sensitivity hepatitis in patients sensitized by previous exposure to halogenated anesthetics. Approach repeated anesthesia with caution. (5.3) • Hypersensitivity Reactions: Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with isoflurane. (5.4) • Abortions: Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions. (5.5) • QT Prolongation: Carefully monitor cardiac rhythm when administering FORANE to susceptible patients. (5.6) • Interactions with Desiccated Carbon Dioxide (CO2) Absorbents: May react with desiccated CO2 absorbents to produce carbon monoxide. Replace desiccated CO2 absorbent before administration of FORANE. (5.7) • Pediatric Neurotoxicity: In developing animals, exposures greater than 3 hours cause neurotoxicity. Weigh benefits against potential risks when considering elective procedures in children under 3 years old. (5.8) ------------------------------ADVERSE REACTIONS------------------------------­ Most common adverse reactions (incidence  5%) are agitation, cough, breath holding, nausea, chills/shivering, vomiting, laryngospasm, delirium. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-800-262-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------­ • Concomitant use of N2O and/or opioids reduces the MAC of FORANE. Adjust dose accordingly. (7.1, 7.2) • FORANE decreases the doses of neuromuscular blocking agents required. Adjust dose accordingly. (7.3) -----------------------USE IN SPECIFIC POPULATIONS-----------------------­ • Geriatric Use: The minimum alveolar concentration (MAC) of FORANE decreases with increasing patient age. (8.5) See 17 for PATIENT COUNSELING INFORMATION. Revised: xx/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information 2.2 Premedication 2.3 Induction 2.4 Maintenance 2.5 Use in Patients with Coronary Artery Disease 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Malignant Hyperthermia 5.2 Perioperative Hyperkalemia 5.3 Hepatic Reactions 5.4 Hypersensitivity Reactions 5.5 Abortions 5.6 QT Prolongation 5.7 Interactions with Desiccated Carbon Dioxide Absorbents 5.8 Pediatric Neurotoxicity 5.9 Laboratory Tests 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-Marketing Experience 7 DRUG INTERACTIONS 7.1 Opioids 7.2 Nitrous Oxide 7.3 Neuromuscular Blocking Agents 7.4 Adrenaline 7.5 Calcium Antagonists 7.6 Concomitant use with Beta Blockers 7.7 Concomitant use with MAO Inhibitors 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safety and Handling 16.2 Storage 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed Reference ID: 5492186 FULL PRESCRIBING INFORMATION 1. INDICATIONS AND USAGE FORANE (isoflurane, USP) may be used for induction and maintenance of general anesthesia. Adequate data have not been developed to establish its application in obstetrical anesthesia. 2. DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information Isoflurane should be administered only by persons trained in the administration of general anesthesia. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Isoflurane is administered by inhalation. Isoflurane should be delivered from a vaporizer specifically designed for use with isoflurane. Dosage for induction and maintenance must be individualized and titrated to the desired effect according to the patient’s age and clinical status. With the exception of neonates, the minimum alveolar concentration (MAC) of isoflurane decreases with increasing patient age. Nitrous oxide decreases the MAC of isoflurane (see Table 1). Opioids decrease the MAC of isoflurane [see Drug Interactions (7)]. Isoflurane potentiates the muscle relaxant effect of all neuromuscular blockers and decreases the required doses of neuromuscular blocking agents [see Drug Interactions (7)] . The dose should be adjusted accordingly. All patients anesthetized with isoflurane should be continually monitored (e.g., monitoring of the electrocardiogram, blood pressure, oxygen saturation, and end tidal CO2). Isoflurane is a profound respiratory depressant. Excessive respiratory depression may be related to depth of anesthesia and respond to decreasing the inspired concentration of isoflurane. The depressant effect is accentuated by concurrent use of opioids and other respiratory depressants. Respiration should be closely monitored and assisted or controlled ventilation employed when necessary. 2.2 Premedication Premedication should be selected according to the need of the individual patient, taking into account that secretions are weakly stimulated by FORANE, and the heart rate tends to be increased. 2.3 Induction Induction with isoflurane in oxygen or in combination with oxygen-nitrous oxide mixtures may produce coughing, breath holding, laryngospasm and bronchospasm, which Reference ID: 5492186 increases with the concentration of isoflurane. These difficulties may be avoided by the use of a hypnotic dose of an ultra-short-acting barbiturate. Inspired concentrations of 1.5 to 3% isoflurane usually produce surgical anesthesia in 7 to 10 minutes. 2.4 Maintenance Isoflurane MAC values according to age are shown below: Table 1: Effect of Age on Minimum Alveolar Concentration of Isoflurane Age Average MAC Value In 100% Oxygen Average MAC Value In 30% Oxygen and 70% N2O Preterm neonates less than 32 weeks gestational age 1.28% Preterm neonates 32-37 weeks gestational age 1.41% 0-1 month 1.60% 1-6 months 1.87% 6-12 months 1.80% 1-5 years 1.60% 6-10 years 1.45% 11-18 years 1.38% 19-30 years 1.28% 0.56% 31-55 years 1.15% 0.50% 55-83 years 1.05% 0.37% Dosage for induction and maintenance must be individualized and titrated to the desired effect according to the patient’s age and clinical status. Surgical levels of anesthesia may be sustained with a 1 to 2.5% concentration when nitrous oxide is used concomitantly. An additional 0.5 to 1% may be required when isoflurane is given using oxygen alone. If added relaxation is required, supplemental doses of neuromuscular blocking agents may be used. The level of blood pressure during maintenance is an inverse function of isoflurane concentration in the absence of other complicating problems. Excessive decreases may be due to depth of anesthesia and in such instances may be corrected by lightening anesthesia. Reference ID: 5492186 - Isoflurane causes a dose-dependent reduction in systemic vascular resistance and blood pressure. Particular care must be taken when selecting the dosage for patients who are hypovolemic, hypotensive, or otherwise hemodynamically compromised, e.g., due to concomitant medications. FORANE markedly increases cerebral blood flow at deeper levels of anesthesia to produce a transient increase in intracranial pressure. In patients with or at risk for elevations of intracranial pressure (ICP), administer isoflurane in conjunction with ICP- reducing strategies, as clinically appropriate. 2.5 Use in Patients with Coronary Artery Disease Regardless of the anesthetics employed, maintenance of normal hemodynamics is important to the avoidance of myocardial ischemia in patients with coronary artery disease. Isoflurane can cause dose-dependent coronary vasodilation and has been shown to divert blood from collateral-dependent myocardium to normally perfused areas in an animal model (“coronary steal”). The extent to which coronary steal occurs in patients with steal- prone coronary anatomy is unclear. Monitor for signs of inadequate myocardial perfusion via hemodynamic monitors (e.g., ECG, blood pressure) during isoflurane administration. Consider additional cardiac monitoring in patients with known coronary artery disease, as clinically necessary. 3. DOSAGE FORMS AND STRENGTHS Isoflurane is a clear, colorless, stable liquid containing no additives or chemical stabilizers, 100% isoflurane. 4. CONTRAINDICATIONS FORANE is contraindicated in patients: • in whom general anesthesia is contraindicated. • with known sensitivity to FORANE or to other halogenated agents [see Warnings and Precautions (5.3)]. • with known or suspected genetic susceptibility to malignant hyperthermia [see Warnings and Precautions (5.1), Clinical Pharmacology (12.5)]. Reference ID: 5492186 • with a history of confirmed hepatitis due to a halogenated inhalational anesthetic or a history of unexplained moderate to severe hepatic dysfunction (e.g., jaundice associated with fever and/or eosinophilia) after anesthesia with isoflurane or other halogenated inhalational anesthetics. 5. WARNINGS AND PRECAUTIONS 5.1 Malignant Hyperthermia In susceptible individuals, volatile anesthetic agents, including FORANE, may trigger malignant hyperthermia, a skeletal muscle hypermetabolic state leading to high oxygen demand. Fatal outcomes of malignant hyperthermia have been reported. The risk of developing malignant hyperthermia increases with the concomitant administration of succinylcholine and volatile anesthetic agents. FORANE can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants [see Contraindications (4), Clinical Pharmacology (12.5)]. Signs consistent with malignant hyperthermia may include hyperthermia, hypoxia, hypercapnia, muscle rigidity (e.g., jaw muscle spasm), tachycardia (e.g., particularly that unresponsive to deepening anesthesia or analgesic medication administration), tachypnea, cyanosis, arrhythmias, hypovolemia, and hemodynamic instability. Skin mottling, coagulopathies, and renal failure may occur later in the course of the hypermetabolic process. Successful treatment of malignant hyperthermia depends on early recognition of the clinical signs. If malignant hyperthermia is suspected, discontinue all triggering agents (i.e., volatile anesthetic agents and succinylcholine), administer intravenous dantrolene sodium, and initiate supportive therapies. Consult prescribing information for intravenous dantrolene sodium for additional information on patient management. Supportive therapies include administration of supplemental oxygen and respiratory support based on clinical need, maintenance of hemodynamic stability and adequate urinary output, management of fluid and electrolyte balance, correction of acid base derangements, and institution of measures to control rising temperature. 5.2 Perioperative Hyperkalemia Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular Reference ID: 5492186 disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. 5.3 Hepatic Reactions Cases of mild, moderate and severe postoperative hepatic dysfunction or hepatitis with or without jaundice, including fatal hepatic necrosis and hepatic failure, have been reported with isoflurane. Such reactions can represent hypersensitivity hepatitis, a known risk of exposure to halogenated anesthetics, including isoflurane. As with other halogenated anesthetic agents, FORANE may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics [see Contraindications (4)]. Clinical judgment should be exercised when isoflurane is used in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction. [see Contraindications (4)]. As with all halogenated anesthetics, repeated anesthetics within a short period of time may result in increased effects, particularly in patients with underlying hepatic conditions, or additive effects in patients treated with drugs known to cause hepatic dysfunction. Evaluate the need for repeated exposure in each individual patient and adjust the dose of isoflurane based on signs and symptoms of adequate depth of anesthesia if repeated exposure in a short period of time is clinically indicated. 5.4 Hypersensitivity Reactions Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with isoflurane. Manifestations of such reactions have included hypotension, rash, difficulty breathing and cardiovascular collapse 5.5 Abortions Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions. Reference ID: 5492186 5.6 QT Prolongation QT prolongation, with rare instances of torsade de pointes, have been reported. Monitor QT interval when administering isoflurane to susceptible patients (e.g., patients with congenital Long QT Syndrome or patients taking drugs that can prolong the QT interval). 5.7 Interactions with Desiccated Carbon Dioxide Absorbents FORANE, like some other inhalational anesthetics, can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide, which may result in elevated levels of carboxyhemoglobin in some patients. Barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO2 absorber canister at high flow rates over many hours or days. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of FORANE. The color indicator of most CO2 absorbents does not necessarily change as a result of desiccation. Therefore, the lack of significant color change should not be taken as assurance of adequate hydration of the CO2 absorbent material. CO2 absorbents should be replaced routinely regardless of the state of color indicator following current manufacturer’s guidelines for use of anesthesiology equipment. 5.8 Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see Use in Specific Populations (8.1,8.4), Nonclinical Toxicology (13.2)]. Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications Reference ID: 5492186 have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks. 5.9 Laboratory Tests Transient increases in BSP retention, blood glucose and serum creatinine with decrease in BUN, serum cholesterol and alkaline phosphatase have been observed. 6. ADVERSE REACTIONS 6.1 Clinical Trials Experience The following adverse reactions were identified from controlled clinical trials of adult and pediatric subjects exposed to FORANE. The trials were conducted using a variety of pre-medications, other anesthetics, and surgical procedures of varying lengths. The most serious reported adverse reactions in alphabetical order are agitation, arrhythmia, breath holding, elevated liver enzyme, hypotension and laryngospasm. The most frequent adverse reactions (incidence  5%) described in Table 1 are agitation, breath holding, chills/shivering, cough, delirium, laryngospasm, nausea, and vomiting. Adverse reactions with an incidence between 1% and 5% are provided in Table 2. Adverse reactions with an incidence less than 1% are provided in Table 3. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 2: Adverse Reactions  5% System Organ Class (SOC) Adverse Reaction Frequency PSYCHIATRIC DISORDERS Delirium 6.2% (N=2830) NERVOUS SYSTEM DISORDERS Agitation (Excitement) Induction 51.8% (N=515) 1 RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Breath holding Induction 23.9% (N=515) 1 Cough Induction 28.2% (N=515) 1 Reference ID: 5492186 System Organ Class (SOC) Adverse Reaction Frequency Laryngospasm Induction 8.0% (N=515) 1 GASTROINTESTINAL DISORDERS Nausea Recovery 15.4 % (N=2830) Vomiting Recovery 9.5% (N=2830) GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS Chills/shivering 14.0% (N=1691) 2 1 Represents patients not receiving intravenous agents or neuromuscular blocking agents for intubation (i.e., patients receiving inhalation induction). 2 Reflects the number of patients with recorded body temperature measurements. Table 3: Adverse Reactions between 1% and 5% System Organ Class (SOC) Adverse Reaction Frequency NERVOUS SYSTEM DISORDERS Movement Maintenance 1.8% (N=2830) CARDIAC DISORDERS Ventricular arrhythmia Induction 2.1% (N=2161) (Intraoperative) Maintenance 2.7% (N=2253) Nodal arrhythmia (Intraoperative) Induction 4.0% (N=2161) Maintenance 1.7% (N=2253) Atrial arrhythmia (Intraoperative) Induction 1.6% (N=2161) Maintenance 2.2% (N=2253) Arrhythmia (Postoperative) 1.1% (N=2830) RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Breath holding Maintenance 1.1% (N=359) 1 Cough Maintenance 4.2 % (N=359) 1 1 Represents patients not receiving intravenous agents or neuromuscular blocking agents for intubation (i.e., patients receiving inhalation induction). Table 4: Adverse Reactions less than 1% Reference ID: 5492186 System Organ Class (SOC) Adverse Reaction Frequency PSYCHIATRIC DISORDERS Mood changes 0.3% (N=2830) Nightmare 0.4% (N=2175) 1 NERVOUS SYSTEM DISORDERS Convulsive pattern on electroencephalogram 0.5% (N=200) 2 Seizure 0.04% (N=2830) VASCULAR DISORDERS Hypotension Postoperative 0.3% (N=2830) Hypertension Postoperative 0.1% (N=2830) RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Laryngospasm Maintenance 0.8% (N=359) 3 Secretions Induction 0.2% (N=515) 3 Maintenance 0.0% (N=359) 3 GASTROINTESTINAL DISORDERS Vomiting Induction 0.8% (N=515) 3 Retching Induction 1.0% (N=515) 3 Maintenance 0.8% (N=359) 3 SKIN AND SUBCUTANEOUS TISSUE DISORDERS Diaphoresis Induction 0.2% (N=515) 3 Maintenance 0.0% (N=359) 3 1 Reflects the number of patients interviewed by a physician in the recovery period. 2 Reflects the number of recorded electroencephalograms. 3 Represents patients not receiving intravenous agents or neuromuscular blocking agents for intubation (i.e., patients receiving inhalation induction). The following adverse reactions (see Table 5) were observed, but due to limited data, frequency could not be determined. Table 5: Adverse Reactions with Unknown Frequency BLOOD AND LYMPHATIC SYSTEM DISORDERS: White blood cell count increased METABOLISM AND NUTRITION DISORDERS: Blood glucose increased Reference ID: 5492186 PSYCHIATRIC DISORDERS: Confused state, Nervousness NERVOUS SYSTEM DISORDERS: Ataxia; Dizziness; Drowsiness; Intellectual function decrease VASCULAR DISORDERS: Hypotension (Intraoperative); Hypertension (Intraoperative) HEPATOBILIARY DISORDERS: Blood bilirubin increased; Bromsulphthalein clearance decreased; Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood alkaline phosphatase increased; Blood lactate dehydrogenase increased MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS: Myalgia GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS: Asthenia; Fatigue 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of FORANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Post-marketing adverse reactions are listed by MedDRA System Organ Class (SOC), then by preferred term in order of decreasing severity. BLOOD AND LYMPHATIC SYSTEM DISORDERS: Carboxyhemoglobin increased IMMUNE SYSTEM DISORDERS: Anaphylactic reaction METABOLISM AND NUTRITION DISORDERS: Hyperkalemia in patients with underlying myopathies PSYCHIATRIC DISORDERS: Withdrawal syndrome (following multi-day exposure; symptoms include seizure, hallucination, ataxia, agitation, confusion) NERVOUS SYSTEM DISORDERS: Brain edema, Intracranial pressure increased, Migraine, Myoclonus, Nystagmus, Pupils unequal, Headache CARDIAC DISORDERS: Cardiac arrest, Ventricular fibrillation, Torsade de pointes, Myocardial infarction, Myocardial ischemia, Atrioventricular block complete, Atrioventricular block second degree, Atrial fibrillation, Electrocardiogram QT Reference ID: 5492186 prolonged, Atrioventricular block first degree, Ventricular tachycardia, Ventricular extrasystoles, Tachycardia, Bradycardia, Cardiac output decreased VASCULAR DISORDERS: Flushing RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Apnea, Hypoxia, Bronchospasm, Airway obstruction, Respiratory depression, Hypercapnia, Stridor, Hiccough GASTROINTESTINAL DISORDERS: Pancreatitis HEPATOBILIARY DISORDERS: Hepatic necrosis, Hepatic failure, Hepatitis fulminant, Cholestatic hepatitis, Hepatitis, Hepatic steatosis, Jaundice, Gamma­ glutamyltransferase increased SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Rash MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS: Rhabdomyolysis RENAL AND URINARY DISORDERS: Acute renal failure**, Oliguria** GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Malignant hyperthermia, hypothermia INJURY, POISONING, AND PROCEDURAL COMPLICATIONS*: Unwanted awareness during anesthesia; Dyspnea, Bronchospasm, Stridor, Cough, Dizziness, Paresthesia, Hepatic reactions, Flushing, Rash, Contact dermatitis, Erythema, Periorbital edema, Eye irritation, Conjunctival hyperemia, Headache *All reactions categorized within this SOC, with the exception of, Unwanted awareness during anesthesia, were from occupational exposure in non-patients. **Cases of acute renal failure and oliguria have been reported after isoflurane anesthesia. These events may be secondary to hypotension or other effects of isoflurane. 7. DRUG INTERACTIONS 7.1 Opioids Reference ID: 5492186 Opioids decrease the Minimum Alveolar Concentration (MAC) of isoflurane. Opioids such as fentanyl and its analogues, when combined with isoflurane, may lead to a synergistic fall in blood pressure and respiratory rate. 7.2 Nitrous Oxide Nitrous oxide decreases the MAC of isoflurane [see Dosage and Administration (2.1)]. 7.3 Neuromuscular Blocking Agents Isoflurane potentiates the muscle relaxant effect of all neuromuscular blocking agents and decreases the required doses of neuromuscular blocking agents. In general, anesthetic concentrations of isoflurane at equilibrium reduce the ED95 of succinylcholine, atracurium, pancuronium, rocuronium and vecuronium by approximately 25 to 40% or more compared to N2O/opioid anesthesia. If added relaxation is required, supplemental doses of neuromuscular blocking agents may be used. 7.4 Adrenaline Isoflurane is similar to sevoflurane in the sensitization of the myocardium to arrhythmogenic effect of exogenously administered adrenaline. Doses of adrenaline greater than 5mcg/kg, when administered submucosally may produce multiple ventricular arrhythmias. 7.5 Calcium Antagonists Isoflurane may lead to marked hypotension in patients treated with calcium antagonists. 7.6 Concomitant use with Beta Blockers Concomitant use of beta blockers may exaggerate the cardiovascular effects of inhalational anesthetics, including hypotension and negative inotropic effects. 7.7 Concomitant use with MAO Inhibitors Concomitant use of MAO inhibitors and inhalational anesthetics may increase the risk of hemodynamic instability during surgery or medical procedures. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Reference ID: 5492186 --- There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, embryofetal toxicity was noted in pregnant mice exposed to 0.075% (increased post implantation losses) and 0.3% isoflurane (increased post implantation losses and decreased livebirth index) during organogenesis. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15­ 20%, respectively. Data Animal Data Pregnant rats were exposed to isoflurane at concentrations of 0%, 0.1%, or 0.4% for two hours per day during organogenesis (Gestational Days 6-15). Isoflurane did not cause malformations or clear maternal toxicity under these conditions. Pregnant mice exposed to isoflurane at concentrations of 0%, 0.075%, or 0.30% for 2 hours per day during organogenesis (Gestational Days 6-15). Isoflurane increased fetal toxicity (higher post implantation losses at 0.075 and 0.3% groups and significantly lower live-birth index in the 0.3% isoflurane treatment group). Isoflurane did not cause malformations or clear maternal toxicity under these conditions. Pregnant rats were exposed to concentrations of isoflurane at 0%, 0.1%, or 0.4% for 2 hours per day during late gestation (GD 15-20). Animals appeared slightly sedated during exposure. No adverse effects on the offspring or evidence of maternal toxicity were reported. This study did not evaluate neurobehavioral function including learning and memory in the first generation (F1) of pups. In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the Reference ID: 5492186 fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits [see Warnings and Precautions (5.8), Nonclinical Toxicology (13.2)]. 8.2 Lactation Due to insufficient information regarding the excretion of isoflurane in human milk, the potential risks and benefits for each specific patient should be carefully considered before isoflurane is administered to nursing women. 8.4 Pediatric Use During the induction of anesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of larynogospasm, particularly in children. Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as FORANE, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans. In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data [see Warnings and Precautions (5.8), Nonclinical Toxicology (13.2)]. Reference ID: 5492186 F H F I I I F-C-C-0-C-H I I I F Cl F 8.5 Geriatric Use The minimum alveolar concentration (MAC) of isoflurane decreases with increasing patient age. The dose should be adjusted accordingly [see Dosage and Administration (2.4)]. 10. OVERDOSAGE The symptoms of overdosage of FORANE can present as a deepening of anesthesia, cardiac and/or respiratory depression in spontaneously breathing patients, and cardiac depression in ventilated patients in whom hypercapnia and hypoxia may occur only at a late stage. In the event of overdosage, or what may appear to be overdosage, the following action should be taken, as appropriate: Stop drug administration, establish a clear airway, and initiate assisted or controlled ventilation with pure oxygen. Monitor cardiovascular function and manage signs of poor end-organ perfusion as clinically indicated. 11. DESCRIPTION FORANE (isoflurane, USP), a nonflammable liquid administered by vaporizing, is a general inhalation anesthetic drug. It is 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether, and its structural formula is: Some physical constants are: Molecular weight Boiling point at 760 mm Hg 20 Refractive index n 𝐷 184.5 48.5°C 1.2990-1.3005 Specific gravity 25°/25°C Vapor pressure in mm Hg** 20°C 25°C 1.496 238 295 30°C 367 35°C 450 **Equation for vapor pressure calculation: Reference ID: 5492186 - log10Pvap = A + B where: A = 8.056 T B = −1664.58 T = °C + 273.16 (Kelvin) Partition coefficients at 37°C Water/gas 0.61 Blood/gas 1.43 Oil/gas 90.8 Partition coefficients at 25°C - rubber and plastic Conductive rubber/gas 62.0 Butyl rubber/gas 75.0 Polyvinyl chloride/gas 110.0 Polyethylene/gas ~2.0 Polyurethane/gas ~1.4 Polyolefin/gas ~1.1 Butyl acetate/gas ~2.5 Purity by gas chromatography >99.9% Lower limit of flammability in None oxygen or nitrous oxide at 9 joules/sec. and 23°C Lower limit of flammability in Greater than useful oxygen or nitrous oxide at 900 concentration in joules/sec. and 23°C anesthesia. Isoflurane is a clear, colorless, stable liquid containing no additives or chemical stabilizers. Isoflurane has a mildly pungent, musty, ethereal odor. Samples stored in indirect sunlight in clear, colorless glass for five years, as well as samples directly exposed for 30 hours to a 2 amp, 115 volt, 60 cycle long wave U.V. light were unchanged in composition as determined by gas chromatography. Isoflurane in one normal sodium methoxide-methanol solution, a strong base, for over six months consumed essentially no alkali, indicative of strong base stability. Isoflurane does not decompose in the presence of soda lime (at normal operating temperatures), and does not attack aluminum, tin, brass, iron or copper. 12. CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Induction of and recovery from isoflurane anesthesia are rapid. Isoflurane has a mild pungency which limits the rate of induction, although excessive salivation or Reference ID: 5492186 tracheobronchial secretions do not appear to be stimulated. Pharyngeal and laryngeal reflexes are readily obtunded. The level of anesthesia may be changed rapidly with isoflurane. Isoflurane is a profound respiratory depressant. As anesthetic dose is increased, tidal volume decreases and respiratory rate is unchanged. This depression is partially reversed by surgical stimulation, even at deeper levels of anesthesia. Isoflurane evokes a sigh response reminiscent of that seen with diethyl ether and enflurane, although the frequency is less than with enflurane. Blood pressure decreases with induction of anesthesia but returns toward normal with surgical stimulation. Progressive increases in depth of anesthesia produce corresponding decreases in blood pressure. Nitrous oxide diminishes the inspiratory concentration of isoflurane required to reach a desired level of anesthesia and may reduce the arterial hypotension seen with isoflurane alone. Heart rhythm is remarkably stable. With controlled ventilation and normal PaCO2, cardiac output is maintained despite increasing depth of anesthesia, primarily through an increase in heart rate which compensates for a reduction in stroke volume. The hypercapnia which attends spontaneous ventilation during isoflurane anesthesia further increases heart rate and raises cardiac output above awake levels. Muscle relaxation is often adequate for intra-abdominal operations at normal levels of anesthesia. Complete muscle paralysis can be attained with small doses of neuromuscular blocking agents. ALL COMMONLY USED NEUROMUSCULAR BLOCKING AGENTS ARE MARKEDLY POTENTIATED WITH ISOFLURANE, THE EFFECT BEING MOST PROFOUND WITH THE NONDEPOLARIZING TYPE. Neostigmine reverses the effect of nondepolarizing neuromuscular blocking agents in the presence of isoflurane. All commonly used neuromuscular blocking agents are compatible with isoflurane. Isoflurane can produce coronary vasodilation at the arteriolar level in selected animal models; the drug is probably also a coronary dilator in humans. Isoflurane, like some other coronary arteriolar dilators, has been shown to divert blood from collateral dependent myocardium to normally perfused areas in an animal model (“coronary steal”). Clinical trials to date evaluating myocardial ischemia, infarction and death as outcome parameters have not established that the coronary arteriolar dilation property of isoflurane is associated with coronary steal or myocardial ischemia in patients with coronary artery disease. Reference ID: 5492186 12.3 Pharmacokinetics Isoflurane undergoes minimal biotransformation in man. In the postanesthesia period, only 0.17% of the isoflurane taken up can be recovered as urinary metabolites. 12.5 Pharmacogenomics RYR1 and CACNA1S are polymorphic genes, and multiple pathogenic variants have been associated with malignant hyperthermia susceptibility (MHS) in patients receiving volatile anesthetic agents, including FORANE. Case reports as well as ex-vivo studies have identified multiple variants in RYR1 and CACNA1S associated with MHS. Variant pathogenicity should be assessed based on prior clinical experience, functional studies, prevalence information, or other evidence [see Contraindications (4), Warnings and Precautions (5.1)]. 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Swiss ICR mice were given isoflurane to determine whether such exposure might induce neoplasia. Isoflurane was given at 1/2, 1/8 and 1/32 MAC for four in-utero exposures and for 24 exposures to the pups during the first nine weeks of life. The mice were killed at 15 months of age. The incidence of tumors in these mice was the same as in untreated control mice, which were given the same background gases, but not the anesthetic. Mutagenesis Isoflurane was negative in the in vivo mouse micronucleus and in vitro human lymphocyte chromosomal aberration assay. In published studies, isoflurane was negative in the in vitro bacterial reverse mutation assay (Ames test) in all strains tested (Salmonella typhimurium strains TA98, TA100, and TA1535) in the presence or absence of metabolic activation. Impairment of Fertility Male and female Sprague-Dawley rats were exposed to isoflurane at concentrations of 0%, 0.15%, and 0.60% (0, 1/8, and 1/2 MAC) 2 hours per day for 14 consecutive days prior to mating. Isoflurane had no effects on either male or female fertility. Reference ID: 5492186 13.2 Animal Toxicology and/or Pharmacology Published studies in animals demonstrate that the use of anesthetic agents during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester through the first several months of life, but may extend out to approximately 3 years of age in humans. In primates, exposure to 3 hours of an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in neonates and young children who require procedures against the potential risks suggested by the nonclinical data [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.4)]. 16. HOW SUPPLIED/STORAGE AND HANDLING FORANE is available in the following presentations: FILL CONTAINER PACK SIZE NDC 100 mL Amber-colored Glass 6 Bottles 10019-360-40 250 mL Amber-colored Glass 6 Bottles 10019-360-60 250 mL Aluminum 6 Bottles 10019-360-64 16.1 Safety and Handling Occupational Caution The following reactions have been reported following occupational exposure to isoflurane: dyspnea, bronchospasm, stridor, cough, dizziness, paresthesia, hepatic reactions, flushing rash, contact dermatitis, erythema, periorbital edema, eye irritation, conjunctival hyperemia, and headache. Reference ID: 5492186 There is no specific work exposure limit established for FORANE. However, the National Institute for Occupational Safety and Health Administration (NIOSH) recommends that no worker should be exposed at ceiling concentrations greater than 2 ppm of any halogenated anesthetic agent over a sampling period not to exceed one hour. The predicted effects of acute overexposure by inhalation of FORANE include headache, dizziness or (in extreme cases) unconsciousness [see Overdosage (10)]. There are no documented adverse effects of chronic exposure to halogenated anesthetic vapors (Waste Anesthetic Gases or WAGs) in the workplace. Although results of some epidemiological studies suggest a link between exposure to halogenated anesthetics and increased health problems (particularly spontaneous abortion), the relationship is not conclusive. Since exposure to WAGs is one possible factor in the findings for these studies, operating room personnel, and pregnant women in particular, should minimize exposure. Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system, work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks. 16.2 Storage Store at room temperature 15°C - 30°C (59°F - 86°F). Isoflurane contains no additives and has been demonstrated to be stable at room temperature for periods in excess of five years. 17. PATIENT COUNSELING INFORMATION Anesthesia providers need to obtain the following information from patients prior to administration of anesthesia: • Medications they are taking, including herbal supplements • Drug allergies, including allergic reactions to anesthetic agents (including hepatic sensitivity) • Any history of severe reactions to prior administration of anesthetic • If the patient or a member of the patient’s family has a history of malignant hyperthermia or if the patient has a history of Duchenne muscular dystrophy or other latent neuromuscular disease Anesthesia providers should inform patients of the following risks associated with FORANE: Reference ID: 5492186 Baxter • Post-operative nausea and vomiting and respiratory adverse effects including coughing. There is no information of the effects of FORANE following anesthesia on the ability to operate an automobile or other heavy machinery. However, patients should be advised that the ability to perform such tasks may be impaired after receiving anesthetic agents. Patients should not undertake hazardous tasks, such as driving, for at least 24 hours following administration of a general anesthetic. Anesthesia providers should inform parents and caregivers of pediatric patients that emergence from anesthesia in children may evoke a brief state of agitation that may hinder cooperation. Anesthesia providers should inform patients that FORANE, as well as other general anesthetics, may cause a slight decrease in intellectual function for 2 or 3 days following anesthesia. As with other anesthetics, small changes in moods and symptoms may persist for up to 6 days after administration. Effect of anesthetic and sedation drugs on early brain development Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs [see Warnings and Precautions (5.8)]. Manufactured for Baxter Healthcare Corporation Deerfield, IL 60015 USA Baxter and Forane are trademarks of Baxter International Inc. For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) 07-19-00-5984 Reference ID: 5492186
custom-source
2025-02-12T15:47:35.904614
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RYBELSUS® safely and effectively. See full prescribing information for RYBELSUS. RYBELSUS (semaglutide) tablets, for oral use Initial U.S. Approval: 2017 WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • In rodents, semaglutide causes thyroid C-cell tumors. It is unknown whether RYBELSUS causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined (5.1, 13.1). • RYBELSUS is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors (4, 5.1). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Warnings and Precautions, Pulmonary Aspiration During General Anesthesia or Deep Sedation (5.9) ……………………………….11/2024 Warning and Precautions, Severe Gastrointestinal Adverse Reactions (5.6) ……………………………………………………………….12/2024 Dosage and Administration, Overview of RYBELUS formulations (2.1), Recommended Dosage (2.3), Switching Patients between OZEMPIC and RYBELSUS (2.4) ………………………………………………...12/2024 ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ RYBELSUS is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1). Limitations of Use • Not for treatment of type 1 diabetes mellitus (1). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • There are two RYBELSUS formulations (i.e., formulation R1 and formulation R2) with different recommended dosages (2.1) o These formulations are not substitutable on a mg per mg basis o Use either formulation but do not use both formulations at the same time. • Take RYBELSUS on an empty stomach in the morning with water (up to 4 ounces of water); do not take with other liquids besides water. (2.2) • After taking RYBELSUS, wait at least 30 minutes before eating food, drinking beverages, or taking other oral medications. (2.2). • Swallow tablets whole. Do not split, crush, or chew tablets (2.2). • See the Full Prescribing Information for instructions on switching from OZEMPIC to RYBELSUS and switching between the two different RYBELSUS formulations (2.4). Recommended Dosage of Starting, Escalation, and Maintenance Dosage of RYBELSUS Formulations R1 and R2 (2.3) RYBELSUS (formulation R1) (2.3) • Day 1 to 30: Recommended starting dosage is 3 mg orally once daily for 30 days (this dosage is not effective for glycemic control) • Days 31to 60: Increase the dosage to 7 mg orally once daily. • On Day 61 or thereafter, if: (2.3) o No additional glycemic control is needed, maintain the dosage at 7 mg orally once daily. o Additional glycemic control is needed, increase the dosage to 14 mg orally once daily. RYBELSUS (formulation R2) (2.3) • Day 1 to 30: Recommended starting dosage is 1.5 mg orally once daily for 30 days (this dosage is not effective for glycemic control). • Days 31to 60: Increase the dosage to 4 mg orally once daily. • On Day 61 or thereafter, if: (2.3) o No additional glycemic control is needed, maintain the dosage at 4 mg orally once daily. o Additional glycemic control is needed, increase the dosage to 9 mg orally once daily. ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Tablets (formulation R1): 3 mg, 7 mg and 14 mg (3). • Tablets (formulation R2): 1.5 mg, 4 mg and 9 mg (3). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Personal or family history of MTC or in patients with MEN-2 syndrome type 2 (4). • Prior serious hypersensitivity reaction to semaglutide or any of the excipients in RYBELSUS (4). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, including RYBELSUS. Discontinue promptly if pancreatitis is suspected. (5.2). • Diabetic Retinopathy Complications: Has been reported in a cardiovascular outcomes trial with semaglutide injection. Patients with a history of diabetic retinopathy should be monitored (5.3). • Hypoglycemia with Concomitant of Insulin Secretagogues or Insulin: May increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dosage of insulin secretagogue or insulin may be necessary (5.4). • Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions (5.5). • Severe Gastrointestinal Adverse Reactions: Use of RYBELSUS has been associated with gastrointestinal adverse reactions, sometimes severe. RYBELSUS is not recommended in patients with severe gastroparesis. (5.6). • Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue RYBELSUS if hypersensitivity reactions occur and monitor until signs and symptoms resolve (5.7). • Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated (5.8). • Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. (5.9). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Most common adverse reactions (incidence ≥5%) are nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-833-457-7455 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS----------------------------------­ Oral Medications: RYBELSUS delays gastric emptying. Consider increased clinical or laboratory monitoring when co-administered with other oral medications that have a narrow therapeutic index or that require clinical monitoring. (7.2). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Pregnancy: See Pregnancy subsection (8.1). • Lactation: Breastfeeding not recommended (8.2). • Females and Males of Reproductive Potential: Discontinue RYBELSUS in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide (8.3). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 12/2024 Reference ID: 5492467 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF THYROID C-CELL TUMORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Overview of RYBELUS formulations 2.2 Important Administration Instructions 2.3 Recommended Starting, Escalation, and Maintenance Dosage of RYBELSUS Formulation R1 and R2 2.4 Switching Between RYBELSUS (Formulations R1 or R2) or from OZEMPIC to RYBELSUS 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors 5.2 Acute Pancreatitis 5.3 Diabetic Retinopathy Complications 5.4 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin 5.5 Acute Kidney Injury 5.6 Severe Gastrointestinal Adverse Reactions 5.7 Hypersensitivity Reactions 5.8 Acute Gallbladder Disease 5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin 7.2 Oral Medications 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies 14.2 Monotherapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus 14.3 Combination Therapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus 14.4 Cardiovascular Outcomes Trial in Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5492467 FULL PRESCRIBING INFORMATION WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether RYBELSUS causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)]. • RYBELSUS is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications (4)]. Counsel patients regarding the potential risk for MTC with the use of RYBELSUS and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS [see Contraindications (4) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE RYBELSUS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use RYBELSUS is not indicated for use in patients with type 1 diabetes mellitus. 2 DOSAGE AND ADMINISTRATION 2.1 Overview of RYBELSUS Formulations • There are two RYBELSUS formulations (i.e., formulation R1 and formulation R2) with different recommended dosages. Refer to recommendations on how to switch from one formulation to another formulation [see Dosage and Administration (2.3, 2.4)]. o RYBELSUS (formulation R1) includes strengths 3 mg, 7 mg, and 14 mg. o RYBELSUS (formulation R2) includes strengths 1.5 mg, 4 mg, and 9 mg. • These formulations are not substitutable on a mg per mg basis. • Use either RYBELSUS formulation R1or formulation R2; do not use both formulations at the same time. • Do not take more than one tablet per day. 2.2 Important Administration Instructions • Take RYBELSUS on an empty stomach in the morning with water (up to 4 ounces of water). Do not take RYBELSUS with other liquids besides water. • After taking RYBELSUS, wait at least 30 minutes before eating food, drinking beverages, or taking other oral medications [see Clinical Pharmacology (12.3)]. • Swallow tablets whole. Do not split crush, or chew. • If a dose is missed, skip the missed dose, and take the next dose the following day. 2.3 Recommended Starting, Escalation, and Maintenance Dosage of RYBELSUS Formulations R1 and R2 RYBELSUS (formulation R1) RYBELSUS (formulation R1) includes the following strengths: 3 mg, 7 mg, and 14 mg. Recommend the following RYBELSUS (formulation R1) dosage to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.6), see Adverse Reactions (6.1)]: Reference ID: 5492467 *Discontinue this formulation and initiate the alternate formulation the day after Switching from OZEMPIC to RYBELSUS (formulation R1) or RYBELSUS (formulation R2) Switching from OZEMPIC to RYBELSUS (formulation R1) • One week after discontinuing 0.5 mg of subcutaneous OZEMPIC, start 7 mg or 14 mg of RYBELSUS (formulation R1) orally once daily. • Switching recommendations for patients taking Ozempic 0.25 mg, 1 mg, or 2 mg subcutaneously once weekly to RYBELSUS (formulation R1) are not available. Switching from OZEMPIC to RYBELSUS (formulation R2) • One week after discontinuing 0.5 mg of subcutaneous OZEMPIC, start 4 mg or 9 mg of RYBELSUS (formulation R2) orally once daily. Reference ID: 5492467 • Starting Dosage (Initiation Phase) (Days 1 to 30): The recommended starting dosage is 3 mg orally once daily (this dosage is not effective for glycemic control). • Escalation and Maintenance Dosage (Days 31 and beyond): o Days 31 to 60: Increase the dosage to 7 mg orally once daily. o On Day 61 or thereafter, if: • No additional glycemic control is needed, maintain the dosage at 7 mg orally once daily. • Additional glycemic control is needed, increase the dosage to 14 mg orally once daily. RYBELSUS (formulation R2) RYBELSUS (formulation R2) includes the following strengths: 1.5 mg, 4 mg, and 9 mg. Recommend the following RYBELSUS (formulation R2) dosage to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.6), Adverse Reactions (6.1)]: • Starting Dosage (Initiation Phase) (Days 1 through 30): The recommended starting dosage is 1.5 mg orally once daily (this dosage is not effective for glycemic control). • Escalation and Maintenance Dosage (Days 31 and beyond): o Days 31 to 60: Increase the dosage to 4 mg orally once daily. o On Day 61 or thereafter, if: • No additional glycemic control is needed maintain the dosage at 4 mg orally once daily. • Additional glycemic control is needed increase the dosage to 9 mg orally once daily. 2.4 Switching Between RYBELSUS (Formulations R1 or R2) or from OZEMPIC to RYBELSUS Switching Between RYBELSUS Formulations • Do not switch between RYBELSUS formulations during the initiation phase (Days 1-30) [see Dosage and Administration (2.3)]. • After 30 days of RYBELSUS treatment (after the initiation phase) [see Dosage and Administration (2.3)], patients may switch between RYBELSUS formulations (see Table 1). • When switching between the formulations, initiate the other RYBELSUS formulation the day after discontinuing the previous RYBELSUS formulation. Table 1. Switching Between Escalation or Maintenance Dosage of RYBELSUS Formulations RYBELSUS (formulation R1) * RYBELSUS (formulation R2) * 7 mg orally once daily 4 mg orally once daily 14 mg orally once daily 9 mg orally once daily • Switching recommendations for patients taking Ozempic 0.25 mg, 1 mg, or 2 mg subcutaneously once weekly to RYBELSUS (formulation R2) are not available. 3 DOSAGE FORMS AND STRENGTHS RYBELSUS (semaglutide) tablets (formulation R1) are available as: 3 mg: white to light yellow, oval shaped debossed with “3” on one side and “novo” on the other side. 7 mg: white to light yellow, oval shaped debossed with “7” on one side and “novo” on the other side. 14 mg: white to light yellow, oval shaped debossed with “14” on one side and “novo” on the other side. RYBELSUS (semaglutide) tablets (formulation R2) are available as: • 1.5 mg: white to light yellow, round shaped debossed with “1.5” on one side and “novo” on the other side. • 4 mg: white to light yellow, round shaped debossed with “4” on one side and “novo” on the other side. • 9 mg: white to light yellow, round shaped debossed with “9” on one side and “novo” on the other side. 4 CONTRAINDICATIONS RYBELSUS is contraindicated in patients with: • A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)]. • A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with RYBELSUS [see Warnings and Precautions (5.7)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures [see Nonclinical Toxicology (13.1)]. It is unknown whether RYBELSUS causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. RYBELSUS is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of RYBELSUS and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. Reference ID: 5492467 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including RYBELSUS [see Adverse Reactions (6.1)]. After initiation of RYBELSUS, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue RYBELSUS and initiate appropriate management. 5.3 Diabetic Retinopathy Complications In a pooled analysis of glycemic control trials with RYBELSUS, patients reported diabetic retinopathy related adverse reactions during the trial (4.2% with RYBELSUS and 3.8% with comparator) [see Adverse Reactions (6.1)]. In a 2-year cardiovascular outcomes trial with semaglutide injection involving patients with type 2 diabetes mellitus and high cardiovascular risk, diabetic retinopathy complications (which was a 4-component adjudicated endpoint) occurred in patients treated with semaglutide injection (3%) compared to placebo (1.8%). The absolute risk increase for diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline (semaglutide injection 8.2%, placebo 5.2%) than among patients without a known history of diabetic retinopathy (semaglutide injection 0.7%, placebo 0.4%). Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been studied. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy. 5.4 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving RYBELSUS in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adverse Reactions (6.1) and Drug Interactions (7)]. The risk of hypoglycemia may be lowered by a reduction in the dosage of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.5 Acute Kidney Injury There have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis, in patients treated with GLP-1 receptor agonists, including semaglutide. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of RYBELSUS in patients reporting severe adverse gastrointestinal reactions. 5.6 Severe Gastrointestinal Adverse Reactions Use of RYBELSUS has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6.1)]. In RYBELSUS clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving RYBELSUS (7 mg 0.6%, 14 mg 2%) than placebo (0.3%). RYBELSUS is not recommended in patients with severe gastroparesis. 5.7 Hypersensitivity Reactions Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with RYBELSUS. If hypersensitivity reactions occur, discontinue use of RYBELSUS; treat promptly per standard of care, and monitor until signs and symptoms resolve. RYBELSUS is contraindicated in patients with a prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS [see Adverse Reactions (6.2)]. Reference ID: 5492467 Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to anaphylaxis with RYBELSUS. 5.8 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg. Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-treated patients [see Adverse Reactions (6.1)]. If cholelithiasis or cholecystitis is suspected, gallbladder studies and appropriate clinical follow-up are indicated [see Adverse Reactions (6.2)]. 5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation RYBELSUS delays gastric emptying [see Clinical Pharmacology (12.2)]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking RYBELSUS, including whether modifying preoperative fasting recommendations or temporarily discontinuing RYBELSUS could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking RYBELSUS. 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)] • Acute Pancreatitis [see Warnings and Precautions (5.2)] • Diabetic Retinopathy Complications [see Warnings and Precautions (5.3)] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.4)] • Acute Kidney Injury [see Warnings and Precautions (5.5)] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.6)] • Hypersensitivity Reactions [see Warnings and Precautions (5.7)] • Acute Gallbladder Disease [see Warnings and Precautions (5.8)] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of RYBELSUS (formulation R2 – 1.5 mg, 4 mg, and 9 mg strengths) [see Dosage and Administration (2.2)] and RYBELSUS (formulation R1 – 3 mg, 7, mg, and 14 mg strengths) [see Dosage and Administration (2.3)] has been established as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus based on adequate and well-controlled studies of RYBELSUS (formulation R1) in adult patients with type 2 diabetes mellitus [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. Below is a display of the safety results of the adequate and well-controlled studies of RYBELSUS (formulation R1) in adult patients with type 2 diabetes mellitus. Reference ID: 5492467 Pool of Placebo-Controlled Trials The data in Table 1 are derived from 2 placebo-controlled trials in adult patients with type 2 diabetes mellitus [see Clinical Studies (14)]. These data reflect exposure of 1071 patients to RYBELSUS with a mean duration of exposure of 41.8 weeks. The mean age of patients was 58 years, 3.9% were 75 years or older and 52% were male. In these trials, 63% were White, 6% were Black or African American, and 27% were Asian; 19% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 mellitus diabetes for an average of 9.4 years and had a mean HbA1c of 8.1%. At baseline, 20.1% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m2) in 66.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 32.4% and moderately impaired (eGFR 30 to 60 mL/min/1.73m2) in 1.4% of patients. Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of adult patients with type 2 diabetes mellitus participating in 9 placebo- and active-controlled trials [see Clinical Studies (14)]. In this pool, 4,116 patients with type 2 diabetes mellitus were treated with RYBELSUS for a mean duration of 59.8 weeks. The mean age of patients was 58 years, 5% were 75 years or older and 55% were male. In these trials, 65% were White, 6% were Black or African American, and 24% were Asian; 15% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes mellitus for an average of 8.8 years and had a mean HbA1c of 8.2%. At baseline, 16.6% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m2) in 65.9%, mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 28.5%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m2) in 5.4% of the patients. Common Adverse Reactions Table 2 shows common adverse reactions, excluding hypoglycemia, associated with the use of RYBELSUS in adult patients with type 2 diabetes mellitus in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on RYBELSUS than on placebo and occurred in at least 5% of patients treated with RYBELSUS. Table 2. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of RYBELSUS-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=362) % RYBELSUS 7 mg (N=356) % RYBELSUS 14 mg (N=356) % Nausea 6 11 20 Abdominal Pain 4 10 11 Diarrhea 4 9 10 Decreased appetite 1 6 9 Vomiting 3 6 8 Constipation 2 6 5 In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1. Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients who received RYBELSUS than placebo: RYBELSUS 14 mg once daily (41%), RYBELSUS 7 mg once daily (32%), and placebo (21%), including severe reactions (RYBELSUS 14 mg 2.0%, RYBELSUS 7 mg 0.6%, placebo 0.3%). The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation. A greater percentage of patients who received RYBELSUS 14 mg once daily (8%) and RYBELSUS 7 mg once daily (4%) discontinued treatment due to gastrointestinal adverse reactions than patients who received placebo (1%). Reference ID: 5492467 In addition to the reactions in Table 1, the following gastrointestinal adverse reactions with a frequency of <5% occurred in RYBELSUS-treated patients (frequencies listed, respectively, as 14 mg once daily, 7 mg once daily, and placebo): abdominal distension (3%, 2%, and 1%), dyspepsia (0.6%, 3%, 0.6%), eructation (2%, 0.6%, 0%,), flatulence (1%, 2%, 0%), gastroesophageal reflux disease (2%, 2%, 0.3%), and gastritis (2%, 2%, 0.8%). Other Adverse Reactions Pancreatitis: In the pool of placebo- and active-controlled trials with RYBELSUS, pancreatitis was reported as a serious adverse event in 6 RYBELSUS-treated patients (0.1 events per 100 patient years) versus 1 in comparator- treated patients (<0.1 events per 100 patient years). Diabetic Retinopathy Complications: In the pool of placebo- and active-controlled trials with RYBELSUS, patients reported diabetic retinopathy related adverse reactions during the trial (4.2% with RYBELSUS and 3.8% with comparator). Hypoglycemia: Table 3 summarizes the incidence of hypoglycemia by various definitions in the placebo- controlled trials. Table 3. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials In Patients with Type 2 Diabetes Mellitus Placebo RYBELSUS 7 mg RYBELSUS 14 mg Monotherapy (26 weeks) N=178 N=175 N=175 Severe* 0% 1% 0% Plasma glucose <54 mg/dL 1% 0% 0% Add-on to metformin and/or sulfonylurea, basal insulin alone or metformin in combination with basal insulin in patients with moderate renal impairment (26 weeks) N=161 - N=163 Severe* 0% - 0% Plasma glucose <54 mg/dL 3% - 6% Add-on to insulin with or without metformin (52 weeks) N=184 N=181 N=181 Severe* 1% 0% 1% Plasma glucose <54 mg/dL 32% 26% 30% *“Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person. Hypoglycemia was more frequent when RYBELSUS was used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Increases in Amylase and Lipase: In placebo-controlled trials, patients exposed to RYBELSUS 7 mg and 14 mg had a mean increase from baseline in amylase of 10% and 13%, respectively, and lipase of 30% and 34%, respectively. These changes were not observed in placebo-treated patients. Cholelithiasis: In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg. Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-treated patients. Reference ID: 5492467 Increases in Heart Rate: In placebo-controlled trials, RYBELSUS 7 mg and 14 mg resulted in a mean increase in heart rate of 1 to 3 beats per minute. There was no change in heart rate in placebo-treated patients. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of RYBELSUS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Gastrointestinal: ileus • Hypersensitivity: anaphylaxis, angioedema, rash, urticaria • Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy • Nervous system disorders: dizziness, dysesthesia, dysgeusia • Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation • Skin and Subcutaneous Tissue: alopecia 7 DRUG INTERACTIONS 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin RYBELSUS stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving RYBELSUS in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating RYBELSUS, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. 7.2 Other Oral Drugs RYBELSUS causes a delay of gastric emptying, and thereby has the potential to impact the absorption of other oral drugs. Levothyroxine exposure was increased 33% (90% CI: 125-142) when administered with RYBELSUS in a drug interaction study [see Clinical Pharmacology (12.3)]. When co-administering RYBELSUS with other oral drugs that have a narrow therapeutic index or that require clinical monitoring, consider increased clinical or laboratory monitoring [see Dosage and Administration (2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data with RYBELSUS use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal reproduction studies, there may be potential risks to the fetus from exposure to RYBELSUS during pregnancy. RYBELSUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant rats administered semaglutide during organogenesis, embryofetal mortality, structural abnormalities and alterations to growth occurred at maternal exposures below the maximum recommended human dose (MRHD) based on AUC. In rabbits and cynomolgus monkeys administered semaglutide during organogenesis, early pregnancy losses and structural abnormalities were observed at exposure below the MRHD (rabbit) and ≥10-fold the MRHD (monkey). These findings coincided with a marked maternal body weight loss in both animal species (see Data). Reference ID: 5492467 The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20–25% in women with a HbA1c >10. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease Associated Maternal and Fetal Risk: Poorly controlled diabetes during pregnancy increases the maternal risk for diabetic ketoacidosis, pre- eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data: In a combined fertility and embryofetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.2-, 0.7-, and 2.1-fold the MRHD) were administered to males for 4 weeks prior to and throughout mating and to females for 2 weeks prior to mating, and throughout organogenesis to Gestation Day 17. In parental animals, pharmacologically mediated reductions in body weight gain and food consumption were observed at all dose levels. In the offspring, reduced growth and fetuses with visceral (heart blood vessels) and skeletal (cranial bones, vertebra, ribs) abnormalities were observed at the human exposure. In an embryofetal development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or 0.0075 mg/kg/day (0.06-, 0.6-, and 4.4-fold the MRHD) were administered throughout organogenesis from Gestation Day 6 to 19. Pharmacologically mediated reductions in maternal body weight gain and food consumption were observed at all dose levels. Early pregnancy losses and increased incidences of minor visceral (kidney, liver) and skeletal (sternebra) fetal abnormalities were observed at ≥0.0025 mg/kg/day, at clinically relevant exposures. In an embryofetal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (1.9-, 9.9-, and 29-fold the MRHD) were administered throughout organogenesis, from Gestation Day 16 to 50. Pharmacologically mediated, marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with the occurrence of sporadic abnormalities (vertebra, sternebra, ribs) at ≥0.075 mg/kg twice weekly (>9X human exposure). In a pre- and postnatal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (1.3-, 6.4-, and 14-fold the MRHD) were administered from Gestation Day 16 to 140. Pharmacologically mediated marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with an increase in early pregnancy losses and led to delivery of slightly smaller offspring at ≥0.075 mg/kg twice weekly (>6X human exposure). Salcaprozate sodium (SNAC), an absorption enhancer in RYBELSUS, crosses the placenta and reaches fetal tissues in rats. In a pre- and postnatal development study in pregnant Sprague Dawley rats, SNAC was administered orally at 1,000 mg/kg/day (exposure levels were not measured) on Gestation Day 7 through lactation day 20. An increase in gestation length, an increase in the number of stillbirths and a decrease in pup viability were observed. 8.2 Lactation Risk Summary A clinical lactation study reported semaglutide concentrations below the lower limit of quantification in human breast milk. However, salcaprozate sodium (SNAC) and/or its metabolites are present in human milk. Since the activity of enzymes involved in SNAC clearance may be lower in infants compared to adults, higher SNAC plasma levels may occur in neonates and infants. Because of the unknown potential for serious adverse reactions in the breastfed infant due to the possible accumulation of SNAC, and because there are alternative formulations of semaglutide that do not contain SNAC that can be used during lactation, advise patients that breastfeeding is not recommended during treatment with RYBELSUS. Reference ID: 5492467 8.3 Females and Males of Reproductive Potential Discontinue RYBELSUS in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide [see Use in Specific Populations (8.1)]. 8.4 Pediatric Use The safety and effectiveness of RYBELSUS have not been established in pediatric patients. 8.5 Geriatric Use In the pool of glycemic control trials, 1,229 (30%) RYBELSUS-treated patients were 65 years of age and over and 199 (5%) RYBELSUS-treated patients were 75 years of age and over [see Clinical Studies (14)]. In PIONEER 6, the cardiovascular outcomes trial, 891 (56%) RYBELSUS-treated patients were 65 years of age and over and 200 (13%) RYBELSUS-treated patients were 75 years of age and over. No overall differences in safety or effectiveness for RYBELSUS have been observed between patients 65 years of age and older and younger adult patients. 8.6 Renal Impairment The recommended dosage of RYBELSUS in patients with renal impairment is the same as those with normal renal function. The safety and effectiveness of RYBELSUS was evaluated in a 26-week clinical study that included 324 patients with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2) [see Clinical Studies (14.1)]. In patients with renal impairment including end-stage renal disease (ESRD), no clinically relevant change in semaglutide pharmacokinetics was observed [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment The recommended dosage in patients with hepatic impairment is the same as those with normal hepatic function. In a study in subjects with different degrees of hepatic impairment, no clinically relevant change in semaglutide pharmacokinetics was observed [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the long half-life of RYBELSUS of approximately 1 week. 11 DESCRIPTION RYBELSUS tablets, for oral use, contain semaglutide, a GLP-1 receptor agonist. The peptide backbone is produced by yeast fermentation. The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid. Furthermore, semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4). A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid. The molecular formula is C187H291N45O59 and the molecular weight is 4113.58 g/mol. Reference ID: 5492467 30 37 F- 1- A- W- L- V- R- G- R- G- OH 0 Structural formula: Semaglutide is a white to almost white hygroscopic powder. Each tablet of: • RYBELSUS (formulation R1) contains 3 mg, 7 mg or 14 mg of semaglutide and the following inactive ingredients: magnesium stearate, microcrystalline cellulose, povidone and salcaprozate sodium (SNAC). • RYBELSUS (formulation R2) contains 1.5 mg, 4 mg, 9 mg of semaglutide and the following inactive ingredients: SNAC and magnesium stearate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1. GLP-1 is a physiological hormone that has multiple actions on glucose, mediated by the GLP-1 receptors. The principal mechanism of protraction resulting in the long half-life of semaglutide is albumin binding, which results in decreased renal clearance and protection from metabolic degradation. Furthermore, semaglutide is stabilized against degradation by the DPP-4 enzyme. Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. 12.2 Pharmacodynamics The pharmacodynamic evaluations described below were in patients with type 2 diabetes mellitus who received once weekly subcutaneous injections of placebo or semaglutide injection over 12 weeks (semaglutide injection- treated patients were started on lower dosages and then titrated up to 1 mg once weekly). RYBELSUS is not approved for subcutaneous use. Fasting and Postprandial Glucose Semaglutide reduces fasting and postprandial glucose concentrations. In patients with type 2 diabetes mellitus, treatment with semaglutide injection 1 mg resulted in reductions in glucose in terms of absolute change from baseline and relative reduction compared to placebo of 29 mg/dL (22%) for fasting glucose, 74 mg/dL (36%) for 2 hour postprandial glucose, and 30 mg/dL (22%) for mean 24 hour glucose concentration. Reference ID: 5492467 Insulin Secretion Both first- and second-phase insulin secretion are increased in patients with type 2 diabetes mellitus treated with semaglutide compared with placebo. Glucagon Secretion Semaglutide lowers the fasting and postprandial glucagon concentrations. Glucose dependent insulin and glucagon secretion Semaglutide lowers high blood glucose concentrations by stimulating insulin secretion and lowering glucagon secretion in a glucose-dependent manner. During induced hypoglycemia, semaglutide did not alter the counter regulatory responses of increased glucagon compared to placebo and did not impair the decrease of C-peptide in patients with type 2 diabetes mellitus. Gastric emptying Semaglutide causes a delay of early postprandial gastric emptying, thereby reducing the rate at which glucose appears in the circulation postprandially. Cardiac Electrophysiology The effect of subcutaneously administered semaglutide on cardiac repolarization was tested in a thorough QTc trial. At an average exposure level 4-fold higher than that of the maximum recommended dose of RYBELSUS, semaglutide does not prolong QTc intervals to any clinically relevant extent. 12.3 Pharmacokinetics Semaglutide estimated mean steady-state concentration was 6.7 nmol/L and 14.6 nmol/L following once daily oral administration of 7 mg and 14 mg of RYBELSUS (formulation R1), respectively, in patients with type 2 diabetes mellitus. Semaglutide exposures increased in a dose-proportional manner. Steady-state exposure was achieved following 4­ 5 weeks of RYBELSUS oral administration. Absorption Semaglutide is co-formulated with salcaprozate sodium which facilitates the absorption of semaglutide after oral RYBELSUS administration. The absorption of semaglutide predominantly occurs in the stomach. Semaglutide estimated absolute bioavailability was approximately: • 0.4-1% after oral administration of 3 mg, 7 mg, and 14 mg of RYBELSUS (formulation R1). • 1-2% after oral administration of 1.5 mg, 4 mg, and 9 mg of RYBELSUS (formulation R2). Semaglutide maximum concentration was reached approximately 1-hour after oral RYBELSUS administration. Effect of RYBELSUS Formulation: There were no clinically significant differences observed in the mean steady state AUC0-24h,SS and Cmax,SS between the 3 mg, 7 mg, and 14 mg doses of RYBELSUS (formulation R1) and the 1.5 mg, 4 mg, and 9 mg doses of RYBELSUS (formulation R2), respectively, in a clinical study conducted in healthy subjects. Effect of Volume and Timing of Water Consumption: Single 10 mg doses of oral semaglutide (formulation R1) were administered with 50 mL or 240 mL of water after an 8-hour overnight fast and a continued fast of 4 hours post-dose in healthy subjects. Semaglutide absorption (i.e., area under the curve (AUC) and peak concentrations (Cmax)) were higher following dosing with 50 mL water compared to that of 240 mL water. Reference ID: 5492467 For 10 days, healthy subjects received 10 mg of oral semaglutide (formulation R1) once daily doses with 50 mL or 120 mL of water under fasting conditions with post-dose fasting period of 15, 30, 60, or 120 minutes. In this study, semaglutide absorption (i.e., AUC and Cmax) was higher after a longer post-dose fasting period. There were no clinically significant differences in semaglutide absorption with administration of 50 mL or 120 mL of water. Distribution Semaglutide absolute volume of distribution is approximately 8 L in patients with type 2 diabetes. Semaglutide is > 99% bound to plasma albumin. Elimination Semaglutide elimination half-life is approximately one week with an absolute clearance of approximately 0.04 L/hour in patients with type 2 diabetes. Semaglutide is present in the circulation for about five weeks after the last RYBELSUS dose. Metabolism: The primary route of elimination for semaglutide is metabolism following proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid side chain. Excretion: The primary excretion routes of semaglutide-related material are via the urine and feces. Approximately 3% of the absorbed dose is excreted in the urine as intact semaglutide. Specific Populations No clinically significant differences in semaglutide pharmacokinetics were observed based on age (≥ 18 years old), sex, race (White, Asian, or Black or African American), ethnicity, body weight (40-188 kg), upper GI disease (i.e. chronic gastritis and/or gastroesophageal reflux disease), hepatic impairment (i.e., mild, moderate, severe based on the Child-Pugh system), and renal impairment (i.e., mild, moderate, severe, end staged renal disease). Drug Interaction Studies Clinical Studies and Model-Informed Approaches: The delay of gastric emptying with semaglutide may influence the absorption of concomitantly administered oral drugs. Trials were conducted to study the potential effect of semaglutide on the absorption of oral drugs taken with semaglutide administered orally at steady-state exposure. Levothyroxine: Total thyroxine (i.e., adjusted for endogenous levels) AUC of was increased by 33% following administration of a single dose of levothyroxine 600 mcg concomitantly administered with oral semaglutide. Maximum exposure (Cmax) was unchanged. Other Drugs: No clinically significant differences in semaglutide pharmacokinetics were observed when used concomitantly with omeprazole. No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with semaglutide: lisinopril, S-warfarin, R-warfarin, metformin, digoxin, ethinyl estradiol, levonorgestrel, furosemide, or rosuvastatin. In Vitro Studies: Semaglutide has very low potential to inhibit or induce CYP enzymes, and to inhibit drug transporters. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of semaglutide or of other semaglutide products. During the 26-78 week treatment periods in 5 clinical trials in adults with type 2 diabetes mellitus [see Clinical Studies (14.2 and 14.3)] and 1 clinical trial in Japanese adults with type 2 diabetes mellitus, 14/2924 (0.5%) of Reference ID: 5492467 - RYBELSUS-treated patients developed anti-semaglutide antibodies. Of these 14 RYBELSUS-treated patients, 7 patients (0.2% of the total RYBELSUS-treated study population) developed antibodies that cross-reacted with native GLP-1. No identified clinically significant effect of anti-semaglutide antibodies on pharmacokinetics of RYBELSUS was observed. There is insufficient information to characterize the effects of anti-semaglutide antibodies on pharmacodynamics, safety, or effectiveness of semaglutide. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in CD-1 mice, subcutaneous doses of 0.3, 1 and 3 mg/kg/day [9-, 33- and 113­ fold the maximum recommended human dose (MRHD) of RYBELSUS 14 mg, based on AUC] were administered to the males, and 0.1, 0.3 and 1 mg/kg/day (3-, 9-, and 33-fold MRHD) were administered to the females. A statistically significant increase in thyroid C-cell adenomas and a numerical increase in C-cell carcinomas were observed in males and females at all dose levels (>3X human exposure). In a 2-year carcinogenicity study in Sprague Dawley rats, subcutaneous doses of 0.0025, 0.01, 0.025 and 0.1 mg/kg/day were administered (below quantification, 0.8-, 1.8- and 11-fold the exposure at the MRHD). A statistically significant increase in thyroid C-cell adenomas was observed in males and females at all dose levels, and a statistically significant increase in thyroid C-cell carcinomas was observed in males at ≥0.01 mg/kg/day, at clinically relevant exposures. Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies [see Boxed Warning and Warnings and Precautions (5.1)]. Semaglutide was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity (Ames), human lymphocyte chromosome aberration, rat bone marrow micronucleus). In a combined fertility and embryo-fetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.2-, 0.7- and 2.1-fold the MRHD) were administered to male and female rats. Males were dosed for 4 weeks prior to mating, and females were dosed for 2 weeks prior to mating and throughout organogenesis until Gestation Day 17. No effects were observed on male fertility. In females, an increase in estrus cycle length was observed at all dose levels, together with a small reduction in numbers of corpora lutea at ≥0.03 mg/kg/day. These effects were likely an adaptive response secondary to the pharmacological effect of semaglutide on food consumption and body weight. 13.2 Animal Toxicology and/or Pharmacology Increase in lactate levels and decrease in glucose levels in the plasma and cerebrospinal fluid (CSF) were observed in mechanistic studies with SNAC in rats. Small but statistically significant increases in lactate levels (up to 2­ fold) were observed in a few animals at approximately the clinical exposure. At higher exposures these findings were associated with moderate to marked adverse clinical signs (lethargy, abnormal respiration, ataxia, and reduced activity, body tone and reflexes) and marked decreases in plasma and CSF glucose levels. These findings are consistent with inhibition of cellular respiration and lead to mortality at SNAC concentrations >100-times the clinical Cmax. 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies RYBELSUS has been studied as monotherapy and in combination with metformin, sulfonylureas, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, insulins, and thiazolidinediones in patients with type 2 diabetes mellius. The efficacy of RYBELSUS was compared with placebo, empagliflozin, sitagliptin, and liraglutide. RYBELSUS has also been studied in patients with type 2 diabetes mellitus with mild and moderate renal impairment. In patients with type 2 diabetes mellitus, RYBELSUS produced clinically significant reduction from baseline in HbA1c compared with placebo. Reference ID: 5492467 The effectiveness of RYBELSUS (formulation R2 – 1.5 mg, 4 mg, and 9 mg strengths) [see Dosage and Administration (2.2)] and RYBELSUS (formulation R1 – 3 mg, 7, mg, and 14 mg strengths) [see Dosage and Administration (2.3)] has been established as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus based on adequate and well-controlled studies of RYBELSUS (formulation R1) in adult patients with type 2 diabetes mellitus [see Clinical Pharmacology (12.3)]. Below is a display of the efficacy results of the adequate and well-controlled studies of RYBELSUS (formulation R1) in adult patients with type 2 diabetes mellitus. The efficacy of RYBELSUS was not impacted by baseline age, sex, race, ethnicity, BMI, body weight, duration of diabetes, and degree of renal impairment. 14.2 Monotherapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus In a 26-week double-blind trial (NCT02906930), 703 adult patients with type 2 diabetes mellitus inadequately controlled with diet and exercise were randomized to RYBELSUS 3 mg, RYBELSUS 7 mg or RYBELSUS 14 mg once daily or placebo. Patients had a mean age of 55 years and 51% were men. The mean duration of type 2 diabetes mellitus was 3.5 years, and the mean BMI was 32 kg/m2. Overall, 75% were White, 5% were Black or African American, and 17% were Asian; 26% identified as Hispanic or Latino ethnicity. Monotherapy with RYBELSUS 7 mg and RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 4). Table 4. Results at Week 26 in a Trial of RYBELSUS as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise Placebo RYBELSUS 7 mg RYBELSUS 14 mg Intent-to-Treat (ITT) Population (N)a 178 175 175 HbA1c (%) Baseline (mean) 7.9 8.0 8.0 Change at week 26b -0.3 -1.2 -1.4 Difference from placebob [95% CI] −0.9 [−1.1; −0.6]c −1.1 [−1.3; −0.9]c Patients (%) achieving HbA1c <7% 31 69 77 FPG (mg/dL) Baseline (mean) 160 162 158 Change at week 26b -3 -28 -33 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 5.6%, 8.6% and 8.6% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. Missing data were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 15%, 2% and 1% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. b Estimated using an ANCOVA model based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 88.6 kg, 89.0 kg and 88.1 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -1.4 kg, -2.3 kg and -3.7 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 7 mg was -0.9 kg (-1.9, 0.1) and for RYBELSUS 14 mg was -2.3 kg (-3.1, -1.5). Reference ID: 5492467 14.3 Combination Therapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus Combination with Metformin In a 26-week trial (NCT02863328), 822 adult patients with type 2 mellitus diabetes were randomized to RYBELSUS 14 mg once daily or empagliflozin 25 mg once daily, all in combination with metformin. Patients had a mean age of 58 years and 50% were men. The mean duration of type 2 diabetes mellitus was 7.4 years, and the mean BMI was 33 kg/m2. Overall, 86% were White, 7% were Black or African American, and 6% were Asian; 24% identified as Hispanic or Latino ethnicity. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c compared to empagliflozin 25 mg once daily (see Table 5). Table 5. Results at Week 26 in a Trial of RYBELSUS Compared to Empagliflozin in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin RYBELSUS 14 mg Empagliflozin 25 mg Intent-to-Treat (ITT) Population (N)a 411 410 HbA1c (%) Baseline (mean) 8.1 8.1 Change at week 26b -1.3 -0.9 Difference from empagliflozinb [95% CI] -0.4 [-0.6, -0.3]c Patients (%) achieving HbA1c <7% 67 40 FPG (mg/dL) Baseline (mean) 172 174 Change at week 26b -36 -36 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 4.6% and 3.7% of patients randomized to RYBELSUS 14 mg and empagliflozin 25 mg, respectively. Missing data were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 1.9% and 1.2% of patients randomized to RYBELSUS 14 mg and empagliflozin 25 mg, respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 91.9 kg and 91.3 kg in the RYBELSUS 14 mg and empagliflozin 25 mg arms, respectively. The mean changes from baseline to week 26 were -3.8 kg and -3.7 kg in the RYBELSUS 14 mg and empagliflozin 25 mg arms, respectively. The difference from empagliflozin (95% CI) for RYBELSUS 14 mg was -0.1 kg (-0.7, 0.5). Combination with Metformin or Metformin with Sulfonylurea In a 26-week, double-blind trial (NCT02607865), 1864 adult patients with type 2 mellitus diabetes on metformin alone or metformin with sulfonylurea were randomized to RYBELSUS 3 mg, RYBELSUS 7 mg, RYBELSUS 14 mg or sitagliptin 100 mg once daily. Patients had a mean age of 58 years and 53% were men. The mean duration of type 2 diabetes mellitus was 8.6 years, and the mean BMI was 32 kg/m2. Overall, 71% were White, 9% were Black or African American, and 13% were Asian; 17% identified as Hispanic or Latino ethnicity. Treatment with RYBELSUS 7 mg and RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c compared to sitagliptin 100 mg once daily (see Table 6). Reference ID: 5492467 Table 6. Results at Week 26 in a Trial of RYBELSUS Compared to Sitagliptin 100 mg Once Daily in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with Sulfonylurea RYBELSUS 7 mg RYBELSUS 14 mg Sitagliptin 100 mg Intent-to-Treat (ITT) Population (N)a 465 465 467 HbA1c (%) Baseline (mean) 8.4 8.3 8.3 Change at week 26b -1.0 -1.3 -0.8 Difference from sitagliptinb [95% CI] -0.3 [-0.4; -0.1]c -0.5 [-0.6; -0.4]c Patients (%) achieving HbA1c <7% 44 56 32 FPG (mg/dL) Baseline (mean) 170 168 172 Change at week 26b -21 -31 -15 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 5.8%, 6.2% and 4.5% of patients randomized to RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 2.4%, 1.1% and 2.8% of patients randomized to RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg, respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 91.3 kg, 91.2 kg and 90.9 kg in the RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg arms, respectively. The mean changes from baseline to week 26 were -2.2 kg, -3.1 kg and ­ 0.6 kg in the RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg arms, respectively. The difference from sitagliptin (95% CI) for RYBELSUS 7 mg was -1.6 kg (-2.0, -1.1) and RYBELSUS 14 mg was -2.5 kg (-3.0, -2.0). Combination with Metformin or Metformin with SGLT-2 Inhibitors In a 26-week, double-blind, double-dummy trial (NCT02863419), 711 adult patients with type 2 diabetes mellitus on metformin alone or metformin with SGLT-2 inhibitors were randomized to RYBELSUS 14 mg once daily, liraglutide 1.8 mg subcutaneous injection once daily or placebo. Patients had a mean age of 56 years and 52% were men. The mean duration of type 2 diabetes mellitus was 7.6 years, and the mean BMI was 33 kg/m2. Overall, 73% were White, 4% were Black or African American, and 13% were Asian; 6% identified as Hispanic or Latino ethnicity. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in statistically significant reductions in HbA1c compared to placebo. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in non-inferior reductions in HbA1c compared to liraglutide 1.8 mg (see Table 7). Table 7. Results at Week 26 in a Trial of RYBELSUS Compared to Liraglutide and Placebo in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with SGLT-2i Placebo RYBELSUS 14 mg Liraglutide 1.8 mg Intent-to-Treat (ITT) Population (N)a 142 285 284 HbA1c (%) Baseline (mean) 7.9 8.0 8.0 Change at week 26b -0.2 -1. 2 -1.1 Difference from placebob [95% CI] -1.1 [-1.2 ; -0.9]c Reference ID: 5492467 Difference from liraglutideb [95% CI] -0.1 [-0.3; 0.0] Patients (%) achieving HbA1c <7% 14 68 62 FPG (mg/dL) Baseline (mean) 167 167 168 Change at week 26b -7 -36 -34 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 5.6%, 4.2% and 2.5% of patients randomized to placebo, liraglutide 1.8 mg and RYBELSUS 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 7.7%, 3.2% and 3.5% of patients randomized to placebo, liraglutide 1.8 mg and RYBELSUS 14 mg respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 93.2 kg, 95.5 kg and 92.9 kg in the placebo, liraglutide 1.8 mg, and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -0.5 kg, -3.1 kg and -4.4 kg in the placebo, liraglutide 1.8 mg, and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 14 mg was -3.8 kg (-4.7, -3.0). The difference from liraglutide 1.8 mg for RYBELSUS 14 mg was -1.2 (-1.9, -0.6). Combination in patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment with Metformin alone, Sulfonylurea alone, Basal Insulin alone, or Metformin in Combination with either Sulfonylurea or Basal Insulin In a 26-week, double-blind trial (NCT02827708), 324 adult patients with moderate renal impairment (eGFRCKD-EPI 30−59 mL/min/1.73 m2) were randomized to RYBELSUS 14 mg or placebo once daily. RYBELSUS was added to the patient’s stable pre-trial antidiabetic regimen. The insulin dose was reduced by 20% at randomization for patients on basal insulin. Dose reduction of insulin and sulfonylurea was allowed in case of hypoglycemia; up titration of insulin was allowed but not beyond the pre-trial dose. Patients had a mean age of 70 years and 48% were men. The mean duration of type 2 diabetes mellitus was 14 years, and the mean BMI was 32 kg/m2. Overall, 96% were White, 4% were Black or African American, and 0.3% were Asian; 6.5% identified as Hispanic or Latino ethnicity. 39.5% of patients had an eGFR value of 30 to 44 mL/min/1.73 m2. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c from baseline compared to placebo (see Table 8). Table 8. Results at Week 26 in a Trial of RYBELSUS Compared to Placebo in Patients with Moderate Renal Impairment Placebo RYBELSUS 14 mg Intent-to-Treat (ITT) Population (N)a 161 163 HbA1c (%) Baseline (mean) 7.9 8.0 Change at week 26b -0.2 -1.0 Difference from placebob [95% CI] -0.8 [-1.0; -0.6]c Patients (%) achieving HbA1c <7% 23 58 FPG (mg/dL) Baseline (mean) 164 164 Change at week 26b -7 -28 Reference ID: 5492467 aThe intent-to-treat population includes all randomized patients including patients on rescue medication. At week 26, the primary HbA1c endpoint was missing for 3.7% and 5.5% of patients randomized to placebo and RYBELSUS 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 10% and 4.3% of patients randomized to placebo and RYBELSUS 14 mg, respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication, renal status and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 90.4 kg and 91.3 kg in the placebo and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -0.9 kg and -3.4 kg in the placebo and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 14 mg was -2.5 kg (-3.2, -1.8). Combination with Insulin with or without Metformin In a 26-week double blind trial (NCT03021187), 731 adult patients with type 2 diabetes mellitus inadequately controlled on insulin (basal, basal/bolus or premixed) with or without metformin, were randomized to RYBELSUS 3 mg, 7 mg and 14 mg once daily or placebo once daily. All patients reduced their insulin dose by 20% at randomization to reduce the risk of hypoglycemia. Patients were allowed to increase the insulin dose only up to the starting insulin dose prior to randomization. Patients had a mean age of 61 years and 54% were men. The mean duration of type 2 diabetes mellitus was 15 years, and the mean BMI was 31 kg/m2. Overall, 51% were White, 7% were Black or African American, and 36% were Asian; 13% identified as Hispanic or Latino ethnicity. Treatment with RYBELSUS 7 mg and 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c from baseline compared to placebo once daily (see Table 9). Table 9. Results at Week 26 in a Trial of RYBELSUS Compared to Placebo in Adult Patients with Type 2 Diabetes Mellitus in Combination with Insulin alone or with Metformin Placebo RYBELSUS 7 mg RYBELSUS 14 mg Intent-to-Treat (ITT) Population (N)a 184 182 181 HbA1c (%) Baseline (mean) 8.2 8.2 8.2 Change at week 26b -0.1 -0.9 -1.3 Difference from placebob [95% CI] -0.9 [-1.1; -0.7]c -1.2 [-1.4; -1.0]c Patients (%) achieving HbA1c <7% 7 43 58 FPG (mg/dL) Baseline (mean) 150 153 150 Change at week 26b 5 -20 -24 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 4.3%, 4.4%, and 4.4% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 4.9%, 1.1 % and 2.2% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 86.0 kg, 87.1 kg and 84.6 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -0.4 kg, -2.4 kg and Reference ID: 5492467 -3.7 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 7 mg was -2.0 kg (-3.0, -1.0), and for RYBELSUS 14 mg was -3.3 kg (-4.2, -2.3). 14.4 Cardiovascular Outcomes Trial in Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease PIONEER 6 (NCT02692716) was a multi-center, multi-national, placebo-controlled, double-blind trial. In this trial, 3,183 adult patients with inadequately controlled type 2 diabetes mellitus and atherosclerotic cardiovascular disease were randomized to RYBELSUS 14 mg once daily or placebo for a median observation time of 16 months. The trial compared the risk of a Major Adverse Cardiovascular Event (MACE) between RYBELSUS 14 mg and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Patients eligible to enter the trial were 50 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or NYHA class II and III heart failure or were 60 years of age or older and had other specified risk factors for cardiovascular disease. In total, 1,797 patients (56.5%) had established cardiovascular disease without chronic kidney disease, 354 patients (11.1%) had chronic kidney disease only, and 544 patients (17.1%) had both cardiovascular disease and kidney disease; 488 patients (15.3%) had cardiovascular risk factors without established cardiovascular disease or chronic kidney disease. The mean age at baseline was 66 years, and 68% were men. The mean duration of diabetes was 14.9 years, and mean BMI was 32 kg/m2. Overall, 72% were White, 6% were Black or African American, and 20% were Asian; 16% identified as Hispanic or Latino ethnicity. Concomitant diseases of patients in this trial included, but were not limited to, heart failure (12%), history of ischemic stroke (8%) and history of a myocardial infarction (36%). In total, 99.7% of the patients completed the trial and the vital status was known at the end of the trial for 100%. For the primary analysis, a Cox proportional hazards model was used to test for non-inferiority of RYBELSUS 14 mg to placebo for time to first MACE using a risk margin of 1.3. Type-1 error was controlled across multiple tests using a hierarchical testing strategy. Non-inferiority to placebo was established, with a hazard ratio equal to 0.79 (95% CI: 0.57, 1.11) over the median observation time of 16-months. The proportion of patients who experienced at least one MACE was 3.8% (61/1591) for RYBELSUS 14 mg and 4.8% (76/1592) for placebo. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied RYBELSUS (formulation R1) strengths are available as follows: Tablet Strength Description Package Configuration NDC Number 3 mg White to light yellow, oval shaped debossed with “3” on one side and “novo” on the other side Bottle of 30 tablets 0169-4303-30 7 mg White to light yellow, oval shaped debossed with “7” on one side and “novo” on the other side Bottle of 30 tablets 0169-4307-30 14 mg White to light yellow, oval shaped debossed with “14” on one side and “novo” on the other side Bottle of 30 tablets 0169-4314-30 RYBELSUS (formulation R2) strengths are available as follows: Tablet Strength Description Package Configuration NDC Number 1.5 mg White to light yellow, round shaped debossed with “1.5” on one side and “novo” on the other side Bottle of 30 tablets 0169-4815-30 Reference ID: 5492467 4 mg White to light yellow, round shaped debossed with “4” on one side and “novo” on the other side Bottle of 30 tablets 0169-4804-30 9 mg White to light yellow, round shaped debossed with “9” on one side and “novo” on the other side Bottle of 30 tablets 0169-4809-30 Storage and Handling Store at 68°F to 77°F (20°C to 25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature]. Store and dispense in the original bottle. Store tablet in the original bottle until use to protect tablets from moisture. Store product in a dry place away from moisture. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risk of Thyroid C-cell Tumors Inform patients that semaglutide causes thyroid C-cell tumors in rodents and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, or dyspnea) to their physician [see Boxed Warning and Warnings and Precautions (5.1)]. Acute Pancreatitis Inform patients of the potential risk for acute pancreatitis and its symptoms: severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting. Instruct patients to discontinue RYBELSUS promptly and contact their physician if pancreatitis is suspected [see Warnings and Precautions (5.2)]. Diabetic Retinopathy Complications Inform patients to contact their physician if changes in vision are experienced during treatment with RYBELSUS [see Warnings and Precautions (5.3)]. Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Inform patients that the risk of hypoglycemia is increased when RYBELSUS is used with an insulin secretagogue (such as a sulfonylurea) or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.4)]. Dehydration and Renal Failure Advise patients treated with RYBELSUS of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs [see Warnings and Precautions (5.5)]. Severe Gastrointestinal Adverse Reactions Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.6)]. Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of RYBELSUS. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking RYBELSUS and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.7)]. Reference ID: 5492467 Acute Gallbladder Disease Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up [see Warnings and Precautions (5.8)]. Pulmonary Aspiration During General Anesthesia or Deep Sedation: Inform patients that RYBELSUS may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking RYBELSUS [see Warnings and Precautions (5.9)]. Pregnancy Advise a pregnant woman of the potential risk to a fetus. Advise women to inform their healthcare provider if they are pregnant or intend to become pregnant [see Use in Specific Populations (8.1), (8.3)]. Lactation RYBELSUS passes into breast milk, and it is not known how it affects your baby. Advise females not to breastfeed during treatment with RYBELSUS [see Use in Specific Populations (8.2)]. Females and Males of Reproductive Potential Discontinue RYBELSUS at least 2 months before a planned pregnancy due to the long washout period for semaglutide [see Use in Specific Populations (8.3)]. Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd Denmark For additional information about RYBELSUS contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-833-457-7455 Version: 8 RYBELSUS® and OZEMPIC® are registered trademarks of Novo Nordisk A/S. Patent Information: http://www.novonordisk-us.com/products/product-patents.html © 2024 Novo Nordisk Reference ID: 5492467 Medication Guide RYBELSUS® (reb-EL-sus) (semaglutide) tablets, for oral use Read this Medication Guide before you start using RYBELSUS and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about RYBELSUS? RYBELSUS may cause serious side effects, including:  Possible thyroid tumors, including cancer. Tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer. In studies with rodents, RYBELSUS and medicines that work like RYBELSUS caused thyroid tumors, including thyroid cancer. It is not known if RYBELSUS will cause thyroid tumors or a type of thyroid cancer called medullary thyroid carcinoma (MTC) in people.  Do not use RYBELSUS if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC), or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). What is RYBELSUS? RYBELSUS is a prescription medicine used along with diet and exercise to improve blood sugar (glucose) in adults with type 2 diabetes.  RYBELSUS is not for use in people with type 1 diabetes. It is not known if RYBELSUS is safe and effective for use in children. Do not use RYBELSUS if:  you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC) or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).  you have had a serious allergic reaction to semaglutide or any of the ingredients in RYBELSUS. See the end of this Medication Guide for a complete list of ingredients in RYBELSUS. Symptoms of a serious allergic reaction include: o swelling of your face, lips, tongue or throat o problems breathing or swallowing o severe rash or itching o fainting or feeling dizzy o very rapid heartbeat Before using RYBELSUS, tell your healthcare provider if you have any other medical conditions, including if you:  have or have had problems with your pancreas or kidneys.  have a history of vision problems related to your diabetes.  are scheduled to have surgery or other procedures that use anesthesia or deep sleepiness (deep sedation).  are pregnant or plan to become pregnant. It is not known if RYBELSUS will harm your unborn baby. You should stop using RYBELSUS 2 months before you plan to become pregnant. Talk to your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.  are breastfeeding or plan to breastfeed. Breastfeeding is not recommended during treatment with RYBELSUS. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. RYBELSUS may affect the way some medicines work and some medicines may affect the way RYBELSUS works. Before using RYBELSUS, talk to your healthcare provider about low blood sugar and how to manage it. Tell your healthcare provider if you are taking other medicines to treat diabetes, including insulin or sulfonylureas. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take RYBELSUS?  Take RYBELSUS exactly as your healthcare provider tells you to.  Do not take more than 1 tablet each day.  Take RYBELSUS by mouth on an empty stomach in the morning. Reference ID: 5492467  Take RYBELSUS with a sip of plain water (no more than 4 ounces). Do not take RYBELSUS with any other liquids besides water.  Do not split, crush or chew. Swallow RYBELSUS whole.  After 30 minutes, you can eat, drink, or take other oral medicines.  If you miss a dose of RYBELSUS, skip the missed dose and go back to your regular schedule.  If you take too much RYBELSUS, call your healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest hospital emergency room right away. Your dose of RYBELSUS and other diabetes medicines may need to change because of: change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, fever, trauma, infection, surgery or because of other medicines you take. What are the possible side effects of RYBELSUS? RYBELSUS may cause serious side effects, including:  See “What is the most important information I should know about RYBELSUS?”  inflammation of your pancreas (pancreatitis). Stop using RYBELSUS and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.  changes in vision. Tell your healthcare provider if you have changes in vision during treatment with RYBELSUS.  low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use RYBELSUS with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include: o dizziness or light-headedness o blurred vision o anxiety, irritability, or mood changes o sweating o slurred speech o hunger o confusion or drowsiness o shakiness o weakness o headache o fast heartbeat o feeling jittery  kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration.  severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use RYBELSUS. Tell your healthcare provider if you have stomach problems that are severe or will not go away.  serious allergic reactions. Stop using RYBELSUS and get medical help right away, if you have any symptoms of a serious allergic reaction including: o swelling of your face, lips, tongue or throat o problems breathing or swallowing o severe rash or itching o fainting or feeling dizzy o very rapid heartbeat  gallbladder problems. Gallbladder problems have happened in some people who take RYBELSUS. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include: o pain in your upper stomach (abdomen) o yellowing of skin or eyes (jaundice) o fever o clay-colored stools  food or liquid getting into the lungs during surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). RYBELSUS may increase the chance of food getting into your lungs during surgery or other procedures. Tell all your healthcare providers that you are taking RYBELSUS before you are scheduled to have surgery or other procedures. The most common side effects of RYBELSUS may include nausea, stomach (abdominal) pain, diarrhea, decreased appetite, vomiting and constipation. Nausea, vomiting and diarrhea are most common when you first start RYBELSUS. Talk to your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of RYBELSUS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store RYBELSUS?  Store RYBELSUS at room temperature between 68°F and 77°F (20°C to 25°C).  Store in a dry place away from moisture. Reference ID: 5492467  Store tablets in the original closed RYBELSUS bottle until you are ready to take one. Do not store in any other container.  Keep RYBELSUS and all medicines out of the reach of children. General information about the safe and effective use of RYBELSUS. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RYBELSUS for a condition for which it was not prescribed. Do not give RYBELSUS to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about RYBELSUS that is written for health professionals. What are the ingredients in RYBELSUS? Active Ingredient: semaglutide Inactive Ingredients:  RYBELSUS (formulation R1): magnesium stearate, microcrystalline cellulose, povidone and salcaprozate sodium  RYBELSUS (formulation R2): salcaprozate sodium and magnesium stearate Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark RYBELSUS® is a registered trademark of Novo Nordisk A/S. PATENT Information: http://www.novonordisk-us.com/products/product-patents.html © 2024 Novo Nordisk For more information, go to www.RYBELSUS.com or call 1-833-GLP-PILL. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2024 Reference ID: 5492467
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2025-02-12T15:47:36.552083
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RYBELSUS® safely and effectively. See full prescribing information for RYBELSUS. RYBELSUS (semaglutide) tablets, for oral use Initial U.S. Approval: 2017 WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • In rodents, semaglutide causes thyroid C-cell tumors. It is unknown whether RYBELSUS causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined (5.1, 13.1). • RYBELSUS is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors (4, 5.1). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Warnings and Precautions, Pulmonary Aspiration During General Anesthesia or Deep Sedation (5.9) ……………………………….11/2024 Warning and Precautions, Severe Gastrointestinal Adverse Reactions (5.6) ……………………………………………………………….12/2024 Dosage and Administration, Overview of RYBELUS formulations (2.1), Recommended Dosage (2.3), Switching Patients between OZEMPIC and RYBELSUS (2.4) ………………………………………………...12/2024 ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ RYBELSUS is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1). Limitations of Use • Not for treatment of type 1 diabetes mellitus (1). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • There are two RYBELSUS formulations (i.e., formulation R1 and formulation R2) with different recommended dosages (2.1) o These formulations are not substitutable on a mg per mg basis o Use either formulation but do not use both formulations at the same time. • Take RYBELSUS on an empty stomach in the morning with water (up to 4 ounces of water); do not take with other liquids besides water. (2.2) • After taking RYBELSUS, wait at least 30 minutes before eating food, drinking beverages, or taking other oral medications. (2.2). • Swallow tablets whole. Do not split, crush, or chew tablets (2.2). • See the Full Prescribing Information for instructions on switching from OZEMPIC to RYBELSUS and switching between the two different RYBELSUS formulations (2.4). Recommended Dosage of Starting, Escalation, and Maintenance Dosage of RYBELSUS Formulations R1 and R2 (2.3) RYBELSUS (formulation R1) (2.3) • Day 1 to 30: Recommended starting dosage is 3 mg orally once daily for 30 days (this dosage is not effective for glycemic control) • Days 31to 60: Increase the dosage to 7 mg orally once daily. • On Day 61 or thereafter, if: (2.3) o No additional glycemic control is needed, maintain the dosage at 7 mg orally once daily. o Additional glycemic control is needed, increase the dosage to 14 mg orally once daily. RYBELSUS (formulation R2) (2.3) • Day 1 to 30: Recommended starting dosage is 1.5 mg orally once daily for 30 days (this dosage is not effective for glycemic control). • Days 31to 60: Increase the dosage to 4 mg orally once daily. • On Day 61 or thereafter, if: (2.3) o No additional glycemic control is needed, maintain the dosage at 4 mg orally once daily. o Additional glycemic control is needed, increase the dosage to 9 mg orally once daily. ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Tablets (formulation R1): 3 mg, 7 mg and 14 mg (3). • Tablets (formulation R2): 1.5 mg, 4 mg and 9 mg (3). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Personal or family history of MTC or in patients with MEN-2 syndrome type 2 (4). • Prior serious hypersensitivity reaction to semaglutide or any of the excipients in RYBELSUS (4). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, including RYBELSUS. Discontinue promptly if pancreatitis is suspected. (5.2). • Diabetic Retinopathy Complications: Has been reported in a cardiovascular outcomes trial with semaglutide injection. Patients with a history of diabetic retinopathy should be monitored (5.3). • Hypoglycemia with Concomitant of Insulin Secretagogues or Insulin: May increase the risk of hypoglycemia, including severe hypoglycemia. Reducing the dosage of insulin secretagogue or insulin may be necessary (5.4). • Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions (5.5). • Severe Gastrointestinal Adverse Reactions: Use of RYBELSUS has been associated with gastrointestinal adverse reactions, sometimes severe. RYBELSUS is not recommended in patients with severe gastroparesis. (5.6). • Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. Discontinue RYBELSUS if hypersensitivity reactions occur and monitor until signs and symptoms resolve (5.7). • Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated (5.8). • Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. (5.9). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ Most common adverse reactions (incidence ≥5%) are nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc., at 1-833-457-7455 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS----------------------------------­ Oral Medications: RYBELSUS delays gastric emptying. Consider increased clinical or laboratory monitoring when co-administered with other oral medications that have a narrow therapeutic index or that require clinical monitoring. (7.2). ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ • Pregnancy: See Pregnancy subsection (8.1). • Lactation: Breastfeeding not recommended (8.2). • Females and Males of Reproductive Potential: Discontinue RYBELSUS in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide (8.3). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 12/2024 Reference ID: 5492467 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF THYROID C-CELL TUMORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Overview of RYBELUS formulations 2.2 Important Administration Instructions 2.3 Recommended Starting, Escalation, and Maintenance Dosage of RYBELSUS Formulation R1 and R2 2.4 Switching Between RYBELSUS (Formulations R1 or R2) or from OZEMPIC to RYBELSUS 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors 5.2 Acute Pancreatitis 5.3 Diabetic Retinopathy Complications 5.4 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin 5.5 Acute Kidney Injury 5.6 Severe Gastrointestinal Adverse Reactions 5.7 Hypersensitivity Reactions 5.8 Acute Gallbladder Disease 5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin 7.2 Oral Medications 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies 14.2 Monotherapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus 14.3 Combination Therapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus 14.4 Cardiovascular Outcomes Trial in Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5492467 FULL PRESCRIBING INFORMATION WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether RYBELSUS causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)]. • RYBELSUS is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications (4)]. Counsel patients regarding the potential risk for MTC with the use of RYBELSUS and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS [see Contraindications (4) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE RYBELSUS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use RYBELSUS is not indicated for use in patients with type 1 diabetes mellitus. 2 DOSAGE AND ADMINISTRATION 2.1 Overview of RYBELSUS Formulations • There are two RYBELSUS formulations (i.e., formulation R1 and formulation R2) with different recommended dosages. Refer to recommendations on how to switch from one formulation to another formulation [see Dosage and Administration (2.3, 2.4)]. o RYBELSUS (formulation R1) includes strengths 3 mg, 7 mg, and 14 mg. o RYBELSUS (formulation R2) includes strengths 1.5 mg, 4 mg, and 9 mg. • These formulations are not substitutable on a mg per mg basis. • Use either RYBELSUS formulation R1or formulation R2; do not use both formulations at the same time. • Do not take more than one tablet per day. 2.2 Important Administration Instructions • Take RYBELSUS on an empty stomach in the morning with water (up to 4 ounces of water). Do not take RYBELSUS with other liquids besides water. • After taking RYBELSUS, wait at least 30 minutes before eating food, drinking beverages, or taking other oral medications [see Clinical Pharmacology (12.3)]. • Swallow tablets whole. Do not split crush, or chew. • If a dose is missed, skip the missed dose, and take the next dose the following day. 2.3 Recommended Starting, Escalation, and Maintenance Dosage of RYBELSUS Formulations R1 and R2 RYBELSUS (formulation R1) RYBELSUS (formulation R1) includes the following strengths: 3 mg, 7 mg, and 14 mg. Recommend the following RYBELSUS (formulation R1) dosage to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.6), see Adverse Reactions (6.1)]: Reference ID: 5492467 *Discontinue this formulation and initiate the alternate formulation the day after Switching from OZEMPIC to RYBELSUS (formulation R1) or RYBELSUS (formulation R2) Switching from OZEMPIC to RYBELSUS (formulation R1) • One week after discontinuing 0.5 mg of subcutaneous OZEMPIC, start 7 mg or 14 mg of RYBELSUS (formulation R1) orally once daily. • Switching recommendations for patients taking Ozempic 0.25 mg, 1 mg, or 2 mg subcutaneously once weekly to RYBELSUS (formulation R1) are not available. Switching from OZEMPIC to RYBELSUS (formulation R2) • One week after discontinuing 0.5 mg of subcutaneous OZEMPIC, start 4 mg or 9 mg of RYBELSUS (formulation R2) orally once daily. Reference ID: 5492467 • Starting Dosage (Initiation Phase) (Days 1 to 30): The recommended starting dosage is 3 mg orally once daily (this dosage is not effective for glycemic control). • Escalation and Maintenance Dosage (Days 31 and beyond): o Days 31 to 60: Increase the dosage to 7 mg orally once daily. o On Day 61 or thereafter, if: • No additional glycemic control is needed, maintain the dosage at 7 mg orally once daily. • Additional glycemic control is needed, increase the dosage to 14 mg orally once daily. RYBELSUS (formulation R2) RYBELSUS (formulation R2) includes the following strengths: 1.5 mg, 4 mg, and 9 mg. Recommend the following RYBELSUS (formulation R2) dosage to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.6), Adverse Reactions (6.1)]: • Starting Dosage (Initiation Phase) (Days 1 through 30): The recommended starting dosage is 1.5 mg orally once daily (this dosage is not effective for glycemic control). • Escalation and Maintenance Dosage (Days 31 and beyond): o Days 31 to 60: Increase the dosage to 4 mg orally once daily. o On Day 61 or thereafter, if: • No additional glycemic control is needed maintain the dosage at 4 mg orally once daily. • Additional glycemic control is needed increase the dosage to 9 mg orally once daily. 2.4 Switching Between RYBELSUS (Formulations R1 or R2) or from OZEMPIC to RYBELSUS Switching Between RYBELSUS Formulations • Do not switch between RYBELSUS formulations during the initiation phase (Days 1-30) [see Dosage and Administration (2.3)]. • After 30 days of RYBELSUS treatment (after the initiation phase) [see Dosage and Administration (2.3)], patients may switch between RYBELSUS formulations (see Table 1). • When switching between the formulations, initiate the other RYBELSUS formulation the day after discontinuing the previous RYBELSUS formulation. Table 1. Switching Between Escalation or Maintenance Dosage of RYBELSUS Formulations RYBELSUS (formulation R1) * RYBELSUS (formulation R2) * 7 mg orally once daily 4 mg orally once daily 14 mg orally once daily 9 mg orally once daily • Switching recommendations for patients taking Ozempic 0.25 mg, 1 mg, or 2 mg subcutaneously once weekly to RYBELSUS (formulation R2) are not available. 3 DOSAGE FORMS AND STRENGTHS RYBELSUS (semaglutide) tablets (formulation R1) are available as: 3 mg: white to light yellow, oval shaped debossed with “3” on one side and “novo” on the other side. 7 mg: white to light yellow, oval shaped debossed with “7” on one side and “novo” on the other side. 14 mg: white to light yellow, oval shaped debossed with “14” on one side and “novo” on the other side. RYBELSUS (semaglutide) tablets (formulation R2) are available as: • 1.5 mg: white to light yellow, round shaped debossed with “1.5” on one side and “novo” on the other side. • 4 mg: white to light yellow, round shaped debossed with “4” on one side and “novo” on the other side. • 9 mg: white to light yellow, round shaped debossed with “9” on one side and “novo” on the other side. 4 CONTRAINDICATIONS RYBELSUS is contraindicated in patients with: • A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)]. • A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with RYBELSUS [see Warnings and Precautions (5.7)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures [see Nonclinical Toxicology (13.1)]. It is unknown whether RYBELSUS causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. RYBELSUS is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of RYBELSUS and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with RYBELSUS. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. Reference ID: 5492467 5.2 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including RYBELSUS [see Adverse Reactions (6.1)]. After initiation of RYBELSUS, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue RYBELSUS and initiate appropriate management. 5.3 Diabetic Retinopathy Complications In a pooled analysis of glycemic control trials with RYBELSUS, patients reported diabetic retinopathy related adverse reactions during the trial (4.2% with RYBELSUS and 3.8% with comparator) [see Adverse Reactions (6.1)]. In a 2-year cardiovascular outcomes trial with semaglutide injection involving patients with type 2 diabetes mellitus and high cardiovascular risk, diabetic retinopathy complications (which was a 4-component adjudicated endpoint) occurred in patients treated with semaglutide injection (3%) compared to placebo (1.8%). The absolute risk increase for diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline (semaglutide injection 8.2%, placebo 5.2%) than among patients without a known history of diabetic retinopathy (semaglutide injection 0.7%, placebo 0.4%). Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been studied. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy. 5.4 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving RYBELSUS in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia [see Adverse Reactions (6.1) and Drug Interactions (7)]. The risk of hypoglycemia may be lowered by a reduction in the dosage of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.5 Acute Kidney Injury There have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis, in patients treated with GLP-1 receptor agonists, including semaglutide. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of RYBELSUS in patients reporting severe adverse gastrointestinal reactions. 5.6 Severe Gastrointestinal Adverse Reactions Use of RYBELSUS has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6.1)]. In RYBELSUS clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving RYBELSUS (7 mg 0.6%, 14 mg 2%) than placebo (0.3%). RYBELSUS is not recommended in patients with severe gastroparesis. 5.7 Hypersensitivity Reactions Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with RYBELSUS. If hypersensitivity reactions occur, discontinue use of RYBELSUS; treat promptly per standard of care, and monitor until signs and symptoms resolve. RYBELSUS is contraindicated in patients with a prior serious hypersensitivity reaction to semaglutide or to any of the excipients in RYBELSUS [see Adverse Reactions (6.2)]. Reference ID: 5492467 Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to anaphylaxis with RYBELSUS. 5.8 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg. Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-treated patients [see Adverse Reactions (6.1)]. If cholelithiasis or cholecystitis is suspected, gallbladder studies and appropriate clinical follow-up are indicated [see Adverse Reactions (6.2)]. 5.9 Pulmonary Aspiration During General Anesthesia or Deep Sedation RYBELSUS delays gastric emptying [see Clinical Pharmacology (12.2)]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking RYBELSUS, including whether modifying preoperative fasting recommendations or temporarily discontinuing RYBELSUS could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking RYBELSUS. 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)] • Acute Pancreatitis [see Warnings and Precautions (5.2)] • Diabetic Retinopathy Complications [see Warnings and Precautions (5.3)] • Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.4)] • Acute Kidney Injury [see Warnings and Precautions (5.5)] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.6)] • Hypersensitivity Reactions [see Warnings and Precautions (5.7)] • Acute Gallbladder Disease [see Warnings and Precautions (5.8)] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of RYBELSUS (formulation R2 – 1.5 mg, 4 mg, and 9 mg strengths) [see Dosage and Administration (2.2)] and RYBELSUS (formulation R1 – 3 mg, 7, mg, and 14 mg strengths) [see Dosage and Administration (2.3)] has been established as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus based on adequate and well-controlled studies of RYBELSUS (formulation R1) in adult patients with type 2 diabetes mellitus [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. Below is a display of the safety results of the adequate and well-controlled studies of RYBELSUS (formulation R1) in adult patients with type 2 diabetes mellitus. Reference ID: 5492467 Pool of Placebo-Controlled Trials The data in Table 1 are derived from 2 placebo-controlled trials in adult patients with type 2 diabetes mellitus [see Clinical Studies (14)]. These data reflect exposure of 1071 patients to RYBELSUS with a mean duration of exposure of 41.8 weeks. The mean age of patients was 58 years, 3.9% were 75 years or older and 52% were male. In these trials, 63% were White, 6% were Black or African American, and 27% were Asian; 19% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 mellitus diabetes for an average of 9.4 years and had a mean HbA1c of 8.1%. At baseline, 20.1% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m2) in 66.2%, mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 32.4% and moderately impaired (eGFR 30 to 60 mL/min/1.73m2) in 1.4% of patients. Pool of Placebo- and Active-Controlled Trials The occurrence of adverse reactions was also evaluated in a larger pool of adult patients with type 2 diabetes mellitus participating in 9 placebo- and active-controlled trials [see Clinical Studies (14)]. In this pool, 4,116 patients with type 2 diabetes mellitus were treated with RYBELSUS for a mean duration of 59.8 weeks. The mean age of patients was 58 years, 5% were 75 years or older and 55% were male. In these trials, 65% were White, 6% were Black or African American, and 24% were Asian; 15% identified as Hispanic or Latino ethnicity. At baseline, patients had type 2 diabetes mellitus for an average of 8.8 years and had a mean HbA1c of 8.2%. At baseline, 16.6% of the population reported retinopathy. Baseline estimated renal function was normal (eGFR ≥90 mL/min/1.73m2) in 65.9%, mildly impaired (eGFR 60 to 90 mL/min/1.73m2) in 28.5%, and moderately impaired (eGFR 30 to 60 mL/min/1.73m2) in 5.4% of the patients. Common Adverse Reactions Table 2 shows common adverse reactions, excluding hypoglycemia, associated with the use of RYBELSUS in adult patients with type 2 diabetes mellitus in the pool of placebo-controlled trials. These adverse reactions occurred more commonly on RYBELSUS than on placebo and occurred in at least 5% of patients treated with RYBELSUS. Table 2. Adverse Reactions in Placebo-Controlled Trials Reported in ≥5% of RYBELSUS-Treated Patients with Type 2 Diabetes Mellitus Adverse Reaction Placebo (N=362) % RYBELSUS 7 mg (N=356) % RYBELSUS 14 mg (N=356) % Nausea 6 11 20 Abdominal Pain 4 10 11 Diarrhea 4 9 10 Decreased appetite 1 6 9 Vomiting 3 6 8 Constipation 2 6 5 In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1. Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients who received RYBELSUS than placebo: RYBELSUS 14 mg once daily (41%), RYBELSUS 7 mg once daily (32%), and placebo (21%), including severe reactions (RYBELSUS 14 mg 2.0%, RYBELSUS 7 mg 0.6%, placebo 0.3%). The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation. A greater percentage of patients who received RYBELSUS 14 mg once daily (8%) and RYBELSUS 7 mg once daily (4%) discontinued treatment due to gastrointestinal adverse reactions than patients who received placebo (1%). Reference ID: 5492467 In addition to the reactions in Table 1, the following gastrointestinal adverse reactions with a frequency of <5% occurred in RYBELSUS-treated patients (frequencies listed, respectively, as 14 mg once daily, 7 mg once daily, and placebo): abdominal distension (3%, 2%, and 1%), dyspepsia (0.6%, 3%, 0.6%), eructation (2%, 0.6%, 0%,), flatulence (1%, 2%, 0%), gastroesophageal reflux disease (2%, 2%, 0.3%), and gastritis (2%, 2%, 0.8%). Other Adverse Reactions Pancreatitis: In the pool of placebo- and active-controlled trials with RYBELSUS, pancreatitis was reported as a serious adverse event in 6 RYBELSUS-treated patients (0.1 events per 100 patient years) versus 1 in comparator- treated patients (<0.1 events per 100 patient years). Diabetic Retinopathy Complications: In the pool of placebo- and active-controlled trials with RYBELSUS, patients reported diabetic retinopathy related adverse reactions during the trial (4.2% with RYBELSUS and 3.8% with comparator). Hypoglycemia: Table 3 summarizes the incidence of hypoglycemia by various definitions in the placebo- controlled trials. Table 3. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials In Patients with Type 2 Diabetes Mellitus Placebo RYBELSUS 7 mg RYBELSUS 14 mg Monotherapy (26 weeks) N=178 N=175 N=175 Severe* 0% 1% 0% Plasma glucose <54 mg/dL 1% 0% 0% Add-on to metformin and/or sulfonylurea, basal insulin alone or metformin in combination with basal insulin in patients with moderate renal impairment (26 weeks) N=161 - N=163 Severe* 0% - 0% Plasma glucose <54 mg/dL 3% - 6% Add-on to insulin with or without metformin (52 weeks) N=184 N=181 N=181 Severe* 1% 0% 1% Plasma glucose <54 mg/dL 32% 26% 30% *“Severe” hypoglycemia adverse reactions are episodes requiring the assistance of another person. Hypoglycemia was more frequent when RYBELSUS was used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Increases in Amylase and Lipase: In placebo-controlled trials, patients exposed to RYBELSUS 7 mg and 14 mg had a mean increase from baseline in amylase of 10% and 13%, respectively, and lipase of 30% and 34%, respectively. These changes were not observed in placebo-treated patients. Cholelithiasis: In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg. Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-treated patients. Reference ID: 5492467 Increases in Heart Rate: In placebo-controlled trials, RYBELSUS 7 mg and 14 mg resulted in a mean increase in heart rate of 1 to 3 beats per minute. There was no change in heart rate in placebo-treated patients. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of RYBELSUS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Gastrointestinal: ileus • Hypersensitivity: anaphylaxis, angioedema, rash, urticaria • Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy • Nervous system disorders: dizziness, dysesthesia, dysgeusia • Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation • Skin and Subcutaneous Tissue: alopecia 7 DRUG INTERACTIONS 7.1 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin RYBELSUS stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving RYBELSUS in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating RYBELSUS, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. 7.2 Other Oral Drugs RYBELSUS causes a delay of gastric emptying, and thereby has the potential to impact the absorption of other oral drugs. Levothyroxine exposure was increased 33% (90% CI: 125-142) when administered with RYBELSUS in a drug interaction study [see Clinical Pharmacology (12.3)]. When co-administering RYBELSUS with other oral drugs that have a narrow therapeutic index or that require clinical monitoring, consider increased clinical or laboratory monitoring [see Dosage and Administration (2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data with RYBELSUS use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal reproduction studies, there may be potential risks to the fetus from exposure to RYBELSUS during pregnancy. RYBELSUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant rats administered semaglutide during organogenesis, embryofetal mortality, structural abnormalities and alterations to growth occurred at maternal exposures below the maximum recommended human dose (MRHD) based on AUC. In rabbits and cynomolgus monkeys administered semaglutide during organogenesis, early pregnancy losses and structural abnormalities were observed at exposure below the MRHD (rabbit) and ≥10-fold the MRHD (monkey). These findings coincided with a marked maternal body weight loss in both animal species (see Data). Reference ID: 5492467 The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20–25% in women with a HbA1c >10. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease Associated Maternal and Fetal Risk: Poorly controlled diabetes during pregnancy increases the maternal risk for diabetic ketoacidosis, pre- eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data: In a combined fertility and embryofetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.2-, 0.7-, and 2.1-fold the MRHD) were administered to males for 4 weeks prior to and throughout mating and to females for 2 weeks prior to mating, and throughout organogenesis to Gestation Day 17. In parental animals, pharmacologically mediated reductions in body weight gain and food consumption were observed at all dose levels. In the offspring, reduced growth and fetuses with visceral (heart blood vessels) and skeletal (cranial bones, vertebra, ribs) abnormalities were observed at the human exposure. In an embryofetal development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or 0.0075 mg/kg/day (0.06-, 0.6-, and 4.4-fold the MRHD) were administered throughout organogenesis from Gestation Day 6 to 19. Pharmacologically mediated reductions in maternal body weight gain and food consumption were observed at all dose levels. Early pregnancy losses and increased incidences of minor visceral (kidney, liver) and skeletal (sternebra) fetal abnormalities were observed at ≥0.0025 mg/kg/day, at clinically relevant exposures. In an embryofetal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (1.9-, 9.9-, and 29-fold the MRHD) were administered throughout organogenesis, from Gestation Day 16 to 50. Pharmacologically mediated, marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with the occurrence of sporadic abnormalities (vertebra, sternebra, ribs) at ≥0.075 mg/kg twice weekly (>9X human exposure). In a pre- and postnatal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (1.3-, 6.4-, and 14-fold the MRHD) were administered from Gestation Day 16 to 140. Pharmacologically mediated marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with an increase in early pregnancy losses and led to delivery of slightly smaller offspring at ≥0.075 mg/kg twice weekly (>6X human exposure). Salcaprozate sodium (SNAC), an absorption enhancer in RYBELSUS, crosses the placenta and reaches fetal tissues in rats. In a pre- and postnatal development study in pregnant Sprague Dawley rats, SNAC was administered orally at 1,000 mg/kg/day (exposure levels were not measured) on Gestation Day 7 through lactation day 20. An increase in gestation length, an increase in the number of stillbirths and a decrease in pup viability were observed. 8.2 Lactation Risk Summary A clinical lactation study reported semaglutide concentrations below the lower limit of quantification in human breast milk. However, salcaprozate sodium (SNAC) and/or its metabolites are present in human milk. Since the activity of enzymes involved in SNAC clearance may be lower in infants compared to adults, higher SNAC plasma levels may occur in neonates and infants. Because of the unknown potential for serious adverse reactions in the breastfed infant due to the possible accumulation of SNAC, and because there are alternative formulations of semaglutide that do not contain SNAC that can be used during lactation, advise patients that breastfeeding is not recommended during treatment with RYBELSUS. Reference ID: 5492467 8.3 Females and Males of Reproductive Potential Discontinue RYBELSUS in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide [see Use in Specific Populations (8.1)]. 8.4 Pediatric Use The safety and effectiveness of RYBELSUS have not been established in pediatric patients. 8.5 Geriatric Use In the pool of glycemic control trials, 1,229 (30%) RYBELSUS-treated patients were 65 years of age and over and 199 (5%) RYBELSUS-treated patients were 75 years of age and over [see Clinical Studies (14)]. In PIONEER 6, the cardiovascular outcomes trial, 891 (56%) RYBELSUS-treated patients were 65 years of age and over and 200 (13%) RYBELSUS-treated patients were 75 years of age and over. No overall differences in safety or effectiveness for RYBELSUS have been observed between patients 65 years of age and older and younger adult patients. 8.6 Renal Impairment The recommended dosage of RYBELSUS in patients with renal impairment is the same as those with normal renal function. The safety and effectiveness of RYBELSUS was evaluated in a 26-week clinical study that included 324 patients with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2) [see Clinical Studies (14.1)]. In patients with renal impairment including end-stage renal disease (ESRD), no clinically relevant change in semaglutide pharmacokinetics was observed [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment The recommended dosage in patients with hepatic impairment is the same as those with normal hepatic function. In a study in subjects with different degrees of hepatic impairment, no clinically relevant change in semaglutide pharmacokinetics was observed [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the long half-life of RYBELSUS of approximately 1 week. 11 DESCRIPTION RYBELSUS tablets, for oral use, contain semaglutide, a GLP-1 receptor agonist. The peptide backbone is produced by yeast fermentation. The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid. Furthermore, semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4). A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid. The molecular formula is C187H291N45O59 and the molecular weight is 4113.58 g/mol. Reference ID: 5492467 30 37 F- 1- A- W- L- V- R- G- R- G- OH 0 Structural formula: Semaglutide is a white to almost white hygroscopic powder. Each tablet of: • RYBELSUS (formulation R1) contains 3 mg, 7 mg or 14 mg of semaglutide and the following inactive ingredients: magnesium stearate, microcrystalline cellulose, povidone and salcaprozate sodium (SNAC). • RYBELSUS (formulation R2) contains 1.5 mg, 4 mg, 9 mg of semaglutide and the following inactive ingredients: SNAC and magnesium stearate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1. GLP-1 is a physiological hormone that has multiple actions on glucose, mediated by the GLP-1 receptors. The principal mechanism of protraction resulting in the long half-life of semaglutide is albumin binding, which results in decreased renal clearance and protection from metabolic degradation. Furthermore, semaglutide is stabilized against degradation by the DPP-4 enzyme. Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. 12.2 Pharmacodynamics The pharmacodynamic evaluations described below were in patients with type 2 diabetes mellitus who received once weekly subcutaneous injections of placebo or semaglutide injection over 12 weeks (semaglutide injection- treated patients were started on lower dosages and then titrated up to 1 mg once weekly). RYBELSUS is not approved for subcutaneous use. Fasting and Postprandial Glucose Semaglutide reduces fasting and postprandial glucose concentrations. In patients with type 2 diabetes mellitus, treatment with semaglutide injection 1 mg resulted in reductions in glucose in terms of absolute change from baseline and relative reduction compared to placebo of 29 mg/dL (22%) for fasting glucose, 74 mg/dL (36%) for 2 hour postprandial glucose, and 30 mg/dL (22%) for mean 24 hour glucose concentration. Reference ID: 5492467 Insulin Secretion Both first- and second-phase insulin secretion are increased in patients with type 2 diabetes mellitus treated with semaglutide compared with placebo. Glucagon Secretion Semaglutide lowers the fasting and postprandial glucagon concentrations. Glucose dependent insulin and glucagon secretion Semaglutide lowers high blood glucose concentrations by stimulating insulin secretion and lowering glucagon secretion in a glucose-dependent manner. During induced hypoglycemia, semaglutide did not alter the counter regulatory responses of increased glucagon compared to placebo and did not impair the decrease of C-peptide in patients with type 2 diabetes mellitus. Gastric emptying Semaglutide causes a delay of early postprandial gastric emptying, thereby reducing the rate at which glucose appears in the circulation postprandially. Cardiac Electrophysiology The effect of subcutaneously administered semaglutide on cardiac repolarization was tested in a thorough QTc trial. At an average exposure level 4-fold higher than that of the maximum recommended dose of RYBELSUS, semaglutide does not prolong QTc intervals to any clinically relevant extent. 12.3 Pharmacokinetics Semaglutide estimated mean steady-state concentration was 6.7 nmol/L and 14.6 nmol/L following once daily oral administration of 7 mg and 14 mg of RYBELSUS (formulation R1), respectively, in patients with type 2 diabetes mellitus. Semaglutide exposures increased in a dose-proportional manner. Steady-state exposure was achieved following 4­ 5 weeks of RYBELSUS oral administration. Absorption Semaglutide is co-formulated with salcaprozate sodium which facilitates the absorption of semaglutide after oral RYBELSUS administration. The absorption of semaglutide predominantly occurs in the stomach. Semaglutide estimated absolute bioavailability was approximately: • 0.4-1% after oral administration of 3 mg, 7 mg, and 14 mg of RYBELSUS (formulation R1). • 1-2% after oral administration of 1.5 mg, 4 mg, and 9 mg of RYBELSUS (formulation R2). Semaglutide maximum concentration was reached approximately 1-hour after oral RYBELSUS administration. Effect of RYBELSUS Formulation: There were no clinically significant differences observed in the mean steady state AUC0-24h,SS and Cmax,SS between the 3 mg, 7 mg, and 14 mg doses of RYBELSUS (formulation R1) and the 1.5 mg, 4 mg, and 9 mg doses of RYBELSUS (formulation R2), respectively, in a clinical study conducted in healthy subjects. Effect of Volume and Timing of Water Consumption: Single 10 mg doses of oral semaglutide (formulation R1) were administered with 50 mL or 240 mL of water after an 8-hour overnight fast and a continued fast of 4 hours post-dose in healthy subjects. Semaglutide absorption (i.e., area under the curve (AUC) and peak concentrations (Cmax)) were higher following dosing with 50 mL water compared to that of 240 mL water. Reference ID: 5492467 For 10 days, healthy subjects received 10 mg of oral semaglutide (formulation R1) once daily doses with 50 mL or 120 mL of water under fasting conditions with post-dose fasting period of 15, 30, 60, or 120 minutes. In this study, semaglutide absorption (i.e., AUC and Cmax) was higher after a longer post-dose fasting period. There were no clinically significant differences in semaglutide absorption with administration of 50 mL or 120 mL of water. Distribution Semaglutide absolute volume of distribution is approximately 8 L in patients with type 2 diabetes. Semaglutide is > 99% bound to plasma albumin. Elimination Semaglutide elimination half-life is approximately one week with an absolute clearance of approximately 0.04 L/hour in patients with type 2 diabetes. Semaglutide is present in the circulation for about five weeks after the last RYBELSUS dose. Metabolism: The primary route of elimination for semaglutide is metabolism following proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid side chain. Excretion: The primary excretion routes of semaglutide-related material are via the urine and feces. Approximately 3% of the absorbed dose is excreted in the urine as intact semaglutide. Specific Populations No clinically significant differences in semaglutide pharmacokinetics were observed based on age (≥ 18 years old), sex, race (White, Asian, or Black or African American), ethnicity, body weight (40-188 kg), upper GI disease (i.e. chronic gastritis and/or gastroesophageal reflux disease), hepatic impairment (i.e., mild, moderate, severe based on the Child-Pugh system), and renal impairment (i.e., mild, moderate, severe, end staged renal disease). Drug Interaction Studies Clinical Studies and Model-Informed Approaches: The delay of gastric emptying with semaglutide may influence the absorption of concomitantly administered oral drugs. Trials were conducted to study the potential effect of semaglutide on the absorption of oral drugs taken with semaglutide administered orally at steady-state exposure. Levothyroxine: Total thyroxine (i.e., adjusted for endogenous levels) AUC of was increased by 33% following administration of a single dose of levothyroxine 600 mcg concomitantly administered with oral semaglutide. Maximum exposure (Cmax) was unchanged. Other Drugs: No clinically significant differences in semaglutide pharmacokinetics were observed when used concomitantly with omeprazole. No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with semaglutide: lisinopril, S-warfarin, R-warfarin, metformin, digoxin, ethinyl estradiol, levonorgestrel, furosemide, or rosuvastatin. In Vitro Studies: Semaglutide has very low potential to inhibit or induce CYP enzymes, and to inhibit drug transporters. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of semaglutide or of other semaglutide products. During the 26-78 week treatment periods in 5 clinical trials in adults with type 2 diabetes mellitus [see Clinical Studies (14.2 and 14.3)] and 1 clinical trial in Japanese adults with type 2 diabetes mellitus, 14/2924 (0.5%) of Reference ID: 5492467 - RYBELSUS-treated patients developed anti-semaglutide antibodies. Of these 14 RYBELSUS-treated patients, 7 patients (0.2% of the total RYBELSUS-treated study population) developed antibodies that cross-reacted with native GLP-1. No identified clinically significant effect of anti-semaglutide antibodies on pharmacokinetics of RYBELSUS was observed. There is insufficient information to characterize the effects of anti-semaglutide antibodies on pharmacodynamics, safety, or effectiveness of semaglutide. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in CD-1 mice, subcutaneous doses of 0.3, 1 and 3 mg/kg/day [9-, 33- and 113­ fold the maximum recommended human dose (MRHD) of RYBELSUS 14 mg, based on AUC] were administered to the males, and 0.1, 0.3 and 1 mg/kg/day (3-, 9-, and 33-fold MRHD) were administered to the females. A statistically significant increase in thyroid C-cell adenomas and a numerical increase in C-cell carcinomas were observed in males and females at all dose levels (>3X human exposure). In a 2-year carcinogenicity study in Sprague Dawley rats, subcutaneous doses of 0.0025, 0.01, 0.025 and 0.1 mg/kg/day were administered (below quantification, 0.8-, 1.8- and 11-fold the exposure at the MRHD). A statistically significant increase in thyroid C-cell adenomas was observed in males and females at all dose levels, and a statistically significant increase in thyroid C-cell carcinomas was observed in males at ≥0.01 mg/kg/day, at clinically relevant exposures. Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies [see Boxed Warning and Warnings and Precautions (5.1)]. Semaglutide was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity (Ames), human lymphocyte chromosome aberration, rat bone marrow micronucleus). In a combined fertility and embryo-fetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.2-, 0.7- and 2.1-fold the MRHD) were administered to male and female rats. Males were dosed for 4 weeks prior to mating, and females were dosed for 2 weeks prior to mating and throughout organogenesis until Gestation Day 17. No effects were observed on male fertility. In females, an increase in estrus cycle length was observed at all dose levels, together with a small reduction in numbers of corpora lutea at ≥0.03 mg/kg/day. These effects were likely an adaptive response secondary to the pharmacological effect of semaglutide on food consumption and body weight. 13.2 Animal Toxicology and/or Pharmacology Increase in lactate levels and decrease in glucose levels in the plasma and cerebrospinal fluid (CSF) were observed in mechanistic studies with SNAC in rats. Small but statistically significant increases in lactate levels (up to 2­ fold) were observed in a few animals at approximately the clinical exposure. At higher exposures these findings were associated with moderate to marked adverse clinical signs (lethargy, abnormal respiration, ataxia, and reduced activity, body tone and reflexes) and marked decreases in plasma and CSF glucose levels. These findings are consistent with inhibition of cellular respiration and lead to mortality at SNAC concentrations >100-times the clinical Cmax. 14 CLINICAL STUDIES 14.1 Overview of Clinical Studies RYBELSUS has been studied as monotherapy and in combination with metformin, sulfonylureas, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, insulins, and thiazolidinediones in patients with type 2 diabetes mellius. The efficacy of RYBELSUS was compared with placebo, empagliflozin, sitagliptin, and liraglutide. RYBELSUS has also been studied in patients with type 2 diabetes mellitus with mild and moderate renal impairment. In patients with type 2 diabetes mellitus, RYBELSUS produced clinically significant reduction from baseline in HbA1c compared with placebo. Reference ID: 5492467 The effectiveness of RYBELSUS (formulation R2 – 1.5 mg, 4 mg, and 9 mg strengths) [see Dosage and Administration (2.2)] and RYBELSUS (formulation R1 – 3 mg, 7, mg, and 14 mg strengths) [see Dosage and Administration (2.3)] has been established as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus based on adequate and well-controlled studies of RYBELSUS (formulation R1) in adult patients with type 2 diabetes mellitus [see Clinical Pharmacology (12.3)]. Below is a display of the efficacy results of the adequate and well-controlled studies of RYBELSUS (formulation R1) in adult patients with type 2 diabetes mellitus. The efficacy of RYBELSUS was not impacted by baseline age, sex, race, ethnicity, BMI, body weight, duration of diabetes, and degree of renal impairment. 14.2 Monotherapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus In a 26-week double-blind trial (NCT02906930), 703 adult patients with type 2 diabetes mellitus inadequately controlled with diet and exercise were randomized to RYBELSUS 3 mg, RYBELSUS 7 mg or RYBELSUS 14 mg once daily or placebo. Patients had a mean age of 55 years and 51% were men. The mean duration of type 2 diabetes mellitus was 3.5 years, and the mean BMI was 32 kg/m2. Overall, 75% were White, 5% were Black or African American, and 17% were Asian; 26% identified as Hispanic or Latino ethnicity. Monotherapy with RYBELSUS 7 mg and RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 4). Table 4. Results at Week 26 in a Trial of RYBELSUS as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise Placebo RYBELSUS 7 mg RYBELSUS 14 mg Intent-to-Treat (ITT) Population (N)a 178 175 175 HbA1c (%) Baseline (mean) 7.9 8.0 8.0 Change at week 26b -0.3 -1.2 -1.4 Difference from placebob [95% CI] −0.9 [−1.1; −0.6]c −1.1 [−1.3; −0.9]c Patients (%) achieving HbA1c <7% 31 69 77 FPG (mg/dL) Baseline (mean) 160 162 158 Change at week 26b -3 -28 -33 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 5.6%, 8.6% and 8.6% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. Missing data were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 15%, 2% and 1% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. b Estimated using an ANCOVA model based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 88.6 kg, 89.0 kg and 88.1 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -1.4 kg, -2.3 kg and -3.7 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 7 mg was -0.9 kg (-1.9, 0.1) and for RYBELSUS 14 mg was -2.3 kg (-3.1, -1.5). Reference ID: 5492467 14.3 Combination Therapy Use of RYBELSUS in Patients with Type 2 Diabetes Mellitus Combination with Metformin In a 26-week trial (NCT02863328), 822 adult patients with type 2 mellitus diabetes were randomized to RYBELSUS 14 mg once daily or empagliflozin 25 mg once daily, all in combination with metformin. Patients had a mean age of 58 years and 50% were men. The mean duration of type 2 diabetes mellitus was 7.4 years, and the mean BMI was 33 kg/m2. Overall, 86% were White, 7% were Black or African American, and 6% were Asian; 24% identified as Hispanic or Latino ethnicity. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c compared to empagliflozin 25 mg once daily (see Table 5). Table 5. Results at Week 26 in a Trial of RYBELSUS Compared to Empagliflozin in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin RYBELSUS 14 mg Empagliflozin 25 mg Intent-to-Treat (ITT) Population (N)a 411 410 HbA1c (%) Baseline (mean) 8.1 8.1 Change at week 26b -1.3 -0.9 Difference from empagliflozinb [95% CI] -0.4 [-0.6, -0.3]c Patients (%) achieving HbA1c <7% 67 40 FPG (mg/dL) Baseline (mean) 172 174 Change at week 26b -36 -36 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 4.6% and 3.7% of patients randomized to RYBELSUS 14 mg and empagliflozin 25 mg, respectively. Missing data were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 1.9% and 1.2% of patients randomized to RYBELSUS 14 mg and empagliflozin 25 mg, respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 91.9 kg and 91.3 kg in the RYBELSUS 14 mg and empagliflozin 25 mg arms, respectively. The mean changes from baseline to week 26 were -3.8 kg and -3.7 kg in the RYBELSUS 14 mg and empagliflozin 25 mg arms, respectively. The difference from empagliflozin (95% CI) for RYBELSUS 14 mg was -0.1 kg (-0.7, 0.5). Combination with Metformin or Metformin with Sulfonylurea In a 26-week, double-blind trial (NCT02607865), 1864 adult patients with type 2 mellitus diabetes on metformin alone or metformin with sulfonylurea were randomized to RYBELSUS 3 mg, RYBELSUS 7 mg, RYBELSUS 14 mg or sitagliptin 100 mg once daily. Patients had a mean age of 58 years and 53% were men. The mean duration of type 2 diabetes mellitus was 8.6 years, and the mean BMI was 32 kg/m2. Overall, 71% were White, 9% were Black or African American, and 13% were Asian; 17% identified as Hispanic or Latino ethnicity. Treatment with RYBELSUS 7 mg and RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c compared to sitagliptin 100 mg once daily (see Table 6). Reference ID: 5492467 Table 6. Results at Week 26 in a Trial of RYBELSUS Compared to Sitagliptin 100 mg Once Daily in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with Sulfonylurea RYBELSUS 7 mg RYBELSUS 14 mg Sitagliptin 100 mg Intent-to-Treat (ITT) Population (N)a 465 465 467 HbA1c (%) Baseline (mean) 8.4 8.3 8.3 Change at week 26b -1.0 -1.3 -0.8 Difference from sitagliptinb [95% CI] -0.3 [-0.4; -0.1]c -0.5 [-0.6; -0.4]c Patients (%) achieving HbA1c <7% 44 56 32 FPG (mg/dL) Baseline (mean) 170 168 172 Change at week 26b -21 -31 -15 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 5.8%, 6.2% and 4.5% of patients randomized to RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 2.4%, 1.1% and 2.8% of patients randomized to RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg, respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 91.3 kg, 91.2 kg and 90.9 kg in the RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg arms, respectively. The mean changes from baseline to week 26 were -2.2 kg, -3.1 kg and ­ 0.6 kg in the RYBELSUS 7 mg, RYBELSUS 14 mg and sitagliptin 100 mg arms, respectively. The difference from sitagliptin (95% CI) for RYBELSUS 7 mg was -1.6 kg (-2.0, -1.1) and RYBELSUS 14 mg was -2.5 kg (-3.0, -2.0). Combination with Metformin or Metformin with SGLT-2 Inhibitors In a 26-week, double-blind, double-dummy trial (NCT02863419), 711 adult patients with type 2 diabetes mellitus on metformin alone or metformin with SGLT-2 inhibitors were randomized to RYBELSUS 14 mg once daily, liraglutide 1.8 mg subcutaneous injection once daily or placebo. Patients had a mean age of 56 years and 52% were men. The mean duration of type 2 diabetes mellitus was 7.6 years, and the mean BMI was 33 kg/m2. Overall, 73% were White, 4% were Black or African American, and 13% were Asian; 6% identified as Hispanic or Latino ethnicity. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in statistically significant reductions in HbA1c compared to placebo. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in non-inferior reductions in HbA1c compared to liraglutide 1.8 mg (see Table 7). Table 7. Results at Week 26 in a Trial of RYBELSUS Compared to Liraglutide and Placebo in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with SGLT-2i Placebo RYBELSUS 14 mg Liraglutide 1.8 mg Intent-to-Treat (ITT) Population (N)a 142 285 284 HbA1c (%) Baseline (mean) 7.9 8.0 8.0 Change at week 26b -0.2 -1. 2 -1.1 Difference from placebob [95% CI] -1.1 [-1.2 ; -0.9]c Reference ID: 5492467 Difference from liraglutideb [95% CI] -0.1 [-0.3; 0.0] Patients (%) achieving HbA1c <7% 14 68 62 FPG (mg/dL) Baseline (mean) 167 167 168 Change at week 26b -7 -36 -34 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 5.6%, 4.2% and 2.5% of patients randomized to placebo, liraglutide 1.8 mg and RYBELSUS 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 7.7%, 3.2% and 3.5% of patients randomized to placebo, liraglutide 1.8 mg and RYBELSUS 14 mg respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 93.2 kg, 95.5 kg and 92.9 kg in the placebo, liraglutide 1.8 mg, and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -0.5 kg, -3.1 kg and -4.4 kg in the placebo, liraglutide 1.8 mg, and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 14 mg was -3.8 kg (-4.7, -3.0). The difference from liraglutide 1.8 mg for RYBELSUS 14 mg was -1.2 (-1.9, -0.6). Combination in patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment with Metformin alone, Sulfonylurea alone, Basal Insulin alone, or Metformin in Combination with either Sulfonylurea or Basal Insulin In a 26-week, double-blind trial (NCT02827708), 324 adult patients with moderate renal impairment (eGFRCKD-EPI 30−59 mL/min/1.73 m2) were randomized to RYBELSUS 14 mg or placebo once daily. RYBELSUS was added to the patient’s stable pre-trial antidiabetic regimen. The insulin dose was reduced by 20% at randomization for patients on basal insulin. Dose reduction of insulin and sulfonylurea was allowed in case of hypoglycemia; up titration of insulin was allowed but not beyond the pre-trial dose. Patients had a mean age of 70 years and 48% were men. The mean duration of type 2 diabetes mellitus was 14 years, and the mean BMI was 32 kg/m2. Overall, 96% were White, 4% were Black or African American, and 0.3% were Asian; 6.5% identified as Hispanic or Latino ethnicity. 39.5% of patients had an eGFR value of 30 to 44 mL/min/1.73 m2. Treatment with RYBELSUS 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c from baseline compared to placebo (see Table 8). Table 8. Results at Week 26 in a Trial of RYBELSUS Compared to Placebo in Patients with Moderate Renal Impairment Placebo RYBELSUS 14 mg Intent-to-Treat (ITT) Population (N)a 161 163 HbA1c (%) Baseline (mean) 7.9 8.0 Change at week 26b -0.2 -1.0 Difference from placebob [95% CI] -0.8 [-1.0; -0.6]c Patients (%) achieving HbA1c <7% 23 58 FPG (mg/dL) Baseline (mean) 164 164 Change at week 26b -7 -28 Reference ID: 5492467 aThe intent-to-treat population includes all randomized patients including patients on rescue medication. At week 26, the primary HbA1c endpoint was missing for 3.7% and 5.5% of patients randomized to placebo and RYBELSUS 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 10% and 4.3% of patients randomized to placebo and RYBELSUS 14 mg, respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication, renal status and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 90.4 kg and 91.3 kg in the placebo and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -0.9 kg and -3.4 kg in the placebo and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 14 mg was -2.5 kg (-3.2, -1.8). Combination with Insulin with or without Metformin In a 26-week double blind trial (NCT03021187), 731 adult patients with type 2 diabetes mellitus inadequately controlled on insulin (basal, basal/bolus or premixed) with or without metformin, were randomized to RYBELSUS 3 mg, 7 mg and 14 mg once daily or placebo once daily. All patients reduced their insulin dose by 20% at randomization to reduce the risk of hypoglycemia. Patients were allowed to increase the insulin dose only up to the starting insulin dose prior to randomization. Patients had a mean age of 61 years and 54% were men. The mean duration of type 2 diabetes mellitus was 15 years, and the mean BMI was 31 kg/m2. Overall, 51% were White, 7% were Black or African American, and 36% were Asian; 13% identified as Hispanic or Latino ethnicity. Treatment with RYBELSUS 7 mg and 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA1c from baseline compared to placebo once daily (see Table 9). Table 9. Results at Week 26 in a Trial of RYBELSUS Compared to Placebo in Adult Patients with Type 2 Diabetes Mellitus in Combination with Insulin alone or with Metformin Placebo RYBELSUS 7 mg RYBELSUS 14 mg Intent-to-Treat (ITT) Population (N)a 184 182 181 HbA1c (%) Baseline (mean) 8.2 8.2 8.2 Change at week 26b -0.1 -0.9 -1.3 Difference from placebob [95% CI] -0.9 [-1.1; -0.7]c -1.2 [-1.4; -1.0]c Patients (%) achieving HbA1c <7% 7 43 58 FPG (mg/dL) Baseline (mean) 150 153 150 Change at week 26b 5 -20 -24 aThe intent-to-treat population includes all randomized patients. At week 26, the primary HbA1c endpoint was missing for 4.3%, 4.4%, and 4.4% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 4.9%, 1.1 % and 2.2% of patients randomized to placebo, RYBELSUS 7 mg and RYBELSUS 14 mg, respectively. bEstimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region. cp<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. The mean baseline body weight was 86.0 kg, 87.1 kg and 84.6 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The mean changes from baseline to week 26 were -0.4 kg, -2.4 kg and Reference ID: 5492467 -3.7 kg in the placebo, RYBELSUS 7 mg, and RYBELSUS 14 mg arms, respectively. The difference from placebo (95% CI) for RYBELSUS 7 mg was -2.0 kg (-3.0, -1.0), and for RYBELSUS 14 mg was -3.3 kg (-4.2, -2.3). 14.4 Cardiovascular Outcomes Trial in Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease PIONEER 6 (NCT02692716) was a multi-center, multi-national, placebo-controlled, double-blind trial. In this trial, 3,183 adult patients with inadequately controlled type 2 diabetes mellitus and atherosclerotic cardiovascular disease were randomized to RYBELSUS 14 mg once daily or placebo for a median observation time of 16 months. The trial compared the risk of a Major Adverse Cardiovascular Event (MACE) between RYBELSUS 14 mg and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Patients eligible to enter the trial were 50 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or NYHA class II and III heart failure or were 60 years of age or older and had other specified risk factors for cardiovascular disease. In total, 1,797 patients (56.5%) had established cardiovascular disease without chronic kidney disease, 354 patients (11.1%) had chronic kidney disease only, and 544 patients (17.1%) had both cardiovascular disease and kidney disease; 488 patients (15.3%) had cardiovascular risk factors without established cardiovascular disease or chronic kidney disease. The mean age at baseline was 66 years, and 68% were men. The mean duration of diabetes was 14.9 years, and mean BMI was 32 kg/m2. Overall, 72% were White, 6% were Black or African American, and 20% were Asian; 16% identified as Hispanic or Latino ethnicity. Concomitant diseases of patients in this trial included, but were not limited to, heart failure (12%), history of ischemic stroke (8%) and history of a myocardial infarction (36%). In total, 99.7% of the patients completed the trial and the vital status was known at the end of the trial for 100%. For the primary analysis, a Cox proportional hazards model was used to test for non-inferiority of RYBELSUS 14 mg to placebo for time to first MACE using a risk margin of 1.3. Type-1 error was controlled across multiple tests using a hierarchical testing strategy. Non-inferiority to placebo was established, with a hazard ratio equal to 0.79 (95% CI: 0.57, 1.11) over the median observation time of 16-months. The proportion of patients who experienced at least one MACE was 3.8% (61/1591) for RYBELSUS 14 mg and 4.8% (76/1592) for placebo. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied RYBELSUS (formulation R1) strengths are available as follows: Tablet Strength Description Package Configuration NDC Number 3 mg White to light yellow, oval shaped debossed with “3” on one side and “novo” on the other side Bottle of 30 tablets 0169-4303-30 7 mg White to light yellow, oval shaped debossed with “7” on one side and “novo” on the other side Bottle of 30 tablets 0169-4307-30 14 mg White to light yellow, oval shaped debossed with “14” on one side and “novo” on the other side Bottle of 30 tablets 0169-4314-30 RYBELSUS (formulation R2) strengths are available as follows: Tablet Strength Description Package Configuration NDC Number 1.5 mg White to light yellow, round shaped debossed with “1.5” on one side and “novo” on the other side Bottle of 30 tablets 0169-4815-30 Reference ID: 5492467 4 mg White to light yellow, round shaped debossed with “4” on one side and “novo” on the other side Bottle of 30 tablets 0169-4804-30 9 mg White to light yellow, round shaped debossed with “9” on one side and “novo” on the other side Bottle of 30 tablets 0169-4809-30 Storage and Handling Store at 68°F to 77°F (20°C to 25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature]. Store and dispense in the original bottle. Store tablet in the original bottle until use to protect tablets from moisture. Store product in a dry place away from moisture. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risk of Thyroid C-cell Tumors Inform patients that semaglutide causes thyroid C-cell tumors in rodents and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, or dyspnea) to their physician [see Boxed Warning and Warnings and Precautions (5.1)]. Acute Pancreatitis Inform patients of the potential risk for acute pancreatitis and its symptoms: severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting. Instruct patients to discontinue RYBELSUS promptly and contact their physician if pancreatitis is suspected [see Warnings and Precautions (5.2)]. Diabetic Retinopathy Complications Inform patients to contact their physician if changes in vision are experienced during treatment with RYBELSUS [see Warnings and Precautions (5.3)]. Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Inform patients that the risk of hypoglycemia is increased when RYBELSUS is used with an insulin secretagogue (such as a sulfonylurea) or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.4)]. Dehydration and Renal Failure Advise patients treated with RYBELSUS of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs [see Warnings and Precautions (5.5)]. Severe Gastrointestinal Adverse Reactions Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.6)]. Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of RYBELSUS. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking RYBELSUS and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.7)]. Reference ID: 5492467 Acute Gallbladder Disease Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up [see Warnings and Precautions (5.8)]. Pulmonary Aspiration During General Anesthesia or Deep Sedation: Inform patients that RYBELSUS may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking RYBELSUS [see Warnings and Precautions (5.9)]. Pregnancy Advise a pregnant woman of the potential risk to a fetus. Advise women to inform their healthcare provider if they are pregnant or intend to become pregnant [see Use in Specific Populations (8.1), (8.3)]. Lactation RYBELSUS passes into breast milk, and it is not known how it affects your baby. Advise females not to breastfeed during treatment with RYBELSUS [see Use in Specific Populations (8.2)]. Females and Males of Reproductive Potential Discontinue RYBELSUS at least 2 months before a planned pregnancy due to the long washout period for semaglutide [see Use in Specific Populations (8.3)]. Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd Denmark For additional information about RYBELSUS contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-833-457-7455 Version: 8 RYBELSUS® and OZEMPIC® are registered trademarks of Novo Nordisk A/S. Patent Information: http://www.novonordisk-us.com/products/product-patents.html © 2024 Novo Nordisk Reference ID: 5492467 Medication Guide RYBELSUS® (reb-EL-sus) (semaglutide) tablets, for oral use Read this Medication Guide before you start using RYBELSUS and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about RYBELSUS? RYBELSUS may cause serious side effects, including:  Possible thyroid tumors, including cancer. Tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer. In studies with rodents, RYBELSUS and medicines that work like RYBELSUS caused thyroid tumors, including thyroid cancer. It is not known if RYBELSUS will cause thyroid tumors or a type of thyroid cancer called medullary thyroid carcinoma (MTC) in people.  Do not use RYBELSUS if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC), or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). What is RYBELSUS? RYBELSUS is a prescription medicine used along with diet and exercise to improve blood sugar (glucose) in adults with type 2 diabetes.  RYBELSUS is not for use in people with type 1 diabetes. It is not known if RYBELSUS is safe and effective for use in children. Do not use RYBELSUS if:  you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC) or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).  you have had a serious allergic reaction to semaglutide or any of the ingredients in RYBELSUS. See the end of this Medication Guide for a complete list of ingredients in RYBELSUS. Symptoms of a serious allergic reaction include: o swelling of your face, lips, tongue or throat o problems breathing or swallowing o severe rash or itching o fainting or feeling dizzy o very rapid heartbeat Before using RYBELSUS, tell your healthcare provider if you have any other medical conditions, including if you:  have or have had problems with your pancreas or kidneys.  have a history of vision problems related to your diabetes.  are scheduled to have surgery or other procedures that use anesthesia or deep sleepiness (deep sedation).  are pregnant or plan to become pregnant. It is not known if RYBELSUS will harm your unborn baby. You should stop using RYBELSUS 2 months before you plan to become pregnant. Talk to your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.  are breastfeeding or plan to breastfeed. Breastfeeding is not recommended during treatment with RYBELSUS. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. RYBELSUS may affect the way some medicines work and some medicines may affect the way RYBELSUS works. Before using RYBELSUS, talk to your healthcare provider about low blood sugar and how to manage it. Tell your healthcare provider if you are taking other medicines to treat diabetes, including insulin or sulfonylureas. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take RYBELSUS?  Take RYBELSUS exactly as your healthcare provider tells you to.  Do not take more than 1 tablet each day.  Take RYBELSUS by mouth on an empty stomach in the morning. Reference ID: 5492467  Take RYBELSUS with a sip of plain water (no more than 4 ounces). Do not take RYBELSUS with any other liquids besides water.  Do not split, crush or chew. Swallow RYBELSUS whole.  After 30 minutes, you can eat, drink, or take other oral medicines.  If you miss a dose of RYBELSUS, skip the missed dose and go back to your regular schedule.  If you take too much RYBELSUS, call your healthcare provider or Poison Help line at 1-800-222-1222, or go to the nearest hospital emergency room right away. Your dose of RYBELSUS and other diabetes medicines may need to change because of: change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, fever, trauma, infection, surgery or because of other medicines you take. What are the possible side effects of RYBELSUS? RYBELSUS may cause serious side effects, including:  See “What is the most important information I should know about RYBELSUS?”  inflammation of your pancreas (pancreatitis). Stop using RYBELSUS and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.  changes in vision. Tell your healthcare provider if you have changes in vision during treatment with RYBELSUS.  low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use RYBELSUS with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include: o dizziness or light-headedness o blurred vision o anxiety, irritability, or mood changes o sweating o slurred speech o hunger o confusion or drowsiness o shakiness o weakness o headache o fast heartbeat o feeling jittery  kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration.  severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use RYBELSUS. Tell your healthcare provider if you have stomach problems that are severe or will not go away.  serious allergic reactions. Stop using RYBELSUS and get medical help right away, if you have any symptoms of a serious allergic reaction including: o swelling of your face, lips, tongue or throat o problems breathing or swallowing o severe rash or itching o fainting or feeling dizzy o very rapid heartbeat  gallbladder problems. Gallbladder problems have happened in some people who take RYBELSUS. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include: o pain in your upper stomach (abdomen) o yellowing of skin or eyes (jaundice) o fever o clay-colored stools  food or liquid getting into the lungs during surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). RYBELSUS may increase the chance of food getting into your lungs during surgery or other procedures. Tell all your healthcare providers that you are taking RYBELSUS before you are scheduled to have surgery or other procedures. The most common side effects of RYBELSUS may include nausea, stomach (abdominal) pain, diarrhea, decreased appetite, vomiting and constipation. Nausea, vomiting and diarrhea are most common when you first start RYBELSUS. Talk to your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of RYBELSUS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store RYBELSUS?  Store RYBELSUS at room temperature between 68°F and 77°F (20°C to 25°C).  Store in a dry place away from moisture. Reference ID: 5492467  Store tablets in the original closed RYBELSUS bottle until you are ready to take one. Do not store in any other container.  Keep RYBELSUS and all medicines out of the reach of children. General information about the safe and effective use of RYBELSUS. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RYBELSUS for a condition for which it was not prescribed. Do not give RYBELSUS to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about RYBELSUS that is written for health professionals. What are the ingredients in RYBELSUS? Active Ingredient: semaglutide Inactive Ingredients:  RYBELSUS (formulation R1): magnesium stearate, microcrystalline cellulose, povidone and salcaprozate sodium  RYBELSUS (formulation R2): salcaprozate sodium and magnesium stearate Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark RYBELSUS® is a registered trademark of Novo Nordisk A/S. PATENT Information: http://www.novonordisk-us.com/products/product-patents.html © 2024 Novo Nordisk For more information, go to www.RYBELSUS.com or call 1-833-GLP-PILL. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2024 Reference ID: 5492467
custom-source
2025-02-12T15:47:36.740531
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use REYATAZ safely and effectively. See full prescribing information for REYATAZ. REYATAZ (atazanavir) capsules, for oral use REYATAZ (atazanavir) oral powder Initial U.S. Approval: 2003 ---------------------------RECENT MAJOR CHANGES--------------------------­ Contraindications (4) 12/2024 --------------------------INDICATIONS AND USAGE---------------------------­ REYATAZ is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg. (1) ------------------------DOSAGE AND ADMINISTRATION---------------------­ • Pretreatment testing: Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Hepatic testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ. (2.2) • Treatment-naive adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food or REYATAZ 400 mg once daily with food. (2.3) • Treatment-experienced adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food. (2.3) • Pediatric patients: REYATAZ capsule dosage is based on body weight not to exceed the adult dose and must be taken with food. (2.4) • REYATAZ oral powder: Must be taken with ritonavir and food and should not be used in pediatric patients who weigh less than 5 kg. (2.5) • Pregnancy: REYATAZ 300 mg with ritonavir 100 mg once daily with food, with dosing modifications for some concomitant medications. (2.6) • Dosing modifications: may be required for concomitant therapy (2.3, 2.4, 2.5, 2.6), renal impairment (2.7), and hepatic impairment. (2.8) ----------------------DOSAGE FORMS AND STRENGTHS--------------------­ • Capsules: 200 mg, 300 mg. (3, 16) • Oral powder: 50 mg packet. (3, 16) ------------------------------CONTRAINDICATIONS------------------------------­ • In patients with previously demonstrated hypersensitivity (eg, Stevens- Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ. (4) • Coadministration with drugs that are strong inducers of CYP3A, due to the potential for loss of therapeutic effect and development of resistance. (4) • Coadministration with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events. (4) --------------------------WARNINGS AND PRECAUTIONS-------------------­ • Cardiac conduction abnormalities: PR interval prolongation may occur in some patients. ECG monitoring should be considered in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval. (5.1, 7.3, 12.2, 17) • Severe Skin Reactions: Discontinue if severe rash develops. (5.2, 17) • Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. Do not dose reduce. If a concomitant transaminase increase occurs, evaluate for alternative etiologies. (5.8) • Phenylketonuria: REYATAZ oral powder contains phenylalanine which can be harmful to patients with phenylketonuria. (5.3) • Hepatotoxicity: Patients with hepatitis B or C virus are at risk of increased transaminases or hepatic decompensation. Monitor hepatic laboratory tests prior to therapy and during treatment. (2.8, 5.4, 8.8) • Chronic kidney disease has been reported during postmarketing surveillance in patients with HIV-1 treated with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Monitor renal laboratory tests prior to therapy and during treatment. Consider discontinuation of REYATAZ in patients with progressive renal disease. (5.5) • Nephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. (5.6) • The concomitant use of REYATAZ with ritonavir and certain other medications may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.7, 7.3) • Patients receiving REYATAZ may develop new onset or exacerbations of diabetes mellitus/hyperglycemia (5.9), immune reconstitution syndrome (5.10), and redistribution/accumulation of body fat. (5.11) • Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. (5.12) -------------------------------ADVERSE REACTIONS-----------------------------­ Most common adverse reactions (≥2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------------------DRUG INTERACTIONS----------------------------- Coadministration of REYATAZ can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir. The potential drug-drug interactions must be considered prior to and during therapy. (4, 7, 12.3) ------------------------USE IN SPECIFIC POPULATIONS----------------------­ • Pregnancy: Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. (8.1) • Hepatitis B or C co-infection: Monitor liver enzymes. (5.4, 6.1) • Renal impairment: REYATAZ is not recommended for use in treatment- experienced patients with end-stage renal disease managed with hemodialysis. (2.7, 8.7) • Hepatic impairment: REYATAZ is not recommended in patients with severe hepatic impairment. REYATAZ with ritonavir is not recommended in patients with any degree of hepatic impairment. (2.8, 8.8) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 12/2024 1 Reference ID: 5490094 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Overview 2.2 Testing Prior to Initiation and During Treatment with REYATAZ 2.3 Dosage of REYATAZ in Adult Patients 2.4 Dosage of REYATAZ Capsules in Pediatric Patients 2.5 Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients 2.6 Dosage Adjustments in Pregnant Patients 2.7 Dosage in Patients with Renal Impairment 2.8 Dosage Adjustments in Patients with Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiac Conduction Abnormalities 5.2 Severe Skin Reactions 5.3 Patients with Phenylketonuria 5.4 Hepatotoxicity 5.5 Chronic Kidney Disease 5.6 Nephrolithiasis and Cholelithiasis 5.7 Risk of Serious Adverse Reactions Due to Drug Interactions 5.8 Hyperbilirubinemia 5.9 Diabetes Mellitus/Hyperglycemia 5.10 Immune Reconstitution Syndrome 5.11 Fat Redistribution 5.12 Hemophilia 5.13 Resistance/Cross-Resistance 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Potential for REYATAZ to Affect Other Drugs 7.2 Potential for Other Drugs to Affect REYATAZ 7.3 Established and Other Potentially Significant Drug Interactions 7.4 Drugs with No Observed Interactions with REYATAZ 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Age/Gender 8.7 Impaired Renal Function 8.8 Impaired Hepatic Function 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Adult Participants without Prior Antiretroviral Therapy 14.2 Adult Participants with Prior Antiretroviral Therapy 14.3 Pediatric Participants 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed 2 Reference ID: 5490094 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE REYATAZ is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg. Limitations of Use: • REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Use in Specific Populations (8.4)]. • Use of REYATAZ with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12.4)]. 2 DOSAGE AND ADMINISTRATION 2.1 Overview • REYATAZ capsules and oral powder must be taken with food. • Do not open the capsules. • The recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.3, 2.4, 2.5, and 2.6) and Drug Interactions (7)]. • REYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14)]. • REYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than 5 kg [see Dosage and Administration (2.5)]. • Efficacy and safety of REYATAZ with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir. 2.2 Testing Prior to Initiation and During Treatment with REYATAZ Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Renal laboratory testing should include serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination [see Warnings and Precautions (5.5, 5.6)]. Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ [see Warnings and Precautions (5.4)]. 2.3 Dosage of REYATAZ in Adult Patients Table 1 displays the recommended dosage of REYATAZ capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of REYATAZ and 3 Reference ID: 5490094 ritonavir when given concomitantly with other antiretroviral drugs and H2-receptor antagonists (H2RA). Ritonavir is required with several REYATAZ dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended. Table 1: Recommended REYATAZ and Ritonavir Dosage in Adultsa,b REYATAZ Once Daily Ritonavir Once Daily Dosage Dosage Treatment-Naive Adult Patients recommended regimen 300 mg 100 mg unable to tolerate ritonavir 400 mg N/A in combination with efavirenz 400 mg 100 mg Treatment-Experienced Adult Patients recommended regimen 300 mg 100 mg in combination with both H2RA and tenofovir DF 400 mg 100 mg a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b For adult patients who cannot swallow the capsules, REYATAZ oral powder is taken once daily with food at the same recommended adult dosage as the capsules along with ritonavir. 2.4 Dosage of REYATAZ Capsules in Pediatric Patients The recommended daily dosage of REYATAZ capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2). Table 2: Recommended Dosage of REYATAZ Capsules and Ritonavir in Pediatric Patients (6 to less than 18 years of age)a,b Body weight REYATAZ Daily Dosage Ritonavir Daily Dosage Treatment-Naive and Treatment-Experiencedc Less than 15 kg Capsules not recommended N/A At least 15 kg to less than 35 kg 200 mg 100 mg At least 35 kg 300 mg 100 mg Treatment-Naive, at least 13 years old and cannot tolerate ritonavir At least 40 kg 400 mg N/A a Administer REYATAZ capsules and ritonavir simultaneously with food. b The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid­ 4 Reference ID: 5490094 reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). c In treatment-experienced patients, REYATAZ capsules must be administered with ritonavir. When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation. 2.5 Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients REYATAZ oral powder is for use in treatment-naive or treatment-experienced pediatric patients who are at least 3 months of age and weighing at least 5 kg. REYATAZ oral powder must be mixed with food or a beverage for administration and ritonavir must be given immediately afterwards. Table 3 displays the recommended dosage of REYATAZ oral powder and ritonavir. Table 3: Recommended Dosage of REYATAZ Oral Powder and Ritonavir in Pediatric Patients (at least 3 months of age and weighing at least 5 kg)a,b Body Weight Daily Dosage of REYATAZ Oral Powder Daily Dosage of Ritonavir Oral Solution 5 kg to less than 15 kg 200 mg (4 packets)c,d 80 mg 15 kg to less than 25 kg 250 mg (5 packets)d 80 mg a The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid- reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b For pediatric patients at least 25 kg who cannot swallow REYATAZ capsules, 300 mg (6 packets) REYATAZ oral powder is taken once daily with food along with 100 mg ritonavir. c Only patients weighing 5 to less than 10 kg who do not tolerate the 200 mg (4 packets) dose of REYATAZ oral powder and have not previously taken an HIV protease inhibitor, may take 150 mg (3 packets) REYATAZ oral powder with close HIV viral load monitoring. d Each packet contains 50 mg of REYATAZ. When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation. Instructions for Mixing REYATAZ Oral Powder [see FDA-approved Instructions for Use] • Determine the number of packets (3, 4, 5 or 6 packets) that are needed. • Prior to mixing, tap the packet to settle the powder. • It is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with a beverage (milk, infant formula, or water) may be used for infants who can drink from a cup. For young infants (less than 6 months) who cannot eat solid 5 Reference ID: 5490094 food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered. • Use a clean pair of scissors to cut each packet along the dotted line. • Mixing with food: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture. • Mixing with a beverage such as milk or water in a small drinking cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time. • Mixing with liquid infant formula using an oral dosing syringe and a small medicine cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant. • Administer ritonavir immediately following REYATAZ powder administration. • Administer the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation [may leave the mixture at a temperature of 68°F to 86°F (20°C to 30°C) for up to one hour]. Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture. 2.6 Dosage Adjustments in Pregnant Patients Table 4 includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults) [see Use in Specific Populations (8.1)]. Table 4: Recommended Dosage of REYATAZ and Ritonavir in Pregnant Patientsa REYATAZ Ritonavir Once Daily Once Daily Dosage Dosage Treatment-Naive and Treatment-Experienced Recommended Regimen 300 mg 100 mg Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovir DFb In combination with EITHER 400 mg 100 mg H2RA OR tenofovir DF 6 Reference ID: 5490094 a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b REYATAZ is not recommended for treatment-experienced pregnant patients during the second and third trimester taking REYATAZ with BOTH tenofovir DF and H2RA. 2.7 Dosage in Patients with Renal Impairment For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end-stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ is not recommended in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis [see Use in Specific Populations (8.7)]. 2.8 Dosage Adjustments in Patients with Hepatic Impairment Table 5 displays the recommended REYATAZ dosage in treatment-naive patients with hepatic impairment. The use of REYATAZ in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of REYATAZ with ritonavir in patients with any degree of hepatic impairment is not recommended. Table 5: Recommended Dosage of REYATAZ Capsules in Treatment-Naive Adults with Hepatic Impairment REYATAZ Once Daily Dosage Mild hepatic impairment (Child-Pugh Class A) 400 mg Moderate hepatic impairment (Child-Pugh Class B) 300 mg Severe hepatic impairment (Child-Pugh Class C) REYATAZ with or without ritonavir is not recommended 3 DOSAGE FORMS AND STRENGTHS REYATAZ Capsules: • 200 mg capsule with blue cap and blue body, printed with white ink “BMS 200 mg” on the cap and with white ink “3631” on the body. • 300 mg capsule with red cap and blue body, printed with white ink “BMS 300 mg” on the cap and with white ink “3622” on the body. REYATAZ Oral Powder: • 50 mg of atazanavir as an oral powder in a packet. 4 CONTRAINDICATIONS REYATAZ is contraindicated: 7 Reference ID: 5490094 • in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens- Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder [see Warnings and Precautions (5.2)]. • when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6). • when coadministered with drugs that are strong inducers of CYP3A due to the potential for loss of therapeutic effect and development of resistance. Coadministration is contraindicated with, but not limited to, the following drugs listed in Table 6: Table 6: Drugs Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Drug Class Drugs within class that are contraindicated with REYATAZ Alpha 1-adrenoreceptor antagonist Antiarrhythmics Anticonvulsants Antimycobacterials Antineoplastics Antipsychotics Benzodiazepines Ergot Derivatives GI Motility Agent Hepatitis C Direct-Acting Antivirals Herbal Products Lipid-Modifying Agents: Phosphodiesterase-5 (PDE-5) Inhibitor Protease Inhibitors Non-nucleoside Reverse Transcriptase Inhibitors Alfuzosin Amiodarone (with ritonavir), quinidine (with ritonavir) Carbamazepine, phenobarbital, phenytoin Rifampin Apalutamide, encorafenib, irinotecan, ivosidenib Lurasidone (with ritonavir), pimozide Orally administered midazolama, triazolam Dihydroergotamine, ergonovine, ergotamine, methylergonovine Cisapride Elbasvir/grazoprevir; glecaprevir/pibrentasvir St. John’s wort (Hypericum perforatum) Lomitapide, lovastatin, simvastatin Sildenafilb when dosed as REVATIO® for the treatment of pulmonary arterial hypertension Indinavir Nevirapine a See Drug Interactions, Table 16 (7) for parenterally administered midazolam. b See Drug Interactions, Table 16 (7) for sildenafil when dosed as VIAGRA® for erectile dysfunction. 8 Reference ID: 5490094 5 WARNINGS AND PRECAUTIONS 5.1 Cardiac Conduction Abnormalities REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some study participants. In healthy participants and in participants with HIV-1 treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions (6.2) and Overdosage (10)]. In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir­ treated participants (n=920), 5.2% of lopinavir/ritonavir-treated participants (n=252), 10.4% of nelfinavir-treated participants (n=48), and 3.0% of efavirenz-treated participants (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir with ritonavir-treated participants and 5% (6/116) of lopinavir/ritonavir-treated participants who had on-study electrocardiogram measurements. Because of limited clinical experience in those with preexisting conduction system disease (eg, marked first-degree AV block or second- or third- degree AV block), ECG monitoring should be considered in these patients [see Clinical Pharmacology (12.2)]. 5.2 Severe Skin Reactions In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of participants with HIV-1 treated with REYATAZ. The median time to onset of rash in clinical studies was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies [see Adverse Reactions (6.1)]. Dosing with REYATAZ was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients receiving REYATAZ [see Contraindications (4) and Adverse Reactions (6.1)]. REYATAZ should be discontinued if severe rash develops. 5.3 Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). Each packet of REYATAZ oral powder contains 35 mg of phenylalanine. REYATAZ capsules do not contain phenylalanine. 5.4 Hepatotoxicity Patients with underlying hepatitis B or C virus or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with REYATAZ and during treatment [see Dosage and Administration (2.2), Adverse Reactions (6.1), and Use in Specific Populations (8.8)]. 9 Reference ID: 5490094 5.5 Chronic Kidney Disease Chronic kidney disease in patients with HIV-1 treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to REYATAZ in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with REYATAZ and continued during treatment with REYATAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking REYATAZ. In patients with progressive kidney disease, discontinuation of REYATAZ may be considered [see Dosage and Administration (2.2 and 2.7) and Adverse Reactions (6.2)]. 5.6 Nephrolithiasis and Cholelithiasis Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 receiving REYATAZ therapy. Some patients required hospitalization for additional management, and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered [see Adverse Reactions (6.2)]. 5.7 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of REYATAZ with ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving REYATAZ with ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of REYATAZ with ritonavir, respectively. These interactions may lead to: • clinically significant adverse reactions potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications. • clinically significant adverse reactions from greater exposures of REYATAZ with ritonavir. • loss of therapeutic effect (virologic response) of REYATAZ with ritonavir and possible development of resistance. See Table 16 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during therapy containing REYATAZ with ritonavir; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7)]. 5.8 Hyperbilirubinemia Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is 10 Reference ID: 5490094 reversible upon discontinuation of REYATAZ. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established [see Adverse Reactions (6.1)]. 5.9 Diabetes Mellitus/Hyperglycemia New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in patients with HIV-1 receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established [see Adverse Reactions (6.2)]. 5.10 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium, cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.11 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.12 Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established. 11 Reference ID: 5490094 5.13 Resistance/Cross-Resistance Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors [see Microbiology (12.4)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • cardiac conduction abnormalities [see Warnings and Precautions (5.1)] • rash [see Warnings and Precautions (5.2)] • hyperbilirubinemia [see Warnings and Precautions (5.8)] • chronic kidney disease [see Warnings and Precautions (5.5)] • nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.6)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Treatment-Naive Adult Participants The safety profile of REYATAZ in treatment-naive adults is based on 1625 participants with HIV­ 1 in clinical trials. 536 participants received REYATAZ 300 mg with ritonavir 100 mg and 1089 participants received REYATAZ 400 mg or higher (without ritonavir). The most common adverse reactions were nausea, jaundice/scleral icterus, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment- naive participants receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively. Table 7: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV- 1,b Study AI424-138 96 weeksc 96 weeksc REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabined (n=441) lopinavir/ritonavird 400 mg/ 100 mg (twice daily) and tenofovir DF/emtricitabinee (n=437) Digestive System Nausea 4% 8% Jaundice/scleral icterus 5% * Diarrhea 2% 12% 12 Reference ID: 5490094 Table 7: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV- 1,b Study AI424-138 Skin and Appendages Rash 3% 2% * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d Administered as a fixed-dose. e As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. Table 8: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV- 1,b Studies AI424-034, AI424-007, and AI424-008 Study AI424-034 Studies AI424-007, -008 64 weeksc REYATAZ 400 mg (once daily) with lamivudine/ zidovudinee (n=404) 64 weeksc efavirenz 600 mg (once daily) with lamivudine/ zidovudinee (n=401) 120 weeksc,d REYATAZ 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279) 73 weeksc,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine (n=191) Body as a Whole Headache 6% 6% 1% 2% Digestive System Nausea 14% 12% 6% 4% Jaundice/scleral icterus 7% * 7% * Vomiting 4% 7% 3% 3% Abdominal pain 4% 4% 4% 2% Diarrhea 1% 2% 3% 16% Nervous System Insomnia 3% 3% <1% * Dizziness 2% 7% <1% * Peripheral neurologic <1% 1% 4% 3% symptoms Skin and Appendages 13 Reference ID: 5490094 Table 8: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV- 1,b Studies AI424-034, AI424-007, and AI424-008 Study AI424-034 Studies AI424-007, -008 64 weeksc REYATAZ 400 mg (once daily) with lamivudine/ zidovudinee (n=404) 64 weeksc efavirenz 600 mg (once daily) with lamivudine/ zidovudinee (n=401) 120 weeksc,d REYATAZ 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279) 73 weeksc,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine (n=191) Rash 7% 10% 5% 1% * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on regimens containing REYATAZ. c Median time on therapy. d Includes long-term follow-up. e As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. Adverse Reactions in Treatment-Experienced Adult Participants The safety profile of REYATAZ in treatment-experienced adults with HIV-1 is based on 119 participants with HIV-1 in clinical trials. The most common adverse reactions are jaundice/scleral icterus and myalgia. Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment- experienced participants receiving REYATAZ with ritonavir are presented in Table 9. Table 9: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1,b Study AI424-045 48 weeksc 48 weeksc REYATAZ with ritonavir lopinavir/ritonavir 400/100 mg 300/100 mg (once daily) and tenofovir DF and (twice dailyd) and tenofovir DF and NRTI NRTI (n=119) (n=118) Body as a Whole Fever 2% * Digestive System 14 Reference ID: 5490094 Table 9: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1,b Study AI424-045 48 weeksc REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) 48 weeksc lopinavir/ritonavir 400/100 mg (twice dailyd) and tenofovir DF and NRTI (n=118) Jaundice/scleral icterus 9% * Diarrhea 3% 11% Nausea 3% 2% Nervous System Depression 2% <1% Musculoskeletal System Myalgia 4% * * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d As a fixed-dose product. Laboratory Abnormalities in Treatment-Naive Participants The percentages of adult treatment-naive participants with HIV-1 treated with combination therapy, including REYATAZ 300 mg with ritonavir 100 mg or REYATAZ 400 mg (without ritonavir) with Grade 3–4 laboratory abnormalities, are presented in Tables 10 and 11, respectively. Table 10: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1,a Study AI424-138 Variable Chemistry SGOT/AST Limite High ≥5.1 × ULN 96 weeksb REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabinec (n=441) 3% 96 weeksb lopinavir/ritonavir 400 mg/100 mgc (twice daily) and tenofovir DF/emtricitabined (n=437) 1% 15 Reference ID: 5490094 Table 10: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1,a Study AI424-138 96 weeksb 96 weeksb REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabinec lopinavir/ritonavir 400 mg/100 mgc (twice daily) and tenofovir DF/emtricitabined Variable Limite (n=441) (n=437) SGPT/ALT ≥5.1 × ULN 3% 2% Total Bilirubin ≥2.6 × ULN 44% <1% Lipase ≥2.1 × ULN 2% 2% Creatine Kinase ≥5.1 × ULN 8% 7% Total Cholesterol ≥240 mg/dL 11% 25% Hematology Neutrophils Low <750 cells/mm3 5% 2% a Based on the regimen containing REYATAZ. b Median time on therapy. c Administered as a fixed-dose product. d As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. e ULN=upper limit of normal. Table 11: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1,a Studies AI424-034, AI424­ 007, and AI424-008 Variable Limitd Study AI424-034 64 weeksb 64 weeksb REYATAZ efavirenz 400 mg 600 mg once daily once daily and and lamivudine/ lamivudine/ zidovudinee zidovudinee (n=404) (n=401) Studies AI424-007, -008 120 weeksb,c 73 weeksb,c REYATAZ nelfinavir 400 mg 750 mg TID or once daily 1250 mg BID with stavudine with stavudine and and lamivudine or lamivudine or with stavudine with stavudine and didanosine and didanosine (n=279) (n=191) Chemistry SGOT/AST High ≥5.1 × ULN 2% 2% 7% 5% 16 Reference ID: 5490094 Table 11: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1,a Studies AI424-034, AI424­ 007, and AI424-008 Study AI424-034 Studies AI424-007, -008 64 weeksb 64 weeksb 120 weeksb,c 73 weeksb,c REYATAZ 400 mg once daily and lamivudine/ zidovudinee efavirenz 600 mg once daily and lamivudine/ zidovudinee REYATAZ 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosine Variable Limitd (n=404) (n=401) (n=279) (n=191) SGPT/ALT ≥5.1 × ULN 4% 3% 9% 7% Total Bilirubin ≥2.6 × ULN 35% <1% 47% 3% Amylase ≥2.1 × ULN * * 14% 10% Lipase ≥2.1 × ULN <1% 1% 4% 5% Creatine Kinase ≥5.1 × ULN 6% 6% 11% 9% Total Cholesterol ≥240 mg/dL 6% 24% 19% 48% Triglycerides ≥751 mg/dL <1% 3% 4% 2% Hematology Low Hemoglobin <8.0 g/dL 5% 3% <1% 4% Neutrophils <750 cells/mm3 7% 9% 3% 7% * None reported in this treatment arm. a Based on regimen(s) containing REYATAZ. b Median time on therapy. c Includes long-term follow-up. d ULN = upper limit of normal. e As a fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. Change in Lipids from Baseline in Treatment-Naive Participants with HIV-1 For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL- cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively. 17 Reference ID: 5490094 Table 12: Lipid Values, Mean Change from Baseline, Study AI424-138 REYATAZ with ritonavira,b lopinavir/ritonavirb,c Baseline Week 48 Week 96 Baseline Week 48 Week 96 mg/dL mg/dL Changed mg/dL Changed mg/dL mg/dL Changed mg/dL Changed (n=428e) (n=372e) (n=372e) (n=342e) (n=342e) (n=424e) (n=335e) (n=335e) (n=291e) (n=291e) LDL- Cholesterolf 92 105 +14% 105 +14% 93 111 +19% 110 +17% HDL- Cholesterolf 37 46 +29% 44 +21% 36 48 +37% 46 +29% Total Cholesterolf 149 169 +13% 169 +13% 150 187 +25% 186 +25% Triglyceridesf 126 145 +15% 140 +13% 129 194 +52% 184 +50% a REYATAZ 300 mg with ritonavir 100 mg once daily with the fixed-dose product: 300 mg tenofovir DF/ 200 mg emtricitabine once daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and 1% in the REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ with ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ with ritonavir arm. c Lopinavir/ritonavir (400 mg/100 mg) twice daily with the fixed-dose product 300 mg tenofovir DF/200 mg emtricitabine once daily. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values, respectively. e Number of participants with LDL-cholesterol measured. f Fasting. Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034 REYATAZa,b efavirenzb,c LDL-Cholesterolf Baseline mg/dL (n=383e) 98 Week 48 mg/dL (n=283e) 98 Week 48 Changed (n=272e) +1% Baseline mg/dL (n=378e) 98 Week 48 mg/dL (n=264e) 114 Week 48 Changed (n=253e) +18% HDL-Cholesterol 39 43 +13% 38 46 +24% Total Cholesterol 164 168 +2% 162 195 +21% Triglyceridesf 138 124 −9% 129 168 +23% a REYATAZ 400 mg once daily with the fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. 18 Reference ID: 5490094 b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and <1% in the REYATAZ arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the REYATAZ arm. c Efavirenz 600 mg once daily with the fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of participants with LDL-cholesterol measured. f Fasting. Laboratory Abnormalities in Treatment-Experienced Participants with HIV-1 The percentages of adult treatment-experienced participants with HIV-1 treated with combination therapy, including REYATAZ with ritonavir having Grade 3–4 laboratory abnormalities, are presented in Table 14. Table 14: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1, Study AI424-045a 48 weeksb 48 weeksb REYATAZ with ritonavir 300/100 mg (once daily) and lopinavir/ritonavir 400/100 mg (twice dailyd) tenofovir DF and NRTI and tenofovir DF and NRTI Variable Limitc (n=119) (n=118) Chemistry High SGOT/AST ≥5.1 × ULN 3% 3% SGPT/ALT ≥5.1 × ULN 4% 3% Total Bilirubin ≥2.6 × ULN 49% <1% Lipase ≥2.1 × ULN 5% 6% Creatine Kinase ≥5.1 × ULN 8% 8% Total Cholesterol ≥240 mg/dL 25% 26% Triglycerides ≥751 mg/dL 8% 12% Glucose ≥251 mg/dL 5% <1% Hematology Low Platelets <50,000 cells/mm3 2% 3% Neutrophils <750 cells/mm3 7% 8% a Based on regimen(s) containing REYATAZ. b Median time on therapy. c ULN = upper limit of normal. 19 Reference ID: 5490094 d As a fixed-dose product. Change in Lipids from Baseline in Treatment-Experienced Participants with HIV-1 For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with REYATAZ with ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated. Table 15: Lipid Values, Mean Change from Baseline, Study AI424-045 REYATAZ with ritonavira,b Lopinavir/ritonavirb,c Baseline mg/dL Week 48 mg/dL Week 48 Changed Baseline mg/dL Week 48 mg/dL Week 48 Changed (n=111e) (n=75e) (n=74e) (n=108e) (n=76e) (n=73e) LDL-Cholesterolf 108 98 −10% 104 103 +1% HDL-Cholesterol 40 39 −7% 39 41 +2% Total Cholesterol 188 170 −8% 181 187 +6% Triglyceridesf 215 161 −4% 196 224 +30% a REYATAZ 300 mg once daily with ritonavir and tenofovir DF, and 1 NRTI. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 4% in the lopinavir/ritonavir treatment arm and 4% in the REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the REYATAZ with ritonavir arm. c Lopinavir/ritonavir (400/100 mg), as a fixed dose regimen, BID with tenofovir DF and 1 NRTI. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of participants with LDL-cholesterol measured. f Fasting. Adverse Reactions in Pediatric Participants with HIV-1: REYATAZ Capsules The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric participants with HIV-1, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A. The safety profile of REYATAZ in pediatric participants with HIV-1 (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 adverse events (≥5%, regardless of causality) reported in pediatric participants were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in <2% of participants. The most 20 Reference ID: 5490094 common Grade 3–4 laboratory abnormalities occurring in pediatric participants taking the capsule formulation were elevation of total bilirubin (≥3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%. Adverse Reactions in Pediatric Participants with HIV-1: REYATAZ Oral Powder The data described below reflect exposure to REYATAZ oral powder in 155 participants weighing at least 5 kg to less than 35 kg, including 134 participants exposed for 48 weeks. These data are from two pooled, open-label, multi-center clinical trials in treatment-naive and treatment- experienced pediatric participants with HIV-1 (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from 3 months to 10 years of age. In these studies, 51% were female and 49% were male. All participants received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs). The safety profile of REYATAZ in pediatric participants taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric participants taking REYATAZ capsules. The most common Grade 3–4 laboratory abnormalities occurring in pediatric participants weighing 5 kg to less than 35 kg taking REYATAZ oral powder were increased amylase (33%), neutropenia (9%), increased SGPT/ALT (9%), elevation of total bilirubin (≥2.6 times ULN, 16%), and increased lipase (8%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%. Adverse Reactions in Participants with HIV-1 and Hepatitis B and/or Hepatitis C Virus In Study AI424-138, 60 participants administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 51 participants treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed-dose tenofovir DF/emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the participants administered REYATAZ with ritonavir and 8% (4/50) of the participants treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the participants administered REYATAZ with ritonavir and none (0/50) of the participants treated with lopinavir/ritonavir. In Study AI424-045, 20 participants administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 18 participants treated with lopinavir/ritonavir 400 mg/100 mg twice daily (as fixed- dose product), were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the participants administered REYATAZ with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir treated. AST levels >5 times ULN developed in 10% (2/20) of the participants administered REYATAZ with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir. In Studies AI424-008 and AI424-034, 74 participants treated with REYATAZ 400 mg once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 15% of the participants treated with REYATAZ, 14% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir. AST levels >5 times ULN developed in 9% of the participants treated with 21 Reference ID: 5490094 REYATAZ, 5% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative participants [see Warnings and Precautions (5.8)]. 6.2 Postmarketing Experience The following events have been identified during postmarketing use of REYATAZ. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: edema Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation [see Warnings and Precautions (5.1)] Gastrointestinal System: pancreatitis Hepatic System: hepatic function abnormalities Hepatobiliary Disorders: cholelithiasis [see Warnings and Precautions (5.6)], cholecystitis, cholestasis Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see Warnings and Precautions (5.9)] Musculoskeletal System: arthralgia Renal System: nephrolithiasis [see Warnings and Precautions (5.6)], interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease [see Warnings and Precautions (5.5)] Skin and Appendages: alopecia, maculopapular rash [see Contraindications (4) and Warnings and Precautions (5.2)], pruritus, angioedema 7 DRUG INTERACTIONS 7.1 Potential for REYATAZ to Affect Other Drugs Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. Atazanavir is a weak inhibitor of CYP2C8. Use of REYATAZ without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected [see Clinical Pharmacology, Table 22 (12.3)]. The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. 22 Reference ID: 5490094 7.2 Potential for Other Drugs to Affect REYATAZ Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect (see Table 16). Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered with REYATAZ [see Dosage and Administration (2.3, 2.4, 2.5 and 2.6)]. 7.3 Established and Other Potentially Significant Drug Interactions Table 16 provides dosing recommendations in adults as a result of drug interactions with REYATAZ. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment HIV Antiviral Agents Nucleoside Reverse ↓ atazanavir It is recommended that REYATAZ be given (with food) 2 h before or 1 h Transcriptase Inhibitors (NRTIs): ↓ didanosine after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine didanosine buffered formulations exposure. Thus, REYATAZ and didanosine EC should be administered at different times. enteric coated (EC) capsules Nucleotide Reverse ↓ atazanavir When coadministered with tenofovir DF in adults, it is recommended that Transcriptase Inhibitors: tenofovir disoproxil fumarate ↑ tenofovir REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is (DF) unknown. Higher tenofovir concentrations could potentiate tenofovir­ associated adverse reactions, including renal disorders. Patients receiving REYATAZ and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking REYATAZ with ritonavir and tenofovir DF, see Dosage and Administration (2.6). Non-nucleoside Reverse ↓ atazanavir In HIV-treatment-naive adult patients: Transcriptase Inhibitors (NNRTIs): efavirenz If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with efavirenz is not recommended. nevirapine ↓ atazanavir ↑ nevirapine Coadministration of REYATAZ with nevirapine is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions [see Contraindications (4)]. 23 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment Protease Inhibitors: saquinavir (soft gelatin capsules) ↑ saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2)]. indinavir Coadministration of REYATAZ with indinavir is contraindicated. Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4)]. ritonavir ↑ atazanavir If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. Others ↑ other protease inhibitor Coadministration with other protease inhibitors is not recommended. Hepatitis C Antiviral Agents elbasvir/grazoprevir ↑ grazoprevir Coadministration of REYATAZ with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4)]. glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of REYATAZ with glecaprevir/pibrentasvir is contraindicated due to the potential for increased the risk of ALT elevations [see Contraindications (4)]. voxilaprevir/sofosbuvir/ velpatasvir ↑ voxilaprevir Coadministration with REYATAZ is not recommended. Other Agents Alpha 1-Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Coadministration of REYATAZ with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4)]. Antacids and buffered medications: ↓ atazanavir REYATAZ should be administered 2 hours before or 1 hour after antacids and buffered medications. Antiarrhythmics: amiodarone, quinidine amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Concomitant use of REYATAZ with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life- threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. Coadministration with REYATAZ without ritonavir has the potential to produce serious and/or life-threatening adverse events but has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ without ritonavir. Anticoagulants: warfarin ↑ warfarin Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that International Normalized Ratio (INR) be monitored. Direct-Acting Oral Anticoagulants: betrixaban, dabigatran, edoxaban ↑ betrixaban ↑ dabigatran ↑ edoxaban Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors. 24 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment rivaroxaban REYATAZ with ritonavir Coadministration of REYATAZ with ritonavir, a strong CYP3A4/P-gp ↑ rivaroxaban inhibitor, and rivaroxaban is not recommended, as it may result in an increased risk of bleeding. REYATAZ Coadministration of REYATAZ, a CYP3A4 inhibitor, and rivaroxaban may ↑ rivaroxaban result in an increased risk of bleeding. Close monitoring is recommended when REYATAZ is coadministered with rivaroxaban. apixaban REYATAZ with ritonavir Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp ↑ apixaban inhibitor, may result in an increased risk of bleeding. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in the apixaban prescribing information. REYATAZ Concomitant use of REYATAZ, a CYP3A4 inhibitor, and apixaban may ↑ apixaban result in an increased risk of bleeding. Close monitoring is recommended when apixaban is coadministered with REYATAZ. Antidepressants: tricyclic ↑ tricyclic Coadministration with REYATAZ has the potential to produce serious and/or antidepressants antidepressants life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ. trazodone ↑ trazodone Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered. Antiepileptics: ↓ atazanavir Coadministration of REYATAZ (with or without ritonavir) with carbamazepine ↑ carbamazepine carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)]. phenytoin, phenobarbital ↓ atazanavir ↓ phenytoin ↓ phenobarbital Coadministration of REYATAZ (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)]. lamotrigine ↓ lamotrigine Coadministration of lamotrigine and REYATAZ with ritonavir may require dosage adjustment of lamotrigine. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir. Antifungals: REYATAZ with Coadministration of ketoconazole has only been studied with REYATAZ ketoconazole, itraconazole ritonavir: ↑ ketoconazole ↑ itraconazole without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously when administering REYATAZ with ritonavir. 25 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment voriconazole REYATAZ with ritonavir in participants with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir REYATAZ with ritonavir in participants without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir The use of voriconazole in patients receiving REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ with ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available. Antigout: colchicine ↑ colchicine The coadministration of REYATAZ with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult dosage of colchicine when administered with REYATAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Antimycobacterials: rifampin ↓ atazanavir Coadministration of REYATAZ with rifampin is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)]. rifabutin ↑ rifabutin A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin­ associated adverse reactions including neutropenia is warranted. Antineoplastics: irinotecan ↑ irinotecan Coadministration of REYATAZ with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications (4)]. 26 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment apalutamide ↓ atazanavir Coadministration of REYATAZ (with or without ritonavir) and apalutamide is contraindicated due to the potential for subsequent loss of virologic response and possible resistance to the class of protease inhibitors [see Contraindications (4)]. ivosidenib ↓ atazanavir ↑ ivosidenib Coadministration of ivosidenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for loss of virologic response and risk of serious adverse events such as QT interval prolongation. encorafenib ↓ atazanavir ↑ encorafenib Coadministration of encorafenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for the loss of virologic response and risk of serious adverse events such as QT interval prolongation. Antiplatelets ticagrelor ↑ ticagrelor Coadministration with ticagrelor is not recommended due to potential increase in the risk of dyspnea, bleeding and other adverse events associated with ticagrelor. clopidogrel ↓ clopidogrel active metabolite Coadministration of REYATAZ (with or without ritonavir) and clopidogrel is not recommended. This is due to the potential reduction of the antiplatelet activity of clopidogrel. Antipsychotics: pimozide ↑ pimozide Coadministration of REYATAZ with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. lurasidone REYATAZ with ritonavir ↑ lurasidone REYATAZ ↑ lurasidone REYATAZ with ritonavir Coadministration of lurasidone with REYATAZ with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications (4)]. REYATAZ without ritonavir If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. quetiapine ↑ quetiapine Initiation of REYATAZ with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking REYATAZ with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Benzodiazepines: ↑ midazolam Coadministration of REYATAZ with either orally administered midazolam or midazolam (oral) triazolam ↑ triazolam triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with REYATAZ can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4)]. 27 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment parenterally administered ↑ midazolam Coadministration with parenteral midazolam should be done in a setting midazolamb which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Calcium channel blockers: diltiazem ↑ diltiazem and desacetyl-diltiazem Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of diltiazem and REYATAZ with ritonavir has not been studied. felodipine, nifedipine, nicardipine, and verapamil ↑ calcium channel blocker Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. Corticosteroids: ↓ atazanavir Coadministration with dexamethasone or other corticosteroids that induce dexamethasone and other corticosteroids (all routes of administration) ↑ corticosteroids CYP3A may result in loss of therapeutic effect of REYATAZ and development of resistance to atazanavir and/or ritonavir. Alternative corticosteroids should be considered. Coadministration with corticosteroids (all routes of administration) that are metabolized by CYP3A, particularly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. For coadministration of cutaneously administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for additional information. Endothelin receptor REYATAZ Coadministration of bosentan and REYATAZ without ritonavir is not antagonists: ↓ atazanavir recommended. bosentan REYATAZ with ritonavir ↑ bosentan For adult patients who have been receiving REYATAZ with ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. For adult patients who have been receiving bosentan, discontinue bosentan at least 36 hours before starting REYATAZ with ritonavir. At least 10 days after starting REYATAZ with ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine ↑ ergot derivatives Coadministration of REYATAZ with ergot derivatives is contraindicated. This is due to the potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4)]. GI Motility Agents: cisapride ↑ cisapride Coadministration of REYATAZ with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. Gonadotropin-releasing ↓ atazanavir Coadministration of elagolix and REYATAZ with or without ritonavir is not hormone Receptor (GnRH) Antagonists: ↑ elagolix recommended due to the potential of loss of virologic response and the potential risk of adverse events such as bone loss and hepatic transaminase elagolix elevations associated with elagolix. In the event coadministration is necessary, limit concomitant use of elagolix 200mg twice daily with REYATAZ with or without ritonavir for up to 1 month or limit concomitant use of elagolix 150 mg once daily with REYATAZ (with or without ritonavir) for up to 6 months and monitor virologic response. 28 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment Herbal Products: St. John’s wort (Hypericum perforatum) ↓ atazanavir Coadministration of products containing St. John’s wort with REYATAZ is contraindicated. This may result in loss of therapeutic effect of REYATAZ and the development of resistance [see Contraindications (4)]. Kinase inhibitors: fostamatinib ↑ R406 (active metabolite of fostamatinib) When coadministering fostamatinib with REYATAZ (with or without ritonavir), monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Coadministration of REYATAZ with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4)]. atorvastatin, rosuvastatin ↑ atorvastatin ↑ rosuvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs. Other Lipid Modifying Agents: lomitapide ↑ lomitapide Coadministration of REYATAZ with lomitapide is contraindicated. This is due to the potential for risk of markedly increased transaminase levels and hepatotoxicity associated with increased plasma concentrations of lomitapide. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir [see Contraindications (4)]. 29 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment H2-Receptor antagonists ↓ atazanavir Coadministration may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist (H2RA). An H2RA dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment- naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2RA. No single dose of the H2RA should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. The use of REYATAZ without ritonavir in pregnant patients is not recommended. In treatment-experienced adult patients: Whenever an H2RA is given to a patient receiving REYATAZ with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ with ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA. • REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA. • REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA. • REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with either tenofovir DF or an H2RA for pregnant patients during the second and third trimester. REYATAZ is not recommended for pregnant patients during the second and third trimester taking REYATAZ with both tenofovir DF and an H2RA. 30 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment Hormonal contraceptives: ↓ ethinyl estradiol Use caution if considering coadministration of oral contraceptives with ethinyl estradiol and norgestimate or norethindrone ↑ norgestimatec ↑ ethinyl estradiol ↑ norethindroned REYATAZ or REYATAZ with ritonavir. If REYATAZ with ritonavir is coadministered with an oral contraceptive, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ with ritonavir and other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. Immunosuppressants: cyclosporine, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with REYATAZ. Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/nasal steroid: REYATAZ Concomitant use of fluticasone propionate and REYATAZ without ritonavir fluticasone ↑ fluticasone should be used with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. REYATAZ with ritonavir ↑ fluticasone With concomitant use of fluticasone propionate and REYATAZ with ritonavir systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ with ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1)]. Macrolide antibiotics: ↑ clarithromycin Increased concentrations of clarithromycin may cause QTc prolongations; clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ with ritonavir and clarithromycin has not been studied. 31 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment Opioids: buprenorphine REYATAZ or REYATAZ with ritonavir ↑ buprenorphine ↑ norbuprenorphine REYATAZ ↓ atazanavir Coadministration of REYATAZ with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. The coadministration of REYATAZ and buprenorphine without ritonavir is not recommended. PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of REYATAZ with REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated [see Contraindications (4)]. The following dose adjustments are recommended for the use of ADCIRCA® (tadalafil) with REYATAZ: Coadministration of ADCIRCA® in patients on REYATAZ (with or without ritonavir): • For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA®: • Avoid the use of ADCIRCA® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use CIALIS® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. REYATAZ with ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. REYATAZ: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions. 32 Reference ID: 5490094 Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment Proton-pump inhibitors: omeprazole ↓ atazanavir Coadministration of REYATAZ with or without ritonavir and omeprazole may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: The proton-pump inhibitor (PPI) dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with PPIs is not recommended. a For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3). b See Contraindications (4), Table 6 for orally administered midazolam. c In combination with atazanavir 300 mg with ritonavir 100 mg once daily. d In combination with atazanavir 400 mg once daily. 7.4 Drugs with No Observed Interactions with REYATAZ No clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see Clinical Pharmacology, Tables 21 and 22 (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2­ 4% and 15-20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to 33 Reference ID: 5490094 rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed [see Data]. Clinical Considerations Dose Adjustments during Pregnancy and the Postpartum Period • REYATAZ must be administered with ritonavir in pregnant patients. • For pregnant patients, no dosage adjustment is required for REYATAZ with the following exceptions: • For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir DF, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antagonist and tenofovir DF in treatment-experienced pregnant patients. • No dosage adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)]. Maternal Adverse Reactions Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take REYATAZ [see Warnings and Precautions (5.8)], including those who are pregnant [see Data]. Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia. Fetal/Neonatal Adverse Reactions All infants, including neonates exposed to REYATAZ in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life [see Data]. Data Human Data In Study AI424-182, REYATAZ with ritonavir (300/100 mg or 400/100 mg) coadministered with lamivudine/zidovudine (150 mg/ 300 mg, as fixed-dose product) was administered to 41 pregnant women with HIV-1, during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV-1 RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ with ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ with ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182. Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 pregnant women with HIV-1, all had 34 Reference ID: 5490094 test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life. Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy). Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis. Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir, and overall birth defects compared with the background birth defect rate. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies is 2-4%. Animal Data In animal reproduction studies, there was no evidence of mortality or teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused neonatal growth retardation during lactation that reversed after weaning. Maternal drug exposure at this dose was 1.3 times the human exposure at the recommended clinical exposure. Minimal maternal toxicity occurred at this exposure level. 8.2 Lactation Risk Summary Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Atazanavir was present in the milk of lactating rats and was associated with neonatal growth retardation that reversed after weaning. Potential risks of breastfeeding include: (1) HIV-1 transmission (in infants without HIV-1), (2) developing viral resistance (in infants with HIV-1), and (3) adverse reactions in a breastfed infant similar to those seen in adults. 35 Reference ID: 5490094 8.4 Pediatric Use REYATAZ is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1, 3 months of age and older weighing at least 5 kg. REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Indications and Usage (1)]. All REYATAZ contraindications, warnings, and precautions apply to pediatric patients [see Contraindications (4) and Warnings and Precautions (5)]. The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 5 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397 [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. The safety profile in pediatric patients was generally similar to that observed in adults [see Adverse Reactions (6.1)]. See Dosage and Administration (2.4, 2.5) for dosing recommendations for the use of REYATAZ capsules and REYATAZ oral powder in pediatric patients. 8.5 Geriatric Use Clinical studies of REYATAZ did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Based on a comparison of mean single-dose pharmacokinetic values for Cmax and AUC, a dose adjustment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring of REYATAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Age/Gender A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18-40 years) and elderly (n=30; ≥65 years) healthy participants. There were no clinically significant pharmacokinetic differences observed due to age or gender. 8.7 Impaired Renal Function REYATAZ is not recommended for use in treatment-experienced patients with HIV-1, who have end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)]. 8.8 Impaired Hepatic Function REYATAZ is not recommended for use in patients with severe hepatic impairment. REYATAZ with ritonavir is not recommended in patients with any degree of hepatic impairment [see Dosage and Administration (2.8) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg (three times the 400 mg maximum recommended dose) have been taken by healthy participants without symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ in a patient with HIV-1 (73 times the 400-mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved 36 Reference ID: 5490094 spontaneously. At REYATAZ doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed [see Warnings and Precautions (5.1, 5.8) and Clinical Pharmacology (12.2)]. Treatment of overdosage with REYATAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with REYATAZ. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine. 11 DESCRIPTION The active ingredient in REYATAZ capsules and oral powder is atazanavir sulfate, which is an HIV-1 protease inhibitor. The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8­ hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13­ pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C38H52N6O7•H2SO4, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula: Atazanavir sulfate is a white to pale-yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3°C. REYATAZ Capsules are available for oral administration in strengths of 200 mg or 300 mg of atazanavir, which are equivalent to 227.8 mg or 341.69 mg of atazanavir sulfate, respectively. The capsules also contain the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue No. 2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue No. 2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol. 37 Reference ID: 5490094 REYATAZ oral powder comes in a packet containing 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 g of powder. The powder is off-white to pale yellow and contains the following inactive ingredients: aspartame, sucrose, and orange-vanilla flavor. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Atazanavir is an HIV-1 antiretroviral drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics Cardiac Electrophysiology Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy participants receiving atazanavir. In placebo-controlled Study AI424-076, the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram [see Warnings and Precautions (5.1)]. Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy participants. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 participants with HIV-1, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy participant or participant with HIV-1 in clinical trials had a QTc interval >500 msec [see Warnings and Precautions (5.1)]. 12.3 Pharmacokinetics The pharmacokinetics of atazanavir were evaluated in adult participants who either were healthy, or with HIV-1, after administration of REYATAZ 400 mg once daily and after administration of REYATAZ 300 mg with ritonavir 100 mg once daily (see Table 17). 38 Reference ID: 5490094 Table 17: Steady-State Pharmacokinetics of Atazanavir in Healthy Participants or Participants with HIV-1 in the Fed State 300 mg with ritonavir 400 mg once daily 100 mg once daily Healthy Participants Healthy Participants Participants with HIV-1 Participants with HIV-1 Parameter (n=14) (n=13) (n=28) (n=10) Cmax (ng/mL) Geometric mean (CV%) 5199 (26) 2298 (71) 6129 (31) 4422 (58) Mean (SD) 5358 (1371) 3152 (2231) 6450 (2031) 5233 (3033) Tmax (h) Median 2.5 2.0 2.7 3.0 AUC (ng•h/mL) Geometric mean (CV%) 28132 (28) 14874 (91) 57039 (37) 46073 (66) Mean (SD) 29303 (8263) 22262 (20159) 61435 (22911) 53761 (35294) T-half (h) Mean (SD) 7.9 (2.9) 6.5 (2.6) 18.1 (6.2)a 8.6 (2.3) Cmin (ng/mL) Geometric mean (CV%) 159 (88) 120 (109) 1227 (53) 636 (97) Mean (SD) 218 (191) 273 (298)b 1441 (757) 862 (838) a n=26. b n=12. Figure 1 displays the mean plasma concentrations of atazanavir at steady state after REYATAZ 400 mg once daily (as two 200-mg capsules) with a light meal and after REYATAZ 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in adult participants with HIV-1. 39 Reference ID: 5490094 10000 100 ~ ATV.ctO0mg 10 Median wild-type ECro=14 ng/ml - ATVIRTV300/100 mg - EC,, 0 2 4 • • 10 12 14 16 19 20 22 21 Time {h) Figure 1: Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10) for Adult Participants with HIV-1 Absorption Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold. Food Effect Administration of REYATAZ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of REYATAZ with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400-mg dose of REYATAZ with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of REYATAZ with either a light meal or high- fat meal decreased the coefficient of variation of AUC and Cmax by approximately one-half compared to the fasting state. Coadministration of a single 300-mg dose of REYATAZ and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Coadministration of 40 Reference ID: 5490094 REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state. Distribution Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in participants with HIV-1 dosed with REYATAZ 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42. Metabolism Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A. Elimination Following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half- life of atazanavir in healthy participants (n=214) and adult participants with HIV-1 (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal. Specific Populations Renal Impairment In healthy participants, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. REYATAZ has been studied in adult participants with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir Cmax was 9% lower, AUC was 19% higher, and Cmin was 96% higher in participants with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched participants with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for Cmax, AUC, and Cmin were approximately 25% to 43% lower compared to participants with normal renal function. The mechanism of this decrease is unknown. REYATAZ is not recommended for use in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7)]. 41 Reference ID: 5490094 Hepatic Impairment REYATAZ has been studied in adult participants with moderate-to-severe hepatic impairment (14 with Child-Pugh B and 2 with Child-Pugh C) after a single 400-mg dose. The mean AUC(0-∞) was 42% greater in participants with impaired hepatic function than in healthy participants. The mean half-life of atazanavir in hepatically impaired participants was 12.1 hours compared to 6.4 hours in healthy participants. A dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of atazanavir are expected. REYATAZ is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of REYATAZ in combination with ritonavir has not been studied in participants with hepatic impairment; thus, coadministration of REYATAZ with ritonavir is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.8)]. Pediatrics The pharmacokinetic parameters for atazanavir at steady state in pediatric participants taking the powder formulation are summarized in Table 18 by weight ranges [see Dosage and Administration (2.5)]. Table 18: Steady-State Pharmacokinetics of Atazanavir (powder formulation) with Ritonavir in Pediatric Participants with HIV-1 Body Weight (range in kg) [n] atazanavir with ritonavir Dose (mg) Cmax ng/mL Geometric Mean (CV%) AUC ng•h/mL Geometric Mean (CV%) Cmin ng/mL Geometric Mean (CV%) 5 to <10 [20] 150/80 4131 (55%) 32503 (61%) 336 (76%) 5 to <10 [10] 200/80 4466 (59%) 39519 (54%) 550 (60%) 10 to <15 [18] 200/80 5197 (53%) 50305 (67%) 572 (111%) 15 to <25 [32] 250/80 5394 (46%) 55687 (45%) 686 (68%) 25 to <35 [8] 300/100 4209 (52%) 44329 (63%) 468 (104%) The pharmacokinetic parameters for atazanavir at steady state in pediatric participants taking the capsule formulation were predicted by a population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses [see Dosage and Administration (2.4)]. 42 Reference ID: 5490094 Table 19: Predicted Steady-State Pharmacokinetics of Atazanavir (capsule formulation) with Ritonavir in Pediatric Participants with HIV-1 Body Weight (range in kg) atazanavir with ritonavir Dose (mg) Cmax ng/mL Geometric Mean (CV%) AUC ng•h/mL Geometric Mean (CV%) Cmin ng/mL Geometric Mean (CV%) 15 to <35 200/100 3303 (86%) 37235 (84%) 538 (99%) ≥35 300/100 2980 (82%) 37643 (83%) 653 (89%) Pregnancy The pharmacokinetic data from pregnant women with HIV-1 receiving REYATAZ Capsules with ritonavir are presented in Table 20. Table 20: Steady-State Pharmacokinetics of Atazanavir with Ritonavir in Pregnant Women with HIV-1 in the Fed State Atazanavir 300 mg with ritonavir 100 mg 2nd Trimester 3rd Trimester Postpartumb (n=20) Pharmacokinetic Parameter (n=5a) (n=34) 3078.85 3291.46 5721.21 Cmax ng/mL (50) (48) (31) Geometric mean (CV%) AUC ng•h/mL 27657.1 34251.5 61990.4 Geometric mean (CV%) (43) (43) (32) 538.70 668.48 1462.59 Cmin ng/mLc (46) (50) (45) Geometric mean (CV%) a Available data during the 2nd trimester are limited. b Atazanavir peak concentrations and AUCs were found to be approximately 28% to 43% higher during the postpartum period (4-12 weeks) than those observed historically in, non-pregnant patients with HIV-1. Atazanavir plasma trough concentrations were approximately 2.2-fold higher during the postpartum period when compared to those observed historically in non-pregnant patients with HIV-1. c Cmin is concentration 24 hours post-dose. Drug Interaction Data Atazanavir is a metabolism-dependent CYP3A inhibitor, with a Kinact value of 0.05 to 0.06 min−1 and Ki value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (Ki=1.9 µM) and CYP2C8 (Ki=2.1 µM). Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, REYATAZ decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced. 43 Reference ID: 5490094 Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for information on other potential drug interactions with ritonavir. Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, Cmax, and Cmin are summarized in Tables 21 and 22. Neither didanosine EC nor diltiazem had a significant effect on atazanavir exposures (see Table 22 for effect of atazanavir on didanosine EC or diltiazem exposures). REYATAZ did not have a significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see Drug Interactions (7). Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 Cmax AUC Cmin atenolol 50 mg QD, d 7–11 (n=19) and d 19–23 400 mg QD, d 1–11 (n=19) 1.00 (0.89, 1.12) 0.93 (0.85, 1.01) 0.74 (0.65, 0.86) clarithromycin 500 mg BID, d 7–10 (n=29) and d 18–21 400 mg QD, d 1–10 (n=29) 1.06 (0.93, 1.20) 1.28 (1.16, 1.43) 1.91 (1.66, 2.21) didanosine (ddI) (buffered tablets) and stavudine (d4T)b ddI: 200 mg × 1 dose, d4T: 40 mg × 1 dose (n=31) 400 mg × 1 dose simultaneously with ddI and d4T (n=31) 0.11 (0.06, 0.18) 0.13 (0.08, 0.21) 0.16 (0.10, 0.27) ddI: 200 mg × 1 dose, d4T: 40 mg × 1 dose (n=32) 400 mg × 1 dose 1 h after ddI + d4T (n=32) 1.12 (0.67, 1.18) 1.03 (0.64, 1.67) 1.03 (0.61, 1.73) efavirenz 600 mg QD, d 7–20 (n=27) 400 mg QD, d 1–20 (n=27) 0.41 (0.33, 0.51) 0.26 (0.22, 0.32) 0.07 (0.05, 0.10) 600 mg QD, d 7–20 400 mg QD, d 1–6 1.14 1.39 1.48 (n=13) (n=23) then 300 mg with ritonavir 100 mg QD, 2 h (0.83, 1.58) (1.02, 1.88) (1.24, 1.76) before efavirenz, d 7–20 (n=13) 44 Reference ID: 5490094 Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 Cmax AUC Cmin 600 mg QD, 300 mg QD with 1.17 1.00 0.58 d 11–24 (pm) (n=14) ritonavir 100 mg QD, d 1–10 (pm) (n=22), then 400 mg QD with (1.08, 1.27) (0.91, 1.10) (0.49, 0.69) ritonavir 100 mg QD, d 11–24 (pm), (simultaneously with efavirenz) (n=14) famotidine 40 mg BID, d 7–12 (n=15) 400 mg QD, d 1–6 (n=45), d 7–12 (simultaneous administration) (n=15) 0.53 (0.34, 0.82) 0.59 (0.40, 0.87) 0.58 (0.37, 0.89) 40 mg BID, d 7–12 400 mg QD (pm), d 1–6 1.08 0.95 0.79 (n=14) (n=14), d 7–12 (10 h after, 2 h before famotidine) (n=14) (0.82, 1.41) (0.74, 1.21) (0.60, 1.04) 40 mg BID, d 11–20 300 mg QD with 0.86 0.82 0.72 (n=14)c ritonavir 100 mg QD, d 1–10 (n=46), d 11–20d (0.79, 0.94) (0.75, 0.89) (0.64, 0.81) (simultaneous administration) (n=14) 20 mg BID, d 11–17 300 mg QD with 0.91 0.90 0.81 (n=18) ritonavir 100 mg QD and tenofovir DF 300 mg (0.84, 0.99) (0.82, 0.98) (0.69, 0.94) QD, d 1–10 (am) (n=39), d 11–17 (am) (simultaneous administration with am famotidine) (n=18)d,e 40 mg QD (pm), 300 mg QD with 0.89 0.88 0.77 d 18–24 (n=20) ritonavir 100 mg QD and tenofovir DF 300 mg QD, d 1–10 (am) (n=39), (0.81, 0.97) (0.80, 0.96) (0.63, 0.93) d 18–24 (am) (12 h after pm famotidine) (n=20)e 40 mg BID, d 18–24 300 mg QD with 0.74 0.79 0.72 (n=18) ritonavir 100 mg QD and tenofovir DF 300 mg (0.66, 0.84) (0.70, 0.88) (0.63, 0.83) QD, d 1–10 (am) (n=39), d 18–24 (am) (10 h after pm famotidine and 2 h before am famotidine) (n=18)e 45 Reference ID: 5490094 Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 Cmax AUC Cmin 40 mg BID, d 11–20 (n=15) 300 mg QD with ritonavir 100 mg QD, d 1–10 (am) (n=46), then 400 mg QD with ritonavir 100 mg QD, d 11–20 (am) (n=15) 1.02 (0.87, 1.18) 1.03 (0.86, 1.22) 0.86 (0.68, 1.08) grazoprevir/ elbasvir grazoprevir 200 mg QD d 1–35 (n = 11) 300 mg QD with ritonavir 100 mg QD, d 1–35 (n = 11) 1.12 (1.01, 1.24) 1.43 (1.30, 1.57) 1.23 (1.13, 1.34) elbasvir 50 mg QD d 1–35 (n = 8) 300 mg QD with ritonavir 100 mg QD, d 1–35 (n = 8) 1.02 (0.96, 1.08) 1.07 (0.98,1.17) 1.15 (1.02, 1.29) ketoconazole 200 mg QD, d 7–13 (n=14) 400 mg QD, d 1–13 (n=14) 0.99 (0.77, 1.28) 1.10 (0.89, 1.37) 1.03 (0.53, 2.01) nevirapinef,g 200 mg BID, d 1–23 (n=23) 300 mg QD with ritonavir 100 mg QD, d 4–13, then 400 mg QD with ritonavir 100 mg QD, d 14–23 (n=23)h 0.72 (0.60, 0.86) 1.02 (0.85, 1.24) 0.58 (0.48, 0.71) 0.81 (0.65, 1.02) 0.28 (0.20, 0.40) 0.41 (0.27, 0.60) omeprazole 40 mg QD, d 7–12 (n=16)i 400 mg QD, d 1–6 (n=48), d 7–12 (n=16) 0.04 (0.04, 0.05) 0.06 (0.05, 0.07) 0.05 (0.03, 0.07) 40 mg QD, d 11–20 (n=15)i 300 mg QD with ritonavir 100 mg QD, d 1–20 (n=15) 0.28 (0.24, 0.32) 0.24 (0.21, 0.27) 0.22 (0.19, 0.26) 20 mg QD, d 17–23 (am) (n=13) 300 mg QD with ritonavir 100 mg QD, d 7–16 (pm) (n=27), d 17– 23 (pm) (n=13)j,k 0.61 (0.46, 0.81) 0.58 (0.44, 0.75) 0.54 (0.41, 0.71) 20 mg QD, d 17–23 (am) (n=14) 300 mg QD with ritonavir 100 mg QD, d 7–16 (am) (n=27), then 400 mg QD with ritonavir 100 mg QD, d 17–23 (am) (n=14)l,m 0.69 (0.58, 0.83) 0.70 (0.57, 0.86) 0.69 (0.54, 0.88) pitavastatin 4 mg QD for 5 days 300 mg QD for 5 days 1.13 (0.96, 1.32) 1.06 (0.90, 1.26) NA rifabutin 150 mg QD, d 15–28 (n=7) 400 mg QD, d 1–28 (n=7) 1.34 (1.14, 1.59) 1.15 (0.98, 1.34) 1.13 (0.68, 1.87) 46 Reference ID: 5490094 Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 Cmax AUC Cmin rifampin 600 mg QD, d 17–26 (n=16) 300 mg QD with ritonavir 100 mg QD, d 7–16 (n=48), d 17–26 (n=16) 0.47 (0.41, 0.53) 0.28 (0.25, 0.32) 0.02 (0.02, 0.03) ritonavirn 100 mg QD, d 11–20 (n=28) 300 mg QD, d 1–20 (n=28) 1.86 (1.69, 2.05) 3.38 (3.13, 3.63) 11.89 (10.23, 13.82) tenofovir DFo 300 mg QD, d 9–16 (n=34) 400 mg QD, d 2–16 (n=34) 0.79 (0.73, 0.86) 0.75 (0.70, 0.81) 0.60 (0.52, 0.68) 300 mg QD, d 15–42 (n=10) 300 mg with ritonavir 100 mg QD, d 1–42 (n=10) 0.72p (0.50, 1.05) 0.75p (0.58, 0.97) 0.77p (0.54, 1.10) voriconazole (Participants with at least one functional CYP2C19 allele) 200 mg BID, d 2–3, 22–30; 400 mg BID, d 1, 21 (n=20) 300 mg with ritonavir 100 mg QD, d 11–30 (n=20) 0.87 (0.80, 0.96) 0.88 (0.82, 0.95) 0.80 (0.72, 0.90) voriconazole (Participants without a functional CYP2C19 allele) 50 mg BID, d 2–3, 22–30; 100 mg BID, d 1, 21 (n=8) 300 mg with ritonavir 100 mg QD, d 11–30 (n=8) 0.81 (0.66, 1.00) 0.80 (0.65, 0.97) 0.69 (0.54, 0.87) a Data provided are under fed conditions unless otherwise noted. b All drugs were given under fasted conditions. c REYATAZ 300 mg with ritonavir 100 mg once daily coadministered with famotidine 40 mg twice daily resulted in atazanavir geometric mean Cmax that was similar and AUC and Cmin values that were 1.79- and 4.46-fold higher relative to REYATAZ 400 mg once daily alone. d Similar results were noted when famotidine 20 mg BID was administered 2 hours after and 10 hours before atazanavir 300 mg with ritonavir 100 mg and tenofovir DF 300 mg. e Coadministration of atazanavir with ritonavir and tenofovir DF was administered after a light meal. f Study was conducted in participants with HIV-1. g Compared with atazanavir 400 mg historical data without nevirapine (n=13), the ratio of geometric means (90% confidence intervals) for Cmax, AUC, and Cmin were 1.42 (0.98, 2.05), 1.64 (1.11, 2.42), and 1.25 (0.66, 2.36), respectively, for atazanavir with ritonavir 300/100 mg; and 2.02 (1.42, 2.87), 2.28 (1.54, 3.38), and 1.80 (0.94, 3.45), respectively, for atazanavir with ritonavir 400/100 mg. h Parallel group design; n=23 for atazanavir with ritonavir and nevirapine, n=22 for atazanavir 300 mg/ritonavir 100 mg without nevirapine. Participants were treated with nevirapine prior to study entry. i Omeprazole 40 mg was administered on an empty stomach 2 hours before REYATAZ. 47 Reference ID: 5490094 j Omeprazole 20 mg was administered 30 minutes prior to a light meal in the morning and REYATAZ 300 mg with ritonavir 100 mg in the evening after a light meal, separated by 12 hours from omeprazole. k REYATAZ 300 mg with ritonavir 100 mg once daily separated by 12 hours from omeprazole 20 mg daily resulted in increases in atazanavir geometric mean AUC (10%) and Cmin (2.4-fold), with a decrease in Cmax (29%) relative to REYATAZ 400 mg once daily in the absence of omeprazole (study days 1–6). l Omeprazole 20 mg was given 30 minutes prior to a light meal in the morning and REYATAZ 400 mg with ritonavir 100 mg once daily after a light meal, 1 hour after omeprazole. Effects on atazanavir concentrations were similar when REYATAZ 400 mg with ritonavir 100 mg was separated from omeprazole 20 mg by 12 hours. m REYATAZ 400 mg with ritonavir 100 mg once daily administered with omeprazole 20 mg once daily resulted in increases in atazanavir geometric mean AUC (32%) and Cmin (3.3-fold), with a decrease in Cmax (26%) relative to REYATAZ 400 mg once daily in the absence of omeprazole (study days 1–6). n Compared with atazanavir 400 mg QD historical data, administration of atazanavir with ritonavir 300/100 mg QD increased the atazanavir geometric mean values of Cmax, AUC, and Cmin by 18%, 103%, and 671%, respectively. o Note that similar results were observed in studies where administration of tenofovir DF and REYATAZ was separated by 12 hours. p Ratio of atazanavir with ritonavir and tenofovir DF to atazanavir with ritonavir. Atazanavir 300 mg with ritonavir 100 mg results in higher atazanavir exposure than atazanavir 400 mg (see footnote o). The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir and tenofovir DF were: Cmax = 3190 ng/mL, AUC = 34459 ng•h/mL, and Cmin = 491 ng/mL. Study was conducted in participants with HIV-1. NA = not available. Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without REYATAZ; No Effect = 1.00 Cmax AUC Cmin acetaminophen 1 g BID, d 1–20 (n=10) 300 mg QD with ritonavir 100 mg QD, d 11–20 (n=10) 0.87 (0.77, 0.99) 0.97 (0.91, 1.03) 1.26 (1.08, 1.46) atenolol 50 mg QD, d 7–11 (n=19) and d 19–23 400 mg QD, d 1–11 (n=19) 1.34 (1.26, 1.42) 1.25 (1.16, 1.34) 1.02 (0.88, 1.19) clarithromycin 500 mg BID, d 7–10 (n=21) and d 18–21 400 mg QD, d 1–10 (n=21) 1.50 (1.32, 1.71) OH-clarithromycin: 0.28 (0.24, 0.33) 1.94 (1.75, 2.16) OH-clarithromycin: 0.30 (0.26, 0.34) 2.60 (2.35, 2.88) OH-clarithromycin: 0.38 (0.34, 0.42) ddI (enteric­ coated [EC] capsules)b 400 mg d 1 (fasted), d 8 (fed) (n=34) 400 mg QD, d 2–8 (n=34) 0.64 (0.55, 0.74) 0.66 (0.60, 0.74) 1.13 (0.91, 1.41) 400 mg d 1 (fasted), d 19 (fed) (n=31) 300 mg QD with ritonavir 100 mg QD, d 9–19 (n=31) 0.62 (0.52, 0.74) 0.66 (0.59, 0.73) 1.25 (0.92, 1.69) 48 Reference ID: 5490094 Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without REYATAZ; No Effect = 1.00 Cmax AUC Cmin diltiazem 180 mg QD, d 7–11 (n=28) and d 19–23 400 mg QD, d 1–11 (n=28) 1.98 (1.78, 2.19) desacetyl-diltiazem: 2.72 (2.44, 3.03) 2.25 (2.09, 2.16) desacetyl-diltiazem: 2.65 (2.45, 2.87) 2.42 (2.14, 2.73) desacetyl-diltiazem: 2.21 (2.02, 2.42) ethinyl estradiol Ortho-Novum 400 mg QD, ethinyl estradiol: 1.15 ethinyl estradiol: 1.48 ethinyl estradiol: 1.91 & norethindronec 7/7/7 QD, d 16–29 (0.99, 1.32) (1.31, 1.68) (1.57, 2.33) d 1–29 (n=19) norethindrone: 1.67 norethindrone: 2.10 norethindrone: 3.62 (n=19) (1.42, 1.96) (1.68, 2.62) (2.57, 5.09) ethinyl estradiol Ortho Tri-Cyclen 300 mg QD with ethinyl estradiol: ethinyl estradiol: ethinyl estradiol: & norgestimated QD, d 1–28 (n=18), then Ortho Tri- Cyclen® LO QD, d 29–42e (n=14) ritonavir 100 mg QD, d 29–42 (n=14) 0.84 (0.74, 0.95) 17-deacetyl norgestimate:f 1.68 (1.51, 1.88) 0.81 (0.75, 0.87) 17-deacetyl norgestimate:f 1.85 (1.67, 2.05) 0.63 (0.55, 0.71) 17-deacetyl norgestimate:f 2.02 (1.77, 2.31) glecaprevir/ pibrentasvir 300 mg glecaprevir (n=12) 300 mg QD with ritonavir 100 mg QD (n=12) ≥4.06g (3.15, 5.23) ≥6.53g (5.24, 8.14) ≥14.3g (9.85, 20.7) 120 mg pibrentasvir (n=12) 300 mg QD with ritonavir 100 mg QD (n=12) ≥1.29g (1.15, 1.45) ≥1.64g (1.48, 1.82) ≥2.29g (1.95, 2.68) grazoprevir/ elbasvir grazoprevir 200 mg QD d 1– 35 (n=12) 300 mg QD with ritonavir 100 mg QD d 1–35 (n=12) 6.24 (4.42, 8.81) 10.58 (7.78, 14.39) 11.64 (7.96, 17.02) elbasvir 50 mg QD d 1–35 (n=10) 300 mg QD with ritonavir 100 mg QD d 1–35 (n=10) 4.15 (3.46, 4.97) 4.76 (4.07, 5.56) 6.45 (5.51, 7.54) methadone Stable maintenance dose, d 1–15 (n=16) 400 mg QD, d 2–15 (n=16) (R)-methadoneh 0.91 (0.84, 1.0) total: 0.85 (0.78, 0.93) (R)-methadoneh 1.03 (0.95, 1.10) total: 0.94 (0.87, 1.02) (R)-methadoneh 1.11 (1.02, 1.20) total: 1.02 (0.93, 1.12) nevirapinei,j 200 mg BID, 300 mg QD with 1.17 1.25 1.32 d 1–23 ritonavir 100 mg (1.09, 1.25) (1.17, 1.34) (1.22, 1.43) (n=23) QD, d 4–13, then 1.21 1.26 1.35 400 mg QD with (1.11, 1.32) (1.17, 1.36) (1.25, 1.47) ritonavir 100 mg QD, d 14–23 (n=23) 49 Reference ID: 5490094 Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without REYATAZ; No Effect = 1.00 Cmax AUC Cmin omeprazolek 40 mg single dose, d 7 and d 20 (n=16) 400 mg QD, d 1–12 (n=16) 1.24 (1.04, 1.47) 1.45 (1.20, 1.76) NA rifabutin 300 mg QD, d 1–10 then 150 mg QD, d 11–20 (n=3) 600 mg QD,l d 11–20 (n=3) 1.18 (0.94, 1.48) 25-O-desacetyl­ rifabutin: 8.20 (5.90, 11.40) 2.10 (1.57, 2.79) 25-O-desacetyl­ rifabutin: 22.01 (15.97, 30.34) 3.43 (1.98, 5.96) 25-O-desacetyl­ rifabutin: 75.6 (30.1, 190.0) 150 mg twice weekly, d 1–15 (n=7) 300 mg QD with ritonavir 100 mg QD, d 1–17 (n=7) 2.49m (2.03, 3.06) 25-O-desacetyl­ rifabutin: 7.77 (6.13, 9.83) 1.48m (1.19, 1.84) 25-O-desacetyl­ rifabutin: 10.90 (8.14, 14.61) 1.40m (1.05, 1.87) 25-O-desacetyl­ rifabutin: 11.45 (8.15, 16.10) pitavastatin 4 mg QD for 5 days 300 mg QD for 5 days 1.60 (1.39, 1.85) 1.31 (1.23, 1.39) NA rosiglitazonen 4 mg single dose, d 1, 7, 17 (n=14) 400 mg QD, d 2–7, then 300 mg QD with ritonavir 100 mg QD, d 8–17 (n=14) 1.08 (1.03, 1.13) 0.97 (0.91, 1.04) 1.35 (1.26, 1.44) 0.83 (0.77, 0.89) NA NA rosuvastatin 10 mg single dose 300 mg QD with ritonavir 100 mg QD for 7 days ↑ 7-foldo ↑ 3-foldo NA saquinavirp (soft gelatin capsules) 1200 mg QD, d 1–13 (n=7) 400 mg QD, d 7–13 (n=7) 4.39 (3.24, 5.95) 5.49 (4.04, 7.47) 6.86 (5.29, 8.91) sofosbuvir/ velpatasvir/ voxilaprevir 400 mg sofosbuvir single dose (n=15) 300 mg with100 mg ritonavir single dose (n=15) 1.29 (1.09, 1.52) sofosbuvir metabolite GS-331007 1.05 (0.99, 1.12) 1.40 (1.25, 1.57) sofosbuvir metabolite GS-331007 1.25 (1.16, 1.36) NA 100 mg velpatasvir single dose (n=15) 300 mg with 100 mg ritonavir single dose (n=15) 1.29 (1.07, 1.56) 1.93 (1.58, 2.36) NA 100 mg voxilaprevir single dose (n=15) 300 mg with 100 mg ritonavir single dose (n=15) 4.42 (3.65, 5.35) 4.31 (3.76, 4.93) NA tenofovir DFq 300 mg QD, d 9–16 (n=33) and d 24–30 (n=33) 400 mg QD, d 2–16 (n=33) 1.14 (1.08, 1.20) 1.24 (1.21, 1.28) 1.22 (1.15, 1.30) 50 Reference ID: 5490094 Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZa Coadministered Drug Coadministered Drug Dose/Schedule REYATAZ Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without REYATAZ; No Effect = 1.00 Cmax AUC Cmin 300 mg QD, d 1–7 (pm) (n=14) d 25–34 (pm) (n=12) 300 mg QD with ritonavir 100 mg QD, d 25–34 (am) (n=12)r 1.34 (1.20, 1.51) 1.37 (1.30, 1.45) 1.29 (1.21, 1.36) voriconazole (Participants with at least one functional CYP2C19 allele) 200 mg BID, d 2–3, 22–30; 400 mg BID, d 1, 21 (n=20) 300 mg with ritonavir 100 mg QD, d 11–30 (n=20) 0.90 (0.78, 1.04) 0.67 (0.58, 0.78) 0.61 (0.51, 0.72) voriconazole (Participants without a functional CYP2C19 allele) 50 mg BID, d 2–3, 22–30; 100 mg BID, d 1, 21 (n=8) 300 mg with ritonavir 100 mg QD, d 11–30 (n=8) 4.38 (3.55, 5.39) 5.61 (4.51, 6.99) 7.65 (5.71, 10.2) lamivudine and zidovudine 150 mg lamivudine and 300 mg zidovudine BID, d 1–12 (n=19) 400 mg QD, d 7–12 (n=19) lamivudine: 1.04 (0.92, 1.16) zidovudine: 1.05 (0.88, 1.24) zidovudine glucuronide: 0.95 (0.88, 1.02) lamivudine: 1.03 (0.98, 1.08) zidovudine: 1.05 (0.96, 1.14) zidovudine glucuronide: 1.00 (0.97, 1.03) lamivudine: 1.12 (1.04, 1.21) zidovudine: 0.69 (0.57, 0.84) zidovudine glucuronide: 0.82 (0.62, 1.08) a Data provided are under fed conditions unless otherwise noted. b 400 mg ddI EC and REYATAZ were administered together with food on Days 8 and 19. c d Upon further dose normalization of ethinyl estradiol 25 mcg with atazanavir relative to ethinyl estradiol 35 mcg without atazanavir, the ratio of geometric means (90% confidence intervals) for Cmax, AUC, and Cmin were 0.82 (0.73, 0.92), 1.06 (0.95, 1.17), and 1.35 (1.11, 1.63), respectively. Upon further dose normalization of ethinyl estradiol 35 mcg with atazanavir with ritonavir relative to ethinyl estradiol 25 mcg without atazanavir with ritonavir, the ratio of geometric means (90% confidence intervals) for Cmax, AUC, and Cmin were 1.17 (1.03, 1.34), 1.13 (1.05, 1.22), and 0.88 (0.77, 1.00), respectively. e f All participants were on a 28-day lead-in period; one full cycle of Ortho Tri-Cyclen® . Ortho Tri-Cyclen® contains 35 mcg of ethinyl estradiol. Ortho Tri-Cyclen® LO contains 25 mcg of ethinyl estradiol. Results were dose normalized to an ethinyl estradiol dose of 35 mcg. 17-deacetyl norgestimate is the active component of norgestimate. g Effect of atazanavir with ritonavir on the first dose of glecaprevir and pibrentasvir is reported. h (R)-methadone is the active isomer of methadone. i Study was conducted in participants with HIV-1. 51 Reference ID: 5490094 j Participants were treated with nevirapine prior to study entry. k Omeprazole was used as a metabolic probe for CYP2C19. Omeprazole was given 2 hours after REYATAZ on Day 7; and was given alone 2 hours after a light meal on Day 20. l Not the recommended therapeutic dose of atazanavir. m When compared to rifabutin 150 mg QD alone d1–10 (n=14). Total of rifabutin and 25-O-desacetyl-rifabutin: AUC 2.19 (1.78, 2.69). n Rosiglitazone used as a probe substrate for CYP2C8. o Mean ratio (with/without coadministered drug). ↑ indicates an increase in rosuvastatin exposure. p The combination of atazanavir and saquinavir 1200 mg QD produced daily saquinavir exposures similar to the values produced by the standard therapeutic dosing of saquinavir at 1200 mg TID. However, the Cmax is about 79% higher than that for the standard dosing of saquinavir (soft gelatin capsules) alone at 1200 mg TID. q Note that similar results were observed in a study where administration of tenofovir DF and REYATAZ was separated by 12 hours. r Administration of tenofovir DF and REYATAZ was temporally separated by 12 hours. NA = not available. 12.4 Microbiology Mechanism of Action Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1-infected cells, thus preventing formation of mature virions. Antiviral Activity in Cell Culture Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC50 values above the EC50 values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity. Resistance In Cell Culture: HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed 52 Reference ID: 5490094 at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant. Clinical Studies of Treatment-Naive Participants: Comparison of Ritonavir-Boosted REYATAZ vs Unboosted REYATAZ: Study AI424-089 compared REYATAZ 300 mg once daily with ritonavir 100 mg vs REYATAZ 400 mg once daily when administered with lamivudine and extended- release stavudine in treatment-naive participants with HIV-1. A summary of the number of virologic failures and virologic failure isolates with atazanavir resistance in each arm is shown in Table 23. Table 23: Summary of Virologic Failuresa at Week 96 in Study AI424-089: Comparison of Ritonavir Boosted REYATAZ vs Unboosted REYATAZ: Randomized Participants REYATAZ 300 mg REYATAZ 400 mg with ritonavir 100 mg (n=95) (n=105) Virologic Failure (≥50 copies/mL) at Week 96 15 (16%) 34 (32%) Virologic Failure with Genotypes and Phenotypes Data 5 17 Virologic Failure Isolates with atazanavir ­ resistance at Week 96 0/5 (0%)b 4/17 (24%)b Virologic Failure Isolates with I50L Emergence at Week 96c 0/5 (0%)b 2/17 (12%)b Virologic Failure Isolates with Lamivudine Resistance at Week 96 2/5 (40%)b 11/17 (65%)b a Virologic failure includes participants who were never suppressed through Week 96 and on study at Week 96, had virologic rebound or discontinued due to insufficient viral load response. b Percentage of Virologic Failure Isolates with genotypic and phenotypic data. c Mixture of I50I/L emerged in 2 other atazanavir 400 mg-treated participants. Neither isolate was phenotypically resistant to atazanavir. Clinical Studies of Treatment-Naive Participants Receiving REYATAZ 300 mg with Ritonavir 100 mg: In Phase 3 Study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from participants who experienced virologic failure (HIV-1 RNA ≥400 copies/mL) or discontinued before achieving suppression on atazanavir with ritonavir (n=39; 9%) and lopinavir/ritonavir (n=39; 9%) through 96 weeks of treatment. In the atazanavir with ritonavir arm, one of the virologic failure isolates had a 56-fold decrease in atazanavir susceptibility emerge on therapy with the development of PI resistance-associated substitutions 53 Reference ID: 5490094 L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M. The NRTI resistance-associated substitution M184V also emerged on treatment in this isolate conferring emtricitabine resistance. Two atazanavir with ritonavir-virologic failure isolates had baseline phenotypic atazanavir resistance and IAS-defined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with a 17-fold decrease in atazanavir susceptibility from baseline and the other failure isolate with baseline atazanavir resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on atazanavir treatment associated with a 3-fold decrease in atazanavir susceptibility from baseline. Five of the treatment failure isolates in the atazanavir with ritonavir arm developed phenotypic emtricitabine resistance with the emergence of either the M184I (n=1) or the M184V (n=4) substitution on therapy and none developed phenotypic tenofovir disoproxil resistance. In the lopinavir/ritonavir arm, one of the virologic failure participant isolates had a 69-fold decrease in lopinavir susceptibility emerge on therapy with the development of PI substitutions L10V, V11I, I54V, G73S, and V82A in addition to baseline PI substitutions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six lopinavir/ritonavir virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance. Clinical Studies of Treatment-Naive Participants Receiving REYATAZ 400 mg without Ritonavir: atazanavir-resistant clinical isolates from treatment-naive participants who experienced virologic failure on REYATAZ 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of atazanavir therapy), often in combination with an A71V substitution, but also developed one or more other PI substitutions (eg, V32I, L33F, G73S, V82A, I85V, or N88S) with or without the I50L substitution. In treatment-naive participants, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to atazanavir but retained in cell culture susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L substitution on the efficacy of subsequently administered PIs. Clinical Studies of Treatment-Experienced Participants: In studies of treatment-experienced participants treated with atazanavir or atazanavir with ritonavir, most atazanavir-resistant isolates from participants who experienced virologic failure developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions to develop in the viral isolates of participants who failed treatment with atazanavir 300 mg once daily and ritonavir 100 mg once daily (together with tenofovir DF and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T. Other substitutions that developed on atazanavir with ritonavir treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of participant isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the participant at baseline, atazanavir resistance developed through substitutions associated with resistance to other PIs and could include the development of the I50L substitution. The I50L substitution has been detected in treatment-experienced participants experiencing 54 Reference ID: 5490094 virologic failure after long-term treatment. Protease cleavage site changes also emerged on atazanavir treatment, but their presence did not correlate with the level of atazanavir resistance. Clinical Studies of Pediatric Participants in AI424-397 (PRINCE I) and AI424-451 (PRINCE II): Treatment-emergent atazanavir with ritonavir resistance-associated amino acid substitution M36I in the protease was detected in the virus of one participant among treatment failures in AI424-397. In addition, three known resistance-associated substitutions for other PIs arose in the viruses from one participant each (L19I/R, H69K/R, and I72I/V). Reduced susceptibility to atazanavir, ritonavir, or atazanavir with ritonavir was not seen with these viruses. In AI424-451, atazanavir with ritonavir resistance-associated substitutions G16E, V82A/I/T, I84V, and/or L90M arose in the viruses of two participants. The virus population harboring the M46M/V, V82V/I, I84I/V, and L90L/M substitutions acquired phenotypic resistance to ritonavir (ritonavir phenotypic fold- change of 3.5, with a ritonavir cutoff of 2.5-fold change). However, these substitutions did not result in phenotypic resistance to atazanavir (atazanavir phenotypic fold-change of <1.8, with an atazanavir cutoff of 2.2-fold change). Secondary PI resistance-associated amino acid substitutions also arose in the viruses of one participant each, including V11V/I, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61E/G emerged in the viruses of two participants who failed treatment with atazanavir with ritonavir. Viruses from nine participants in the two studies developed NRTI resistance-associated substitutions: K65K/R (n=1), M184V (n=7), and T215I (n=1). Cross-Resistance Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from atazanavir clinical trials of PI-experienced participants showed that isolates cross-resistant to multiple PIs were cross-resistant to atazanavir. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to atazanavir. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to atazanavir, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to atazanavir. Isolates resistant to atazanavir were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced participants, PI-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other PIs. Baseline Genotype/Phenotype and Virologic Outcome Analyses Genotypic and/or phenotypic analysis of baseline virus may aid in determining atazanavir susceptibility before initiation of atazanavir with ritonavir therapy. An association between virologic response at 48 weeks and the number and type of primary PI resistance-associated substitutions detected in baseline HIV-1 isolates from antiretroviral-experienced participants receiving atazanavir with ritonavir once daily or lopinavir / ritonavir (fixed-dose product) twice daily in Study AI424-045 is shown in Table 24. Overall, both the number and type of baseline PI substitutions affected response rates in treatment- experienced participants. In the atazanavir with ritonavir group, participants had lower response 55 Reference ID: 5490094 rates when 3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were present compared to participants with 1–2 PI substitutions, including one of these substitutions. Table 24: HIV-1 RNA Response by Number and Type of Baseline PI Substitution, Antiretroviral-Experienced Participants in Study AI424-045, As-Treated Analysis Virologic Response = HIV RNA <400 copies/mLb Number and Type of Baseline PI atazanavir with ritonavir lopinavir/ritonavirc Substitutionsa (n=110) (n=113) 3 or more primary PI substitutions includingd: D30N 75% (6/8) 50% (3/6) M36I/V 19% (3/16) 33% (6/18) M46I/L/T 24% (4/17) 23% (5/22) I54V/L/T/M/A 31% (5/16) 31% (5/16) A71V/T/I/G 34% (10/29) 39% (12/31) G73S/A/C/T 14% (1/7) 38% (3/8) V77I 47% (7/15) 44% (7/16) V82A/F/T/S/I 29% (6/21) 27% (7/26) I84V/A 11% (1/9) 33% (2/6) N88D 63% (5/8) 67% (4/6) L90M 10% (2/21) 44% (11/25) Number of baseline primary PI substitutionsa All patients, as-treated 58% (64/110) 59% (67/113) 0–2 PI substitutions 75% (50/67) 75% (50/67) 3–4 PI substitutions 41% (14/34) 43% (12/28) 5 or more PI substitutions 0% (0/9) 28% (5/18) a Primary substitutions include any change at D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90. b Results should be interpreted with caution because the subgroups were small. c Administered as a fixed-dose product. d There were insufficient data (n<3) for PI substitutions V32I, I47V, G48V, I50V, and F53L. The response rates of antiretroviral-experienced participants in Study AI424-045 were analyzed by baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The analyses are based on a select population with 62% of participants receiving an NNRTI-based 56 Reference ID: 5490094 regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for REYATAZ. Table 25: Baseline Phenotype by Outcome, Antiretroviral-Experienced Participants in Study AI424-045, As-Treated Analysis Baseline Phenotypea Virologic Response = HIV-1 RNA <400 copies/mLb atazanavir with ritonavir (n=111) lopinavir/ritonavirc (n=111) 0–2 71% (55/78) 70% (56/80) >2–5 53% (8/15) 44% (4/9) >5–10 13% (1/8) 33% (3/9) >10 10% (1/10) 23% (3/13) a Fold change susceptibility in cell culture relative to the wild-type reference. b Results should be interpreted with caution because the subgroups were small. c Administered as a fixed-dose product. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose. Mutagenesis Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay). Impairment of Fertility At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir boosted with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed. 57 Reference ID: 5490094 14 CLINICAL STUDIES 14.1 Adult Participants without Prior Antiretroviral Therapy Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of either REYATAZ or lopinavir/ritonavir, each in combination with fixed-dose tenofovir DF-emtricitabine in treatment-naive participants with HIV-1 infection. Study AI424-138 (NCT00272779) was a 96­ week, open-label, randomized, multicenter study, comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with the fixed-dose product, tenofovir DF/emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive participants. Participants had a mean age of 36 years (range: 19-72), 49% were Caucasian, 18% Black, 9% Asian, 23% Hispanic/Mestizo/mixed race, and 68% were male. The median baseline plasma CD4+ cell count was 204 cells/mm3 (range: 2 to 810 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.94 log10 copies/mL (range: 2.60 to 5.88 log10 copies/mL). Treatment response and outcomes through Week 96 are presented in Table 26. Table 26: Outcomes of Treatment Through Week 96 in Treatment-Naive Adults (Study AI424-138) REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine (once daily)a (n=441) lopinavir/ritonavirb 400 mg/100 mg (twice daily) with tenofovir DF/emtricitabine (once daily)a (n=437) Outcome 96 Weeks 96 Weeks Responderc,d,e 75% 68% Virologic failuref 17% 19% Rebound 8% 10% Never suppressed through Week 96 9% 9% Death 1% 1% Discontinued due to adverse event 3% 5% Discontinued for other reasonsg 4% 7% a As a fixed-dose product: 300 mg tenofovir DF/200 mg emtricitabine once daily. b As a fixed-dose product: 400 mg lopinavir/100 mg ritonavir (twice daily). c Participants achieved HIV-1 RNA <50 copies/mL at Week 96. Roche Amplicor, v1.5 ultra-sensitive assay. d Pre-specified ITT analysis at Week 48 using as-randomized cohort: atazanavir with ritonavir 78% and lopinavir/ritonavir 76% (difference estimate: 1.7% [95% confidence interval: −3.8%, 7.1%]). e Pre-specified ITT analysis at Week 96 using as-randomized cohort: atazanavir with ritonavir 74% and lopinavir/ritonavir 68% (difference estimate: 6.1% [95% confidence interval: 0.3%, 12.0%]). 58 Reference ID: 5490094 f Includes viral rebound and failure to achieve confirmed HIV-1 RNA <50 copies/mL through Week 96. g Includes lost to follow-up, participant’s withdrawal, noncompliance, protocol violation, and other reasons. Through 96 weeks of therapy, the proportion of responders among participants with high viral loads (ie, baseline HIV-1 RNA ≥100,000 copies/mL) was comparable for the REYATAZ with ritonavir (165 of 223 participants, 74%) and lopinavir/ritonavir (148 of 222 participants, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm3 for the REYATAZ with ritonavir arm and 273 cells/mm3 for the lopinavir/ritonavir arm. Study AI424-034: REYATAZ once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine/zidovudine twice daily. Study AI424-034 (NCT00013897) was a randomized, double-blind, multicenter trial comparing REYATAZ (400 mg once daily) to efavirenz (600 mg once daily), each in combination with the fixed-dose product of lamivudine /zidovudine (150 mg/300 mg) given twice daily, in 810 antiretroviral treatment-naive participants. Participants had a mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian, and 65% were male. The mean baseline CD4+ cell count was 321 cells/mm3 (range: 64 to 1424 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.8 log10 copies/mL (range: 2.2 to 5.9 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 27. Table 27: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-034) REYATAZ efavirenz 400 mg once daily 600 mg once daily and lamivudine/ and lamivudine/ zidovudined zidovudined Outcome (n=405) (n=405) Respondera 67% (32%) 62% (37%) Virologic failureb 20% 21% Rebound 17% 16% Never suppressed through Week 48 3% 5% Death – <1% Discontinued due to adverse event 5% 7% Discontinued for other reasonsc 8% 10% a Participants achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor HIV-1 Monitor Assay, test version 1.0 or 1.5 as geographically appropriate. b Includes viral rebound and failure to achieve confirmed HIV-1 RNA <400 copies/mL through Week 48. c Includes lost to follow-up, participant’s withdrawal, noncompliance, protocol violation, and other reasons. d As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. 59 Reference ID: 5490094 Through 48 weeks of therapy, the proportion of responders among participants with high viral loads (ie, baseline HIV-1 RNA ≥100,000 copies/mL) was comparable for the REYATAZ and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm3 for the REYATAZ arm and 160 cells/mm3 for the efavirenz arm. Study AI424-008: REYATAZ 400 mg once daily compared to REYATAZ 600 mg once daily, and compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine twice daily. Study AI424-008 (NCT identifier not available) was a 48-week, randomized, multicenter trial, blinded to dose of REYATAZ, comparing REYATAZ at two dose levels (400 mg and 600 mg once daily) to nelfinavir (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive participants. Participants had a mean age of 35 years (range: 18 to 69), 55% were Caucasian, and 63% were male. The mean baseline CD4+ cell count was 295 cells/mm3 (range: 4 to 1003 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.7 log10 copies/mL (range: 1.8 to 5.9 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 28. Table 28: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-008) REYATAZ nelfinavir 400 mg once daily with lamivudine and stavudine 1250 mg twice daily with lamivudine and stavudine Outcome (n=181) (n=91) Respondera 67% (33%) 59% (38%) Virologic failureb 24% 27% Rebound 14% 14% Never suppressed through Week 48 10% 13% Death <1% – Discontinued due to adverse event 1% 3% Discontinued for other reasonsc 7% 10% a Participants achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor HIV-1 Monitor Assay, test version 1.0 or 1.5 as geographically appropriate. b Includes viral rebound and failure to achieve confirmed HIV-1 RNA <400 copies/mL through Week 48. c Includes lost to follow-up, participant’s withdrawal, noncompliance, protocol violation, and other reasons. Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm3 for the REYATAZ 400-mg arm and 211 cells/mm3 for the nelfinavir arm. 60 Reference ID: 5490094 14.2 Adult Participants with Prior Antiretroviral Therapy Study AI424-045: REYATAZ once daily with ritonavir once daily compared to REYATAZ once daily and saquinavir (soft gelatin capsules) once daily, and compared to lopinavir/ritonavir twice daily, each in combination with tenofovir DF and one NRTI. Study AI424-045 (NCT00035932): was a randomized, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatin capsules (1200 mg once daily), and to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with tenofovir DF and one NRTI, in 347 (of 358 randomized) participants who experienced virologic failure on highly active antiretroviral therapy regimens containing PIs, NNRTIs, and NRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 85 weeks for NNRTIs, and 283 weeks for NRTIs. The mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male. The mean baseline CD4+ cell count was 338 cells/mm3 (range: 14 to 1543 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/mL (range: 2.6 to 5.88 log10 copies/mL). Treatment outcomes through Week 48 for the REYATAZ with ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. REYATAZ with ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV-1 RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that REYATAZ with ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV-1 RNA lower limit of quantification [see Microbiology, Tables 24 and 25 (12.4)]. 61 Reference ID: 5490094 Table 29: Outcomes of Treatment Through Week 48 in Study AI424-045 (Participants with Prior Antiretroviral Experience) REYATAZ 300 mg with ritonavir 100 mg lopinavir/ritonavir Differencea once daily and (400/100 mg) twice (REYATAZ­ tenofovir DF and daily and tenofovir DF 1 NRTI and 1 NRTI lopinavir/ritonavir)b Outcome (n=119) (n=118) (CI) HIV-1 RNA Change from −1.58 −1.70 +0.12c Baseline (log10 copies/mL)c (−0.17, 0.41) CD4+ Change from Baseline 116 123 −7 (cells/mm3)e (−67, 52) Percent of Participants Respondinge 55% 57% −2.2% HIV-1 RNA <400 copies/mLc (−14.8%, 10.5%) 38% 45% HIV-1 RNA <50 copies/mLc −7.1% (−19.6%, 5.4%) a Time-averaged difference through Week 48 for HIV-1 RNA; Week 48 difference in HIV-1 RNA percentages and CD4+ mean changes, REYATAZ with ritonavir vs lopinavir/ritonavir; CI = 97.5% confidence interval for change in HIV-1 RNA; 95% confidence interval otherwise. b Administered as a fixed-dose product. c Roche Amplicor HIV-1 Monitor Assay, test version 1.5. d Protocol-defined primary efficacy outcome measure. e Based on participants with baseline and Week 48 CD4+ cell count measurements (REYATAZ with ritonavir, n=85; lopinavir/ritonavir, n=93). f Participants achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48. No participants in the REYATAZ with ritonavir treatment arm and three participants in the lopinavir/ritonavir treatment arm experienced a new-onset CDC Category C event during the study. In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for REYATAZ 400 mg with saquinavir (n=115) was −1.55 log10 copies/mL, and the time-averaged difference in change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33. The corresponding mean increase in CD4+ cell count was 72 cells/mm3. Through 48 weeks of treatment, the proportion of participants in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%). In this study, coadministration of REYATAZ and saquinavir did not provide adequate efficacy [see Drug Interactions (7)]. 62 Reference ID: 5490094 Study AI424-045 also compared changes from baseline in lipid values. [See Adverse Reactions (6.1).] Study AI424-043 (NCT00028301): Study AI424-043 was a randomized, open-label, multicenter trial comparing REYATAZ (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with two NRTIs, in 300 participants who experienced virologic failure to only one prior PI-containing regimen. Through 48 weeks, the proportion of participants with plasma HIV-1 RNA <400 (<50) copies/mL was 49% (35%) for participants randomized to REYATAZ (n=144) and 69% (53%) for participants randomized to lopinavir/ritonavir (n=146). The mean change from baseline was −1.59 log10 copies/mL in the REYATAZ treatment arm and −2.02 log10 copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, REYATAZ without ritonavir was inferior to lopinavir/ritonavir in PI- experienced participants with prior virologic failure and is not recommended for such patients. 14.3 Pediatric Participants Pediatric Trials with REYATAZ Capsules Study AI424-040; PACTG 1020A (NCT00006604): Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ capsules was based on data from this open-label, multicenter clinical trial which included participants from 6 years to 21 years of age. In this study, 105 participants (43 antiretroviral-naive and 62 antiretroviral-experienced) received once daily REYATAZ capsule formulation, with or without ritonavir, in combination with two NRTIs. One-hundred five (105) participants (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated. Using an intent-to-treat (ITT) analysis, the overall proportions of antiretroviral-naive and -experienced participants with HIV-1 RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced participants with HIV-1 RNA <50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm3 in antiretroviral-naive participants and 220 cells/mm3 in antiretroviral-experienced participants. Pediatric Trials with REYATAZ Oral Powder Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ oral powder was based on data from two open-label, multicenter clinical trials. • AI424-397 (PRINCE I; NCT01099579): In pediatric participants from 3 months to less than 6 years of age • AI424-451 (PRINCE II; NCT01335698): In pediatric participants from 3 months to less than 11 years of age In these studies, 155 participants (59 antiretroviral-naive and 96 antiretroviral-experienced) received once daily REYATAZ oral powder with ritonavir, in combination with two NRTIs. For inclusion in both trials, treatment-naive participants had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced participants had to have documented 63 Reference ID: 5490094 genotypic and phenotypic sensitivity at screening to REYATAZ and at least 2 NRTIs. Participants exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Participants who received REYATAZ or REYATAZ with ritonavir at any time prior to study enrollment or who had a history of treatment failure on two or more protease inhibitors were excluded from the trials. One hundred thirty-four (134) participants from both studies weighing 5 kg to less than 35 kg treated with REYATAZ oral powder with ritonavir were evaluated. Participants 5 kg to less than 10 kg received either 150 mg or 200 mg REYATAZ and 80 mg ritonavir oral solution; participants 10 kg to less than 15 kg received 200 mg REYATAZ and 80 mg ritonavir oral solution; participants 15 kg to less than 25 kg received 250 mg REYATAZ and 80 mg ritonavir oral solution; and participants 25 kg to less than 35 kg received 300 mg REYATAZ and 100 mg ritonavir. Using a modified ITT analysis, the overall proportions of antiretroviral-naive and antiretroviral­ experienced participants with HIV-1 RNA <400 copies/mL at Week 48 were 79% (41/52) and 62% (51/82), respectively in participants who received REYATAZ oral powder with ritonavir. The overall proportions of antiretroviral-naive and antiretroviral-experienced participants with HIV-1 RNA <50 copies/mL at Week 48 were 54% (28/52) and 50% (41/82), respectively, in participants who received REYATAZ oral powder with ritonavir. The median increase from baseline in absolute CD4 count (percent) at 48 weeks of therapy (last observation carried forward) was 215 cells/mm3 (6%) in antiretroviral-naive participants and 133 cells/mm3 (4%) in antiretroviral-experienced participants who received REYATAZ oral powder with ritonavir. 16 HOW SUPPLIED/STORAGE AND HANDLING REYATAZ Capsules REYATAZ (atazanavir) capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures. Product Strength* Capsule Shell Color (cap/body) Markings on Capsule (ink color) Capsules per Bottle NDC Number cap body 200 mg blue/blue BMS 200 mg (white) 3631 (white) 60 0003-3631-12 300 mg red/blue BMS 300 mg (white) 3622 (white) 30 0003-3622-12 * 200 mg atazanavir equivalent to 227.8 mg atazanavir sulfate. 300 mg atazanavir equivalent to 341.69 mg atazanavir sulfate. Keep capsules in a tightly closed container. Store REYATAZ capsules at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 64 Reference ID: 5490094 REYATAZ Oral Powder REYATAZ oral powder is an orange-vanilla flavored powder, packed in child-resistant packets. Each packet contains 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 g of powder. REYATAZ oral powder is supplied in cartons (NDC 0003-3638-10) of 30 packets each. [See Dosage and Administration (2.5)]. Store REYATAZ oral powder at a temperature of 68°F to 86°F (20°C to 30°C). Store REYATAZ oral powder in the original packet. Do not open until ready to use. After REYATAZ oral powder is mixed with food or liquid, it may be kept at a temperature 68°F to 86°F (20°C to 30°C) for up to 1 hour. Take REYATAZ oral powder within 1 hour after mixing with food or liquid. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). REYATAZ is not a cure for HIV-1 infection. Advise patients to remain under the care of a healthcare provider while using REYATAZ. Cardiac Conduction Abnormalities Inform patients that atazanavir may produce changes in the electrocardiogram (eg, PR prolongation). Tell patients to consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness [see Warnings and Precautions (5.1)]. Severe Skin Reaction Inform patients that there have been reports of severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with REYATAZ use. Advise patients that if signs or symptoms of severe skin reactions or hypersensitivity reactions develop, they must discontinue REYATAZ and seek medical evaluation immediately [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Hyperbilirubinemia Inform patients that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns [see Warnings and Precautions (5.8)]. Patients with Phenylketonuria Advise caregivers of patients with phenylketonuria that REYATAZ oral powder contains phenylalanine [see Warnings and Precautions (5.3)]. Chronic Kidney Disease Inform patients that treatment with REYATAZ may lead to the development of chronic kidney disease, and to maintain adequate hydration while taking REYATAZ [see Warnings and Precautions (5.5)]. 65 Reference ID: 5490094 Nephrolithiasis and Cholelithiasis Inform patients that kidney stones and/or gallstones have been reported with REYATAZ use. Some patients with kidney stones and/or gallstones required hospitalization for additional management, and some had complications. Discontinuation of REYATAZ may be necessary as part of the medical management of these adverse events [see Warnings and Precautions (5.6)]. Drug Interactions REYATAZ may lead to significant interaction with some drugs; therefore, advise patients to report the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort, to their healthcare provider prior to use [see Contraindications (4), Warnings and Precautions (5.7)]. Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV-1, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV-1 treatment is started [see Warnings and Precautions (5.10)]. Fat Redistribution Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.11)]. Dosing Instructions Advise patients to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always be used in combination with other antiretroviral drugs. Advise patients that they should not alter the dose or discontinue therapy without consulting with their healthcare provider. Tell patients if a dose of REYATAZ is missed, they should take the dose as soon as possible and then return to their normal schedule; however, if a dose is skipped the patient should not double the next dose. Pregnancy Inform pregnant patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in pregnant patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry [see Use in Specific Populations (8.1)]. Lactation Instruct patients with HIV-1 that the potential risks of breastfeeding include: (1) HIV-1 transmission to infants without HIV-1, (2) developing viral resistance in infants with HIV-1, and (3) adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)]. 66 Reference ID: 5490094 PATIENT INFORMATION REYATAZ® (RAY-ah-taz) REYATAZ® (RAY-ah-taz) (atazanavir) (atazanavir) capsules oral powder Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with REYATAZ. For more information, see “Do not take REYATAZ if you” and “Before taking REYATAZ”. What is REYATAZ? REYATAZ is a prescription medicine that is used to treat human immunodeficiency virus-1 (HIV-1) infection, in combination with other HIV-1 medicines in adults and children 3 months of age and older and who weigh at least 11 pounds (5 kg). HIV-1 is the virus that causes AIDS (Acquired Immunodeficiency Syndrome). REYATAZ should not be used in children younger than 3 months of age. Do not take REYATAZ if you: • are allergic to atazanavir or any of the ingredients in REYATAZ. See the end of this leaflet for a complete list of ingredients in REYATAZ. • are taking any of the following medicines. Taking REYATAZ with these medicines may affect how REYATAZ works. REYATAZ may cause serious or life-threatening side effects, or death when used with these medicines: o alfuzosin o lurasidone (when REYATAZ is used with o amiodarone (when REYATAZ is used with ritonavir) ritonavir) o lomitapide o apalutamide o lovastatin o carbamazepine o midazolam, when taken by mouth for sedation o cisapride o nevirapine o elbasvir and grazoprevir o phenobarbital o encorafenib o phenytoin o ergot medicines including: o pimozide • dihydroergotamine o quinidine (when REYATAZ is used with ritonavir) • ergonovine o rifampin • ergonovine ergotamine o sildenafil, when used for the treatment of • methylergonovine pulmonary arterial hypertension o glecaprevir and pibrentasvir o simvastatin o indinavir o St. John’s wort o irinotecan o triazolam o ivosidenib Before taking REYATAZ, tell your healthcare provider about all of your medical conditions, including if you: • have heart problems • have liver problems, including hepatitis B or C virus • have phenylketonuria (PKU). The artificial sweetener aspartame in REYATAZ oral powder contains phenylalanine, which can be harmful to people with PKU. • have kidney problems • are receiving dialysis treatment • have diabetes • have hemophilia • are pregnant or plan to become pregnant. o REYATAZ must be taken with ritonavir during pregnancy. o Hormonal forms of birth control, such as injections, vaginal rings or implants, contraceptive patch, and some birth control pills may not work during treatment with REYATAZ. Talk to your healthcare provider about forms of birth control that may be used during treatment with REYATAZ. o Pregnancy Exposure Registry. There is a pregnancy exposure registry for people who take REYATAZ during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. 67 Reference ID: 5490094 o After your baby is born, tell your healthcare provider if your baby’s skin or the white part of their eyes turns yellow. • are breastfeeding or plan to breastfeed. REYATAZ can pass into your breast milk. o Talk to your healthcare provider about the following risks of breastfeeding during treatment with REYATAZ: • The HIV-1 virus may pass to your baby if your baby does not have the HIV-1 virus. • The HIV-1 virus may become harder to treat if your baby has the HIV-1 virus. • Your baby may get side effects from REYATAZ. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with REYATAZ. Keep a list of your medicines to show your healthcare provider and pharmacist. • You can ask your healthcare provider or pharmacist for a list of medicines that interact with REYATAZ. • Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take REYATAZ with other medicines. How should I take REYATAZ? • Take REYATAZ exactly as your healthcare provider tells you to. • Do not change your dose or stop taking REYATAZ unless your healthcare provider tells you to. • Stay under the care of your healthcare provider during treatment with REYATAZ. • REYATAZ must be used with other HIV-1 medicines. • Take REYATAZ 1 time each day. • REYATAZ comes as capsules and oral powder. • Take REYATAZ capsules and oral powder with food. • Swallow the capsules whole. Do not open the capsules. • REYATAZ oral powder must be mixed with food or liquid. Your child’s healthcare provider will prescribe the right dose of REYATAZ based on your child’s weight. See the detailed “Instructions for Use” that comes with REYATAZ oral powder for information about the correct way to mix and give a dose of REYATAZ oral powder to your child. • REYATAZ oral powder must be taken with ritonavir. • If you miss a dose of REYATAZ, take it as soon as you remember. Then take the next dose at your regular time. Do not take 2 doses at the same time. • If you take too much REYATAZ, call your healthcare provider or go to the nearest hospital emergency room right away. When your supply of REYATAZ starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of REYATAZ. The amount of HIV-1 in your blood may increase if the medicine is stopped for even a short time. The virus may become resistant to REYATAZ and harder to treat. What are the possible side effects of REYATAZ? REYATAZ can cause serious side effects, including: • A change in the way your heart beats (heart rhythm change). Tell your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of a heart problem. • Skin rash. Skin rash is common with REYATAZ but can sometimes be severe. Severe rash may develop with other symptoms which could be serious. If you develop a severe rash or a rash with any of the following symptoms, stop taking REYATAZ and call your healthcare provider or go to the nearest hospital emergency room right away: o general feeling of discomfort or “flu-like” symptoms o blisters o fever o mouth sores o muscle or joint aches o swelling of your face o red or inflamed eyes, like “pink eye” (conjunctivitis) o painful, warm, or red lump under your skin • Liver problems. If you have liver problems, including hepatitis B or C virus, your liver problems may get worse when you take REYATAZ. Your healthcare provider will do blood tests to check your liver before you start REYATAZ and during treatment. Tell your healthcare provider right away if you get any of the following symptoms: o dark “tea-colored” urine o nausea o your skin or the white part of your eyes turns yellow o itching o light colored stools o stomach-area pain 68 Reference ID: 5490094 • Chronic kidney disease. REYATAZ may affect how well your kidneys work. Your healthcare provider will do blood and urine tests to check your kidneys before you start REYATAZ and during treatment. Drink plenty of fluids during treatment with REYATAZ. • Kidney stones have happened in some people who take REYATAZ, and sometimes may lead to hospitalization. Tell your healthcare provider right away if you get symptoms of kidney stones which may include pain in your low back or low stomach area, blood in your urine, or pain when you urinate. • Gallbladder stones have happened in some people who take REYATAZ, and sometimes may lead to hospitalization. Tell your healthcare provider right away if you get symptoms of a gallbladder problem which may include: o pain in the right or middle upper stomach area o nausea and vomiting o fever o your skin or the white part of your eyes turns yellow • Yellowing of your skin or the white part of your eyes is common with REYATAZ but may be a symptom of a serious problem. These symptoms may be due to increases in bilirubin levels in your blood (bilirubin is made by the liver). Tell your healthcare provider right away if your skin or the white part of your eyes turns yellow. • New or worsening diabetes and high blood sugar (hyperglycemia) have happened in some people who take protease inhibitor medicines like REYATAZ. Some people have had to start taking medicine to treat diabetes or have changes to their dose of their diabetes medicine. Tell your healthcare provider if you notice an increase in thirst or if you start urinating more often while taking REYATAZ. • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider if you start having new symptoms after starting REYATAZ. • Changes in body fat can happen in people taking HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known. • Increased bleeding problems in people with hemophilia have happened when taking protease inhibitors like REYATAZ. The most common side effects of REYATAZ include: • nausea • dizziness • headache • muscle pain • stomach-area pain • diarrhea • vomiting • depression • trouble sleeping • fever • numbness, tingling, or burning of hands or feet Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of REYATAZ. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store REYATAZ? REYATAZ capsules: • Store REYATAZ capsules at room temperature, between 68°F to 77°F (20°C to 25°C). • Keep capsules in a tightly closed container. • The REYATAZ bottle comes with a child-resistant closure. REYATAZ oral powder: • Store REYATAZ oral powder at a temperature of 68°F to 86°F (20°C to 30°C). • Store REYATAZ oral powder in the original packet. Do not open until ready to use. • After REYATAZ oral powder is mixed with food or liquid it may be kept at a temperature of 68°F to 86°F (20°C to 30°C) for up to 1 hour. Take REYATAZ oral powder within 1 hour after mixing with food or liquid. Keep REYATAZ and all medicines out of the reach of children. General information about the safe and effective use of REYATAZ 69 Reference ID: 5490094 Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use REYATAZ for a condition for which it was not prescribed. Do not give REYATAZ to other people, even if they have the o same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about REYATAZ that is written for health professionals. For more information, go to www.reyataz.com or call 1-800-321-1335. What are the ingredients in REYATAZ? Active ingredient: atazanavir sulfate Inactive ingredients: REYATAZ capsules: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain gelatin, FD&C Blue No. 2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue No. 2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol. REYATAZ oral powder: aspartame, sucrose, and orange-vanilla flavor. Distributed by: Bristol-Myers Squibb Company, Princeton, NJ 08543 USA. REYATAZ® is a registered trademark of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: December 2024 [print code] 70 Reference ID: 5490094 Instructions for Use REYATAZ (RAY-ah-taz) (atazanavir) oral powder Read this Instructions for Use before you prepare your child’s first dose of REYATAZ oral powder, each time you get a refill, and as needed. There may be new information. This information does not take the place of talking to your child’s healthcare provider about their medical condition or treatment. Ask your child’s healthcare provider or pharmacist if you have questions about how to mix or give a dose of REYATAZ oral powder. Important information: • For more information about REYATAZ oral powder, see the Patient Information leaflet. • REYATAZ oral powder must be mixed with food or liquid. If REYATAZ oral powder is mixed with water, your child must eat food right after taking REYATAZ oral powder. • REYATAZ oral powder must be taken with ritonavir. • Talk with your child’s healthcare provider to help decide the best schedule for giving your child REYATAZ oral powder. Instructions for mixing REYATAZ oral powder: REYATAZ oral powder should be mixed with food such as applesauce or yogurt, instead of a liquid (milk, infant formula, or water) in young children and infants who can take food. • Infants less than 6 months old and who cannot eat solid food or drink from a cup should be given REYATAZ oral powder mixed with infant formula using an oral dosing syringe. • REYATAZ oral powder that is mixed in infant formula or liquid should not be given using a baby bottle. When preparing REYATAZ oral powder with either food or liquid, choose a clean, flat work surface. Place a clean paper towel on the work surface. Place the supplies you will need on the paper towel. Wash and dry your hands before and after preparing REYATAZ oral powder. Preparing a dose of REYATAZ oral powder mixed with food: Before you prepare a dose of REYATAZ oral powder mixed with food, gather the following supplies: • paper towel • tablespoon • small clean container (such as a small cup or bowl) • a food such as applesauce or yogurt • the correct number of packets of REYATAZ oral powder needed for the prescribed dose • a clean pair of scissors 71 Reference ID: 5490094 ~~ ~· ({: : - Step 1. Place at least 1 tablespoon of a food such as applesauce or yogurt in the small container (see Figure A). Figure A Step 2. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure B). Figure B Step 3. Using a clean pair of scissors, cut open the packet on the dotted line (see Figure C). Figure C Step 4. Empty the contents of the packet into the small container onto the food (see Figure D). Figure D 72 Reference ID: 5490094 Repeat Steps 2 through 4 for each packet of REYATAZ oral powder needed for the total prescribed dose. Step 5. Use a tablespoon to gently mix the powder and the food together (see Figure E). Figure E Steps 6 through 8 must be completed within 1 hour of mixing the medicine. Step 6. Use the tablespoon or a small spoon to feed the REYATAZ oral powder and food mixture to your child. Look in your child’s mouth to make sure that all of the mixture is swallowed. Step 7. Add 1 tablespoon more of food to the empty container and gently stir to mix with any contents that may still be in the container. Step 8. Use the tablespoon or a small spoon to feed your child the mixture, making sure your child has swallowed all of the mixture. Step 9. Give your child ritonavir as prescribed right after taking REYATAZ oral powder. Step 10. Wash the container and tablespoon. Allow the container and spoon to dry. Throw away the paper towel and clean the work surface. Preparing a dose of REYATAZ oral powder mixed with liquid in a small drinking cup: Before you prepare a dose of REYATAZ oral powder mixed with liquid in a small drinking cup, gather the following supplies: 73 Reference ID: 5490094 30 mL MEDICINE CUP -30ml -25ml -2omL -15mL • paper towel • spoon • 30 milliliter (mL) medicine cup (ask your pharmacist for this). See Figure F. • small drinking cup • liquid such as milk or water • the correct number of packets of REYATAZ oral powder needed for the prescribed dose • a clean pair of scissors Figure F Step 1. Using the 30 mL medicine cup, pour at least 30 mL of liquid into the small drinking cup (see Figure G). Figure G Step 2. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure H). Figure H Step 3. Using a clean pair of scissors, cut open the packet on the dotted line (see Figure I). Figure I 74 Reference ID: 5490094 Step 4. Empty the contents of the packet into the small drinking cup (see Figure J). Figure J Repeat Steps 2 through 4 for each packet of REYATAZ oral powder needed for the total prescribed dose. Step 5. Hold the small drinking cup with one hand. With your other hand, use the spoon to gently mix the powder and the liquid (see Figure K). Figure K Steps 6 and 7 must be completed within 1 hour of mixing the medicine. Step 6. Have your child drink all of the mixture in the small drinking cup. Step 7. To make sure there is no mixture left in the small drinking cup add 15 mL more liquid to the small drinking cup: • Stir with the spoon. • Repeat Step 6 above. If REYATAZ oral powder is mixed with water, your child must eat food right after taking REYATAZ oral powder. Step 8. Give your child ritonavir as prescribed right after taking REYATAZ oral powder. Step 9. Wash the small drinking cup, medicine cup, and spoon. Allow the small drinking cup, medicine cup, and spoon to dry. Throw away the paper towel and clean the work surface. 75 Reference ID: 5490094 ORAL DOSING SYRINGE _.,­ - 2'- -,o- -,~ ...... -1om1.. Preparing a dose of REYATAZ oral powder mixed with liquid infant formula using an oral dosing syringe and a small medicine cup: Before you prepare a dose of REYATAZ oral powder mixed with infant formula using an oral dosing syringe, gather the following supplies: • paper towel • small spoon • 30 milliliter (mL) medicine cup (ask your pharmacist for this). See Figure L. • 10 mL oral dosing syringe (ask your pharmacist for this). See Figure L. • infant formula • the correct number of packets of REYATAZ oral powder needed for the prescribed dose • a clean pair of scissors Figure L Step 1. Prepare the infant formula according to the directions on the infant formula package. Step 2. Pour 10 mL of infant formula into the medicine cup (see Figure M). Figure M Step 3. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure N). Figure N 76 Reference ID: 5490094 Step 4. Using a clean pair of scissors, cut open the packet on the dotted line (see Figure O). Figure O Step 5. Empty the contents of the packet into the medicine cup (see Figure P). Figure P Repeat Steps 3 through 5 for each packet of REYATAZ oral powder needed for the total prescribed dose. Step 6. Hold the medicine cup with one hand. With your other hand, use the small spoon to gently mix the powder and the infant formula (see Figure Q). Figure Q Steps 7 through 9 must be completed within 1 hour of mixing the medicine. 77 Reference ID: 5490094 Step 7. Draw up the powder and infant formula mixture into the oral dosing syringe as follows: • Check that the plunger is completely pushed into barrel of the syringe (see Figure R). Figure R • Place the tip of the syringe into the powder and infant formula mixture in the medicine cup (see Figure S). Figure S • Slowly pull back on the plunger and draw up 10 mL of the mixture (see Figure T). Figure T Step 8. Place the tip of the oral dosing syringe in your baby’s mouth along the inner cheek on either the right or left side (see Figure U). Slowly push on the plunger to give your baby all of the REYATAZ oral powder and infant formula mixture. • Draw up any remaining mixture with the oral dosing syringe and repeat until all of the mixture has been given to the baby. Figure U 78 Reference ID: 5490094 Step 9. To make sure there is no mixture left in the medicine cup or syringe: • Repeat Step 1 above to add 10 mL more infant formula to the medicine cup. • Stir with a small spoon. • Then repeat Steps 7 through 8 above. To make sure that your baby gets all of the medicine, do not give REYATAZ oral powder in a baby bottle. Step 10. Give your baby ritonavir as prescribed right after taking REYATAZ oral powder. Step 11. Remove the plunger from the oral dosing syringe. Wash the medicine cup, spoon, and oral dosing syringe. Allow the medicine cup, spoon, and oral dosing syringe to dry. Throw away the paper towel and clean the work surface. How should I store REYATAZ oral powder? • Store REYATAZ oral powder at a temperature of 68°F to 86°F (20°C to 30°C). • Store REYATAZ oral powder in the original packet. Do not open until ready to use. • After REYATAZ oral powder is mixed with food or liquid, it may be kept at a temperature of 68°F to 86°F (20°C to 30°C) for up to 1 hour. Take REYATAZ oral powder within 1 hour after mixing with food or liquid. Keep REYATAZ oral powder and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA [print code] Revised: September 2020 79 Reference ID: 5490094
custom-source
2025-02-12T15:47:37.524439
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION safely and effectively. See full prescribing information for HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION. HEPARIN SODIUM IN SODIUM CHLORIDE INJECTION, for intravenous use Initial U.S. Approval: 1939 ---------------------------RECENT MAJOR CHANGES --------------------------­ Warnings and Precautions, Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia with Thrombosis (5.2) 11/2024 Warnings and Precautions, Heparin Resistance (5.4) 11/2024 Warnings and Precautions, Hypersensitivity Reactions (5.5) 11/2024 Warnings and Precautions, Hyperkalemia (5.7) 7/2024 Warnings and Precautions, Elevations of Serum Aminotransferases (5.8) 11/2024 --------------------------- INDICATIONS AND USAGE --------------------------­ Heparin Sodium in Sodium Chloride Injection at a concentration of 2 units/mL is indicated as an anticoagulant to maintain catheter patency. (1) ----------------------- DOSAGE AND ADMINISTRATION ---------------------­ Infuse through intravenous catheter at a rate of 6 units per hour. (2.2) --------------------- DOSAGE FORMS AND STRENGTHS --------------------­  Injection: 1,000 USP units in Sodium Chloride per 500 mL single-dose infusion bag (2 units per mL) (3)  Injection: 2,000 USP units in Sodium Chloride per 1,000 mL single-dose infusion bag (2 units per mL) (3) ------------------------------ CONTRAINDICATIONS ----------------------------­ Heparin Sodium in Sodium Chloride Injection is contraindicated in patients with the following conditions: (4)  Uncontrollable active bleeding state, except when this is due to disseminated intravascular coagulation (5.1)  History of heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITT) (5.2)  Severe thrombocytopenia (5.2, 5.3)  Known hypersensitivity to heparin or pork products (5.5, 6.1) ----------------------- WARNINGS AND PRECAUTIONS ----------------------­  Hemorrhage: Fatal hemorrhages have occurred. Monitor for signs of bleeding and manage promptly. (5.1)  HIT and HITT: Monitor for signs and symptoms and discontinue if indicative of HIT or HITT. (5.2)  Thrombocytopenia: Monitor platelet count during therapy; discontinue heparin if HIT or HITT is suspected. (5.3)  Heparin Resistance: Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients. (5.4)  Hypersensitivity Reactions: Use in patients with prior reactions only in life-threatening situations. (5.5)  Increased Risk of Bleeding in Older Patients, Especially Women: A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age. (5.6)  Hyperkalemia: Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients. (5.7)  Elevations of Serum Aminotransferases: Interpret elevation of these enzymes with caution. (5.8)  Laboratory Tests: Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration. (5.9) ------------------------------ ADVERSE REACTIONS -----------------------------­ Most common adverse reactions are: hemorrhage, thrombocytopenia, HIT and HITT, hypersensitivity reactions, heparin resistance, hyperkalemia, and elevations of aminotransferase levels. (6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS -----------------------------­ Drugs that interfere with platelet aggregation or drugs that counteract coagulation may induce bleeding. (7) -------------------------USE IN SPECIFIC POPULATIONS---------------------­ Geriatric Use: A higher incidence of bleeding has been reported in patients over 60 years of age, especially women. (5.6, 8.5) See 17 for PATIENT COUNSELING INFORMATION. Revised: 11/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration 2.2 Recommended Dosage for Maintenance of Catheter Patency 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage 5.2 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia with Thrombosis 5.3 Thrombocytopenia 5.4 Heparin Resistance 5.5 Hypersensitivity Reactions 5.6 Increased Risk of Bleeding in Older Patients, Especially Women 5.7 Hyperkalemia 5.8 Elevations of Serum Aminotransferases 5.9 Laboratory Tests 6 ADVERSE REACTIONS 6.1 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Oral Anticoagulants 7.2 Platelet Inhibitors 7.3 Other Medications that May Interfere with Heparin 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5493395 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Heparin Sodium in Sodium Chloride Injection at a concentration of 2 units/mL is indicated as an anticoagulant to maintain catheter patency. 2 DOSAGE AND ADMINISTRATION 2.1 Preparation for Administration Do not administer unless solution is clear and seal is intact. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Warning: Do not use plastic containers in series connection. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Do not use Heparin Sodium in Sodium Chloride Injection as a “catheter lock flush” product. Do not admix with other drugs. Discard unused portion. To Open Tear outer wrap and remove solution container. Preparation for Administration (Use aseptic technique) 1. Close flow control clamp of administration set. 2. Remove cover from outlet port at bottom of container. 3. Insert piercing pin of administration set into port with a twisting motion until the set is firmly seated. NOTE: When using a vented administration set, replace bacterial retentive air filter with piercing pin cover. Insert piercing pin with twisting motion until shoulder of air filter housing rests against the outlet port flange. 4. Suspend container from hanger. 5. Squeeze and release drip chamber to establish proper fluid level in chamber. 6. Attach venipuncture device to set. 7. Open clamp to expel air from set and venipuncture device. Close clamp. 8. Perform venipuncture. 9. Regulate rate of administration with flow control clamp. 2.2 Recommended Dosage for Maintenance of Catheter Patency The recommended starting dose is 6 units per hour by intravenous infusion through an intravenous catheter to maintain catheter patency. 3 DOSAGE FORMS AND STRENGTHS  Injection: 1,000 USP units per 500 mL (2 units per mL) clear solution in a single-dose infusion bag  Injection: 2,000 USP units per 1,000 mL (2 units per mL) clear solution in a single-dose infusion bag Page 2 of 12 Reference ID: 5493395 4 CONTRAINDICATIONS The use of Heparin Sodium in Sodium Chloride Injection is contraindicated in patients with the following conditions:  Uncontrollable active bleeding state, except when this is due to disseminated intravascular coagulation [see Warnings and Precautions (5.1)]  History of heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITT) [see Warnings and Precautions (5.2)]  Severe thrombocytopenia [see Warnings and Precautions (5.2, 5.3)]  Known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Warnings and Precautions (5.5), Adverse Reactions (6.1)] 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage Avoid using heparin in the presence of major bleeding, except when the benefits of heparin therapy outweigh the potential risks. Hemorrhage can occur at virtually any site in patients receiving heparin. Fatal hemorrhages have occurred. An unexplained fall in hematocrit or fall in blood pressure, or any other unexplained symptom should lead to serious consideration of a hemorrhagic event. Use heparin sodium with caution in disease states in which there is increased risk of hemorrhage, including:  Cardiovascular — Subacute bacterial endocarditis. Severe hypertension.  Surgical — During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery, especially involving the brain, spinal cord or eye.  Hematologic — Conditions associated with increased bleeding tendencies, such as hemophilia, thrombocytopenia and some vascular purpuras.  Gastrointestinal — Ulcerative lesions and continuous tube drainage of the stomach or small intestine.  Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy – The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, reduce the heparin dose during concomitant treatment with antithrombin III (human).  Other — Menstruation, liver disease with impaired hemostasis. 5.2 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia with Thrombosis Heparin-induced thrombocytopenia (HIT) is a serious immune-mediated reaction. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor-4-heparin complex that induce in vivo platelet aggregation. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia with thrombosis (HITT). Thrombotic events may also be the initial presentation for HITT. These serious thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, Page 3 of 12 Reference ID: 5493395 myocardial infarction, mesenteric thrombosis, thrombus formation on a prosthetic cardiac valve, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to amputation, and possibly death. Once HIT or HITT is diagnosed or strongly suspected, discontinue all heparin sources (including heparin flushes) and use an alternative anticoagulant. Immune-mediated HIT is diagnosed based on clinical findings supplemented by laboratory tests confirming the presence of antibodies to heparin, or platelet activation induced by heparin. Obtain platelet counts at baseline and periodically during heparin administration. A drop in platelet count greater than 50% from baseline is considered indicative of HIT. Platelet counts begin to fall 5 to 10 days after exposure to heparin in heparin–naive individuals and reach a threshold by days 7 to 14. In contrast, “rapid onset” HIT can occur very quickly (within 24 hours following heparin initiation), especially in patients with a recent exposure to heparin (i.e., previous 3 months). Thrombosis development shortly after documenting thrombocytopenia is a characteristic finding in almost half of all patients with HIT. If the platelet count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin sodium should be evaluated for HIT or HITT. 5.3 Thrombocytopenia Thrombocytopenia in patients receiving heparin has been reported at frequencies up to 30%. It can occur 2 to 20 days (average 5 to 9) following the onset of heparin therapy. Obtain platelet counts before and periodically during heparin therapy. If the count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant [see Warnings and Precautions (5.2)]. 5.4 Heparin Resistance Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction, cancer, in postsurgical patients, and patients with antithrombin deficiency. Consider measurement of antithrombin levels if heparin resistance is suspected. Monitor coagulation tests frequently in such patients. It may be necessary to adjust the dose of heparin based on coagulation test monitoring, such as anti-Factor Xa levels and/or partial thromboplastin time. 5.5 Hypersensitivity Reactions Hypersensitivity reactions with chills, fever, and urticaria as the most usual manifestations and also asthma, rhinitis, lacrimation, and anaphylactoid reactions have been reported. Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations. Because Heparin Sodium in Sodium Chloride Injection is derived from animal tissue, it should be used with caution in patients with a history of allergy to pork products. 5.6 Increased Risk of Bleeding in Older Patients, Especially Women A higher incidence of bleeding has been reported in patients, particularly women, over 60 years of age [see Use in Specific Populations (8.5)]. Page 4 of 12 Reference ID: 5493395 5.7 Hyperkalemia Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible upon discontinuation of heparin. Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients treated for more than 5 days or earlier as deemed fit by the clinician. 5.8 Elevations of Serum Aminotransferases Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. Elevation of these enzymes in patients receiving heparin should be interpreted with caution. These elevations typically resolve upon heparin discontinuation. 5.9 Laboratory Tests Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:  Hemorrhage [see Warnings and Precautions (5.1)]  Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia with Thrombosis [see Warnings and Precautions (5.2)]  Thrombocytopenia [see Warnings and Precautions (5.3)]  Heparin Resistance [see Warnings and Precautions (5.4)]  Hypersensitivity Reactions [see Warnings and Precautions (5.5)]  Increased Risk of Bleeding in Older Patients, Especially Women [see Warnings and Precautions (5.6)]  Hyperkalemia [see Warnings and Precautions (5.7)]  Elevations of Serum Aminotransferases [see Warnings and Precautions (5.8)] 6.1 Postmarketing Experience The following adverse reactions have been identified during postapproval use of heparin sodium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hemorrhage – Hemorrhage is the chief complication that may result from heparin therapy [see Warnings and Precautions (5.1)]. An overly prolonged clotting time or minor bleeding during therapy can usually be controlled by withdrawing the drug [see Overdosage (10)]. Gastrointestinal or urinary tract bleeding during anticoagulant therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect: Page 5 of 12 Reference ID: 5493395 - Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy, including fatal cases. - Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive age receiving short- or long-term anticoagulant therapy. - Retroperitoneal hemorrhage. Vascular disorders – Contusion, vasospastic reactions (including episodes of painful, ischemic, and cyanosed limbs). HIT and HITT, including delayed onset [see Warnings and Precautions (5.2)] Histamine-like reactions – Such reactions have been observed at the site of injections. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin, occasionally requiring skin grafting. Hypersensitivity – Generalized hypersensitivity reactions have been reported with chills, fever, and urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning, especially on the plantar site of the feet, may occur [see Warnings and Precautions (5.5)]. Musculoskeletal, connective tissue and bone disorders – Osteoporosis with long-term administration of heparin. Metabolism and nutrition disorders – Hyperkalemia. General disorders and administration site conditions – Erythema, mild pain, ulceration. Elevations of serum aminotransferases – Significant elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received heparin. Others – Cutaneous necrosis after systemic administration, delayed transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been reported. 7 DRUG INTERACTIONS 7.1 Oral Anticoagulants Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained. 7.2 Platelet Inhibitors Drugs such as NSAIDS (including acetylsalicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIv/IIa antagonists (including abciximab, eptifobatide, and tirofiban), and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium. To reduce the risk of bleeding, a reduction in the dose of the antiplatelet agent or heparin is recommended. 7.3 Other Medications that May Interfere with Heparin Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium. Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of nitroglycerin. Page 6 of 12 Reference ID: 5493395 Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin. Antithrombin III (human) – The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, a reduced dosage of heparin is recommended during treatment with antithrombin III (human). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on Heparin Sodium in Sodium Chloride Injection use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans (see Data). Consider the benefits and risks of Heparin Sodium in Sodium Chloride Injection for the mother and possible risks to the fetus when prescribing Heparin Sodium in Sodium Chloride Injection. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data The maternal and fetal outcomes associated with uses of heparin via various dosing methods and administration routes during pregnancy have been investigated in numerous studies. These studies generally reported normal deliveries with no maternal or fetal bleeding and no other complications. Animal Data In a published study conducted in rats and rabbits, pregnant animals received heparin intravenously during organogenesis at a dose of 10,000 USP units/kg/day, approximately >50 times the human daily dose. The number of early resorptions increased in both species. There was no evidence of teratogenic effects. 8.2 Lactation Risk Summary There is no information regarding the presence of heparin in human milk, the effects on the breastfed child, or the effects on milk production. Due to its large molecular weight, heparin is not likely to be excreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Heparin Sodium in Sodium Chloride Injection and any potential adverse effects on the breastfed child from Heparin Sodium in Sodium Chloride Injection or from the underlying maternal condition [see Use in Specific Populations (8.4)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use A higher incidence of bleeding has been reported in patients over 60 years of age, especially women [see Page 7 of 12 Reference ID: 5493395 Warnings and Precautions (5.6)]. 10 OVERDOSAGE An overdose requires immediate medical attention and treatment. Symptoms Bleeding is the chief sign of heparin overdosage. Easy bruising, petechial formations, nosebleeds, blood in urine or tarry stools may be the first signs or symptoms of a heparin overdose. In the event of symptomatic heparin overdose, consider stopping heparin infusion. Treatment Neutralization of heparin effect: When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very slowly, in any 10 minute period. Each mg of protamine sulfate neutralizes approximately 100 USP Heparin units. The amount of protamine required decreases over time as heparin is metabolized. Although the metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to have a half-life of about 30 minutes after intravenous injection. Ideally, the dose required to neutralize the action of heparin should be guided by blood coagulation tests or calculated from a protamine neutralization test. Because fatal reactions often resembling anaphylaxis have been reported, protamine sulfate should be given only when resuscitation techniques and treatment of anaphylactoid shock are readily available. For additional information, consult the prescribing information for Protamine Sulfate Injection, USP. Blood or plasma transfusions may be necessary; these dilute but do not neutralize heparin. 11 DESCRIPTION Intravenous solutions with heparin sodium (derived from porcine intestinal mucosa) are sterile, nonpyrogenic fluids for intravenous administration. Each 100 mL contains heparin sodium 200 USP units; sodium chloride, 0.9 g; citric acid, monohydrate, 40 mg and dibasic sodium phosphate, heptahydrate, 434 mg added as buffers. Each liter contains the following electrolytes: Sodium 186.4 mEq; phosphate (as HPO4=) 32.4 mEq, citrate 5.7 mEq and chloride 154 mEq. Osmolar concentration, 378 mOsmol/liter (calc.); pH 7.0 (5.0 – 7.5). Heparin Sodium, USP is a heterogeneous group of straight-chain anionic mucopolysaccharides, called glycosaminoglycans having anticoagulant properties. Although others may be present, the main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2-sulfamino-α-D-glucose-6-sulfate, (3) β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose, and (5) α-L-iduronic acid. These sugars are present in decreasing amounts, usually in the order (2) > (1) > (4) > (3) > (5), and are joined by glycosidic linkages, forming polymers of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are partially replaced by sodium ions. The potency is determined by a biological assay using a USP reference standard based on units of heparin activity per milligram. Page 8 of 12 Reference ID: 5493395 0 coo- OH HO OSO3- (1) CH20SO3- 0 OH coo- NHSO3- (2) (3) CH2COOH I HOCCOOH I CH2COOH CH20H 0 HO OH OH 0 NHAc 0 OH OH coo- OH HO OH OH (4) (5) Structure of Heparin Sodium (representative subunits): Sodium Chloride, USP is chemically designated NaCl, a white crystalline compound freely soluble in water. Dibasic Sodium Phosphate, USP (heptahydrate), is chemically designated (Na2HPO4 • 7H2O), colorless or white granular salt freely soluble in water. Citric Acid, USP, hydrous (monohydrate) is chemically designated C6H8O7 • H2O, colorless, translucent crystals or white crystalline powder very soluble in water. It has the following structural formula: Water for Injection, USP is chemically designated H2O. The flexible plastic container is fabricated from either polyvinylchloride or polyolefin plastic. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions inside the plastic container also can leach out certain of its chemical components in very small amounts before the expiration period is attained. However, the safety of the plastic has been confirmed by tests in animals according to USP biological standards for plastic containers. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Heparin interacts with the naturally occurring plasma protein, Antithrombin III, to induce a conformational change, which markedly enhances the serine protease activity of Antithrombin II, thereby inhibiting the activated coagulation factors involved in the closing sequence, particularly Xa and IIa. Small amounts of heparin inhibit Factor Xa, and larger amounts inhibit thrombin (Factor IIa). Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. Page 9 of 12 Reference ID: 5493395 12.2 Pharmacodynamics Various times (activated clotting time, activated partial thromboplastin time, prothrombin time, whole blood clotting time) are prolonged by full therapeutic doses of heparin; in most cases, they are not measurably affected by low doses of heparin. Bleeding time is usually unaffected by heparin. 12.3 Pharmacokinetics Absorption Heparin is not absorbed through the gastrointestinal tract and therefore administered via parenteral route. Peak plasma concentration and the onset of action are achieved immediately after intravenous administration. Distribution Heparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases and lipoproteins. The volume of distribution is 0.07 L/kg. Elimination Metabolism Heparin does not undergo enzymatic degradation. Excretion Heparin is mainly cleared from the circulation by liver and reticuloendothelial cells mediated uptake into extravascular space. Heparin undergoes biphasic clearance, a) rapid saturable clearance (zero-order process due to binding to proteins, endothelial cells and macrophages) and b) slower first order elimination. Low doses of heparin are cleared mostly by a saturable, rapid, zero-order process. Slower first order elimination usually occurs with very high doses of heparin and is dependent on renal function. The plasma half-life is dose-dependent and it ranges from 0.5 to 2 h. Specific Populations Geriatric Patients Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age [see Use in Specific Populations (8.5)]. Patients with Renal and Hepatic Impairment The rate of clearance of unfractionated heparin may be decreased in patients with renal or hepatic impairment. Patients with renal or hepatic impairment, following similar doses of heparin may have higher plasma levels of heparin compared with patient with normal renal and hepatic function [see Warnings and Precautions (5.1)]. Page 10 of 12 Reference ID: 5493395 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate carcinogenic potential of heparin. Also, no reproduction studies in animals have been performed concerning mutagenesis or impairment of fertility. 16 HOW SUPPLIED/STORAGE AND HANDLING Heparin Sodium in Sodium Chloride Injection is a clear solution and is available in single-dose containers as follows: Unit of Sale Concentration NDC 0409-7620-03 Case of 18 Single-dose flexible plastic containers 1,000 USP Units/500 mL (2 USP Units/mL) NDC 0409-1005-20 Case of 20 Single-dose flexible plastic containers 1,000 USP Units/500 mL (2 USP Units/mL) NDC 0409-7620-59 Case of 12 Single-dose flexible plastic containers 2,000 USP Units/1,000 mL (2 USP Units/mL) NDC 0409-2222-12 Case of 12 Single-dose flexible plastic containers 2,000 USP Units/1,000 mL (2 USP Units/mL) Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] Protect from freezing. 17 PATIENT COUNSELING INFORMATION Hemorrhage Inform patients that it may take them longer than usual to stop bleeding, that they may bruise and/or bleed more easily when they are treated with heparin, and that they should report any unusual bleeding or bruising to their physician. Hemorrhage can occur at virtually any site in patients receiving heparin. Fatal hemorrhages have occurred [see Warnings and Precautions (5.1)]. Prior to Surgery Advise patients to inform physicians and dentists that they are receiving heparin before any surgery is scheduled [see Warnings and Precautions (5.1)]. Heparin-InducedThrombocytopenia Inform patients of the risk of heparin-induced thrombocytopenia (HIT). HIT may progress to the development of venous and arterial thromboses, a condition known as heparin-induced thrombocytopenia and thrombosis (HITT). HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy [see Warnings and Precautions (5.2)]. Hypersensitivity Inform patients that generalized hypersensitivity reactions have been reported. Necrosis of the skin has been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions (5.5), Adverse Reactions (6.1)]. Other Medications Because of the risk of hemorrhage, advise patients to inform their physicians and dentists of all Page 11 of 12 Reference ID: 5493395 ~ Hosp1ra medications they are taking, including non-prescription medications, and before starting any new medication [see Drug Interactions (7)]. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. For medical information about Heparin Sodium in Sodium Chloride, please visit www.pfizermedinfo.com or call 1-800-438-1985. Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-0807-7.0 Page 12 of 12 Reference ID: 5493395
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2025-02-12T15:47:37.770104
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80,568
Recommended Dosage: see Prescribing Information. Each tablet contains 0.25 mg of brexpiprazole. Store REXULTI® tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA © 2024, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Active ingredient made in Japan. 0.25 mg NDC 59148-035-13 30 Tablets DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT Rx only Keep out of the reach of children 0.25 mg NDC 59148-035-13 30 Tablets 0.25 mg 0.25 mg 516652AE DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT Rx only Marketed by Lundbeck Deerfield, IL 60015 USA GTIN: 00359148000000 SN: 100000000001 EXP: YYYY/MMM LOT: XXXXXXXX F (b) (4) Recommended Dosage: see Prescribing Information. Each tablet contains 0.5 mg of brexpiprazole. Store REXULTI® tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA © 2024, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Active ingredient made in Japan. 0.5 mg NDC 59148-036-13 30 Tablets DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT Rx only Keep out of the reach of children NDC 59148-036-13 30 Tablets 0.5 mg 516658AE 0.5 mg 0.5 mg DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT Rx only Marketed by Lundbeck Deerfield, IL 60015 USA GTIN: 00359148000000 SN: 100000000001 EXP: YYYY/MMM LOT: XXXXXXXX F (b) (4) Recommended Dosage: see Prescribing Information. Each tablet contains 1 mg of brexpiprazole. Store REXULTI® tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA © 2024, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Active ingredient made in Japan. 1 mg NDC 59148-037-13 30 Tablets DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT Rx only Keep out of the reach of children NDC 59148-037-13 30 Tablets 1 mg 516667AE 1 mg 1 mg DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT Rx only Marketed by Lundbeck Deerfield, IL 60015 USA GTIN: 00359148000000 SN: 100000000001 EXP: YYYY/MMM LOT: XXXXXXXX F (b) (4) Recommended Dosage: see Prescribing Information. Each tablet contains 2 mg of brexpiprazole. Store REXULTI® tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA © 2024, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Active ingredient made in Japan. 2 mg NDC 59148-038-13 30 Tablets DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT Rx only Keep out of the reach of children NDC 59148-038-13 30 Tablets 2 mg Rx only 516766AE 2 mg 2 mg Marketed by Lundbeck Deerfield, IL 60015 USA GTIN: 00359148000000 SN: 100000000001 EXP: YYYY/MMM LOT: XXXXXXXX F (b) (4) Recommended Dosage: see Prescribing Information. Each tablet contains 3 mg of brexpiprazole. Store REXULTI® tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA © 2024, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Active ingredient made in Japan. Marketed by Lundbeck Deerfield, IL 60015 USA 3 mg NDC 59148-039-13 30 Tablets DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT Rx only Keep out of the reach of children NDC 59148-039-13 30 Tablets 3 mg 516673AE 3 mg 3 mg DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT Rx only GTIN: 00359148000000 SN: 100000000001 EXP: YYYY/MMM LOT: XXXXXXXX F (b) (4) Recommended Dosage: see Prescribing Information. Each tablet contains 4 mg of brexpiprazole. Store REXULTI® tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA © 2024, Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan Active ingredient made in Japan. 4 mg NDC 59148-040-13 30 Tablets DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT Rx only Keep out of the reach of children NDC 59148-040-13 30 Tablets 4 mg 516677AE 4 mg 4 mg DISPENSE THE ACCOMPANYING MEDICATION GUIDE TO EACH PATIENT Rx only Marketed by Lundbeck Deerfield, IL 60015 USA GTIN: 00359148000000 SN: 100000000001 EXP: YYYY/MMM LOT: XXXXXXXX F (b) (4)
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2025-02-12T15:47:38.863706
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80,569
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NURTEC ODT safely and effectively. See full prescribing information for NURTEC ODT. NURTEC ODT (rimegepant) orally disintegrating tablets, for sublingual or oral use Initial U.S. Approval: 2020 -------------------------------INDICATIONS AND USAGE--------------------------- NURTEC ODT is a calcitonin gene-related peptide receptor antagonist indicated for the: • acute treatment of migraine with or without aura in adults (1.1) • preventive treatment of episodic migraine in adults (1.2) ----------------------------DOSAGE AND ADMINISTRATION-------------------- • Recommended dosage for acute treatment of migraine: 75 mg taken orally, as needed. (2.1) • The safety of using more than 18 doses in a 30-day period has not been established. (2.1) • Recommended dosage for preventive treatment of episodic migraine: 75 mg taken orally every other day. (2.2) • The maximum dose in a 24-hour period is 75 mg. (2.1) ------------------------DOSAGE FORMS AND STRENGTHS-------------------- NURTEC ODT orally disintegrating tablets: 75 mg (3) -----------------------------------CONTRAINDICATIONS------------------------------ Patients with a history of hypersensitivity reaction to rimegepant, NURTEC ODT, or to any of its components. (4) ------------------------WARNINGS AND PRECAUTIONS------------------- Hypersensitivity Reactions: If a serious hypersensitivity reaction occurs, discontinue NURTEC ODT and initiate appropriate therapy. Severe hypersensitivity reactions have included dyspnea and rash, and can occur days after administration. (5.1) -----------------------------ADVERSE REACTIONS---------------------------- Acute treatment of migraine: the adverse reaction reported in ≥ 1% of patients treated with NURTEC ODT is nausea. (6.1) Preventive treatment of episodic migraine: adverse reactions reported in ≥ 2% for rimegepant and ≥ 1% higher than placebo are nausea and abdominal pain/dyspepsia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------------DRUG INTERACTIONS----------------------------- • Strong CYP3A4 Inhibitors: Avoid concomitant administration. (7.1) • Moderate CYP3A4 Inhibitors: Avoid another dose within 48 hours when administered with a moderate CYP3A4 inhibitor. (7.1) • Strong and Moderate CYP3A Inducers: Avoid concomitant administration. (7.2) • Potent Inhibitors of P-gp: Avoid another dose of NURTEC ODT within 48 hours when administered with a potent P-gp inhibitor. (7.3) -----------------------USE IN SPECIFIC POPULATIONS-------------------- • Exposures were significantly higher in subjects with severe hepatic impairment. Avoid use in patients with severe hepatic impairment (Child-Pugh C). (8.6) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 4/2023 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Acute Treatment of Migraine 1.2 Preventive Treatment of Episodic Migraine 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage for Acute Treatment of Migraine 2.2 Recommended Dosage for Preventive Treatment of Episodic Migraine 2.3 Administration Information 2.4 Concomitant Administration with Strong or Moderate CYP3A4 Inhibitors 2.5 Concomitant Administration with Strong or Moderate CYP3A Inducers 2.6 Concomitant Administration with Potent Inhibitors of P-gp 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 CYP3A4 Inhibitors 7.2 CYP3A Inducers 7.3 P-gp Inhibitors 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Acute Treatment of Migraine 14.2 Preventive Treatment of Episodic Migraine 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5502035 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Acute Treatment of Migraine NURTEC ODT is indicated for the acute treatment of migraine with or without aura in adults. 1.2 Preventive Treatment of Episodic Migraine NURTEC ODT is indicated for the preventive treatment of episodic migraine in adults. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing for Acute Treatment of Migraine The recommended dose of NURTEC ODT is 75 mg taken orally, as needed. The maximum dose in a 24-hour period is 75 mg. The safety of using more than 18 doses in a 30-day period has not been established. 2.2 Recommended Dosing for Preventive Treatment of Episodic Migraine The recommended dosage of NURTEC ODT is 75 mg taken orally every other day. 2.3 Administration Information Instruct the patient on the following administration instructions: • Use dry hands when opening the blister pack. • Peel back the foil covering of one blister and gently remove the orally disintegrating tablet (ODT). Do not push the ODT through the foil. • As soon as the blister is opened, remove the ODT and place on the tongue; alternatively, the ODT may be placed under the tongue. • The ODT will disintegrate in saliva so that it can be swallowed without additional liquid. • Take the ODT immediately after opening the blister pack. Do not store the ODT outside the blister pack for future use. 2.4 Concomitant Administration with Strong or Moderate CYP3A4 Inhibitors Avoid concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with moderate inhibitors of CYP3A4 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. 2.5 Concomitant Administration with Strong or Moderate CYP3A Inducers Avoid concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A, which may lead to loss of efficacy of NURTEC ODT [see Drug Interactions (7.2), Clinical Pharmacology (12.3)]. Reference ID: 5502035 2.6 Concomitant Administration with Potent Inhibitors of P-gp Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with potent inhibitors of P-gp [see Drug Interactions (7.3), Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS Orally disintegrating tablets: white to off-white, circular, and debossed with the symbol , each containing 75 mg of rimegepant. 4 CONTRAINDICATIONS NURTEC ODT is contraindicated in patients with a history of hypersensitivity reaction to rimegepant, NURTEC ODT, or any of its components. Delayed serious hypersensitivity has occurred [see Warnings and Precautions (5.1)]. 5 WARNING AND PRECAUTIONS 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including dyspnea and rash, have occurred with NURTEC ODT in clinical studies. Hypersensitivity reactions can occur days after administration, and delayed serious hypersensitivity has occurred. If a hypersensitivity reaction occurs, discontinue NURTEC ODT and initiate appropriate therapy [see Contraindications (4)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Acute Treatment of Migraine The safety of NURTEC ODT for the acute treatment of migraine in adults has been evaluated in a randomized, double-blind, placebo-controlled trial (Study 1) in 682 patients with migraine who received one 75 mg dose of NURTEC ODT [see Clinical Studies (14)]. Approximately 85% were female, 74% were White, 21% were Black, and 17% were Hispanic or Latino. The mean age at study entry was 40 years (range 18-75 years of age). Long-term safety was assessed in an open-label extension study using a different oral dosage form of rimegepant. That study evaluated 1,798 patients, dosing intermittently for up to one year, including 1,131 patients who were exposed to rimegepant 75 mg for at least 6 months, and 863 who were exposed for at least one year, all of whom treated an average of at least two migraine attacks per month. Reference ID: 5502035 The most common adverse reaction in Study 1 was nausea (2% in patients who received NURTEC ODT compared to 0.4% of patients who received placebo). Hypersensitivity, including dyspnea and severe rash, occurred in less than 1% of patients treated with NURTEC ODT [see Contraindications (4) and Warnings and Precautions (5.1)]. Preventive Treatment of Episodic Migraine The safety of NURTEC ODT for the preventive treatment of episodic migraine in adults has been established in a randomized, double-blind, placebo-controlled trial with an open-label extension (Study 2) using a different oral dosage form of rimegepant [see Clinical Studies (14)]. In the 12-week, double-blind treatment period, 370 patients with migraine received one 75 mg dose of rimegepant every other day. Approximately 81% were female, 80% were White, 17% were Black, and 28% were Hispanic or Latino. The mean age at study entry was 41 years (range 18-74 years of age). Long-term safety was assessed in an open-label extension study that included 603 patients who were treated for up to one year. Overall, 527 patients were exposed to rimegepant 75 mg for at least 6 months, and 311 were exposed for at least one year. The most common adverse reactions (occurring in at least 2% of rimegepant-treated patients and at a frequency of at least 1% higher than placebo) in Study 2 were nausea (2.7% in patients who received rimegepant compared with 0.8% of patients who received placebo) and abdominal pain/dyspepsia (2.4% in patients who received rimegepant compared with 0.8% of patients who received placebo). 7 DRUG INTERACTIONS 7.1 CYP3A4 Inhibitors Concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 results in a significant increase in rimegepant exposure. Avoid concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 [see Clinical Pharmacology (12.3)]. Concomitant administration of NURTEC ODT with moderate inhibitors of CYP3A4 may result in increased exposure of rimegepant. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with moderate inhibitors of CYP3A4 [see Clinical Pharmacology (12.3)]. 7.2 CYP3A Inducers Concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A can result in a significant reduction in rimegepant exposure, which may lead to loss of efficacy of NURTEC ODT. Avoid concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A [see Clinical Pharmacology (12.3)]. 7.3 P-gp Inhibitors Concomitant administration of NURTEC ODT with potent inhibitors of P-gp (e.g., amiodarone, cyclosporine, lapatinib, quinidine, ranolazine) may result in increased exposure of rimegepant. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with potent inhibitors of P-gp [see Clinical Pharmacology (12.3)]. Reference ID: 5502035 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NURTEC ODT during pregnancy. For more information, healthcare providers or patients are encouraged to contact: 1-877-366-0324, email nurtecpregnancyregistry@ppd.com, or visit nurtecpregnancyregistry.com. Risk Summary There are no adequate data on the developmental risk associated with the use of NURTEC ODT in pregnant women. In animal studies, oral administration of rimegepant during organogenesis resulted in adverse effects on development in rats (decreased fetal body weight and increased incidence of skeletal variations) at exposures greater than those used clinically and which were associated with maternal toxicity (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated rate of major birth defects (2.2 to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. Data Animal Data Oral administration of rimegepant (0, 10, 60, or 300 mg/kg/day) to pregnant rats during the period of organogenesis resulted in decreased fetal body weight and an increased incidence of fetal skeletal variations at the highest dose tested (300 mg/kg/day), which was associated with maternal toxicity. Plasma exposures (AUC) at the no-effect dose (60 mg/kg/day) for adverse effects on embryofetal development were approximately 45 times that in humans at the maximum recommended human dose (MRHD) of 75 mg/day. Oral administration of rimegepant (0, 10, 25, or 50 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in no adverse effects on embryofetal development. The highest dose tested (50 mg/kg/day) was associated with plasma exposures (AUC) approximately 10 times that in humans at the MRHD. Oral administration of rimegepant (0, 10, 25, or 60 mg/kg/day) to rats throughout gestation and lactation resulted in no effects on pre- or postnatal development. The highest dose tested (60 mg/kg/day) was associated with plasma exposures (AUC) approximately 24 times that in humans at the MRHD. Reference ID: 5502035 8.2 Lactation Risk Summary A lactation study was conducted, and the results have established a relative infant dose of less than 1% of the maternal weight-adjusted dose and the milk-to-plasma ratio of 0.20 (see Data). These data support that transfer of rimegepant into breastmilk is low. There are no data on the effects of rimegepant on a breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NURTEC ODT and any potential adverse effects on the breastfed infant from NURTEC ODT or from the underlying maternal condition. Data A study was conducted in twelve healthy adult lactating women who were between 2 weeks and 6 months postpartum and were administered a single oral dose of rimegepant 75 mg. The relative infant dose was < 1%. The average milk to plasma ratio was 0.20. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In pharmacokinetic studies, no clinically significant pharmacokinetic differences were observed between elderly and younger subjects. Clinical studies of NURTEC ODT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment No dosage adjustment of NURTEC ODT is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Plasma concentrations of rimegepant were significantly higher in subjects with severe (Child-Pugh C) hepatic impairment. Avoid use of NURTEC ODT in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dosage adjustment of NURTEC ODT is required in patients with mild, moderate, or severe renal impairment. NURTEC ODT has not been studied in patients with end-stage renal disease and in patients on dialysis. Avoid use of NURTEC ODT in patients with end-stage renal disease (CLcr < 15 mL/min) [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is limited clinical experience with NURTEC ODT overdosage. Treatment of an overdose of NURTEC ODT should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. No specific antidote for the treatment of rimegepant overdose is available. Rimegepant is unlikely to be significantly removed by dialysis because of high serum protein binding [see Clinical Pharmacology (12.3)]. Reference ID: 5502035 11 DESCRIPTION NURTEC ODT contains rimegepant sulfate, a calcitonin gene-related peptide receptor antagonist. Rimegepant sulfate is described chemically as (5S,6S,9R)-5-amino-6-(2,3- difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxylate hemisulfate sesquihydrate and its structural formula is: Its empirical formula is C28H28F2N6O3 0.5 H2SO4 1.5 H2O, representing a molecular weight of 610.63. Rimegepant free base has a molecular weight of 534.56. Rimegepant sulfate is a white to off-white, crystalline solid that is slightly soluble in water. NURTEC ODT (orally disintegrating tablets) is for sublingual or oral use and contains 85.7 mg rimegepant sulfate, equivalent to 75 mg rimegepant free base, and the following inactive ingredients: benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillin. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Rimegepant is a calcitonin gene-related peptide receptor antagonist. 12.2 Pharmacodynamics The relationship between pharmacodynamic activity and the mechanism(s) by which rimegepant exerts its clinical effects is unknown. No clinically relevant differences in resting blood pressure were observed when rimegepant was concomitantly administered with sumatriptan (12 mg subcutaneous, given as two 6 mg doses separated by one hour) compared with sumatriptan alone to healthy volunteers. Cardiac Electrophysiology At a single dose 4 times the recommended dose, rimegepant does not prolong the QT interval to any clinically relevant extent. Reference ID: 5502035 12.3 Pharmacokinetics Absorption Following oral administration of NURTEC ODT, rimegepant is absorbed with the maximum concentration at 1.5 hours. The absolute oral bioavailability of rimegepant is approximately 64%. Effects of Food Following administration of NURTEC ODT under fed conditions with a high-fat or low-fat meal, Tmax was delayed by approximately 1 to 1.5 hours. A high-fat meal reduced Cmax by 42 to 53% and AUC by 32 to 38%. A low-fat meal reduced Cmax by 36% and AUC by 28%. NURTEC ODT was administered without regard to food in clinical safety and efficacy studies. The impact of the reduction in rimegepant exposure because of administration with food on its efficacy is unknown. Distribution The steady state volume of distribution of rimegepant is 120 L. Plasma protein binding of rimegepant is approximately 96%. Elimination Metabolism Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Rimegepant is the primary form (~77%) with no major metabolites (i.e., > 10%) detected in plasma. Excretion The elimination half-life of rimegepant is approximately 11 hours in healthy subjects. Following oral administration of [14C]-rimegepant to healthy male subjects, 78% of the total radioactivity was recovered in feces and 24% in urine. Unchanged rimegepant is the major single component in excreted feces (42%) and urine (51%). Specific Populations Renal Impairment In a dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild (estimated creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min), and severe (CLcr 15-29 mL/min) renal impairment to that with normal subjects (healthy matched control), the exposure of rimegepant following single 75 mg dose was approximately 40% higher in subjects with moderate renal impairment. However, there was no clinically meaningful difference in the exposure of rimegepant in subjects with severe renal impairment compared to subjects with normal renal function (CLcr >= 90 mL/min). NURTEC ODT has not been studied in patients with end-stage renal disease (CLcr < 15 mL/min) [see Use in Specific Populations (8.7)]. Hepatic Impairment In a dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild, moderate, and severe hepatic impairment to that with normal subjects (healthy matched control), the exposure of rimegepant (Cmax and AUC) following single 75 mg dose was approximately 2-fold higher in subjects with severe impairment (Child-Pugh class C). There Reference ID: 5502035 were no clinically meaningful differences in the exposure of rimegepant in subjects with mild (Child-Pugh class A) and moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function [see Use in Specific Populations (8.6)]. Other Specific Populations No clinically significant differences in the pharmacokinetics of rimegepant were observed based on age, sex, race/ethnicity, body weight, or CYP2C9 genotype [see Clinical Pharmacology (12.5)]. Drug Interaction Studies In Vitro Studies • Enzymes Rimegepant is a substrate of CYP3A4 and CYP2C9 (see In Vivo Studies). Rimegepant is not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, 2D6, or UGT1A1 at clinically relevant concentrations. However, rimegepant is a weak inhibitor of CYP3A4 with time-dependent inhibition. Rimegepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations. • Transporters Rimegepant is a substrate of P-gp and BCRP (see In Vivo Studies). Rimegepant is not a substrate of OATP1B1 or OATP1B3. Considering its low renal clearance, rimegepant was not evaluated as a substrate of the OAT1, OAT3, OCT2, MATE1, or MATE2-K. Rimegepant is not an inhibitor of P-gp, BCRP, OAT1, or MATE2-K at clinically relevant concentrations. It is a weak inhibitor of OATP1B1 and OAT3. Rimegepant is an inhibitor of OATP1B3, OCT2, and MATE1. In a dedicated interaction study, concomitant administration of 75 mg rimegepant at steady state with metformin, a MATE1 transporter substrate, at steady state resulted in no clinically significant impact on either metformin pharmacokinetics or on glucose utilization. No clinical drug interactions are expected for NURTEC ODT with OATP1B3 or OCT2, at clinically relevant concentrations. In Vivo Studies CYP3A4 Inhibitors In a dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with itraconazole, a strong CYP3A4 inhibitor, at steady state resulted in increased exposures of rimegepant (AUC by 4-fold and Cmax by ~1.5-fold) [see Drug Interactions (7.1)]. No dedicated drug interaction study was conducted to assess the effect of concomitant administration of a weak inhibitor of CYP3A4 on the pharmacokinetics of rimegepant. The concomitant administration of rimegepant with a moderate inhibitor of CYP3A4 may increase rimegepant exposures (AUC) by less than 2-fold [see Drug Interactions (7.1)]. Concomitant administration of rimegepant with a weak inhibitor of CYP3A4 is not expected to have a clinically significant impact on rimegepant exposures. Reference ID: 5502035 CYP3A Inducers In a dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with rifampin, a strong CYP3A4 inducer, at steady state resulted in decreased exposures of rimegepant (AUC by 80% and Cmax by 64%), which may lead to loss of efficacy [see Drug Interactions (7.2)]. No dedicated drug interaction study was conducted to assess the effect of concomitant administration of a moderate or weak inducer of CYP3A4 on the pharmacokinetics of rimegepant. Since rimegepant is a moderately sensitive substrate for CYP3A4, drugs that are moderate inducers of CYP3A4 can also cause significant reduction in rimegepant exposure resulting in loss of efficacy [see Drug Interactions (7.2)]. Clinically significant interaction is not expected with concomitant administration of weak inducers of CYP3A4 and rimegepant. CYP2C9 Inhibitors In a dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with fluconazole, a combined moderate CYP3A4 and CYP2C9 inhibitor, resulted in increased exposures of rimegepant (AUC by 1.8-fold) with no relevant effect on Cmax. Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Increase in the exposure of rimegepant can be attributed to combined inhibition of CYP2C9 and CYP3A4 with fluconazole administration suggesting a minor contribution from CYP2C9. Thus, CYP2C9 inhibition alone is not expected to significantly affect rimegepant exposures. P-gp and BCRP Inhibitors In a dedicated drug interaction study, concomitant administration of NURTEC ODT with cyclosporine (a potent P-gp and BCRP inhibitor) and with quinidine (a potent P-gp inhibitor) resulted in an increase of similar magnitude in rimegepant exposure (AUC and Cmax by 1.6 and 1.4 fold with cyclosporine, and by 1.6 and 1.7 fold with quinidine, respectively) [see Drug Interactions (7.3)]. Therefore, concomitant administration of NURTEC ODT with BCRP inhibitors is not expected to have a clinically significant impact on rimegepant exposures. Other Drugs: No significant pharmacokinetic interactions were observed when rimegepant was concomitantly administered with oral contraceptives (norelgestromin, ethinyl estradiol), midazolam (a sensitive CYP3A4 substrate), metformin (a MATE1 substrate), or sumatriptan [see Clinical Pharmacology (12.2)]. 12.5 Pharmacogenomics CYP2C9 activity is reduced in individuals with genetic variants such as the CYP2C9*2 and CYP2C9*3 alleles. Rimegepant Cmax and AUC0-inf were similar in CYP2C9 intermediate metabolizers (i.e., *1/*2, *2/*2, *1/*3, n=43) as compared to normal metabolizers (i.e., *1/*1, N=72). Adequate PK data are not available from CYP2C9 poor metabolizers (i.e., *2/*3). Since the contribution of CYP2C9 to rimegepant metabolism is considered minor, CYP2C9 polymorphism is not expected to significantly affect its exposure. Reference ID: 5502035 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Oral administration of rimegepant to Tg.rasH2 mice (0, 10, 100, or 300 mg/kg/day) for 26 weeks and to rats (0, 5, 20, or 45 mg/kg/day) for 91-100 weeks resulted in no evidence of drug-induced tumors in either species. In rats, the plasma exposure (AUC) at the highest dose tested (45 mg/kg/day) was approximately 30 times that at the maximum recommended human dose (MRHD) of 75 mg/day. Mutagenesis Rimegepant was negative in in vitro (bacterial reverse-mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (rat micronucleus) assays. Impairment of Fertility Oral administration of rimegepant (0, 30, 60, or 150 mg/kg/day) to male and female rats prior to and during mating and continuing in females to gestation day (GD) 7 resulted in reduced fertility at the highest dose tested. In a second fertility study testing lower doses (0, 5, 15, or 25 mg/kg/day), no adverse effects on fertility, uterine histopathology, or early embryonic development were observed. The no-effect dose for impairment of fertility and early embryonic development in rats (60 mg/kg/day) was associated with plasma drug exposures (AUC) approximately 30 times that in humans at the MRHD. 14 CLINICAL STUDIES 14.1 Acute Treatment of Migraine The efficacy of NURTEC ODT for the acute treatment of migraine with and without aura in adults was demonstrated in a randomized, double-blind, placebo-controlled trial: Study 1 (NCT03461757). Patients in the study were randomized to receive 75 mg of NURTEC ODT (N=732) or placebo (N=734). Patients were instructed to treat a migraine of moderate to severe headache pain intensity. Rescue medication (i.e., NSAIDs, acetaminophen, and/or an antiemetic) was allowed 2 hours after the initial treatment. Other forms of rescue medication such as triptans were not allowed within 48 hours of initial treatment. Approximately 14% of patients were taking preventive medications for migraine at baseline. None of the patients in Study 1 were on concomitant preventive medication that act on the CGRP pathway. The primary efficacy analyses were conducted in patients who treated a migraine with moderate to severe pain. NURTEC ODT 75 mg demonstrated an effect on pain freedom and most bothersome symptom (MBS) freedom at two hours after dosing, compared to placebo. Pain freedom was defined as a reduction of moderate or severe headache pain to no headache pain, and MBS freedom was defined as the absence of the self-identified MBS (i.e., photophobia, phonophobia, or nausea). Among patients who selected an MBS, the most commonly selected symptom was photophobia (54%), followed by nausea (28%), and phonophobia (15%). Reference ID: 5502035 In Study 1, the percentage of patients achieving headache pain freedom and MBS freedom two hours after a single dose was statistically significantly greater in patients who received NURTEC ODT compared to those who received placebo (Table 1). Table 1: Efficacy Endpoints for the Acute Treatment of Migraine in Study 1 Study 1 NURTEC ODT 75 mg Placebo Pain Free at 2 hours n/N* 142/669 74/682 % Responders 21.2 10.9 Difference from placebo (%) 10.3 p-value <0.001 MBS Free at 2 hours n/N* 235/669 183/682 % Responders 35.1 26.8 Difference from placebo (%) 8.3 p-value 0.001 *n=number of responders/N=number of patients in that treatment group Figure 1 presents the percentage of patients achieving migraine pain freedom within 2 hours following treatment in Study 1. Reference ID: 5502035 Figure 1: Percentage of Patients Achieving Pain Freedom within 2 Hours in Study 1 Figure 2 presents the percentage of patients achieving MBS freedom within 2 hours in Study 1. Reference ID: 5502035 Figure 2: Percentage of Patients Achieving MBS Freedom within 2 Hours in Study 1 In Study 1, statistically significant effects of NURTEC ODT compared to placebo were demonstrated for the additional efficacy endpoints of pain relief at 2 hours, sustained pain freedom 2-48 hours, use of rescue medication within 24 hours, and the percentage of patients reporting normal function at two hours after dosing (Table 2). Pain relief was defined as a reduction in migraine pain from moderate or severe severity to mild or none. The measurement of the percentage of patients reporting normal function at two hours after dosing was derived from a single item questionnaire, asking patients to select one response on a 4-point scale; normal function, mild impairment, severe impairment, or required bedrest. Reference ID: 5502035 Table 2: Additional Acute Treatment of Migraine Efficacy Endpoints in Study 1 Study 1 NURTEC ODT 75 mg Placebo Pain Relief at 2 hours n/N* 397/669 295/682 % Responders 59.3 43.3 Difference from placebo 16.1 p-value <0.001 Sustained Pain Freedom 2-48 hours n/N* 90/669 37/682 % Responders 13.5 5.4 Difference from placebo 8.0 p-value <0.001 Use of Rescue Medication within 24 hours** n/N* 95/669 199/682 % Responders 14.2 29.2 Difference from placebo -15.0 p-value <0.001 Percentage of Patients Reporting Normal Function at 2 hours n/N* 255/669 176/682 % Responders 38.1 25.8 Difference from placebo 12.3 p-value <0.001 *n=number of responders/N=number of patients in that treatment group **This analysis includes only the use of NSAIDs, acetaminophen, or antiemetics, within 24 hours post-dose; the use of triptans, or other acute migraine medication, was not allowed. The incidence of photophobia and phonophobia was reduced following administration of NURTEC ODT 75 mg as compared to placebo. 14.2 Preventive Treatment of Episodic Migraine The efficacy of NURTEC ODT for the preventive treatment of episodic migraine in adults was demonstrated in one randomized, double-blind, placebo-controlled trial of a different oral dosage form of rimegepant (Study 2; NCT03732638). Reference ID: 5502035 Study 2 enrolled adult patients with at least a 1-year history of migraine (with or without aura). Patients experienced an average of 10.9 headache days during the 28-day observational period, which included an average of 10.2 migraine days, prior to randomization into the trial. Patients were randomized to receive every other day dosing of rimegepant 75 mg (N=373) or placebo (N=374) for 12 weeks. Patients were allowed to use acute headache treatments (i.e., triptans, NSAIDs, acetaminophen, antiemetics, muscle relaxants, and aspirin) as needed. Approximately 10% of patients were taking one preventive medication for migraine at baseline. The use of a concomitant medication that acts on the CGRP pathway was not permitted for either the acute or preventive treatment of migraine. The study excluded patients with myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, cardiac surgery, stroke, or transient ischemic attack within six months of screening. The primary efficacy endpoint for Study 2 was the change from baseline in the mean number of monthly migraine days (MMDs) during Weeks 9 through 12 of the double-blind treatment phase. The percentage of patients who achieved at least a 50% reduction from baseline in moderate to severe MMDs during Weeks 9 through 12 of the double-blind treatment phase compared to placebo was also evaluated. Rimegepant 75 mg dosed every other day demonstrated statistically significant improvements for these efficacy endpoints compared to placebo, as summarized in Table 3. Table 3: Efficacy Endpoints for the Preventive Treatment of Episodic Migraine in Study 2 Rimegepant 75 mg Every Other Day Placebo Every Other Day Monthly Migraine Days (MMD), Weeks 9-12 N=348 N=347 Change from baseline -4.3 -3.5 Change from placebo -0.8 p-value 0.010 ≥ 50% Responders (Moderate to Severe MMDs), Weeks 9-12 N=348 N=347 % Responders 49.1 41.5 Difference from placebo 7.6 p-value 0.044 Reference ID: 5502035 Figure 3: Change from Baseline in Monthly Migraine Days in Study 2a aLeast-square means and 95% confidence intervals are presented. Figure 4: Distribution of Change from Baseline in Mean Monthly Migraine Days at Month 3 by Treatment Group in Study 2a aFigure excludes patients with missing data. Reference ID: 5502035 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied NURTEC ODT 75 mg orally disintegrating tablets are white to off-white, circular, debossed with the symbol , and supplied in cartons containing a blister pack of 8 orally disintegrating tablets. Each ODT contains 75 mg rimegepant. NDC: 72618-3000-2 16.2 Storage and Handling Store NURTEC ODT at controlled room temperature, 20°C to 25°C (68°F to 77°F); with excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. 17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Patient Information). Handling of Orally Disintegrating Tablets Packaging Instruct patients not to remove the blister from the outer aluminum pouch until ready to use the orally disintegrating tablet inside [see Dosage and Administration (2.3)]. Hypersensitivity Reactions Inform patients about the signs and symptoms of hypersensitivity reactions and that these reactions can occur days after administration of NURTEC ODT. Advise patients to contact their healthcare provider immediately if signs or symptoms of hypersensitivity reactions occur [see Warnings and Precautions (5.1)]. Pregnancy Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NURTEC ODT during pregnancy. Encourage participation and advise patients about how they may enroll in the registry [see Use in Specific Populations (8.1)]. This product’s labeling may have been updated. For the most recent Prescribing Information, please visit www.pfizer.com. LAB-1547-2.0 Reference ID: 5502035 PATIENT INFORMATION NURTEC® ODT (NUR-tek) (rimegepant) orally disintegrating tablets (ODT), for sublingual or oral use What is NURTEC ODT? NURTEC ODT is a prescription medicine used in adults for the: • acute treatment of migraine attacks with or without aura • preventive treatment of episodic migraine It is not known if NURTEC ODT is safe and effective in children. Do not take NURTEC ODT if you are: • allergic to rimegepant, NURTEC ODT, or any of the ingredients in NURTEC ODT. See the end of this leaflet for a complete list of ingredients in NURTEC ODT. Before you take NURTEC ODT, tell your healthcare provider about all of your medical conditions, including if you: • have liver problems. • have kidney problems. • are pregnant or plan to become pregnant. It is not known if NURTEC ODT will harm your unborn baby. There is a pregnancy exposure registry for women who take NURTEC ODT during pregnancy. The study is named MONITOR (Migraine Observational NURTEC Pregnancy Registry). A registry is a study. The purpose of this registry is to collect information about your health and the health of your baby. Your healthcare provider can help you enroll in this registry. You may also enroll yourself or get more information about the registry by calling 1-877-366-0324, emailing nurtecpregnancyregistry@ppd.com, or by visiting nurtecpregnancyregistry.com. • are breastfeeding or plan to breastfeed. Very small amounts of NURTEC ODT pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you take NURTEC ODT. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I take NURTEC ODT? • Take NURTEC ODT exactly how your healthcare provider tells you to. • For the acute treatment of migraine attacks when they occur, NURTEC ODT can be taken 1 time each day as needed. You should not take more than 1 tablet in 24 hours. o It is not known if it is safe to take more than 18 doses of NURTEC ODT in 30 days. • For the preventive treatment of episodic migraine, take NURTEC ODT 1 time every other day. • To take NURTEC ODT: o Use dry hands when opening the blister pack. o Peel back the foil covering of one blister and gently remove NURTEC ODT. Do not push NURTEC ODT through the foil. o As soon as the blister is opened, remove NURTEC ODT and place on or under the tongue. o NURTEC ODT will dissolve and no drink or water is needed. o Take NURTEC ODT immediately after opening the blister pack. Do not store NURTEC ODT outside the blister pack for future use. • If you take too much NURTEC ODT, go to the nearest emergency room right away. What are the possible side effects of NURTEC ODT? NURTEC ODT may cause serious side effects including: • Allergic reactions. Allergic reactions, including trouble breathing and rash, can happen after you take NURTEC ODT. This can happen days after you take NURTEC ODT. Call your healthcare provider or get emergency help right away if you have any of the following symptoms, which may be part of an allergic reaction: o Swelling of the face, mouth, tongue, or throat o Trouble breathing The most common side effect of NURTEC ODT in acute treatment of migraine attacks with or without aura is: • nausea The most common side effects of NURTEC ODT in preventive treatment of episodic migraine are: • nausea • stomach pain • indigestion These are not the only possible side effects of NURTEC ODT. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800 FDA-1088. How should I store NURTEC ODT? • Store NURTEC ODT in the blister package that it comes in. • Store NURTEC ODT at room temperature between 68°F to 77°F (20°C to 25°C). Keep NURTEC ODT and all medicines out of the reach of children. Reference ID: 5502035 General information about the safe and effective use of NURTEC ODT: Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use NURTEC ODT for a condition for which it was not prescribed. Do not give NURTEC ODT to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about NURTEC ODT that is written for health professionals. What are the ingredients in NURTEC ODT? Active ingredient in NURTEC ODT: rimegepant Inactive ingredients in NURTEC ODT: benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillin For more information, go to www.nurtec.com or call 1-833-4NURTEC. LAB-1548-2.0 This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 4/2023 Reference ID: 5502035
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2025-02-12T15:47:39.149267
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HIGHLIGHTS OF PRESCRIBING INFORMATION Patients less than 100 kg 162 mg administered subcutaneously every These highlights do not include all the information needed to use weight other week, followed by an increase to ACTEMRA safely and effectively. See full prescribing information for every week based on clinical response ACTEMRA. Patients at or above 100 162 mg administered subcutaneously every kg weight week ACTEMRA® (tocilizumab) injection, for intravenous or subcutaneous use Initial U.S. Approval: 2010 Giant Cell Arteritis (2.3) Recommended Adult Intravenous Dosage: The recommended dose is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids. ACTEMRA can be used alone following discontinuation of glucocorticoids. Recommended Adult Subcutaneous Dosage: The recommended dose is 162 mg given once every week as a subcutaneous injection, in combination with a tapering course of glucocorticoids. A dose of 162 mg given once every other week as a subcutaneous injection, in combination with a tapering course of glucocorticoids, may be prescribed based on clinical considerations. ACTEMRA can be used alone following discontinuation of glucocorticoids. Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD) (2.4) Recommended Adult Subcutaneous Dosage: The recommended dose of ACTEMRA for adult patients with SSc-ILD is 162 mg given once every week as a subcutaneous injection. Polyarticular Juvenile Idiopathic Arthritis (2.5) Systemic Juvenile Idiopathic Arthritis (2.6) Cytokine Release Syndrome (2.7) Coronavirus Disease 2019 (2.8) The recommended dosage of ACTEMRA for adult patients with COVID-19 is 8 mg per kg administered by a 60-minute intravenous infusion. Administration of Intravenous formulation (2.9) • For patients with RA, GCA, COVID-19, CRS, PJIA, and SJIA patients at or above 30 kg, dilute to 100 mL in 0.9% or 0.45% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique. • For PJIA, SJIA and CRS patients less than 30 kg, dilute to 50 mL in 0.9% or 0.45% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique. • Administer as a single intravenous drip infusion over 1 hour; do not administer as bolus or push. Administration of Subcutaneous formulation (2.10) • Follow the Instructions for Use for prefilled syringe and prefilled ACTPen® autoinjector Dose Modifications (2.11) WARNING: RISK OF SERIOUS INFECTIONS See full prescribing information for complete boxed warning. • Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections have occurred in patients receiving ACTEMRA. (5.1) • If a serious infection develops, interrupt ACTEMRA until the infection is controlled. (5.1) • Perform test for latent TB (except patients with COVID-19); if positive, start treatment for TB prior to starting ACTEMRA. (5.1) • Monitor all patients for active TB during treatment, even if initial latent TB test is negative. (5.1) ---------------------------RECENT MAJOR CHANGES --------------------------­ Warnings and Precautions (5.6) 09/2024 --------------------------- INDICATIONS AND USAGE---------------------------­ ACTEMRA® (tocilizumab) is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of: Rheumatoid Arthritis (RA) (1.1) • Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). Giant Cell Arteritis (GCA) (1.2) • Adult patients with giant cell arteritis. Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD) (1.3) • Slowing the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) Polyarticular Juvenile Idiopathic Arthritis (PJIA) (1.4) • Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis. Systemic Juvenile Idiopathic Arthritis (SJIA) (1.5) • Patients 2 years of age and older with active systemic juvenile idiopathic arthritis. Cytokine Release Syndrome (CRS) (1.6) • Adults and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome. Coronavirus Disease 2019 (COVID-19) (1.7) • Hospitalized adult patients with coronavirus disease 2019 (COVID-19) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). -----------------------DOSAGE AND ADMINISTRATION ----------------------­ For RA, pJIA and sJIA, ACTEMRA may be used alone or in combination with methotrexate: and in RA, other non-biologic DMARDs may be used. (2) General Administration and Dosing Information (2.1) • RA, GCA, SSc-ILD, PJIA and SJIA – It is recommended that ACTEMRA not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or ALT or AST above 1.5 times the upper limit of normal (ULN)(5.3, 5.4). • COVID-19 – It is recommended that ACTEMRA not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm3, platelet count below 50,000 mm3, or ALT or AST above 10 times ULN (5.3, 5.4). • In RA, CRS or COVID-19 patients, ACTEMRA doses exceeding 800 mg per infusion are not recommended. (2.2, 2.7, 12.3) • In GCA patients, ACTEMRA doses exceeding 600 mg per infusion are not recommended. (2.3, 12.3) Rheumatoid Arthritis (2.2) Recommended Adult Intravenous Dosage: When used in combination with non-biologic DMARDs or as monotherapy the recommended starting dose is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response. Recommended Adult Subcutaneous Dosage: Recommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous PJIA Dosage Patients less than 30 kg weight 162 mg once every three weeks Patients at or above 30 kg weight 162 mg once every two weeks Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous SJIA Dosage Patients less than 30 kg weight 162 mg every two weeks Patients at or above 30 kg weight 162 mg every week Recommended Intravenous CRS Dosage Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Alone or in combination with corticosteroids. Reference ID: 5493108 1 ____________________________________________________________________________________________________________________________________ • Recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia. --------------------- DOSAGE FORMS AND STRENGTHS---------------------­ Intravenous Infusion Injection: 80 mg/4 mL (20 mg/mL), 200 mg/10 mL (20 mg/mL), 400 mg/20 mL (20 mg/mL) in single-dose vials for further dilution prior to intravenous infusion (3) Subcutaneous Injection Injection: 162 mg/0.9 mL in a single-dose prefilled syringe or single-dose prefilled ACTPen® autoinjector (3) ------------------------------ CONTRAINDICATIONS -----------------------------­ Known hypersensitivity to ACTEMRA. (4) ----------------------- WARNINGS AND PRECAUTIONS-----------------------­ • Serious Infections – do not administer ACTEMRA during an active infection, including localized infections. If a serious infection develops, interrupt ACTEMRA until the infection is controlled. (5.1) • Gastrointestinal (GI) perforation—use with caution in patients who may be at increased risk. (5.2) • Hepatotoxicity- Monitor patients for signs and symptoms of hepatic injury. Modify or discontinue ACTEMRA if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (2.10, 5.3) • Laboratory monitoring—recommended due to potential consequences of treatment-related changes in neutrophils, platelets, lipids, and liver function tests. (2.10, 5.4) • Hypersensitivity reactions, including anaphylaxis and death and serious cutaneous reactions including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) – discontinue ACTEMRA, treat promptly, and monitor until reaction resolves. (5.6) • Live vaccines—Avoid use with ACTEMRA. (5.9, 7.3) ------------------------------ ADVERSE REACTIONS -----------------------------­ Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, injection site reactions. (6) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ----------------------- USE IN SPECIFIC POPULATIONS ----------------------­ • Pregnancy: Based on animal data, may cause fetal harm. (8.1) • Lactation: Discontinue drug or nursing taking into consideration importance of drug to mother. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 09/2024 Reference ID: 5493108 2 ____________________________________________________________________________________________________________________________________ FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS INFECTIONS 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis (RA) 1.2 Giant Cell Arteritis (GCA) 1.3 Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD) 1.4 Polyarticular Juvenile Idiopathic Arthritis (PJIA) 1.5 Systemic Juvenile Idiopathic Arthritis (SJIA) 1.6 Cytokine Release Syndrome (CRS) 1.7 Coronavirus Disease 2019 (COVID-19) 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations for Administration 2.2 Recommended Dosage for Rheumatoid Arthritis 2.3 Recommended Dosage for Giant Cell Arteritis 2.4 Recommended Dosage for Systemic Sclerosis-Associated Interstitial Lung Disease 2.5 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis 2.6 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis 2.7 Recommended Dosage for Cytokine Release Syndrome 2.8 Coronavirus Disease 2019 (COVID-19) 2.9 Preparation and Administration Instructions for Intravenous Infusion 2.10 Preparation and Administration Instructions for Subcutaneous Injection 2.11 Dosage Modifications due to Serious Infections or Laboratory Abnormalities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections 5.2 Gastrointestinal Perforations 5.3 Hepatotoxicity 5.4 Changes in Laboratory Parameters 5.5 Immunosuppression 5.6 Hypersensitivity Reactions, Including Anaphylaxis 5.7 Demyelinating Disorders 5.8 Active Hepatic Disease and Hepatic Impairment 5.9 Vaccinations 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous ACTEMRA (ACTEMRA-IV) 6.2 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC) 6.3 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC) 6.4 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Intravenous ACTEMRA (ACTEMRA-IV) 6.5 Clinical Trials Experience in Systemic Sclerosis-Associated Interstitial Lung Disease Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC) 6.6 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Intravenous ACTEMRA (ACTEMRA-IV) 6.7 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Subcutaneous ACTEMRA (ACTEMRA-SC) 6.8 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous ACTEMRA (ACTEMRA-IV) 6.9 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC) 6.10 Clinical Trials Experience in Patients with Cytokine Release Syndrome Treated with Intravenous ACTEMRA (ACTEMRA-IV) 6.11 Clinical Trials Experience in COVID-19 Patients Treated with Intravenous ACTEMRA (ACTEMRA-IV) 6.12 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Drugs for Treatment of Adult Indications 7.2 Interactions with CYP450 Substrates 7.3 Live Vaccines 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 9 DRUG ABUSE AND DEPENDENCE 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis – Intravenous Administration 14.2 Rheumatoid Arthritis – Subcutaneous Administration 14.3 Giant Cell Arteritis – Subcutaneous Administration 14.4 Giant Cell Arteritis – Intravenous Administration 14.5 Systemic Sclerosis-Associated Interstitial Lung Disease – Subcutaneous Administration 14.6 Polyarticular Juvenile Idiopathic Arthritis – Intravenous Administration 14.7 Polyarticular Juvenile Idiopathic Arthritis – Subcutaneous Administration 14.8 Systemic Juvenile Idiopathic Arthritis – Intravenous Administration 14.9 Systemic Juvenile Idiopathic Arthritis – Subcutaneous Administration 14.10 Cytokine Release Syndrome – Intravenous Administration 14.11 COVID-19 – Intravenous Administration 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS INFECTIONS Patients treated with ACTEMRA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt ACTEMRA until the infection is controlled. Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients, except those with COVID-19, should be tested for latent tuberculosis before ACTEMRA use and during therapy. Treatment for latent infection should be initiated prior to ACTEMRA use. Reference ID: 5493108 3 • Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. • Bacterial, viral and other infections due to opportunistic pathogens. The risks and benefits of treatment with ACTEMRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ACTEMRA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis (RA) ACTEMRA® (tocilizumab) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). 1.2 Giant Cell Arteritis (GCA) ACTEMRA® (tocilizumab) is indicated for the treatment of giant cell arteritis (GCA) in adult patients. 1.3 Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD) ACTEMRA® (tocilizumab) is indicated for slowing the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease. 1.4 Polyarticular Juvenile Idiopathic Arthritis (PJIA) ACTEMRA® (tocilizumab) is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. 1.5 Systemic Juvenile Idiopathic Arthritis (SJIA) ACTEMRA® (tocilizumab) is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older. 1.6 Cytokine Release Syndrome (CRS) ACTEMRA® (tocilizumab) is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome in adults and pediatric patients 2 years of age and older. 1.7 Coronavirus Disease 2019 (COVID-19) ACTEMRA® (tocilizumab) is indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adult patients who are receiving systemic corticosteroids and require supplemental oxygen, non­ invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations for Administration Not Recommended for Concomitant Use with Biological DMARDs ACTEMRA has not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection. Avoid using ACTEMRA with biological DMARDs. Baseline Laboratory Evaluation Prior to Treatment Obtain and assess baseline complete blood count (CBC) and liver function tests prior to treatment. Reference ID: 5493108 4 • RA, GCA, SSc-ILD, PJIA and SJIA – It is recommended that ACTEMRA not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or ALT or AST above 1.5 times the upper limit of normal (ULN) [see Warnings and Precautions (5.3, 5.4)]. • CRS – Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the lymphodepleting chemotherapy or the CRS. The decision to administer ACTEMRA should take into account the potential benefit of treating the CRS versus the risks of short-term treatment with ACTEMRA. • COVID-19 – It is recommended that ACTEMRA not be initiated in patients with an absolute neutrophil count (ANC) below 1000 per mm3, platelet count below 50,000 mm3, or ALT or AST above 10 times ULN [see Warnings and Precautions (5.3, 5.4)]. 2.2 Recommended Dosage for Rheumatoid Arthritis ACTEMRA may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection. Recommended Intravenous Dosage Regimen: The recommended dosage of ACTEMRA for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response. • Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.1)]. • Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology (12.3)]. Recommended Subcutaneous Dosage Regimen: Patients less than 100 kg weight 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response Patients at or above 100 kg weight 162 mg administered subcutaneously every week When transitioning from ACTEMRA intravenous therapy to subcutaneous administration administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.2)]. 2.3 Recommended Dosage for Giant Cell Arteritis Recommended Intravenous Dosage Regimen: The recommended dosage of ACTEMRA for adult patients given as a 60-minute single intravenous drip infusion is 6 mg per kg every 4 weeks in combination with tapering course of glucocorticoids. ACTEMRA can be used alone following discontinuation of glucocorticoids. • Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11)]. • Doses exceeding 600 mg per infusion are not recommended in GCA patients [see Clinical Pharmacology (12.3)]. Reference ID: 5493108 5 I I Recommended Subcutaneous Dosage Regimen: The recommended dose of ACTEMRA for adult patients with GCA is 162 mg given once every week as a subcutaneous injection in combination with a tapering course of glucocorticoids. A dose of 162 mg given once every other week as a subcutaneous injection in combination with a tapering course of glucocorticoids may be prescribed based on clinical considerations. ACTEMRA can be used alone following discontinuation of glucocorticoids. When transitioning from ACTEMRA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11)]. 2.4 Recommended Dosage for Systemic Sclerosis-Associated Interstitial Lung Disease The recommended dose of ACTEMRA for adult patients with SSc-ILD is 162 mg given once every week as a subcutaneous injection. • Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11)]. • Subcutaneous administration with the prefilled ACTPen® autoinjector has not been studied in SSc-ILD. • Intravenous administration is not approved for SSc-ILD. 2.5 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis ACTEMRA may be used as an intravenous infusion or as a subcutaneous injection alone or in combination with methotrexate. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. Recommended Intravenous Dosage Regimen: The recommended dosage of ACTEMRA for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is: Recommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous Dosage Regimen: Recommended Subcutaneous PJIA Dosage Patients less than 30 kg weight 162 mg once every 3 weeks Patients at or above 30 kg weight 162 mg once every 2 weeks When transitioning from ACTEMRA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11]. 2.6 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis ACTEMRA may be used as an intravenous infusion or as a subcutaneous injection alone or in combination with methotrexate. Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate. Reference ID: 5493108 6 I I I I I I Recommended Intravenous Dosage Regimen: The recommended dose of ACTEMRA for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is: Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous Dosage Regimen: Recommended Subcutaneous SJIA Dosage Patients less than 30 kg weight 162 mg once every two weeks Patients at or above 30 kg weight 162 mg once every week When transitioning from ACTEMRA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose when the next scheduled intravenous dose is due. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.11)]. 2.7 Recommended Dosage for Cytokine Release Syndrome (CRS) Use only the intravenous route for treatment of CRS. The recommended dose of ACTEMRA for treatment of CRS given as a 60-minute intravenous infusion is: Recommended Intravenous CRS Dosage Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Alone or in combination with corticosteroids • If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, up to 3 additional doses of ACTEMRA may be administered. The interval between consecutive doses should be at least 8 hours. • Doses exceeding 800 mg per infusion are not recommended in CRS patients. • Subcutaneous administration is not approved for CRS. 2.8 Coronavirus Disease 2019 (COVID-19) Administer ACTEMRA by intravenous infusion only. The recommended dosage of ACTEMRA for treatment of adult patients with COVID-19 is 8 mg per kg administered as a single 60-minute intravenous infusion. If clinical signs or symptoms worsen or do not improve after the first dose, one additional infusion of ACTEMRA may be administered at least 8 hours after the initial infusion. • Doses exceeding 800 mg per infusion are not recommended in patients with COVID-19. • Subcutaneous administration is not approved for COVID-19. 2.9 Preparation and Administration Instructions for Intravenous Infusion ACTEMRA for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows: Reference ID: 5493108 7 • Use a sterile needle and syringe to prepare ACTEMRA. • Patients less than 30 kg: use a 50 mL infusion bag or bottle of 0.9% or 0.45% Sodium Chloride Injection, USP, and then follow steps 1 and 2 below. • Patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps 1 and 2 below. • Step 1. Withdraw a volume of 0.9% or 0.45% Sodium Chloride Injection, USP, equal to the volume of the ACTEMRA injection required for the patient’s dose from the infusion bag or bottle [see Dosage and Administration (2.2, 2.5, 2.6, 2.7)]. For Intravenous Use: Volume of ACTEMRA Injection per kg of Body Weight Dosage Indication Volume of ACTEMRA injection per kg of body weight 4 mg/kg Adult RA 0.2 mL/kg 6 mg/kg Adult GCA 0.3 mL/kg 8 mg/kg Adult RA Adult COVID-19 SJIA, PJIA and CRS (greater than or equal to 30 kg of body weight) 0.4 mL/kg 10 mg/kg PJIA (less than 30 kg of body weight) 0.5 mL/kg 12 mg/kg SJIA and CRS (less than 30 kg of body weight) 0.6 mL/kg • Step 2. Withdraw the amount of ACTEMRA for intravenous infusion from the vial(s) and add slowly into the 0.9% or 0.45% Sodium Chloride Injection, USP infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming. • The fully diluted ACTEMRA solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored at 36°F to 46°F (2°C to 8°C) or room temperature for up to 24 hours and should be protected from light. • The fully diluted ACTEMRA solutions for infusion using 0.45% Sodium Chloride Injection, USP may be stored at 36°F to 46°F (2°C to 8°C) for up to 24 hours or room temperature for up to 4 hours and should be protected from light. • ACTEMRA solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used. • Allow the fully diluted ACTEMRA solution to reach room temperature prior to infusion. • The infusion should be administered over 60 minutes, and must be administered with an infusion set. Do not administer as an intravenous push or bolus. • ACTEMRA should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of ACTEMRA with other drugs. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used. • Fully diluted ACTEMRA solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles. 2.10 Preparation and Administration Instructions for Subcutaneous Injection • ACTEMRA for subcutaneous injection is not intended for intravenous drip infusion. • Assess suitability of patient for subcutaneous home use and instruct patients to inform a healthcare professional before administering the next dose if they experience any symptoms of allergic reaction. Patients should seek immediate medical attention if they develop symptoms of serious allergic reactions. ACTEMRA subcutaneous injection is intended for use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject ACTEMRA or the patient’s caregiver may Reference ID: 5493108 8 administer ACTEMRA if a healthcare practitioner determines that it is appropriate. PJIA and SJIA patients may self-inject with the ACTEMRA prefilled syringe or ACTPen® autoinjector, or the patient’s caregiver may administer ACTEMRA if both the healthcare practitioner and the parent/legal guardian determines it is appropriate [see Use in Specific Populations (8.4)]. Patients, or patient caregivers, should be instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication administration. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use ACTEMRA prefilled syringes (PFS) or prefilled ACTPen® autoinjectors exhibiting particulate matter, cloudiness, or discoloration. ACTEMRA for subcutaneous administration should be clear and colorless to pale yellow. Do not use if any part of the PFS or ACTPen® autoinjector appears to be damaged. • Patients using ACTEMRA for subcutaneous administration should be instructed to inject the full amount in the syringe (0.9 mL) or full amount in the ACTPen® autoinjector (0.9 mL), which provides 162 mg of ACTEMRA, according to the directions provided in the IFU. • Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. 2.11 Dosage Modifications due to Serious Infections or Laboratory Abnormalities Serious Infections Hold ACTEMRA treatment if a patient develops a serious infection until the infection is controlled. Laboratory Abnormalities Rheumatoid Arthritis, Giant Cell Arteritis and Systemic Sclerosis-Associated Interstitial Lung Disease Liver Enzyme Abnormalities [see Warnings and Precautions (5.3,5.4)] Lab Value Recommendation for RA and SSc-ILD Recommendation for GCA Greater than 1 to 3x ULN Dose modify concomitant DMARDs if appropriate For persistent increases in this range: • For patients receiving intravenous ACTEMRA, reduce dose to 4 mg per kg or hold ACTEMRA until ALT or AST have normalized • For patients receiving subcutaneous ACTEMRA, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume ACTEMRA at every other week and increase frequency to every week as clinically appropriate. Dose modify immunomodulatory agents if appropriate For persistent increases in this range: • For patients receiving intravenous ACTEMRA, hold ACTEMRA until ALT or AST have normalized • For patients receiving subcutaneous ACTEMRA, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume ACTEMRA at every other week and increase frequency to every week as clinically appropriate Greater than 3 to 5x ULN (confirmed by repeat testing) Hold ACTEMRA dosing until less than 3x ULN and follow recommendations above for greater than 1 to 3x ULN For persistent increases greater than 3x ULN, discontinue ACTEMRA Hold ACTEMRA dosing until less than 3x ULN and follow recommendations above for greater than 1 to 3x ULN For persistent increases greater than 3x ULN, discontinue ACTEMRA Reference ID: 5493108 9 Greater 5x ULN than Discontinue ACTEMRA Discontinue ACTEMRA Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5.4)] Lab Value (cells per mm3) Recommendation for RA and SSc- ILD Recommendation for GCA ANC greater than 1000 Maintain dose Maintain dose ANC 500 to 1000 Hold ACTEMRA dosing When ANC greater than 1000 cells 3 per mm : • For patients receiving intravenous ACTEMRA, resume ACTEMRA at 4 mg per kg and increase to 8 mg per kg as clinically appropriate • For patients receiving subcutaneous ACTEMRA, resume ACTEMRA at every other week and increase frequency to every week as clinically appropriate Hold ACTEMRA dosing When ANC greater than 1000 cells per 3 mm : • For patients receiving intravenous ACTEMRA, resume ACTEMRA at 6 mg per kg • For patients receiving subcutaneous ACTEMRA, resume ACTEMRA at every other week and increase frequency to every week as clinically appropriate ANC less than 500 Discontinue ACTEMRA Discontinue ACTEMRA Low Platelet Count [see Warnings and Precautions (5.4)] Lab Value (cells per mm3) Recommendation for RA and SSc-ILD Recommendation for GCA 50,000 to 100,000 Hold ACTEMRA dosing When platelet count is greater than 100,000 cells per mm3: • For patients receiving intravenous ACTEMRA, resume ACTEMRA at 4 mg per kg and increase to 8 mg per kg as clinically appropriate • For patients receiving subcutaneous ACTEMRA, resume ACTEMRA at every other week and increase Hold ACTEMRA dosing When platelet count is greater than 100,000 cells per mm3: • For patients receiving intravenous ACTEMRA, resume ACTEMRA at 6 mg per kg • For patients receiving subcutaneous ACTEMRA, resume ACTEMRA at every other week and increase Reference ID: 5493108 10 frequency to every clinically appropriate week as frequency to every clinically appropriate week as Less 50,000 than Discontinue ACTEMRA Discontinue ACTEMRA Polyarticular and Systemic Juvenile Idiopathic Arthritis Dose reduction of ACTEMRA has not been studied in the PJIA and SJIA populations. Dose interruptions of ACTEMRA are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined above for patients with RA and GCA. If appropriate, dose modify or stop concomitant methotrexate and/or other medications and hold ACTEMRA dosing until the clinical situation has been evaluated. In PJIA and SJIA the decision to discontinue ACTEMRA for a laboratory abnormality should be based upon the medical assessment of the individual patient. 3 DOSAGE FORMS AND STRENGTHS Intravenous Infusion Injection: 80 mg/4 mL, 200 mg/10 mL, 400 mg/20 mL as a clear, colorless to pale yellow solution in 20 mg/mL single-dose vials for further dilution prior to intravenous infusion. Subcutaneous Injection Injection: 162 mg/0.9 mL clear, colorless to slightly yellowish solution in a single-dose prefilled syringe or single- dose prefilled ACTPen® autoinjector. 4 CONTRAINDICATIONS ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA [see Warnings and Precautions (5.6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including ACTEMRA. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with ACTEMRA. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections. Do not administer ACTEMRA in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating ACTEMRA in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of serious or an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection. Reference ID: 5493108 11 Closely monitor patients for the development of signs and symptoms of infection during and after treatment with ACTEMRA, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.8), Adverse Reactions (6.1), and Patient Counseling Information (17)]. Hold ACTEMRA if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with ACTEMRA should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient. COVID-19 In patients with COVID-19, monitor for signs and symptoms of new infections during and after treatment with ACTEMRA. There is limited information regarding the use of ACTEMRA in patients with COVID-19 and concomitant active serious infections. The risks and benefits of treatment with ACTEMRA in COVID-19 patients with other concurrent infections should be considered. Tuberculosis Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating ACTEMRA. In patients with COVID-19, testing for latent infection is not necessary prior to initiating treatment with ACTEMRA. Consider anti-tuberculosis therapy prior to initiation of ACTEMRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti- tuberculosis therapy is appropriate for an individual patient. Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating ACTEMRA. Viral Reactivation Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with ACTEMRA. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded. 5.2 Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with ACTEMRA. Use ACTEMRA with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with fever, new onset abdominal symptoms, and a change in bowel habits for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)]. 5.3 Hepatotoxicity Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous ACTEMRA. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from months to years after treatment initiation with tocilizumab. While most cases presented with marked elevations of transaminases (> 5 times ULN), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases. During randomized controlled studies, treatment with ACTEMRA was associated with a higher incidence of transaminase elevations [see Adverse Reactions (6.1, 6.2, 6.6, 6.8)]. Increased frequency and magnitude of these Reference ID: 5493108 12 elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with ACTEMRA. For RA, GCA and SSc-ILD patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating ACTEMRA, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter. It is not recommended to initiate ACTEMRA treatment in RA, GCA or SSc-ILD patients with elevated transaminases ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than 5x ULN, discontinue ACTEMRA. For recommended modifications based upon increase in transaminases see Dosage and Administration (2.11). Patients hospitalized with COVID-19 may have elevated ALT or AST levels. Multi-organ failure with involvement of the liver is recognized as a complication of severe COVID-19. The decision to administer ACTEMRA should balance the potential benefit of treating COVID-19 against the potential risks of acute treatment with ACTEMRA. It is not recommended to initiate ACTEMRA treatment in COVID-19 patients with elevated ALT or AST above 10 x ULN. Monitor ALT and AST during treatment. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (e.g., ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range), ACTEMRA treatment should be interrupted and investigation done to establish the probable cause. ACTEMRA should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests. A similar pattern of liver enzyme elevation is noted with ACTEMRA treatment in the PJIA and SJIA populations. Monitor liver test panel at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. 5.4 Changes in Laboratory Parameters Patients with Rheumatoid Arthritis, Giant Cell Arteritis, Systemic Sclerosis-Associated Interstitial Lung Disease and Coronavirus Disease 2019 Neutropenia Treatment with ACTEMRA was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience. – It is not recommended to initiate ACTEMRA treatment in RA, GCA and SSc-ILD patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm3. In patients who develop an absolute neutrophil count less than 500 per mm3 treatment is not recommended. – Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter [see Clinical Pharmacology (12.2)]. For recommended modifications based on ANC results see Dosage and Administration (2.11). – It is not recommended to initiate ACTEMRA treatment in COVID-19 patients with an ANC less than 1000 per mm 3. Neutrophils should be monitored. Thrombocytopenia Treatment with ACTEMRA was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials [see Adverse Reactions (6.1, 6.2)]. Reference ID: 5493108 13 – It is not recommended to initiate ACTEMRA treatment in RA, GCA and SSc-ILD patients with a platelet count below 100,000 per mm3. In patients who develop a platelet count less than 50,000 per mm3 treatment is not recommended. – Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts see Dosage and Administration (2.11). – In COVID-19 patients with a platelet count less than 50,000 per mm3, treatment is not recommended. Platelets should be monitored. Elevated Liver Enzymes Refer to 5.3 Hepatotoxicity. For recommended modifications [see Dosage and Administration (2.11)] Lipid Abnormalities Treatment with ACTEMRA was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol [see Adverse Reactions (6.1, 6.2)]. – Assess lipid parameters approximately 4 to 8 weeks following initiation of ACTEMRA therapy. – Subsequently, manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia. Patients with Polyarticular and Systemic Juvenile Idiopathic Arthritis A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with ACTEMRA treatment in the PJIA and SJIA populations. Monitor neutrophils, platelets, ALT and AST at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Monitor lipids as above for approved adult indications [see Dosage and Administration (2.11)]. 5.5 Immunosuppression The impact of treatment with ACTEMRA on the development of malignancies is not known but malignancies were observed in clinical studies [see Adverse Reactions (6.1)]. ACTEMRA is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies. 5.6 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis, have been reported in association with ACTEMRA and anaphylactic events with a fatal outcome have been reported with intravenous infusion of ACTEMRA. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous ACTEMRA, 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1465) of patients in the subcutaneous all-exposure population. In the SJIA controlled trial with intravenous ACTEMRA, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous ACTEMRA, 0 out of 188 patients (0%) in the ACTEMRA all-exposure population experienced hypersensitivity reactions that required treatment discontinuation. Reactions that required treatment discontinuation included generalized erythema, rash, and urticaria. Injection site reactions were categorized separately [see Adverse Reactions (6)]. In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous ACTEMRA, with or without concomitant therapies. Events have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of ACTEMRA [see Adverse Reactions (6.12)]. In addition, serious cutaneous reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported in patients with autoinflammatory conditions treated with ACTEMRA. Reference ID: 5493108 14 6 ACTEMRA for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. For ACTEMRA subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If a hypersensitivity reaction occurs, immediately discontinue ACTEMRA, treat promptly and monitor until signs and symptoms resolve. 5.7 Demyelinating Disorders The impact of treatment with ACTEMRA on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of ACTEMRA in patients with preexisting or recent onset demyelinating disorders. 5.8 Active Hepatic Disease and Hepatic Impairment Treatment with ACTEMRA is not recommended in patients with active hepatic disease or hepatic impairment [see Adverse Reactions (6.1), Use in Specific Populations (8.6)]. 5.9 Vaccinations Avoid use of live vaccines concurrently with ACTEMRA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ACTEMRA. No data are available on the effectiveness of vaccination in patients receiving ACTEMRA. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly pediatric or elderly patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ACTEMRA therapy. The interval between live vaccinations and initiation of ACTEMRA therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: • Serious Infections [see Warnings and Precautions (5.1)] • Gastrointestinal Perforations [see Warnings and Precautions (5.2)] • Laboratory Parameters [see Warnings and Precautions (5.4)] • Immunosuppression [see Warnings and Precautions (5.5)] • Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.6)] • Demyelinating Disorders [see Warnings and Precautions (5.7)] • Active Hepatic Disease and Hepatic Impairment [see Warnings and Precautions (5.8)] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. 6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous ACTEMRA (ACTEMRA-IV) The ACTEMRA-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of ACTEMRA-IV 8 mg per kg monotherapy (288 patients), ACTEMRA­ IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or ACTEMRA-IV 4 mg per kg in combination with methotrexate (774 patients). Reference ID: 5493108 15 The all exposure population includes all patients in registration studies who received at least one dose of ACTEMRA-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years. All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian. The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1)]. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with ACTEMRA-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT. The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking ACTEMRA-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of ACTEMRA-IV were increased hepatic transaminase values (per protocol requirement) and serious infections. Overall Infections In the 24 week, controlled clinical studies, the rate of infections in the ACTEMRA-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group was 133 and 127 events per 100 patient- years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis. The overall rate of infections with ACTEMRA-IV in the all exposure population remained consistent with rates in the controlled periods of the studies. Serious Infections In the 24 week, controlled clinical studies, the rate of serious infections in the ACTEMRA-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group. In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported [see Warnings and Precautions (5.1)]. In the cardiovascular outcomes Study WA25204, the rate of serious infections in the ACTEMRA 8 mg/kg IV every 4 weeks group, with or without DMARD, was 4.5 per 100 patient-years, and the rate in the etanercept 50 mg weekly SC group, with or without DMARD, was 3.2 per 100 patient-years [see Clinical Studies (14.1)]. Gastrointestinal Perforations During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with ACTEMRA-IV therapy. In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti- inflammatory medications (NSAIDs), corticosteroids, or methotrexate [see Warnings and Precautions (5.2)]. The relative contribution of these concomitant medications versus ACTEMRA-IV to the development of GI perforations is not known. Reference ID: 5493108 16 Infusion Reactions In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting. Anaphylaxis Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with ACTEMRA-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of ACTEMRA-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction [see Warnings and Precautions (5.6)]. Laboratory Abnormalities Neutropenia In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm3 occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm3 occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm3 and the occurrence of serious infections. In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.4)]. Thrombocytopenia In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm3 occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events. In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.4)]. Elevated Liver Enzymes Liver enzyme abnormalities are summarized in Table 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of ACTEMRA-IV, or reduction in ACTEMRA-IV dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration (2.11)]. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency [see Warnings and Precautions (5.3, 5.4)]. Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V* ACTEMRA 8 mg per kg MONOTHERAPY N = 288 (%) Methotrexate N = 284 (%) ACTEMRA 4 mg per kg + DMARDs N = 774 (%) ACTEMRA 8 mg per kg + DMARDs N = 1582 (%) Placebo + DMARDs N = 1170 (%) AST (U/L) Reference ID: 5493108 17 > ULN to 3x ULN 22 26 34 41 17 > 3x ULN to 5x ULN 0.3 2 1 2 0.3 > 5x ULN 0.7 0.4 0.1 0.2 < 0.1 ALT (U/L) > ULN to 3x ULN 36 33 45 48 23 > 3x ULN to 5x ULN 1 4 5 5 1 > 5x ULN 0.7 1 1.3 1.5 0.3 ULN = Upper Limit of Normal *For a description of these studies, see Section 14, Clinical Studies. In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials. In Study WA25204, of the 1538 patients with moderate to severe RA [see Clinical Studies (14.1)] and treated with tocilizumab, elevations in ALT or AST >3 x ULN occurred in 5.3% and 2.2% patients, respectively. One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with tocilizumab. Lipids Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of ACTEMRA-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below: – Mean LDL increased by 13 mg per dL in the ACTEMRA 4 mg per kg+DMARD arm, 20 mg per dL in the ACTEMRA 8 mg per kg+DMARD, and 25 mg per dL in ACTEMRA 8 mg per kg monotherapy. – Mean HDL increased by 3 mg per dL in the ACTEMRA 4 mg per kg+DMARD arm, 5 mg per dL in the ACTEMRA 8 mg per kg+DMARD, and 4 mg per dL in ACTEMRA 8 mg per kg monotherapy. – Mean LDL/HDL ratio increased by an average of 0.14 in the ACTEMRA 4 mg per kg+DMARD arm, 0.15 in the ACTEMRA 8 mg per kg+DMARD, and 0.26 in ACTEMRA 8 mg per kg monotherapy. – ApoB/ApoA1 ratios were essentially unchanged in ACTEMRA-treated patients. Elevated lipids responded to lipid lowering agents. In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to tocilizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies. Malignancies During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving ACTEMRA-IV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the ACTEMRA-IV groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years). Reference ID: 5493108 18 In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period [see Warnings and Precautions (5.5)]. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg ACTEMRA-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2. Table 2 Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per kg ACTEMRA plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD 24 Week Phase 3 Controlled Study Population Preferred Term ACTEMRA 8 mg per kg MONOTHERAPY N = 288 (%) Methotrexate N = 284 (%) ACTEMRA 4 mg per kg + DMARDs N = 774 (%) ACTEMRA 8 mg per kg + DMARDs N = 1582 (%) Placebo + DMARDs N = 1170 (%) Upper Respiratory Tract Infection 7 5 6 8 6 Nasopharyngitis 7 6 4 6 4 Headache 7 2 6 5 3 Hypertension 6 2 4 4 3 ALT increased 6 4 3 3 1 Dizziness 3 1 2 3 2 Bronchitis 3 2 4 3 3 Rash 2 1 4 3 1 Mouth Ulceration 2 2 1 2 1 Abdominal Pain Upper 2 2 3 3 2 Gastritis 1 2 1 2 1 Transaminase increased 1 5 2 2 1 Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with ACTEMRA-IV in controlled trials were: Infections and Infestations: oral herpes simplex Gastrointestinal disorders: stomatitis, gastric ulcer Investigations: weight increased, total bilirubin increased Blood and lymphatic system disorders: leukopenia General disorders and administration site conditions: edema peripheral Respiratory, thoracic, and mediastinal disorders: dyspnea, cough Eye disorders: conjunctivitis Renal disorders: nephrolithiasis Endocrine disorders: hypothyroidism 6.2 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC) The ACTEMRA-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously and 8 mg/kg intravenously every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week subcutaneously or placebo in 656 patients. All patients in both studies received background non-biologic DMARDs. Reference ID: 5493108 19 The safety observed for ACTEMRA-SC administered subcutaneously was consistent with the known safety profile of intravenous ACTEMRA, with the exception of injection site reactions (ISRs), which were more common with ACTEMRA-SC compared with placebo SC injections (IV arm). Injection Site Reactions In the 6-month control period, in SC-I, the frequency of ISRs was 10.1% (64/631) and 2.4% (15/631) for the weekly ACTEMRA-SC and placebo SC (IV-arm) groups, respectively. In SC-II, the frequency of ISRs was 7.1% (31/437) and 4.1% (9/218) for the every other week ACTEMRA-SC and placebo groups, respectively. These ISRs (including erythema, pruritus, pain and hematoma) were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation. Immunogenicity In the 6-month control period in SC-I, 0.8% (5/625) in the ACTEMRA-SC arm and 0.8% (5/627) in the IV arm developed anti-tocilizumab antibodies; of these, all developed neutralizing antibodies. In SC-II, 1.6% (7/434) in the ACTEMRA-SC arm compared with 1.4 % (3/217) in the placebo arm developed anti- tocilizumab antibodies; of these, 1.4% (6/434) in the ACTEMRA-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies. A total of 1454 (>99%) patients who received ACTEMRA-SC in the all exposure group have been tested for anti­ tocilizumab antibodies. Thirteen patients (0.9%) developed anti-tocilizumab antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies. The rate is consistent with previous intravenous experience. No correlation of antibody development to adverse events or loss of clinical response was observed. Laboratory Abnormalities Neutropenia During routine laboratory monitoring in the 6-month controlled clinical trials, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% and 3.7% of patients receiving ACTEMRA-SC weekly and every other week, respectively. There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections. Thrombocytopenia During routine laboratory monitoring in the ACTEMRA-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤50,000/mm3. Elevated Liver Enzymes During routine laboratory monitoring in the 6-month controlled clinical trials, elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively, receiving ACTEMRA-SC weekly and 3.4% and 0.7% receiving ACTEMRA-SC every other week. Lipid Parameters Elevations During routine laboratory monitoring in the ACTEMRA-SC 6-month clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and 10.2% of patients on placebo experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l (160 mg/dL) receiving ACTEMRA-SC weekly, every other week and placebo, respectively. 6.3 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC) The safety of subcutaneous ACTEMRA (tocilizumab) has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the ACTEMRA-SC GCA all exposure population was 138.5 patient years during the 12-month double blind, placebo-controlled phase of the study. The overall safety Reference ID: 5493108 20 profile observed in the ACTEMRA-SC treatment groups was generally consistent with the known safety profile of ACTEMRA. There was an overall higher incidence of infections in GCA patients relative to RA patients. The rate of infection/serious infection events was 200.2/9.7 events per 100 patient years in the ACTEMRA-SC weekly group and 160.2/4.4 events per 100 patient years in the ACTEMRA-SC every other week group as compared to 156.0/4.2 events per 100 patient years in the placebo + 26 week prednisone taper and 210.2/12.5 events per 100 patient years in the placebo + 52 week taper groups. 6.4 Clinical Trials Experience in Giant Cell Arteritis Patients Treated With Intravenous ACTEMRA (ACTEMRA-IV) The safety of ACTEMRA-IV was studied in an open label PK-PD and safety study in 24 patients with GCA who were in remission on ACTEMRA-IV at time of enrollment. Patients received ACTEMRA 7 mg/kg every 4 weeks for 20 weeks, followed by 6 mg/kg every 4 weeks for 20 weeks. The total patient years exposure to treatment was 17.5 years. The overall safety profile observed for ACTEMRA administered intravenously in GCA patients was consistent with the known safety profile of ACTEMRA. 6.5 Clinical Trials Experience in Systemic Sclerosis-Associated Interstitial Lung Disease Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC) The safety of subcutaneous ACTEMRA was evaluated in two double-blind, placebo-controlled, multicenter studies (WA29767 and WA27788). In the Phase 3 Study WA29767, 212 patients with SSc were randomized to tocilizumab 162 mg administered every week subcutaneously or placebo for 48 weeks, followed by open-label tocilizumab 162 mg administered subcutaneously every week for another 48 weeks. In the Phase 2/3 Study WA27788, 87 patients were randomized to tocilizumab 162 mg administered every week subcutaneously or placebo for 48 weeks, followed by open-label tocilizumab 162 mg administered subcutaneously every week for another 48 weeks. The safety profile for ACTEMRA through week 48 in WA29767 was comparable for SSc-ILD and SSc patients overall, and in both studies was consistent with the known safety profile of ACTEMRA. Immunogenicity In the two clinical studies, WA29767 and WA27788, the incidence of treatment-induced anti-TCZ antibodies at week 96 was low (3 out of 169 patients, 1.8%). These anti-drug antibodies were of neutralizing potential, and none of the patients experienced hypersensitivity reactions. 6.6 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Intravenous ACTEMRA (ACTEMRA-IV) The safety of ACTEMRA-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the ACTEMRA-IV all exposure population (defined as patients who received at least one dose of ACTEMRA-IV) was 184.4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients [see Adverse Reactions (6.1 and 6.8)]. Infections The rate of infections in the ACTEMRA-IV all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%). Infusion Reactions In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the ACTEMRA-IV all exposure population, 11 patients (6%) experienced an event during the infusion, Reference ID: 5493108 21 and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and SJIA patients [see Adverse Reactions (6.1 and 6.8)]. No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported. Immunogenicity One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study. Laboratory Abnormalities Neutropenia During routine laboratory monitoring in the ACTEMRA-IV all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 3.7% of patients. There was no clear relationship between decreases in neutrophils below 1 x 109 per L and the occurrence of serious infections. Thrombocytopenia During routine laboratory monitoring in the ACTEMRA-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50,000 per mm3 without associated bleeding events. Elevated Liver Enzymes During routine laboratory monitoring in the ACTEMRA-IV all exposure population, elevation in ALT or AST at or greater than 3 x ULN occurred in 4% and less than 1% of patients, respectively. Lipids During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol greater than 1.5-2 x ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 x ULN occurred in one patient (0.5%). 6.7 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Subcutaneous ACTEMRA (ACTEMRA-SC) The safety of ACTEMRA-SC was studied in 52 pediatric patients 1 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the PJIA ACTEMRA-SC population (defined as patients who received at least one dose of ACTEMRA-SC and accounting for treatment discontinuation) was 49.5 patient years. In general, the safety observed for ACTEMRA administered subcutaneously was consistent with the known safety profile of intravenous ACTEMRA, with the exception of injection site reactions (ISRs), and neutropenia. Injection Site Reactions During the 1-year study, a frequency of 28.8% (15/52) ISRs was observed in ACTEMRA-SC treated PJIA patients. These ISRs occurred in a greater proportion of patients at or above 30 kg (44.0%) compared with patients below 30 kg (14.8%). All ISRs were mild in severity and none of the ISRs required patient withdrawal from treatment or dose interruption. A higher frequency of ISRs was observed in ACTEMRA-SC treated PJIA patients compared to what was seen in adult RA or GCA patients [see Adverse Reactions (6.2 and 6.3)]. Immunogenicity Three patients, 1 patient below 30 kg and 2 patients at or above 30 kg, developed positive anti-tocilizumab antibodies with neutralizing potential without developing a serious or clinically significant hypersensitivity reaction. One patient subsequently withdrew from the study. Reference ID: 5493108 22 Neutropenia During routine laboratory monitoring in the ACTEMRA-SC all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 15.4% of patients, and was more frequently observed in the patients less than 30 kg (25.9%) compared to patients at or above 30 kg (4.0%). There was no clear relationship between decreases in neutrophils below 1 x 109 per L and the occurrence of serious infections. 6.8 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous ACTEMRA (ACTEMRA-IV) The data described below reflect exposure to ACTEMRA-IV in one randomized, double-blind, placebo- controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy. At baseline, approximately half of the patients were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension. In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with ACTEMRA­ IV (8 or 12 mg per kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated with ACTEMRA-IV in the open-label extension phase. The most common adverse events (at least 5%) seen in ACTEMRA-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea. Infections In the 12 week controlled phase, the rate of all infections in the ACTEMRA-IV group was 345 per 100 patient- years and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years. In the 12 week controlled phase, the rate of serious infections in the ACTEMRA-IV group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media. Macrophage Activation Syndrome In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with ACTEMRA-IV. One patient in the placebo group escaped to ACTEMRA-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had ACTEMRA-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the ACTEMRA-IV SJIA clinical development experience; however no definitive conclusions can be made. Infusion Reactions Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA. Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of ACTEMRA-IV and 0% of placebo treated patients experienced events occurring during infusion. One event (angioedema) was considered serious and life- threatening, and the patient was discontinued from study treatment. Within 24 hours after infusion, 16% of patients in the ACTEMRA-IV treatment group and 5% of patients in the placebo group experienced an event. In the ACTEMRA-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious. Reference ID: 5493108 23 Anaphylaxis Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with ACTEMRA-IV during the controlled and open label extension study [see Warnings and Precautions (5.6)]. Immunogenicity All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti­ tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study. Laboratory Abnormalities Neutropenia During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 × 109 per L occurred in 7% of patients in the ACTEMRA-IV group, and in no patients in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the ACTEMRA-IV group. There was no clear relationship between decrease in neutrophils below 1 x 109 per L and the occurrence of serious infections. Thrombocytopenia During routine monitoring in the 12 week controlled phase, 1% of patients in the ACTEMRA-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100,000 per mm3. In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the ACTEMRA-IV group, with no associated bleeding. Elevated Liver Enzymes During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3x ULN occurred in 5% and 3% of patients, respectively in the ACTEMRA-IV group and in 0% of placebo patients. In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3x ULN occurred in 13% and 5% of ACTEMRA-IV treated patients, respectively. Lipids During routine laboratory monitoring in the 12 week controlled phase, elevation in total cholesterol greater than 1.5x ULN – 2x ULN occurred in 1.5% of the ACTEMRA-IV group and in 0% of placebo patients. Elevation in LDL greater than 1.5x ULN – 2x ULN occurred in 1.9% of patients in the ACTEMRA-IV group and 0% of the placebo group. In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data. 6.9 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC) The safety profile of ACTEMRA-SC was studied in 51 pediatric patients 1 to 17 years of age with SJIA who had an inadequate clinical response to NSAIDs and corticosteroids. In general, the safety observed for ACTEMRA administered subcutaneously was consistent with the known safety profile of intravenous ACTEMRA, with the exception of ISRs where a higher frequency was observed in ACTEMRA-SC treated SJIA patients compared to PJIA patients and adult RA or GCA patients [see Adverse Reactions (6.2, 6.3 and 6.7)]. Injection Site Reactions (ISRs) A total of 41.2% (21/51) SJIA patients experienced ISRs to ACTEMRA-SC. The most common ISRs were erythema, pruritus, pain, and swelling at the injection site. The majority of ISRs reported were Grade 1 events and all ISRs reported were non-serious and none required patient withdrawal from treatment or dose interruption. Reference ID: 5493108 24 Immunogenicity Forty-six of the 51 (90.2%) patients who were tested for anti-tocilizumab antibodies at baseline had at least one post-baseline screening assay result. No patient developed positive anti-tocilizumab antibodies post-baseline. 6.10 Clinical Trials Experience in Patients with Cytokine Release Syndrome Treated with Intravenous ACTEMRA (ACTEMRA-IV) In a retrospective analysis of pooled outcome data from multiple clinical trials 45 patients were treated with tocilizumab 8 mg/kg (12 mg/kg for patients less than 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CAR T-cell-induced CRS. A median of 1 dose of tocilizumab (range, 1-4 doses) was administered. No adverse reactions related to tocilizumab were reported [see Clinical Studies (14.10)]. 6.11 Clinical Trials Experience in COVID-19 Patients Treated with Intravenous ACTEMRA (ACTEMRA-IV) The safety of ACTEMRA in hospitalized COVID-19 patients was evaluated in a pooled safety population that includes patients enrolled in EMPACTA, COVACTA, AND REMDACTA. The analysis of adverse reactions included a total of 974 patients exposed to ACTEMRA. Patients received a single, 60-minute infusion of intravenous ACTEMRA 8 mg/kg (maximum dose of 800 mg). If clinical signs or symptoms worsened or did not improve, one additional dose of ACTEMRA 8 mg/kg could be administered between 8- 24 hours after the initial dose. Adverse reactions summarized in Table 3 occurred in at least 3% of ACTEMRA-treated patients and more commonly than in patients on placebo in the pooled safety population. Table 3 Adverse Reactions1 Identified From the Pooled COVID-19 Safety Population Adverse Reaction ACTEMRA 8 mg per kg N = 974 (%) Placebo N = 483 (%) Hepatic Transaminases increased 10% 8% Constipation 9 % 8% Urinary tract infection 5% 4% Hypertension 4% 1% Hypokalaemia 4% 3% Anxiety 4% 2% Diarrhea 4% 2% Insomnia 4% 3% Nausea 3% 2% 1 Patients are counted once for each category regardless of the number of reactions In the pooled safety population, the rates of infection/serious infection events were 30%/19% in patients receiving ACTEMRA versus 32%/23% receiving placebo. Laboratory Abnormalities In the pooled safety population of EMPACTA, COVACTA, and REMDACTA, neutrophil counts <1000 cells/mcl occurred in 3.4% of patients who received ACTEMRA and 0.5% of patients who received placebo. Platelet counts <50,000 cells/mcl occurred in 3.2% of patients who received ACTEMRA and 1.5% of patients who received placebo. ALT or AST at or above 5x ULN occurred in 11.7% of patients who received ACTEMRA and 9.9% of patients who received placebo. Reference ID: 5493108 25 6.12 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ACTEMRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Hypersensitivity Reactions: Fatal anaphylaxis, Stevens-Johnson Syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)] • Pancreatitis • Drug-induced liver injury, Hepatitis, Hepatic failure, Jaundice [see Warnings and Precautions (5.3)] 7 DRUG INTERACTIONS 7.1 Concomitant Drugs for Treatment of Adult Indications In RA patients, population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non- steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. Concomitant administration of a single intravenous dose of 10 mg/kg ACTEMRA with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. ACTEMRA has not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration (2.2)]. In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed. 7.2 Interactions with CYP450 Substrates Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effect on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of ACTEMRA, respectively. The effect of tocilizumab on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of ACTEMRA, in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise caution when coadministering ACTEMRA with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12.3)]. 7.3 Live Vaccines Avoid use of live vaccines concurrently with ACTEMRA [see Warnings and Precautions (5.9)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The available data with ACTEMRA from a pregnancy exposure registry, retrospective cohort study, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. These studies had methodological limitations, including small sample size of tocilizumab exposed groups, missing exposure and outcomes information, and lack of adjustment for cofounders. Monoclonal antibodies, such as tocilizumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in Reference ID: 5493108 26 utero exposed infant [see Clinical Considerations]. In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition [see Data]. Based on the animal data, there may be a potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to ACTEMRA in utero [see Warnings and Precautions 5.9)]. Disease-associated Maternal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Data Animal Data An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring. Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6 -/- null mice restored the normal timing of delivery. 8.2 Lactation Risk Summary No information is available on the presence of tocilizumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of ACTEMRA to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ACTEMRA and the potential adverse effects on the breastfed child from tocilizumab or from the underlying maternal condition. Reference ID: 5493108 27 8.4 Pediatric Use ACTEMRA by intravenous use is indicated for the treatment of pediatric patients with: • Active systemic juvenile idiopathic arthritis in patients 2 years of age and older • Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older • Severe or life-threatening CAR T cell-induced cytokine release syndrome (CRS) in patients 2 years of age and older. ACTEMRA by subcutaneous use is indicated for the treatment of pediatric patients with: • Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older • Active systemic juvenile idiopathic arthritis in patients 2 years of age and older The safety and effectiveness of ACTEMRA in pediatric patients with conditions other than PJIA, SJIA or CRS have not been established. The safety and effectiveness in pediatric patients below the age of 2 have not been established in PJIA, SJIA, or CRS. Systemic Juvenile Idiopathic Arthritis – Intravenous Use A multicenter, open-label, single arm study to evaluate the PK, safety and exploratory PD and efficacy of ACTEMRA over 12-weeks in SJIA patients (N=11) under 2 years of age was conducted. Patients received intravenous ACTEMRA 12 mg/kg every two weeks. Concurrent use of stable background treatment with corticosteroids, MTX, and/or non-steroidal anti-inflammatory drugs was permitted. Patients who completed the 12-week period could continue to the optional extension period (a total of 52-weeks or until the age of 2 years, whichever was longer). The primary PK endpoints (Cmax, Ctrough and AUC2weeks) of ACTEMRA at steady-state in this study were within the ranges of these parameters observed in patients with SJIA aged 2 to 17 years. The safety and immunogenicity of ACTEMRA for patients with SJIA under 2 years of age was assessed descriptively. SAEs, AEs leading to discontinuation, and infectious AEs were reported by 27.3%, 36.4%, and 81.8% of patients. Six patients (54.5%) experienced hypersensitivity reactions, defined as all adverse events occurring during or within 24 hours after an infusion considered related to ACTEMRA. Three of these patients experienced serious hypersensitivity reactions and were withdrawn from the study. Three patients with hypersensitivity reactions (two with serious hypersensitivity reactions) developed treatment induced anti­ tocilizumab antibodies after the event. There were no cases of MAS based on the protocol-specified criteria, but 2 cases of suspected MAS based on Ravelli criteria1. Cytokine Release Syndrome – Intravenous Use In the retrospective analysis of pooled outcome data for patients treated with ACTEMRA for CAR T cell-induced CRS, 25 patients were children (2 years up to 12 years of age), and 17 patients were adolescents (12 years up to 18 years of age). There were no differences between the pediatric patients and the adults for safety or efficacy. 8.5 Geriatric Use Of the 2644 patients who received ACTEMRA in Studies I to V [see Clinical Studies (14)], a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. Of the 1069 patients who received ACTEMRA-SC in studies SC-I and SC-II there were 295 patients 65 years of age 1 Ravelli A, Minoia F, Davì S on behalf of the Paediatric Rheumatology International Trials Organisation, the Childhood Arthritis and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis. Annals of the Rheumatic Diseases 2016;75:481-489. Reference ID: 5493108 28 9 and older, including 41 patients 75 years and older. The frequency of serious infection among ACTEMRA treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly. Clinical studies that included ACTEMRA for CRS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In the EMPACTA, COVACTA, and REMDACTA studies, of the 974 COVID-19 patients in the ACTEMRA arm, 375 (39%) were 65 years of age or older. No overall differences in safety or effectiveness of ACTEMRA were observed between patients 65 years of age and older and those under the age of 65 years of age in these studies [see Adverse Reactions (6.1) and Clinical Studies (14.11)]. In the RECOVERY study, of the 2022 COVID-19 patients in the ACTEMRA arm, 930 (46%) were 65 years of age or older. No overall differences in effectiveness of ACTEMRA were observed between patients 65 years of age and older and those under the age 65 years of age in this study [see Clinical Studies (14.11)]. 8.6 Hepatic Impairment The safety and efficacy of ACTEMRA have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology [see Warnings and Precautions (5.8)]. 8.7 Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. ACTEMRA has not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. DRUG ABUSE AND DEPENDENCE No studies on the potential for ACTEMRA to cause dependence have been performed. However, there is no evidence from the available data that ACTEMRA treatment results in dependence. 10 OVERDOSAGE There are limited data available on overdoses with ACTEMRA. One case of accidental overdose was reported with intravenous ACTEMRA in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment. 11 DESCRIPTION Tocilizumab is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H2L2 polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. ACTEMRA has a molecular weight of approximately 148 kDa. The antibody is produced in mammalian (Chinese hamster ovary) cells. Intravenous Infusion ACTEMRA (tocilizumab) injection is a sterile, clear, colorless to pale yellow, preservative-free solution for further dilution prior to intravenous infusion with a pH of approximately 6.5. Each single-dose vial, formulated with a disodium phosphate dodecahydrate/sodium dihydrogen phosphate dihydrate buffered solution, is available at a concentration of 20 mg/mL containing 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL of ACTEMRA. Each mL of solution contains polysorbate 80 (0.5 mg), sucrose (50 mg), and Water for Injection, USP. Subcutaneous Injection Reference ID: 5493108 29 ACTEMRA (tocilizumab) injection is a sterile, clear, colorless to slightly yellowish, preservative-free, histidine buffered solution for subcutaneous use with a pH of approximately 6.0. It is supplied in a ready-to-use, single-dose 0.9 mL prefilled syringe (PFS) with a needle safety device or a ready­ to-use, single-dose 0.9 mL autoinjector that delivers 162 mg tocilizumab, L-arginine hydrochloride (19 mg), L- histidine (1.52 mg), L-histidine hydrochloride monohydrate (1.74 mg), L-methionine (4.03 mg), polysorbate 80 (0.18 mg), and Water for Injection, USP. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tocilizumab binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis. 12.2 Pharmacodynamics In clinical studies in RA patients with the 4 mg per kg and 8 mg per kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of ACTEMRA, decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen and increases in hemoglobin) with doses, however the greatest improvements were observed with 8 mg per kg ACTEMRA. Pharmacodynamic changes were also observed to occur after ACTEMRA administration in GCA, SSc-ILD, PJIA, and SJIA patients (decreases in CRP, ESR, and increases in hemoglobin). The relationship between these pharmacodynamic findings and clinical efficacy is not known. In healthy subjects administered ACTEMRA in doses from 2 to 28 mg per kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to the nadir 3 to 5 days following ACTEMRA administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis and GCA patients demonstrated a similar pattern of absolute neutrophil counts following ACTEMRA administration [see Warnings and Precautions (5.4)]. 12.3 Pharmacokinetics PK of tocilizumab is characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of tocilizumab elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies. Rheumatoid Arthritis - Intravenous and Subcutaneous Administration The pharmacokinetics in healthy subjects and RA patients suggest that PK is similar between the two populations. The population PK model was developed from an analysis dataset composed of an IV dataset of 1793 patients from Study I, Study III, Study IV, and Study V, and from an IV and SC dataset of 1759 patients from Studies SC­ I and SC-II. Cmean is included in place of AUCtau, since for dosing regimens with different inter-dose intervals, the mean concentration over the dosing period characterizes the comparative exposure better than AUCtau. Reference ID: 5493108 30 At high serum concentrations, when total clearance of tocilizumab is dominated by linear clearance, a terminal half-life of approximately 21.5 days was derived from the population parameter estimates. For doses of 4 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab at steady state were 86.1 (44.8–202) mcg/mL, 0.1 (0.0–14.6) mcg/mL, and 18.0 (8.9– 50.7) mcg/mL, respectively. For doses of 8 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 176 (75.4–557) mcg/mL, 13.4 (0.1–154) mcg/mL, and 54.0 (17–260) mcg/mL, respectively. Cmax increased dose-proportionally between doses of 4 and 8 mg/kg IV every 4 weeks, while a greater than dose-proportional increase was observed in Cmean and Ctrough. At steady-state, Cmean and Ctrough were 3.0 and 134 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively. The accumulation ratios for AUC and Cmax after multiple doses of 4 and 8 mg/kg IV Q4W are low, while the accumulation ratios for Ctrough are higher (2.62 and 2.47, respectively). For Cmax, greater than 90% of the steady- state value was reached after the 1st IV infusion. For AUCtau and Cmean, 90% of the steady-state value was reached after the 1st and 3rd infusion for 4 mg/kg and 8 mg/kg IV, while for Ctrough, approximately 90% of the steady- state value was reached after the 4th IV infusion after both doses. For doses of 162 mg given every other week subcutaneously, the estimated median (range) steady-state Cmax, Ctrough, and Cmean of tocilizumab were 12.1 (0.4–49.3) mcg/mL, 4.1 (0.0–34.2) mcg/mL, and 9.2 (0.2– 43.6) mcg/mL, respectively. For doses of 162 mg given every week subcutaneously, the estimated median (range) steady-state Cmax, Ctrough, and Cmean of tocilizumab were 49.8 (3–150) mcg/mL, 42.9 (1.3–144) mcg/mL, and 47.3 (2.4–147) mcg/mL, respectively. Exposures after the 162 mg SC QW regimen were greater by 5.1 (Cmean) to 10.5 fold (Ctrough) compared to the 162 mg SC Q2W regimen. Accumulation ratios after multiple doses of either SC regimen were higher than after IV regimen with the highest ratios for Ctrough (6.02 and 6.30, for 162 mg SC Q2W and 162 mg SC QW, respectively). The higher accumulation for Ctrough was expected based on the nonlinear clearance contribution at lower concentrations. For Cmax, greater than 90% of the steady-state value was reached after the 5th SC and the 12th SC injection with the Q2W and QW regimens, respectively. For AUCtau and Cmean, 90% of the steady-state value was reached after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens, respectively. For Ctrough, approximately 90% of the steady- state value was reached after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens, respectively. Population PK analysis identified body weight as a significant covariate impacting the pharmacokinetics of tocilizumab. When given IV on a mg/kg basis, individuals with body weight ≥ 100 kg are predicted to have mean steady-state exposures higher than mean values for the patient population. Therefore, tocilizumab doses exceeding 800 mg per infusion are not recommended in patients with RA [see Dosage and Administration (2.2)]. Due to the flat dosing employed for SC administration of tocilizumab, no modifications are necessary by this dosing route. Giant Cell Arteritis – Subcutaneous and Intravenous Administration The pharmacokinetics of tocilizumab SC in GCA patients was determined using a population pharmacokinetic analysis on a dataset composed of 149 GCA patients treated with 162 mg subcutaneously every week or with 162 mg subcutaneously every other week. For the 162 mg every week dose, the estimated median (range) steady-state Cmax, Ctrough and Cmean of tocilizumab SC were 72.1 (12.2–151) mcg/mL, 67.2 (10.7–145) mcg/mL, and 70.6 (11.7–149) mcg/mL, respectively. The accumulation ratios for Cmean or AUCtau, Ctrough, and Cmax were 10.9, 9.6, and 8.9, respectively. Steady state was reached after 17 weeks. For the 162 mg every other week dose, the estimated median (range) steady-state Cmax, Ctrough, and Cmean of tocilizumab were 17.2 (1.1–56.2) mcg/mL, 7.7 (0.1–37.3) mcg/mL, and 13.7 (0.5– 49) mcg/mL, respectively. The accumulation ratios for Cmean or AUCtau, Ctrough, and Cmax were 2.8, 5.6, and 2.3 respectively. Steady-state was reached after 14 weeks. Reference ID: 5493108 31 The pharmacokinetics of tocilizumab IV in GCA patients was characterized by a non-compartmental pharmacokinetic analysis which included 22 patients treated with 6 mg/kg intravenously every 4 weeks for 20 weeks. The median (range) Cmax, Ctrough and Cmean of tocilizumab at steady state were 178 (115-320) mcg/mL, 22.7 (3.38-54.5) mcg/mL and 57.5 (32.9-110) mcg/mL, respectively. Steady state trough concentrations were within the range observed in GCA patients treated with 162 mg TCZ SC administered every week or every other week. Based on pharmacokinetic exposure and extrapolation between RA and GCA patients, when given IV on a mg/kg basis, tocilizumab doses exceeding 600 mg per infusion are not recommended in patients with GCA [see Dosage and Administration (2.3)]. Systemic Sclerosis-Associated Interstitial Lung Disease – Subcutaneous Administration The pharmacokinetics of tocilizumab in SSc-ILD patients was determined using a population pharmacokinetic analysis on a dataset composed of 66 SSc-ILD patients treated with 162 mg tocilizumab SC every week. The estimated median (range) steady-state Cmax, Ctrough and Cmean of tocilizumab were 52.5 (14.8-121) mcg/mL, 47.2 (10.8-114) mcg/mL, and 50.4 (13.4-119) mcg/mL, respectively. The accumulation ratios for Cmean or AUCtau, Ctrough, and Cmax were 7.11, 6.56, and 5.89, respectively. Steady-state was reached after 13 weeks. Polyarticular Juvenile Idiopathic Arthritis – Intravenous and Subcutaneous Administration The pharmacokinetics of tocilizumab (TCZ) in PJIA patients was characterized by a population pharmacokinetic analysis which included 188 patients who were treated with TCZ IV or 52 patients treated with TCZ SC. For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab at steady state were 181 (114–331) mcg/mL, 3.28 (0.02–35.4) mcg/mL, and 38.6 (22.2–83.8) mcg/mL, respectively. For doses of 10 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 167 (125–220) mcg/mL, 0.35 (0– 11.8) mcg/mL, and 30.8 (16.0–48.0) mcg/mL, respectively. The accumulation ratios were 1.05 and 1.16 for AUC4weeks, and 1.43 and 2.22 for Ctrough for 10 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. No accumulation for Cmax was observed. Following 10 mg/kg and 8 mg/kg TCZ IV every 4 weeks doses in PJIA patients (aged 2 to 17 years), steady state concentrations (trough and average) were within the range of exposures in adult RA patients following 4 mg/kg and 8 mg/kg every 4 weeks, and steady state peak concentrations in PJIA patients were comparable to those following 8 mg/kg every 4 weeks in adult RA patients. For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks subcutaneously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 29.7 (7.56– 50.3) mcg/mL, 12.7 (0.19–23.8) mcg/mL, and 23.0 (3.86–36.9) mcg/mL, respectively. For doses of 162 mg tocilizumab (patients with a body weight less than 30 kg) given every 3 weeks subcutaneously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 62.4 (39.4–121) mcg/mL, 13.4 (0.21– 52.3) mcg/mL, and 35.7 (17.4–91.8) mcg/mL, respectively. The accumulation ratios were 1.46 and 2.04 for AUC4weeks, 2.08 and 3.58 for Ctrough, and 1.32 and 1.72 for Cmax, for 162 mg given every 3 weeks (BW less than 30 kg) and 162 mg given every 2 weeks (BW at or above 30 kg) subcutaneous doses, respectively. Following subcutaneous dosing, steady state Ctrough was comparable for patients in the two body weight groups, while steady-state Cmax and Cmean were higher for patients in the less than 30 kg group compared to the group at or above 30 kg. All patients treated with TCZ SC had steady-state Ctrough at or higher than that achieved with TCZ IV across the spectrum of body weights. The average and trough concentrations in patients after subcutaneous dosing were within the range of those achieved in adult patients with RA following the subcutaneous administration of the recommended regimens. Reference ID: 5493108 32 Systemic Juvenile Idiopathic Arthritis – Intravenous and Subcutaneous Administration The pharmacokinetics of tocilizumab (TCZ) in SJIA patients was characterized by a population pharmacokinetic analysis which included 89 patients who were treated with TCZ IV or 51 patients treated with TCZ SC. For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 253 (120– 404) mcg/mL, 70.7 (5.26–127) mcg/mL, and 117 (37.6–199) mcg/mL, respectively. For doses of 12 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 274 (149–444) mcg/mL, 65.9 (19.0–135) mcg/mL, and 124 (60–194) mcg/mL, respectively. The accumulation ratios were 1.95 and 2.01 for AUC4weeks, and 3.41 and 3.20 for Ctrough for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. Accumulation data for Cmax were 1.37 and 1.42 for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. Following every other week dosing with tocilizumab IV, steady state was reached by 8 weeks for both body weight groups. Mean estimated tocilizumab exposure parameters were similar between the two dose groups defined by body weight. For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every week subcutaneously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 89.8 (26.4– 190) mcg/mL, 72.4 (19.5–158) mcg/mL, and 82.4 (23.9–169) mcg/mL, respectively. For doses of 162 mg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks subcutaneously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 127 (51.7–266) mcg/mL, 64.2 (16.6–136) mcg/mL, and 92.7 (38.5–199) mcg/mL, respectively. The accumulation ratios were 2.27 and 4.28 for AUC4weeks, 3.21 and 4.39 for Ctrough, and 1.88 and 3.66 for Cmax, for 162 mg given every 2 weeks (BW less than 30 kg) and 162 mg given every week (BW at or above 30 kg) subcutaneous doses, respectively. Following subcutaneous dosing, steady state was reached by 12 weeks for both body weight groups. All patients treated with tocilizumab SC had steady-state Cmax lower than that achieved with tocilizumab IV across the spectrum of body weights. Trough and mean concentrations in patients after SC dosing were similar to those achieved with tocilizumab IV across body weights. COVID-19 -Intravenous Administration The pharmacokinetics of tocilizumab in COVID-19 patients was characterized by a population pharmacokinetic analysis of a dataset composed of 380 adult patients treated with tocilizumab 8mg/kg intravenously (IV) in the COVACTA study [see Clinical Studies (14.11)] and another clinical study. For one dose of 8 mg/kg tocilizumab IV, the estimated median (range) Cmax and Cday28 of tocilizumab were 151 (77.5-319) mcg/mL and 0.229 (0.00119-19.4) mcg/mL, respectively. For two doses of 8 mg/kg tocilizumab IV separated by at least 8 hours, the estimated median (range) Cmax and Cday28 of tocilizumab was 290 (152-604) mcg/mL and 7.04 (0.00474-54.8) mcg/mL, respectively. The weight-tiered dosing used in RECOVERY study, 800 mg for patients >90 kg, 600 mg for patients >65 and ≤90 kg, 400 mg for patients >40 and ≤65 kg, and 8mg/kg for patients ≤40 kg, is comparable to 8 mg/kg dosing and is expected to have similar exposure. Absorption Following subcutaneous dosing, the absorption half-life was around 4 days in RA and GCA patients and 3 days in SSc-ILD patients. The bioavailability for the subcutaneous formulation was 80%. Following subcutaneous dosing in PJIA patients, the absorption half-life was around 2 days, and the bioavailability for the subcutaneous formulation in PJIA patients was 96%. Reference ID: 5493108 33 Following subcutaneous dosing in SJIA patients, the absorption half-life was around 2 days, and the bioavailability for the SC formulation in SJIA patients was 95%. In RA patients the median values of Tmax were 2.8 days after the tocilizumab every week dose and 4.7 days after the tocilizumab every other week dose. In GCA patients, the median values of Tmax were 3 days after the tocilizumab every week dose and 4.5 days after the tocilizumab every other week dose. In SSc-ILD patients, the median value of Tmax was 2.8 days after the tocilizumab every week dose. Distribution Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L. In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution was 3.37 L resulting in a volume of distribution at steady state of 7.46 L. In SSc-ILD patients, the central volume of distribution was 4.16 L, the peripheral volume of distribution was 2.58 L resulting in a volume of distribution at steady state of 6.74 L. In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L. In pediatric patients with SJIA, the central volume of distribution was 1.87 L, the peripheral volume of distribution was 2.14 L resulting in a volume of distribution at steady state of 4.01 L. In COVID-19 patients treated with one or two infusions of tocilizumab 8 mg/kg intravenously separated by 8 hours, the estimated central volume of distribution was 4.52 L, and the estimated peripheral volume of distribution was 4.23 L, resulting in a volume of distribution of 8.75 L. Elimination ACTEMRA is eliminated by a combination of linear clearance and nonlinear elimination. The concentration- dependent nonlinear elimination plays a major role at low tocilizumab concentrations. Once the nonlinear pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance. The saturation of the nonlinear elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of ACTEMRA do not change with time. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies. The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA patients, 6.7 mL per h in GCA patients, 8.8 mL per h in SSc-ILD patients, 5.8 mL per h in pediatric patients with PJIA, and 5.7 mL per h in pediatric patients with SJIA. In COVID-19 patients, serum concentrations were below the limit of quantification after 35 days on average following one infusion of tocilizumab 8 mg/kg intravenously. The average linear clearance in the population pharmacokinetic analysis was estimated to be 17.6 mL per hour in patients with baseline ordinal scale category 3 (OS 3, patients requiring supplemental oxygen), 22.5 mL per hour in patients with baseline OS 4 (patients requiring high-flow oxygen or non-invasive ventilation), 29 mL per hour in patients with baseline OS 5 (patients requiring mechanical ventilation), and 35.4 mL per hour in patients with baseline OS 6 (patients requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support). Due to the dependence of total clearance on ACTEMRA serum concentrations, the half-life of ACTEMRA is also concentration-dependent and varies depending on the serum concentration level. Reference ID: 5493108 34 For intravenous administration in RA patients, the concentration-dependent apparent t1/2 is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For subcutaneous administration in RA patients, the concentration-dependent apparent t1/2 is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state. In GCA patients at steady state, the effective t1/2 of tocilizumab varied between 18.3 and 18.9 days for 162 mg subcutaneously every week dosing regimen and between 4.2 and 7.9 days for 162 mg subcutaneously every other week dosing regimen. For intravenous administration in GCA patients, the TCZ concentration-dependent apparent t1/2 was 13.2 days following 6 mg/kg every 4 weeks. In SSc-ILD patients at steady state, the effective t1/2 of tocilizumab varied between 12.1 and 13.0 days for the 162 mg subcutaneous every week dosing regimen. The t1/2 of tocilizumab in children with PJIA is up to 17 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg or 10 mg/kg for body weight below 30 kg) during a dosing interval at steady state. For subcutaneous administration, the t1/2 of tocilizumab in PJIA patients is up to 10 days for the two body weight categories (every other week regimen for body weight at or above 30 kg or every 3 week regimen for body weight less than 30 kg) during a dosing interval at steady state. The t1/2 of tocilizumab intravenous in pediatric patients with SJIA is up to 16 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg and 12 mg/kg for body weight below 30 kg every other week) during a dosing interval at steady-state. Following subcutaneous administration, the effective t1/2 of tocilizumab subcutaneous in SJIA patients is up to 14 days for both the body weight categories (162 mg every week for body weight at or above 30 kg and 162 mg every two weeks for body weight below 30 kg) during a dosing interval at steady state. Specific Populations Population pharmacokinetic analyses in adult rheumatoid arthritis patients and GCA patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. In RA patients, the body weight-based dose (8 mg per kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg. There was an inverse relationship between tocilizumab exposure and body weight for flat dose subcutaneous regimens. In GCA patients treated with ACTEMRA-SC, higher exposure was observed in patients with lower body weight. For the 162 mg every week subcutaneous dosing regimen, the steady-state Cmean was 51% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. For the 162 mg every other week subcutaneous regimen, the steady-state Cmean was 129% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. There is limited data for patients above 100 kg (n=7). In COVID-19 patients, exposure following body-weight-based intravenous dosing (8 mg per kg tocilizumab up to 100 kg body weight with a maximum dose of 800 mg) was dependent on body weight and disease severity assessed by an ordinal scale (OS). Within an OS category, compared to patients with a mean body weight of 80 kg, exposure was 20% lower in patients weighing less than 60 kg. Exposure in patients weighing more than 100 kg was in the same range as exposure in patients with a mean body weight of 80 kg. For an 80 kg patient, exposure decreases as OS category increases; for each category increase, exposure decreases by 13%. Patients with Hepatic Impairment No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted. Patients with Renal Impairment No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted. Most of the RA, GCA, and SSc-ILD patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance less than 80 mL per min and at or above 50 mL per min based on Cockcroft-Gault formula) did not impact the pharmacokinetics of tocilizumab. Reference ID: 5493108 35 Approximately one-third of the patients in the ACTEMRA-SC GCA clinical trial had moderate renal impairment at baseline (estimated creatinine clearance of 30-59 mL/min). No impact on tocilizumab exposure was noted in these patients. No dose adjustment is required in patients with mild or moderate renal impairment. Drug Interaction Studies In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of ACTEMRA, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when ACTEMRA is coadministered with drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives (CYP3A4 substrates) [see Drug Interactions (7.2)]. Simvastatin Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with ACTEMRA, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of ACTEMRA (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of ACTEMRA in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of ACTEMRA (due to normalization of CYP3A4) or higher exposures after discontinuation of ACTEMRA. Omeprazole Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after ACTEMRA infusion (8 mg per kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects. Dextromethorphan Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of ACTEMRA (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after ACTEMRA infusion. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab. Literature indicates that the IL-6 pathway can mediate anti-tumor responses by promoting increased immune cell surveillance of the tumor microenvironment. However, available published evidence also supports that IL-6 signaling through the IL-6 receptor may be involved in pathways that lead to tumorigenesis. The malignancy risk in humans from an antibody that disrupts signaling through the IL-6 receptor, such as tocilizumab, is presently unknown. Reference ID: 5493108 36 Fertility and reproductive performance were unaffected in male and female mice that received a murine analogue of tocilizumab administered by the intravenous route at a dose of 50 mg/kg every three days. 14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis – Intravenous Administration The efficacy and safety of intravenously administered ACTEMRA was assessed in five randomized, double-blind, multicenter studies in patients greater than 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. ACTEMRA was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V). Study I (NCT00109408) evaluated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 24 weeks prior to randomization, or who had not discontinued previous methotrexate treatment as a result of clinically important toxic effects or lack of response. In this study, 67% of patients were MTX-naïve, and over 40% of patients had rheumatoid arthritis less than 2 years. Patients received ACTEMRA 8 mg per kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly). The primary endpoint was the proportion of ACTEMRA patients who achieved an ACR 20 response at Week 24. Study II (NCT00106535) was a 104-week study with an optional 156-week extension phase that evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received ACTEMRA 8 mg per kg, ACTEMRA 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). Upon completion of 52-weeks, patients received open-label treatment with ACTEMRA 8 mg per kg through 104 weeks or they had the option to continue their double-blind treatment if they maintained a greater than 70% improvement in swollen/tender joint count. Two pre-specified interim analyses at week 24 and week 52 were conducted. The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At weeks 52 and 104, the primary endpoints were change from baseline in modified total Sharp-Genant score and the area under the curve (AUC) of the change from baseline in HAQ-DI score. Study III (NCT00106548) evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received ACTEMRA 8 mg per kg, ACTEMRA 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Study IV (NCT00106574) evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received ACTEMRA 8 mg per kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Study V (NCT00106522) evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomization. Patients received ACTEMRA 8 mg per kg, ACTEMRA 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Clinical Response The percentages of intravenous ACTEMRA-treated patients achieving ACR 20, 50 and 70 responses are shown in Table 4. In all intravenous studies, patients treated with 8 mg per kg ACTEMRA had higher ACR 20, ACR 50, and ACR 70 response rates versus MTX- or placebo-treated patients at week 24. During the 24 week controlled portions of Studies I to V, patients treated with ACTEMRA at a dose of 4 mg per kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with ACTEMRA 8 mg per kg. Reference ID: 5493108 37 Table 4 Clinical Response at Weeks 24 and 52 in Active and Placebo Controlled Trials of Intravenous ACTEMRA (Percent of Patients) Percent of Patients Response Rate Study I Study II Study III Study IV Study V MTX ACTEMRA 8 mg per kg N=284 N=286 a (95% CI) Placebo + ACTEMRA ACTEMRA MTX 4 mg per kg 8 mg per kg + MTX + MTX N=393 N=399 N=398 a a ( 95% CI) (95% CI) Placebo + ACTEMRA ACTEMRA MTX 4 mg per kg 8 mg per kg + MTX + MTX N=204 N=213 N=205 a a ( 95% CI) (95% CI) Placebo + ACTEMRA DMARDs 8 mg per kg + DMARDs N=413 N=803 a (95% CI) Placebo + ACTEMRA ACTEMRA MTX 4 mg per kg 8 mg per kg + MTX + MTX N=158 N=161 N=170 a a ( 95% CI) (95% CI) ACR 20 Week 24 53% 70% 27% 51% 56% 27% 48% 59% 24% 61% 10% 30% 50% (0.11, 0.27) (0.17, 0.29) (0.23, 0.35) (0.15, 0.32) (0.23, 0.41) (0.30, 0.40) (0.15, 0.36) (0.36, 0.56) Week 52 N/A N/A 25% 47% 56% N/A N/A N/A N/A N/A N/A N/A N/A ACR 50 (0.15, 0.28) (0.25, 0.38) Week 24 34% 44% 10% 25% 32% 11% 32% 44% 9% 38% 4% 17% 29% (0.04, 0.20) (0.09, 0.20) (0.16, 0.28) (0.13, 0.29) (0.25, 0.41) (0.23, 0.33) (0.05, 0.25) (0.21, 0.41) Week 52 N/A N/A 10% 29% 36% N/A N/A N/A N/A N/A N/A N/A N/A ACR 70 (0.14, 0.25) (0.21, 0.32) Week 24 15% 28% 2% 11% 13% 2% 12% 22% 3% 21% 1% 5% 12% (0.07, 0.22) (0.03, 0.13) (0.05, 0.15) (0.04, 0.18) (0.12, 0.27) (0.13, 0.21) (-0.06, 0.14) (0.03, 0.22) Week 52 N/A N/A 4% 16% 20% N/A N/A N/A N/A N/A N/A N/A N/A Major Clinical b Responses (0.08, 0.17) (0.12, 0.21) Week 52 N/A N/A 1% 4% 7% N/A N/A N/A N/A N/A N/A N/A N/A (0.01, 0.06) (0.03, 0.09) a CI: 95% confidence interval of the weighted difference to placebo adjusted for site (and disease duration for Study I only) b Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week period Reference ID: 5493108 38 In study II, a greater proportion of patients treated with 4 mg per kg and 8 mg per kg ACTEMRA + MTX achieved a low level of disease activity as measured by a DAS 28-ESR less than 2.6 compared with placebo +MTX treated patients at week 52. The proportion of ACTEMRA-treated patients achieving DAS 28-ESR less than 2.6, and the number of residual active joints in these responders in Study II are shown in Table 5. Table 5 Proportion of Patients with DAS28-ESR Less Than 2.6 with Number of Residual Active Joints in Trials of Intravenous ACTEMRA Study II Placebo + MTX N = 393 ACTEMRA 4 mg per kg + MTX N = 399 ACTEMRA 8 mg per kg + MTX N = 398 DAS28-ESR less than 2.6 Proportion of responders at week 52 (n) 95% confidence interval 3% (12) 18% (70) 0.10, 0.19 32% (127) 0.24, 0.34 Of responders, proportion with 0 active joints (n) 33% (4) 27% (19) 21% (27) Of responders, proportion with 1 active joint (n) 8% (1) 19% (13) 13% (16) Of responders, proportion with 2 active joints (n) 25% (3) 13% (9) 20% (25) Of responders, proportion with 3 or more active joints (n) 33% (4) 41% (29) 47% (59) *n denotes numerator of all the percentage. Denominator is the intent-to-treat population. Not all patients received DAS28 assessments at Week 52. The results of the components of the ACR response criteria for Studies III and V are shown in Table 6. Similar results to Study III were observed in Studies I, II and IV. Table 6 Components of ACR Response at Week 24 in Trials of Intravenous ACTEMRA Study III Study V ACTEMRA 4 mg per kg + MTX N=213 ACTEMRA 8 mg per kg + MTX N=205 Placebo + MTX N=204 ACTEMRA 4 mg per kg + MTX N=161 ACTEMRA 8 mg per kg + MTX N=170 Placebo + MTX N=158 Component (mean) Baseline a Week 24 Baseline a Week 24 Baseline Week 24 Baseline a Week 24 Baseline a Week 24 Baseline Week 24 Number of tender joints (0-68) 33 19 -7.0 (-10.0, -4.1) 32 14.5 -9.6 (-12.6, -6.7) 33 25 31 21 -10.8 (-14.6, -7.1) 32 17 -15.1 (-18.8, -11.4) 30 30 Number of swollen joints (0-66) 20 10 -4.2 (-6.1, -2.3) 19.5 8 -6.2 (-8.1, -4.2) 21 15 19.5 13 -6.2 (-9.0, -3.5) 19 11 -7.2 (-9.9, -4.5) 19 18 b Pain 61 33 -11.0 (-17.0, -5.0) 60 30 -15.8 (-21.7, -9.9) 57 43 63.5 43 -12.4 (-22.1, -2.1) 65 33 -23.9 (-33.7, -14.1) 64 48 Patient global b assessment 66 34 -10.9 (-17.1, -4.8) 65 31 -14.9 (-20.9, -8.9) 64 45 70 46 -10.0 (-20.3, 0.3) 70 36 -17.4 (-27.8, -7.0) 71 51 Physician global b assessment 64 26 -5.6 (-10.5, -0.8) 64 23 -9.0 (-13.8, -4.2) 64 32 66.5 39 -10.5 (-18.6, -2.5) 66 28 -18.2 (-26.3, -10.0) 67.5 43 Disability index c (HAQ) 1.64 1.01 -0.18 (-0.34, -0.02) 1.55 0.96 -0.21 (-0.37, -0.05) 1.55 1.21 1.67 1.39 -0.25 (-0.42, -0.09) 1.75 1.34 -0.34 (-0.51, -0.17) 1.70 1.58 CRP (mg per dL) 2.79 1.17 -1.30 (-2.0, -0.59) 2.61 0.25 -2.156 (-2.86, -1.46) 2.36 1.89 3.11 1.77 -1.34 (-2.5, -0.15) 2.80 0.28 -2.52 (-3.72, -1.32) 3.705 3.06 a Data shown is mean at week 24, difference in adjusted mean change from baseline compared with placebo + MTX at week 24 and 95% confidence interval for that difference b Visual analog scale: 0 = best, 100 = worst c Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities Reference ID: 5493108 35 100 95 90 85 80 75 70 UJ "' 65 1 12 60 ~ C 0 a. 55 ll a: 0 "' 50 a: u <( 0 45 ~ .. 40 "' s ii " 35 ~ a.. 30 25 20 15 10 5 0 WK2 WK4 WK8 WK12 WK16 WK20 WK24 Visit Treatment Group e e e Placebo+ MTX (N: 204) • • • ACTEMRA8 mg/kg+ MTX (N: 205) 0 0 □ ACTEMRA4 mg/kg+ MTX (N=213) The percent of ACR 20 responders by visit for Study III is shown in Figure 1. Similar response curves were observed in studies I, II, IV, and V. Figure 1 Percent of ACR 20 Responders by Visit for Study III (Inadequate Response to MTX)* *The same patients may not have responded at each timepoint. Radiographic Response In Study II, structural joint damage was assessed radiographically and expressed as change in total Sharp-Genant score and its components, the erosion score and joint space narrowing score. Radiographs of hands/wrists and forefeet were obtained at baseline, 24 weeks, 52 weeks, and 104 weeks and scored by readers unaware of treatments group and visit number. The results from baseline to week 52 are shown in Table 7. ACTEMRA 4 mg per kg slowed (less than 75% inhibition compared to the control group) and ACTEMRA 8 mg per kg inhibited (at least 75% inhibition compared to the control group) the progression of structural damage compared to placebo plus MTX at week 52. Reference ID: 5493108 36 Table 7 Mean Radiographic Change from Baseline to Week 52 in Study II Placebo + MTX N=294 ACTEMRA 4 mg per kg + MTX N=343 ACTEMRA 8 mg per kg + MTX N=353 Week 52* Total Sharp-Genant Score, Mean (SD) 1.17 (3.14) 0.33 (1.30) 0.25 (0.98) Adjusted Mean difference** (95%CI) -0.83 (-1.13, -0.52) -0.90 (-1.20, -0.59) Erosion Score, Mean (SD) 0.76 (2.14) 0.20 (0.83) 0.15 (0.77) Adjusted Mean difference** (95%CI) -0.55 (-0.76, -0.34) -0.60 (-0.80, -0.39) Joint Space Narrowing Score, Mean (SD) 0.41 (1.71) 0.13 (0.72) 0.10 (0.49) Adjusted Mean difference** (95%CI) -0.28 (-0.44, -0.11) -0.30 (-0.46, -0.14) * Week 52 analysis employs linearly extrapolated data for patients after escape, withdrawal, or loss to follow up. ** Difference between the adjusted means (ACTEMRA + MTX - Placebo + MTX) SD = standard deviation The mean change from baseline to week 104 in Total Sharp-Genant Score for the ACTEMRA 4 mg per kg groups was 0.47 (SD = 1.47) and for the 8 mg per kg groups was 0.34 (SD = 1.24). By the week 104, most patients in the control (placebo + MTX) group had crossed over to active treatment, and results are therefore not included for comparison. Patients in the active groups may have crossed over to the alternate active dose group, and results are reported per original randomized dose group. In the placebo group, 66% of patients experienced no radiographic progression (Total Sharp-Genant Score change ≤ 0) at week 52 compared to 78% and 83% in the ACTEMRA 4 mg per kg and 8 mg per kg, respectively. Following 104 weeks of treatment, 75% and 83% of patients initially randomized to ACTEMRA 4 mg per kg and 8 mg per kg, respectively, experienced no progression of structural damage compared to 66% of placebo treated patients. Health Related Outcomes In Study II, physical function and disability were assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI). Both dosing groups of ACTEMRA demonstrated a greater improvement compared to the placebo group in the AUC of change from baseline in the HAQ-DI through week 52. The mean change from baseline to week 52 in HAQ-DI was 0.6, 0.5, and 0.4 for ACTEMRA 8 mg per kg, ACTEMRA 4 mg per kg, and placebo treatment groups, respectively. Sixty-three percent (63%) and sixty percent (60%) of patients in the ACTEMRA 8 mg per kg and ACTEMRA 4 mg per kg treatment groups, respectively, achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) at week 52 compared to 53% in the placebo treatment group. Other Health-Related Outcomes General health status was assessed by the Short Form Health Survey (SF-36) in Studies I – V. Patients receiving ACTEMRA demonstrated greater improvement from baseline compared to placebo in the Physical Component Summary (PCS), Mental Component Summary (MCS), and in all 8 domains of the SF-36. Reference ID: 5493108 37 Cardiovascular Outcomes Study WA25204 (NCT01331837) was a randomized, open-label (sponsor-blinded), 2-arm parallel-group, multicenter, non-inferiority, cardiovascular (CV) outcomes trial in patients with a diagnosis of moderate to severe RA. This CV safety study was designed to exclude a moderate increase in CV risk in patients treated with ACTEMRA compared with a TNF inhibitor standard of care (etanercept). The study included 3,080 seropositive RA patients with active disease and an inadequate response to non- biologic disease-modifying anti-rheumatic drugs, who were aged ≥50 years with at least one additional CV risk factor beyond RA. Patients were randomized 1:1 to IV ACTEMRA 8 mg/kg Q4W or SC etanercept 50 mg QW and followed for an average of 3.2 years. The primary endpoint was the comparison of the time-to-first occurrence of any component of a composite of major adverse CV events (MACE; non-fatal myocardial infarction, non-fatal stroke, or CV death), with the final intent-to-treat analysis based on a total of 161 confirmed CV events (83/1538 [5.4%] for ACTEMRA; 78/1542 [5.1%] for etanercept) reviewed by an independent and blinded adjudication committee. Non-inferiority of ACTEMRA to etanercept for cardiovascular risk was determined by excluding >80% relative increase in the risk of MACE. The estimated hazard ratio (HR) for the risk of MACE comparing ACTEMRA to etanercept was 1.05; 95% CI (0.77, 1.43). 14.2 Rheumatoid Arthritis – Subcutaneous Administration The efficacy and safety of subcutaneously administered ACTEMRA was assessed in two double-blind, controlled, multicenter studies in patients with active RA. One study, SC-I (NCT01194414), was a non-inferiority study that compared the efficacy and safety of ACTEMRA 162 mg administered every week subcutaneously to 8 mg per kg intravenously every four weeks. The second study, SC-II (NCT01232569), was a placebo controlled superiority study that evaluated the safety and efficacy of ACTEMRA 162 mg administered every other week subcutaneously to placebo. Both SC-I and SC-II required patients to be >18 years of age with moderate to severe active rheumatoid arthritis diagnosed according to ACR criteria who had at least 4 tender and 4 swollen joints at baseline (SC-I) or at least 8 tender and 6 swollen joints at baseline (SC-II), and an inadequate response to their existing DMARD therapy, where approximately 20% also had a history of inadequate response to at least one TNF inhibitor. All patients in both SC studies received background non-biologic DMARD(s). In SC-I, 1262 patients were randomized 1:1 to receive ACTEMRA-SC 162 mg every week or intravenous ACTEMRA 8 mg/kg every four weeks in combination with DMARD(s). In SC-II, 656 patients were randomized 2:1 to ACTEMRA-SC 162 mg every other week or placebo, in combination with DMARD(s). The primary endpoint in both studies was the proportion of patients who achieved an ACR20 response at Week 24. The clinical response to 24 weeks of ACTEMRA-SC therapy is shown in Table 8. In SC-I, the primary outcome measure was ACR20 at Week 24. The pre-specified non-inferiority margin was a treatment difference of 12%. The study demonstrated non-inferiority of ACTEMRA with respect to ACR20 at Week 24; ACR50, ACR70, and DAS28 responses are also shown in Table 8. In SC-II, a greater portion of patients treated with ACTEMRA 162 mg subcutaneously every other week achieved ACR20, ACR50, and ACR70 responses compared to placebo-treated patients (Table 8). Further, a greater proportion of patients treated with ACTEMRA 162 mg subcutaneously every other week achieved a low level of disease activity as measured by a DAS28-ESR less than 2.6 at Week 24 compared to those treated with placebo (Table 8). Table 8 Clinical Response at Week 24 in Trials of Subcutaneous ACTEMRA (Percent of Patients) SC-Ia SC-IIb TCZ SC 162 mg every week + DMARD N=558 TCZ IV 8mg/kg + DMARD N=537 TCZ SC 162 mg every other week + DMARD N=437 Placebo + DMARD N=219 ACR20 Reference ID: 5493108 38 I I I I I I I I I I I I I I I I I I I I I I Week 24 69% 73.4% 61% 32% Weighted difference (95% CI) -4% (-9.2, 1.2) 30% (22.0, 37.0) ACR50 Week 24 47% 49% 40% 12% Weighted difference (95% CI) -2% (-7.5, 4.0) 28% (21.5, 34.4) ACR70 Week 24 24% 28% 20% 5% Weighted difference (95% CI) -4% (-9.0, 1.3) 15% (9.8, 19.9) Change in DAS28 [Adjusted mean] Week 24 -3.5 -3.5 -3.1 -1.7 Adjusted mean difference (95% CI) 0 (-0.2, 0.1) -1.4 (-1.7; -1.1) DAS28 < 2.6 Week 24 38.4% 36.9% 32.0% 4.0% Weighted difference (95% CI) 0.9 (-5.0, 6.8) 28.6 (22.0, 35.2) TCZ = tocilizumab a Per Protocol Population b Intent To Treat Population The results of the components of the ACR response criteria and the percent of ACR20 responders by visit for ACTEMRA-SC in Studies SC-I and SC-II were consistent with those observed for ACTEMRA-IV. Radiographic Response In study SC-II, the progression of structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde modified total Sharp score (mTSS). At week 24, significantly less radiographic progression was observed in patients receiving ACTEMRA-SC every other week plus DMARD(s) compared to placebo plus DMARD(s); mean change from baseline in mTSS of 0.62 vs. 1.23, respectively, with an adjusted mean difference of -0.60 (-1.1, -0.1). These results are consistent with those observed in patients treated with intravenous ACTEMRA. Health Related Outcomes In studies SC-I and SC-II, the mean decrease from baseline to week 24 in HAQ-DI was 0.6, 0.6, 0.4 and 0.3, and the proportion of patients who achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) was 65%, 67%, 58% and 47%, for the subcutaneous every week, intravenous 8 mg/kg, subcutaneous every other week, and placebo treatment groups, respectively. Other Health-Related Outcomes General health status was assessed by the SF-36 in Studies SC-I and SC-II. In Study SC-II, patients receiving ACTEMRA every other week demonstrated greater improvement from baseline compared to placebo in the PCS, MCS, and in all 8 domains of the SF-36. In Study SC-I, improvements in these scores were similar between ACTEMRA-SC every week and ACTEMRA-IV 8 mg/kg. 14.3 Giant Cell Arteritis – Subcutaneous Administration The efficacy and safety of subcutaneously administered ACTEMRA was assessed in a single, randomized, double-blind, multicenter study in patients with active GCA. In Study WA28119 (NCT01791153), 251 screened patients with new-onset or relapsing GCA were randomized to one of four treatment arms. Two subcutaneous doses of ACTEMRA (162 mg every week and 162 mg every other week) were compared to two different placebo control groups (pre-specified prednisone-taper regimen over 26 weeks and 52 weeks) randomized 2:1:1:1. The study consisted of a 52-week blinded period, followed by a 104-week open-label extension. All patients received background glucocorticoid (prednisone) therapy. Each of the ACTEMRA-treated groups and one of the placebo-treated groups followed a pre-specified prednisone-taper regimen with the aim to reach Reference ID: 5493108 39 0 mg by 26 weeks, while the second placebo-treated group followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 52 weeks designed to be more in keeping with standard practice. The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Sustained remission was defined by a patient attaining a sustained (1) absence of GCA signs and symptoms from Week 12 through Week 52, (2) normalization of erythrocyte sedimentation rate (ESR) (to < 30 mm/hr without an elevation to ≥ 30 mm/hr attributable to GCA) from Week 12 through Week 52, (3) normalization of C-reactive protein (CRP) (to < 1 mg/dL, with an absence of successive elevations to ≥ 1mg/dL) from Week 12 through Week 52, and (4) successful adherence to the prednisone taper defined by not more than 100 mg of excess prednisone from Week 12 through Week 52. ACTEMRA 162 mg weekly and 162 mg every other week + 26 weeks prednisone taper both showed superiority in achieving sustained remission from Week 12 through Week 52 compared with placebo + 26 weeks prednisone taper (Table 9). Both ACTEMRA treatment arms also showed superiority compared to the placebo + 52 weeks prednisone taper (Table 9). Table 9 Efficacy Results from Study WA28119 PBO + 26 weeks prednisone taper N=50 PBO + 52 weeks prednisone taper N=51 TCZ 162mg SC QW + 26 weeks prednisone taper N=100 TCZ 162 mg SC Q2W + 26 weeks prednisone taper N=49 Sustained remission a Responders, n (%) 7 (14.0%) 9 (17.6%) 56 (56.0%) 26 (53.1%) Unadjusted difference in proportions vs PBO + 26 weeks taper (99.5% CI) N/A N/A 42.0% (18.0, 66.0) 39.1% (12.5 , 65.7) Unadjusted difference in proportions vs PBO + 52 weeks taper (99.5% CI) N/A N/A 38.4% (14.4, 62.3) 35.4% (8.6, 62.2) Components of Sustained Remission Sustained absence of GCA signs and symptomsb , n (%) Sustained ESR<30 mm/hrc , n (%) Sustained CRP normalizationd , n (%) Successful prednisone taperinge , n (%) 20 (40.0%) 20 (40.0%) 17 (34.0%) 10 (20.0%) 23 (45.1%) 22 (43.1%) 13 (25.5%) 20 (39.2%) 69 (69.0%) 83 (83.0%) 72 (72.0%) 60 (60.0%) 28 (57.1%) 37 (75.5%) 34 (69.4%) 28 (57.1%) a Sustained remission was achieved by a patient meeting all of the following components: absence of GCA signs and symptomsb, normalization of ESRc, normalization of CRPd and adherence to the prednisone taper regimene. b Patients who did not have any signs or symptoms of GCA recorded from Week 12 up to Week 52. c Patients who did not have an elevated ESR ≥30 mm/hr which was classified as attributed to GCA from Week 12 up to Week 52. d Patients who did not have two or more consecutive CRP records of ≥ 1mg/dL from Week 12 up to Week 52. e Patients who did not enter escape therapy and received ≤ 100mg of additional concomitant prednisone from Week 12 up to Week 52. Patients not completing the study to week 52 were classified as non-responders in the primary and key secondary analysis: PBO+26: 6 (12.0%), PBO+52: 5 (9.8%), TCZ QW: 15 (15.0%), TCZ Q2W: 9 (18.4%). CRP = C-reactive protein ESR = erythrocyte sedimentation rate PBO = placebo Q2W = every other week dose QW = every week dose TCZ = tocilizumab The estimated annual cumulative prednisone dose was lower in the two ACTEMRA dose groups (medians of 1887 mg and 2207 mg on ACTEMRA QW and Q2W, respectively) relative to the placebo arms (medians of 3804 mg and 3902 mg on placebo + 26 weeks prednisone and placebo + 52 weeks prednisone taper, respectively). Reference ID: 5493108 40 14.4 Giant Cell Arteritis – Intravenous Administration Intravenously administered ACTEMRA in patients with GCA was assessed in WP41152 (NCT03923738), an open-label PK-PD and safety study to determine the appropriate intravenous dose of ACTEMRA that achieved comparable PK-PD profiles to the ACTEMRA-SC regimen. At enrollment, all patients (n=24) were in remission on ACTEMRA-IV. In Period 1, all patients received open- label ACTEMRA-IV 7 mg/kg every 4 weeks for 20 weeks. Patients who completed Period 1 and remained in remission (n=22) were eligible to enter Period 2, and received open-label ACTEMRA-IV 6 mg/kg every 4 weeks for 20 weeks. The efficacy of intravenous ACTEMRA 6 mg/kg in adult patients with GCA is based on pharmacokinetic exposure and extrapolation to the efficacy established for subcutaneous ACTEMRA in patients with GCA [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. 14.5 Systemic Sclerosis-Associated Interstitial Lung Disease – Subcutaneous Administration The clinical efficacy of ACTEMRA was assessed in a phase 3 multicenter, randomized, double-blind, placebo controlled study in patients with SSc (Study WA29767). A phase 2/3 multicenter, randomized, double-blind, placebo controlled study in patients with SSc (Study WA27788) provided supportive information. Study WA29767 (NCT02453256) enrolled adult patients with SSc defined by the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc, with onset of disease (first non-Raynaud symptom) of ≤ 5 years, modified Rodnan Skin Score (mRSS) of ≥ 10 and ≤ 35 at screening, elevated inflammatory markers (or platelets), and active disease based on at least one of the following: disease duration ≤ 18 months, increase in mRSS ≥ 3 units over 6 months, involvement of one new body area and an increase in mRSS of ≥ 2 over 6 months, or involvement of two new body areas within the previous 6 months, or presence of at least one tendon friction rub. Study WA27788 (NCT01532869) enrolled adult patients with SSc with onset of disease ≤ 5 years, mRSS of ≥ 15 and ≤ 40 at screening, active disease, and elevated inflammatory markers or platelets. Patients in both studies were not permitted to use biologic agents (such as TNF antagonists), alkylating agents, or cyclophosphamide. In Study WA29767, 212 patients were randomized in a 1:1 ratio to receive weekly SC injections of 162 mg of ACTEMRA or placebo during the 48-week, double-blinded, placebo controlled period. Rescue treatment was allowed during the treatment period after 16 weeks for >10% percent predicted FVC (ppFVC) decline or after 24 weeks for worsening skin fibrosis. The primary efficacy endpoint was change from baseline at Week 48 in mRSS. Change from baseline in FVC at Week 48 was a key secondary endpoint. In the overall population of Study WA29767, there was not a statistically significant difference in the mean change from baseline to Week 48 in mRSS (primary endpoint) in patients receiving ACTEMRA compared to placebo (difference: -1.73; 95% CI: -3.78, 0.32). There also was not a statistically significant effect on the primary endpoint of mRSS in Study WA27788. In the overall population of Study WA29767, patients treated with ACTEMRA, as compared to placebo treated patients, were observed to have less decline from baseline in ppFVC and observed FVC at 48 weeks. FVC results from Study WA27788 were similar. Of the 212 patients who were randomized in Study WA29767, 68 patients (65%) in the ACTEMRA arm and 68 patients (64%) in the placebo arm had SSc-ILD at baseline, as confirmed by a visual read of high resolution computed tomograph (HRCT) by blinded thoracic radiologists. The mean ppFVC at baseline for patients with Reference ID: 5493108 41 SSc-ILD identified by HRCT was 79.6% (median 80.5%). Post-hoc analyses were performed to evaluate results within the subgroups of patients with and without SSc-ILD. Table 10 shows results from Study WA29767 for the changes from baseline to Week 48 in ppFVC, observed FVC, and mRSS both in the overall population and within subgroups based on SSc-ILD status at baseline. The ppFVC and observed FVC results in the overall population were primarily driven by results in the SSc-ILD subgroup. In the SSc-ILD subgroup, the differences in mean changes from baseline to Week 48 for ACTEMRA, as compared to placebo, were 6.47% and 241 mL for ppFVC and observed FVC, respectively. Figure 2 illustrates the mean change from baseline through Week 48 in observed FVC in patients with SSc-ILD. The results of the key FVC secondary endpoints from Study WA29767 support a conclusion of effectiveness of ACTEMRA in reducing the rate of progressive loss of lung function in the study population. However, in settings where a trial does not provide evidence of an effect on the primary endpoint, the estimated magnitude of effect on other endpoints should be interpreted with caution, and comparisons to results of other products and studies may be misleading. Table 10 Efficacy Results from Study WA29767 Overall Population Subgroup Without SSc-ILD* SSc-ILD Subgroup* PBO QW TCZ 162 mg QW PBO QW TCZ 162 mg QW PBO QW TCZ 162 mg QW Number of patients 106 104 36 34 68 68 Change from Baseline in mRSS at Week 48 LSM Difference in LSM, TCZ-placebo (95% CI) -4.41 -6.14 -6.16 -8.56 -3.77 -5.88 -1.73 (-3.78, 0.32) -2.40 (-5.59, 0.79) -2.11 (-4.89, 0.67) Change from Baseline in ppFVC at Week 48 LSM Difference in LSM, TCZ-placebo (95% CI) -4.58 -0.38 -0.82 -0.32 -6.40 0.07 4.20 (2.00, 6.40) 0.50 (-2.27, 3.27) 6.47 (3.43, 9.50) Change from Baseline in Observed FVC (mL) at Week 48 LSM Difference in LSM, TCZ-placebo (95% CI) -190 -24 -53 -11 -255 -14 167 (83, 250) 43 (-60, 145) 241 (124, 358) PBO=placebo; TCZ=tocilizumab; ppFVC = percent predicted forced vital capacity; LSM=least squares mean; mRSS = modified Rodnan skin score; CI=confidence interval *Post-hoc results are shown for these subgroups. Four patients had ILD status missing at baseline. Reference ID: 5493108 42 l --------1 ----------------------- _J ___________ --------------I i-·------- 1 t=~i-----1------t---I L __ :---- 16 8 24 Week PB0182mgqwSC r....,.,.,,, Gloup = TCZ 16" n-,iqw SC Figure 2 Mean Change from Baseline to Week 48 in Observed Forced Vital Capacity in SSc-ILD Patients from Study WA29767 PBO = placebo; TCZ = tocilizumab; QW = every week dose 14.6 Polyarticular Juvenile Idiopathic Arthritis – Intravenous Administration The efficacy of ACTEMRA was assessed in a three-part study, WA19977 (NCT00988221), including an open- label extension in children 2 to 17 years of age with active polyarticular juvenile idiopathic arthritis (PJIA), who had an inadequate response to methotrexate or inability to tolerate methotrexate. Patients had at least 6 months of active disease (mean disease duration of 4.2 ± 3.7 years), with at least five joints with active arthritis (swollen or limitation of movement accompanied by pain and/or tenderness) and/or at least 3 active joints having limitation of motion (mean, 20 ± 14 active joints). The patients treated had subtypes of JIA that at disease onset included Rheumatoid Factor Positive or Negative Polyarticular JIA, or Extended Oligoarticular JIA. Treatment with a stable dose of methotrexate was permitted but was not required during the study. Concurrent use of disease modifying antirheumatic drugs (DMARDs), other than methotrexate, or other biologics (e.g., TNF antagonists or T cell costimulation modulator) were not permitted in the study. Part I consisted of a 16-week active ACTEMRA treatment lead-in period (n=188) followed by Part II, a 24-week randomized double-blind placebo-controlled withdrawal period, followed by Part III, a 64-week open-label period. Eligible patients weighing at or above 30 kg received ACTEMRA at 8 mg/kg intravenously once every four weeks. Patients weighing less than 30 kg were randomized 1:1 to receive either ACTEMRA 8 mg/kg or 10 mg/kg intravenously every four weeks. At the conclusion of the open-label Part I, 91% of patients taking background MTX in addition to tocilizumab and 83% of patients on tocilizumab monotherapy achieved an ACR 30 response at week 16 compared to baseline and entered the blinded withdrawal period (Part II) of the study. The proportions of patients with JIA ACR 50/70 responses in Part I were 84.0%, and 64%, respectively for patients taking background MTX in addition to tocilizumab and 80% and 55% respectively for patients on tocilizumab monotherapy. In Part II, patients (ITT, n=163) were randomized to ACTEMRA (same dose received in Part I) or placebo in a 1:1 ratio that was stratified by concurrent methotrexate use and concurrent corticosteroid use. Each patient continued in Part II of the study until Week 40 or until the patient satisfied JIA ACR 30 flare criteria (relative to Week 16) and qualified for escape. The primary endpoint was the proportion of patients with a JIA ACR 30 flare at week 40 relative to week 16. JIA ACR 30 flare was defined as 3 or more of the 6 core outcome variables worsening by at least 30% with no more than 1 of the remaining variables improving by more than 30% relative to Week 16. ACTEMRA treated patients experienced significantly fewer disease flares compared to placebo-treated patients (26% [21/82] versus 48% [39/81]; adjusted difference in proportions -21%, 95% CI: -35%, -8%). Reference ID: 5493108 43 During the withdrawal phase (Part II), more patients treated with ACTEMRA showed JIA ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo. 14.7 Polyarticular Juvenile Idiopathic Arthritis – Subcutaneous Administration Subcutaneously administered ACTEMRA in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA) was assessed in WA28117 (NCT01904279), a 52-week, open-label, multicenter, PK-PD and safety study to determine the appropriate subcutaneous dose of ACTEMRA that achieved comparable PK/PD profiles to the ACTEMRA-IV regimen. PJIA patients aged 1 to 17 years with an inadequate response or inability to tolerate MTX, including patients with well-controlled disease on treatment with ACTEMRA-IV and ACTEMRA-naïve patients with active disease, were treated with subcutaneous ACTEMRA based on body weight. Patients weighing at or above 30 kg (n = 25) were treated with 162 mg of ACTEMRA-SC every 2 weeks and patients weighing less than 30 kg (n = 27) received 162 mg of ACTEMRA-SC every 3 weeks for 52 weeks. Of these 52 patients, 37 (71%) were naive to ACTEMRA and 15 (29%) had been receiving ACTEMRA-IV and switched to ACTEMRA-SC at baseline. The efficacy of subcutaneous ACTEMRA in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of intravenous ACTEMRA in polyarticular JIA patients and subcutaneous ACTEMRA in patients with RA [see Clinical Pharmacology (12.3) and Clinical Studies (14.2 and 14.6)]. 14.8 Systemic Juvenile Idiopathic Arthritis – Intravenous Administration The efficacy of ACTEMRA for the treatment of active SJIA was assessed in WA18221 (NCT00642460), a 12­ week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients treated with or without MTX, were randomized (ACTEMRA:placebo = 2:1) to one of two treatment groups: 75 patients received ACTEMRA infusions every two weeks at either 8 mg per kg for patients at or above 30 kg or 12 mg per kg for patients less than 30 kg and 37 were randomized to receive placebo infusions every two weeks. Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR 70 response. After 12 weeks or at the time of escape, due to disease worsening, patients were treated with ACTEMRA in the open-label extension phase at weight appropriate dosing. The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set (JIA ACR 30 response) at Week 12 and absence of fever (no temperature at or above 37.5°C in the preceding 7 days). JIA ACR (American College of Rheumatology) responses are defined as the percentage improvement (e.g., 30%, 50%, 70%) in 3 of any 6 core outcome variables compared to baseline, with worsening in no more than 1 of the remaining variables by 30% or more. Core outcome variables consist of physician global assessment, parent per patient global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability (childhood health assessment questionnaire-CHAQ). Primary endpoint result and JIA ACR response rates at Week 12 are shown in Table 11. Table 11 Efficacy Findings at Week 12 ACTEMRA N=75 Placebo N=37 Primary Endpoint: JIA ACR 30 response + absence of fever Responders 85% 24% Weighted difference (95% CI) 62 (45, 78) - JIA ACR Response Rates at Week 12 JIA ACR 30 Responders Weighted differencea 91% 67 24% - Reference ID: 5493108 44 I I (95% CI)b (51, 83) JIA ACR 50 Responders Weighted differencea (95% CI) b 85% 74 (58, 90) 11% - JIA ACR 70 Responders Weighted differencea (95% CI) b 71% 63 (46, 80) 8% - aThe weighted difference is the difference between the ACTEMRA and Placebo response rates, adjusted for the stratification factors (weight, disease duration, background oral corticosteroid dose and background methotrexate use). b CI: confidence interval of the weighted difference. The treatment effect of ACTEMRA was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks). Systemic Features Of patients with fever or rash at baseline, those treated with ACTEMRA had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to 5 out of 24 (21%) of placebo-treated patients, and 14 out of 22 (64%) became free of rash compared to 2 out of 18 (11%) of placebo-treated patients. Responses were consistent in the open label extension (data available through 44 weeks). Corticosteroid Tapering Of the patients receiving oral corticosteroids at baseline, 8 out of 31 (26%) placebo and 48 out of 70 (69%), ACTEMRA patients achieved a JIA ACR 70 response at week 6 or 8 enabling corticosteroid dose reduction. Seventeen (24%) ACTEMRA patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR 30 flare or occurrence of systemic symptoms to week 12. In the open label portion of the study, by week 44, there were 44 out of 103 (43%) ACTEMRA patients off oral corticosteroids. Of these 44 patients 50% were off corticosteroids 18 weeks or more. Health Related Outcomes Physical function and disability were assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). Seventy-seven percent (58 out of 75) of patients in the ACTEMRA treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of ≥ 0.13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group. 14.9 Systemic Juvenile Idiopathic Arthritis – Subcutaneous Administration Subcutaneously administered ACTEMRA in pediatric patients with systemic juvenile idiopathic arthritis (SJIA) was assessed in WA28118 (NCT01904292), a 52-week, open-label, multicenter, PK-PD and safety study to determine the appropriate subcutaneous dose of ACTEMRA that achieved comparable PK/PD profiles to the ACTEMRA-IV regimen. Eligible patients received ACTEMRA subcutaneously dosed according to body weight, with patients weighing at or above 30 kg (n = 26) dosed with 162 mg of ACTEMRA every week and patients weighing below 30 kg (n = 25) dosed with 162 mg of ACTEMRA every 10 days (n=8) or every 2 weeks (n=17) for 52 weeks. Of these 51 patients, 26 (51%) were naive to subcutaneous ACTEMRA and 25 (49%) had been receiving ACTEMRA intravenously and switched to subcutaneous ACTEMRA at baseline. The efficacy of subcutaneous ACTEMRA in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of intravenous ACTEMRA in systemic JIA patients [see Clinical Pharmacology (12.3) and Clinical Studies (14.8)]. Reference ID: 5493108 45 14.10 Cytokine Release Syndrome – Intravenous Administration The efficacy of ACTEMRA for the treatment of CRS was assessed in a retrospective analysis of pooled outcome data from clinical trials of CAR T-cell therapies for hematological malignancies. Evaluable patients had been treated with tocilizumab 8 mg/kg (12 mg/kg for patients < 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CRS; only the first episode of CRS was included in the analysis. The study population included 24 males and 21 females (total 45 patients) of median age 12 years (range, 3–23 years); 82% were Caucasian. The median time from start of CRS to first dose of tocilizumab was 4 days (range, 0-18 days). Resolution of CRS was defined as lack of fever and off vasopressors for at least 24 hours. Patients were considered responders if CRS resolved within 14 days of the first dose of tocilizumab, if no more than 2 doses of tocilizumab were needed, and if no drugs other than tocilizumab and corticosteroids were used for treatment. Thirty-one patients (69%; 95% CI: 53%–82%) achieved a response. Achievement of resolution of CRS within 14 days was confirmed in a second study using an independent cohort that included 15 patients (range: 9–75 years old) with CAR T cell-induced CRS. 14.11 COVID-19 – Intravenous Administration The efficacy of ACTEMRA for the treatment of COVID-19 was based on RECOVERY (NCT04381936), a randomized, controlled, open-label, platform study, and supported by the results from EMPACTA (NCT04372186), a randomized, double-blind, placebo-controlled study. Results of two other randomized, double-blind, placebo-controlled studies, COVACTA (NCT04320615) and REMDACTA (NCT04409262), which evaluated the efficacy of ACTEMRA for the treatment of COVID-19 are also summarized. RECOVERY (Randomised Evaluation of COVID-19 Therapy) Collaborative Group Study in Hospitalized Adults Diagnosed with COVID-19 RECOVERY was a randomized, controlled, open-label, multicenter platform study conducted in the United Kingdom to evaluate the efficacy and safety of potential treatments in hospitalized adult patients with severe COVID-19 pneumonia. Eligible patients for the ACTEMRA portion of the study had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical contraindications to any of the treatments and had clinical evidence of progressive COVID-19 (defined as oxygen saturation <92% on room air or receiving oxygen therapy, and CRP ≥75 mg/L). Patients were then randomized to receive either standard of care (SoC) or intravenous ACTEMRA at a weight-tiered dosing comparable to the recommended dosage [see Clinical Pharmacology (12.3)] in addition to SoC. Efficacy analyses were performed in the intent-to-treat (ITT) population comprising 4116 adult patients who were randomized to the ACTEMRA + SoC arm (n=2022) or to the SoC arm (n=2094). The mean age of participants was 64 years (range: 20 to 101), and patients were 67% male, 76% White, 11% Asian, 3% Black or African American, and 1% mixed race. At baseline, 0.2% of patients were not on supplemental oxygen, 45% of patients required low flow oxygen, 41% of patients required non-invasive ventilation or high-flow oxygen, and 14% of patients required invasive mechanical ventilation; 82% of patients were reported to be receiving systemic corticosteroids. The primary efficacy endpoint was time to death through Day 28. The results for the overall population and the subgroups of patients who were or were not receiving systemic corticosteroids at time of randomization are summarized in Table 12. Table 12 Mortality through Day 28 in RECOVERY ACTEMRA+ SoC N=2022 n (%)1 SoC N=2094 n (%)1 Hazard Ratio (95% CI) Risk Difference (95% CI) Reference ID: 5493108 46 Mortality 621 (30.7%) 729 (34.9%) 0.85 (0.76, 0.94) p= 0.00281 -4.1% (-7.0, -1.3) By baseline receipt of corticosteroid use Mortality for patients receiving systemic corticosteroids at randomization2 482/1664 (29.0%) 600/1721 (34.9%) 0.79 (0.70, 0.89) -5.9% (-9.1, -2.8) Mortality for patients not receiving systemic corticosteroids at randomization2 139/357 (39.0%) 127/367 (34.6%) 1.16 (0.91, 1.48) 4.4% (-2.6, 11.5) 1 P-value reflects that the RECOVERY trial primary analysis results were statistically significant at the two-sided significance level of 𝛼 = 0.05. 2 Probabilities of dying by Day 28 were estimated by the Kaplan-Meier method. EMPACTA EMPACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous ACTEMRA 8 mg/kg in combination with SoC in hospitalized, non-ventilated adult patients with COVID-19 pneumonia. Eligible patients were at least 18 years of age, had confirmed SARS-CoV-2 infection by a positive reverse-transcriptase polymerase chain reaction (RT-PCR) result, had pneumonia confirmed by radiography, and had SpO2 < 94% on ambient air. Of the 389 patients randomized, efficacy analyses were performed in the modified intent-to-treat (mITT) population comprising 377 patients who were randomized and received study medication (249 in the ACTEMRA arm; 128 in the placebo arm). The mean age of participants was 56 years (range: 20 to 95); 59% of patients were male, 56% were of Hispanic or Latino ethnicity, 53% were White, 20% were American Indian/Alaska Native, 15% were Black/African American and 2% were Asian. At baseline, 9% patients were not on supplemental oxygen, 64% patients required low flow oxygen, 27% patients required high-flow oxygen, and 73% were on corticosteroids. The primary efficacy endpoint evaluated time to progression to mechanical ventilation or death through Day 28. The hazard ratio comparing ACTEMRA to placebo was 0.56 (95% CI, 0.33 to 0.97), a statistically significant result (log-rank, p-value = 0.036). The cumulative proportion of patients who required mechanical ventilation or died by Day 28 was 12.0% (95% CI, 8.5% to 16.9%) in the ACTEMRA arm and 19.3% (95% CI, 13.3% to 27.4%) in the placebo arm. Mortality at Day 28 was 10.4% in the ACTEMRA arm versus 8.6% in the placebo arm (weighted difference (ACTEMRA arm - placebo arm): 2.0% [95% CI, -5.2% to 7.8%]). COVACTA COVACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous ACTEMRA 8 mg/kg in combination with SoC for the treatment of adult patients hospitalized with severe COVID­ 19 pneumonia. The study randomized 452 patients who were at least 18 years of age with confirmed SARS-CoV­ 2 infection by a positive RT-PCR result, had pneumonia confirmed by radiography, and had oxygen saturation of 93% or lower on ambient air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mmHg or less. At baseline, 3% of patients were not on supplemental oxygen, 28% were on low flow oxygen, 30% were on non-invasive ventilation or high flow oxygen, 38% were on invasive mechanical ventilation, and 22% Reference ID: 5493108 47 were on corticosteroids. The primary efficacy endpoint was clinical status on Day 28 assessed on a 7-category ordinal scale that ranged from “discharged” to “death.” There were no statistically significant differences observed in the distributions of clinical status on the 7-category ordinal scale at Day 28 when comparing the ACTEMRA arm to the placebo arm. Mortality at Day 28 was 19.7% in the ACTEMRA arm versus 19.4% in the placebo arm (weighted difference (ACTEMRA arm - placebo arm): 0.3% [95% CI, -7.6 to 8.2]). REMDACTA REMDACTA was a randomized, double-blind, placebo-controlled, multicenter study to evaluate intravenous ACTEMRA 8 mg/kg in combination with intravenous remdesivir (RDV) 200 mg on Day 1 followed by 100 mg once daily for a total of 10 days in hospitalized patients with severe COVID-19 pneumonia. The study randomized 649 adult patients with SARS-CoV-2 infection confirmed by a positive polymerase chain reaction (PCR) result, pneumonia confirmed by radiography, and who required supplemental oxygen > 6 L/min to maintain SpO2 >93%. At baseline, 7% of patients were on low flow oxygen, 80% were on non-invasive ventilation or high flow oxygen, 14% were on invasive mechanical ventilation, and 84% were on corticosteroids. The primary efficacy endpoint was time from randomization to hospital discharge or ‘ready for discharge’ up to Day 28. There was no statistically significant difference between the treatment arms with respect to time to hospital discharge or “ready for discharge” through Day 28. Mortality at Day 28 was 18.1% in the ACTEMRA+ RDV arm versus 19.5% in the placebo +RDV arm (weighted difference (ACTEMRA arm - placebo arm): -1.3% [95% CI, -7.8% to 5.2%]). Mortality Across Studies in Patients Receiving Baseline Corticosteroids A study-level meta-analysis was conducted on EMPACTA, COVACTA, REMDACTA and RECOVERY studies. For each of the four studies, the risk difference through Day 28 was estimated by the Kaplan-Meier method in the subgroup of patients receiving baseline corticosteroids, summarized in Figure 3. Patients from the RECOVERY trial represent 78.8% of the total sample size in this meta-analysis. The combined risk difference showed that ACTEMRA treatment (n=2261) resulted in a 4.61% absolute reduction in the risk of death at Day 28 (risk difference=-4.6%; 95% CI: -7.3% to -1.9%) compared to SoC (n=2034). Figure 3 Risk Differences Through Day 28 for Baseline Corticosteroid Use Subpopulation in RECOVERY, EMPACTA, COVACTA and REMDACTA studies Reference ID: 5493108 48 soc Actemra + SOC Favors Risk Study Total n Deaths(%) n Deaths(%) Actemra + SOC soc Difference (95% Cl) COVACTA 97 41 12 (33.5%) 56 14 (29.5%) -4.1 [-24.7, 16.6] EMPACTA 274 91 10 (11.4%) 183 23 (13.3%) 1.8 [ -6.6, 10.2] REMDACTA 539 181 39 (21 .8%) 358 69 (19.5%) -2.3 [ -9.6, 5.0] RECOVERY 3385 1721 600 (34.9%) 1664 482 (29.0%) ............... -5.9 [ -9.1 , -2.8] Overall - -4.6 [-7.3, -1.9] -20.0 -10.0 0.0 10.0 20.0 Risk Difference (95% Cl) 16 HOW SUPPLIED/STORAGE AND HANDLING For Intravenous Infusion ACTEMRA (tocilizumab) injection is a preservative-free, sterile clear, colorless to pale yellow solution. ACTEMRA is supplied as 80 mg/4 mL (NDC 50242-135-01), 200 mg/10 mL (NDC 50242-136-01), and 400 mg/20 mL (NDC 50242-137-01) individually packaged 20 mg/mL single-dose vials for further dilution prior to intravenous infusion. For Subcutaneous Injection ACTEMRA (tocilizumab) injection is supplied as a preservative-free, sterile, clear, colorless to slightly yellowish solution for subcutaneous administration. The following packaging configurations are available: • Each single-dose prefilled syringe delivers 162 mg/0.9 mL (NDC 50242-138-01). • Each single-dose ACTPen® autoinjector delivers 162 mg/0.9 mL (NDC 50242-143-01). Storage and Handling: Do not use beyond expiration date on the container, package, prefilled syringe, or autoinjector. ACTEMRA must be refrigerated at 36°F to 46°F (2ºC to 8ºC). Do not freeze. Protect the vials, syringes, and autoinjectors from light by storage in the original package until time of use, and keep syringes and autoinjectors dry. Once removed from the refrigerator, the prefilled syringe and autoinjector can be stored up to 2 weeks at or below 86°F (30°C). The prefilled syringe and autoinjector must always be kept in the carton. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Serious Infections Inform patients that ACTEMRA may lower their resistance to infections [see Warnings and Precautions (5.1)]. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment. Gastrointestinal Perforation Inform patients that some patients who have been treated with ACTEMRA have had serious side effects in the stomach and intestines [see Warnings and Precautions (5.2)]. Instruct the patient of the importance of contacting Reference ID: 5493108 49 their doctor immediately when symptoms of fever, severe, persistent abdominal pain, and change in bowel habits appear to assure rapid evaluation and appropriate treatment. Hypersensitivity and Serious Allergic Reactions Inform patients that some patients who have been treated with ACTEMRA have developed serious allergic reactions, including anaphylaxis, as well as serious skin reactions [see Warnings and Precautions (5.6)]. Advise patients to stop taking ACTEMRA and seek immediate medical attention if they experience any symptom of serious allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing). Instruction on Injection Technique Assess patient suitability for home use for subcutaneous injection. Perform the first injection under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer subcutaneous ACTEMRA, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous ACTEMRA and the suitability for home use [see Instructions for Use]. Prior to use, remove the prefilled syringe (PFS) or autoinjector from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes (PFS) or 45 minutes (autoinjector), out of the reach of children. Do not warm ACTEMRA in any other way. Advise patients to consult their healthcare provider if the full dose is not received. A puncture-resistant container for disposal of needles, syringes and autoinjectors should be used and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper needle, syringe and autoinjector disposal, and caution against reuse of these items. Pregnancy Inform female patients of reproductive potential that ACTEMRA may cause fetal harm and to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)]. ACTEMRA (tocilizumab) Manufactured by: ACTEMRA is a registered trademark of Chugai Seiyaku Kabushiki Genentech, Inc. Kaisha Corp., a member of the Roche Group A Member of the Roche Group © 2024 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No.: 1048 Reference ID: 5493108 50 Medication Guide ACTEMRA® (AC-TEM-RA) (tocilizumab) injection for intravenous use ACTEMRA® (AC-TEM-RA) (tocilizumab) injection for subcutaneous use What is the most important information I should know about ACTEMRA? ACTEMRA can cause serious side effects including: 1. Serious Infections. ACTEMRA is a medicine that affects your immune system. ACTEMRA can lower the ability of your immune system to fight infections. Some people have serious infections while taking ACTEMRA, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections. Your healthcare provider should assess you for TB before starting ACTEMRA (except if you have COVID-19). If you have COVID-19, your healthcare provider should monitor you for signs and symptoms of new infections during and after treatment with ACTEMRA. Your healthcare provider should monitor you closely for signs and symptoms of TB during and after treatment with ACTEMRA. • You should not start taking ACTEMRA if you have any kind of infection unless your healthcare provider says it is okay. Before starting ACTEMRA, tell your healthcare provider if you: • think you have an infection or have symptoms of an infection, with or without a fever, such as: o sweating or chills o feel very tired o cough o shortness of breath o muscle aches o weight loss o warm, red, or painful skin or o blood in phlegm o burning when you urinate or urinating sores on your body o diarrhea or stomach pain more often than normal • are being treated for an infection. • get a lot of infections or have infections that keep coming back. • have diabetes, HIV, or a weak immune system. People with these conditions have a higher chance for infections. • have TB, or have been in close contact with someone with TB. • live or have lived, or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections (histoplasmosis, coccidiomycosis, or blastomycosis). These infections may happen or become more severe if you use ACTEMRA. Ask your healthcare provider, if you do not know if you have lived in an area where these infections are common. • have or have had hepatitis B. After starting ACTEMRA, call your healthcare provider right away if you have any symptoms of an infection. ACTEMRA can make you more likely to get infections or make worse any infection that you have. 2. Tears (perforation) of the stomach or intestines. • Tell your healthcare provider if you have had diverticulitis (inflammation in parts of the large intestine) or ulcers in your stomach or intestines. Some people taking ACTEMRA get tears in their stomach or intestine. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. • Tell your healthcare provider right away if you have fever and new onset stomach-area pain that does not go away, and a change in your bowel habits. 3. Liver problems (Hepatotoxicity): Some people have experienced serious life-threatening liver problems, which required a liver transplant or led to death. Your healthcare provider may tell you to stop taking ACTEMRA if you develop new or worse liver problems during treatment with ACTEMRA. Tell your healthcare provider right away if you have any of the following symptoms: • feeling tired (fatigue) • weakness • lack of appetite for several days or longer • nausea and vomiting (anorexia) • yellowing of your skin or the whites of your • confusion eyes (jaundice) Reference ID: 5493108 51 • abdominal swelling and pain on the right side • dark “tea-colored” urine of your stomach-area • light colored stools 4. Changes in certain laboratory test results. Your healthcare provider should do blood tests before you start receiving ACTEMRA. If you have rheumatoid arthritis (RA), giant cell arteritis (GCA), or systemic sclerosis- interstitial lung disease (SSc-ILD) your healthcare provider should do blood tests every 4 to 8 weeks after you start receiving ACTEMRA for the first 6 months and then every 3 months after that. If you have polyarticular juvenile idiopathic arthritis (PJIA) you will have blood tests done every 4 to 8 weeks during treatment. If you have systemic juvenile idiopathic arthritis (SJIA) you will have blood tests done every 2 to 4 weeks during treatment. These blood tests are to check for the following side effects of ACTEMRA: • low neutrophil count. Neutrophils are white blood cells that help the body fight off bacterial infections. • low platelet count. Platelets are blood cells that help with blood clotting and stop bleeding. • increase in certain liver function tests. • increase in blood cholesterol levels. You may also have changes in other laboratory tests, such as your blood cholesterol levels. Your healthcare provider should do blood tests to check your cholesterol levels 4 to 8 weeks after you start receiving ACTEMRA. Your healthcare provider will determine how often you will have follow-up blood tests. Make sure you get all your follow-up blood tests done as ordered by your healthcare provider. You should not receive ACTEMRA if your neutrophil or platelet counts are too low or your liver function tests are too high. Your healthcare provider may stop your ACTEMRA treatment for a period of time or change your dose of medicine if needed because of changes in these blood test results. 5. Cancer. ACTEMRA may increase your risk of certain cancers by changing the way your immune system works. Tell your healthcare provider if you have ever had any type of cancer. See “What are the possible side effects with ACTEMRA?” for more information about side effects. What is ACTEMRA? ACTEMRA is a prescription medicine called an Interleukin-6 (IL-6) receptor antagonist. ACTEMRA is used: • To treat adults with moderately to severely active rheumatoid arthritis (RA), after at least one other medicine called a Disease-Modifying Anti-Rheumatic Drug (DMARD) has been used and did not work well. • To treat adults with giant cell arteritis (GCA). • For slowing the rate of decline in lung function in adults with systemic sclerosis-associated interstitial lung disease (SSc-ILD) (also known as scleroderma associated ILD). • To treat people with active PJIA ages 2 and above. • To treat people with active SJIA ages 2 and above. • To treat people age 2 years and above who experience severe or life-threatening Cytokine Release Syndrome (CRS) following chimeric antigen receptor (CAR) T cell treatment. • To treat hospitalized adults with coronavirus disease 2019 (COVID-19) receiving systemic corticosteroids and requiring supplemental oxygen or mechanical ventilation. • ACTEMRA is not approved for subcutaneous use in people with CRS or COVID-19. It is not known if ACTEMRA is safe and effective in children with PJIA, SJIA, or CRS under 2 years of age or in children with conditions other than PJIA, SJIA or CRS. Do not take ACTEMRA: if you are allergic to tocilizumab, or any of the ingredients in ACTEMRA. See the end of this Medication Guide for a complete list of ingredients in ACTEMRA. Before you receive ACTEMRA, tell your healthcare provider about all of your medical conditions, including if you: • have an infection. See “What is the most important information I should know about ACTEMRA?” • have liver problems. • have any stomach-area (abdominal) pain or been diagnosed with diverticulitis or ulcers in your stomach or intestines. • have had a reaction to tocilizumab or any of the ingredients in ACTEMRA before. • have or had a condition that affects your nervous system, such as multiple sclerosis. • have recently received or are scheduled to receive a vaccine: o All vaccines should be brought up-to-date before starting ACTEMRA, unless urgent treatment initiation is required. o People who take ACTEMRA should not receive live vaccines. Reference ID: 5493108 52 o People taking ACTEMRA can receive non-live vaccines. • plan to have surgery or a medical procedure. • are pregnant or plan to become pregnant. ACTEMRA may harm your unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with ACTEMRA. • are breastfeeding or plan to breastfeed. It is not known if ACTEMRA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take ACTEMRA. Tell your healthcare provider about all of the medicines you take, including prescription, over-the-counter medicines, vitamins and herbal supplements. ACTEMRA and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take: • any other medicines to treat your RA. Taking ACTEMRA with these medicines may increase your risk of infection. • medicines that affect the way certain liver enzymes work. Ask your healthcare provider if you are not sure if your medicine is one of these. Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. How will I receive ACTEMRA? Into a vein (IV or intravenous infusion) for Rheumatoid Arthritis, Giant Cell Arteritis, PJIA, SJIA, CRS or COVID­ 19: • If your healthcare provider prescribes ACTEMRA as an IV infusion, you will receive ACTEMRA from a healthcare provider through a needle placed in a vein in your arm. The infusion will take about 1 hour to give you the full dose of medicine. • For rheumatoid arthritis, giant cell arteritis or PJIA you will receive a dose of ACTEMRA about every 4 weeks. • For SJIA you will receive a dose of ACTEMRA about every 2 weeks. • For CRS you will receive a single dose of ACTEMRA, and if needed, additional doses. • For COVID-19, you will receive a single dose of ACTEMRA, and if needed one additional dose. • While taking ACTEMRA, you may continue to use other medicines that help treat your rheumatoid arthritis, PJIA, SJIA or COVID-19 such as methotrexate, non-steroidal anti-inflammatory drugs (NSAIDs) and prescription steroids, as instructed by your healthcare provider. • Keep all of your follow-up appointments and get your blood tests as ordered by your healthcare provider. Under the skin (SC or subcutaneous injection) for Rheumatoid Arthritis, Giant Cell Arteritis, SSc-ILD, PJIA or SJIA: • See the Instructions for Use at the end of this Medication Guide for instructions about the right way to prepare and give your ACTEMRA injections at home. • ACTEMRA is available as a single-dose Prefilled Syringe or single-dose prefilled ACTPen® autoinjector. • You may also receive ACTEMRA as an injection under your skin (subcutaneous). If your healthcare provider decides that you or a caregiver can give your injections of ACTEMRA at home, you or your caregiver should receive training on the right way to prepare and inject ACTEMRA. Do not try to inject ACTEMRA until you have been shown the right way to give the injections by your healthcare provider. • For PJIA or SJIA, you may self-inject with the Prefilled Syringe or prefilled ACTPen® autoinjector, or your caregiver can give you ACTEMRA, if both your healthcare provider and parent/legal guardian find it appropriate. • Your healthcare provider will tell you how much ACTEMRA to use and when to use it. What are the possible side effects with ACTEMRA? ACTEMRA can cause serious side effects, including: • See “What is the most important information I should know about ACTEMRA?” • Hepatitis B infection in people who carry the virus in their blood. If you are a carrier of the hepatitis B virus (a virus that affects the liver), the virus may become active while you use ACTEMRA. Your healthcare provider may do blood tests before you start treatment with ACTEMRA and while you are using ACTEMRA. Tell your healthcare provider if you have any of the following symptoms of a possible hepatitis B infection: o feel very tired o skin or eyes look yellow o little or no appetite o vomiting o clay-colored bowel movements o fevers o chills o stomach discomfort o muscle aches o dark urine o skin rash • Serious Allergic Reactions. Serious allergic reactions, including death, can happen with ACTEMRA. These reactions can happen with any infusion or injection of ACTEMRA, even if they did not occur with an earlier infusion or injection. Stop taking ACTEMRA, contact your healthcare provider, and get emergency help right away if you have any of the following signs of a serious allergic reaction: o swelling of your face, lips, mouth, or tongue Reference ID: 5493108 53 o trouble breathing o wheezing o severe itching o skin rash, hives, redness, or swelling outside of the injection site area o dizziness or fainting o fast heartbeat or pounding in your chest (tachycardia) o sweating • Nervous system problems. While rare, Multiple Sclerosis has been diagnosed in people who take ACTEMRA. It is not known what effect ACTEMRA may have on some nervous system disorders. The most common side effects of ACTEMRA include: • upper respiratory tract infections (common cold, sinus infections) • headache • increased blood pressure (hypertension) • injection site reactions Tell your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of ACTEMRA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Genentech at 1-888-835-2555. General information about the safe and effective use of ACTEMRA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not give ACTEMRA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ACTEMRA that is written for health professionals. What are the ingredients in ACTEMRA? Active ingredient: tocilizumab. Inactive ingredients of Intravenous ACTEMRA: disodium phosphate dodecahydrate/sodium dihydrogen phosphate dihydrate buffered solution, polysorbate 80, sucrose, and water for Injection. Inactive ingredients of Subcutaneous ACTEMRA: L-arginine hydrochloride, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, and water for Injection. ACTEMRA is a registered trademark of Chugai Seiyaku Kabushiki Kaisha Corp., a member of the Roche Group. ACTPen is a registered trademark of Chugai Seiyaku Kabushiki Kaisha Corp., a member of the Roche Group. Genentech, Inc., A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990 U.S. License No.: 1048 © 2024 Genentech, Inc. All rights reserved. For more information, go to www.ACTEMRA.com or call 1-800-ACTEMRA. Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 09/2024 Reference ID: 5493108 54 Pre-filled Syringe parts Before use: I Needle cap After use: Expiration date Needle-shield (extended and locked) Trigger fingers (Do not touch as this may release the needle-shield early) Plunger Instructions for Use ACTEMRA® (AC-TEM-RA) (tocilizumab) Injection, For Subcutaneous Use Single-dose Prefilled Syringe Read and follow the Instructions for Use that come with your ACTEMRA prefilled syringe before you start using it and each time you get a prescription refill. Before you use ACTEMRA prefilled syringe for the first time, make sure your healthcare provider shows you the right way to use it. • Do not remove the needle cap until you are ready to inject ACTEMRA. • Do not try to take apart the syringe at any time. • Do not reuse the same syringe. Parts of your ACTEMRA Prefilled Syringe (See Figure A). Figure A Supplies needed for your ACTEMRA Prefilled Syringe Injection (See Figure B): • ACTEMRA prefilled syringe • alcohol pad • sterile cotton ball or gauze • puncture-resistant container or sharps container for safe disposal of needle cap and used syringe (See Step 4 “Dispose of the syringe”) Reference ID: 5493108 55 Sharps container Alcohol pad [D]l Sterile cotton ball ACTEMRA prefilled syringe Figure B Step 1. Preparing for an ACTEMRA Injection Find a comfortable space with a clean, flat, working surface. • Take the box containing the syringe out of the refrigerator and open the box. Do not touch the trigger fingers on the syringe as this may damage the syringe. • Remove 1 single-use ACTEMRA prefilled syringe from the box and let it warm up for 30 minutes to allow it to reach room temperature. If the syringe does not reach room temperature, this could cause your injection to feel uncomfortable and make it difficult to push the plunger in. • Do not speed up the warming process in any way, such as using the microwave or placing the syringe in warm water. • Check the expiration date on the ACTEMRA prefilled syringe (See Figure A). Do not use it if the expiration date has passed because it may not be safe to use. If the expiration date has passed safely dispose of the syringe in a sharps container and get a new one. Do not remove the needle cap while allowing your ACTEMRA prefilled syringe to reach room temperature. • Keep your unused syringes in the original carton and keep in the refrigerator at 36˚F to 46˚F (2˚C to 8˚C). Do not freeze. • Once removed from the refrigerator, your prefilled syringe can be stored up to 2 weeks at or below 86°F (30°C). Your prefilled syringe must always be kept in the original carton in order to protect from light and moisture. Hold your ACTEMRA prefilled syringe with the covered needle pointing down (See Figure C). Figure C • Check the liquid in the ACTEMRA prefilled syringe. It should be clear and colorless to pale yellow. Do not inject ACTEMRA if the liquid is cloudy, discolored, or has lumps or particles in it because it may not be safe to use. Safely dispose of the syringe in a sharps container and get a new one. • Wash your hands well with soap and water. Reference ID: 5493108 56 front back ■ = injection sites Step 2. Choose and Prepare an Injection Site Choose an Injection Site • The front of your thigh and your abdomen except for the 2-inch area around your navel are the recommended injection sites (See Figure D). • The outer area of the upper arms may also be used only if the injection is being given by a caregiver. Do not attempt to use the upper arm area by yourself (See Figure D). Rotate Injection Site • Choose a different injection site for each new injection at least 1-inch from the last area you injected. • Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard or not intact. Figure D Prepare the Injection Site • Wipe the injection site with an alcohol pad in a circular motion and let it air dry to reduce the chance of getting an infection. Do not touch the injection site again before giving the injection. • Do not fan or blow on the clean area. Step 3. Inject ACTEMRA • Hold the ACTEMRA prefilled syringe with 1 hand and pull the needle cap straight off with your other hand (See Figure E). Do not hold the plunger while you remove the needle cap. If you cannot remove the needle cap you should ask a caregiver for help or contact your healthcare provider. Figure E • Throw away the needle cap in a sharps container. Reference ID: 5493108 57 • There may be a small air bubble in the ACTEMRA prefilled syringe. You do not need to remove it. • You may see a drop of liquid at the end of the needle. This is normal and will not affect your dose. • Do not touch the needle or let it touch any surfaces. • Do not use the prefilled syringe if it is dropped. • If it is not used within 5 minutes of needle cap removal, the syringe should be disposed of in the puncture resistant container or sharps container and a new syringe should be used. • Never reattach the needle cap after removal. • Hold the ACTEMRA prefilled syringe in 1 hand between the thumb and index finger (See Figure F). Figure F • Do not pull back on the plunger of the syringe. • Use your other hand and gently pinch the area of skin you cleaned. Hold the pinched skin firmly. Pinching the skin is important to make sure that you inject under the skin (into fatty tissue) but not any deeper (into muscle). Injection into muscle could cause the injection to feel uncomfortable. • Do not hold or push on the plunger while inserting the needle into the skin. • Use a quick, dart-like motion to insert the needle all the way into the pinched skin at an angle between 45° to 90° (See Figure G). It is important to use the correct angle to make sure the medicine is delivered under the skin (into fatty tissue), or the injection could be painful and the medicine may not work. Figure G • Keep the syringe in position and let go of the pinch of skin. • Slowly inject all of the medicine by gently pushing the plunger all the way down (See Figure H). You must press the plunger all the way down to get the full dose of medicine and to ensure the trigger fingers are completely pushed to the side. If the plunger is not fully depressed the needle shield will not extend to cover the needle when it is removed. If the needle is not covered, carefully place the syringe into the puncture resistant container to avoid injury with the needle. Reference ID: 5493108 58 Figure H • After the plunger is pushed all the way down, keep pressing down on the plunger to be sure all of the medicine is injected before taking the needle out of the skin. • Keep pressing down on the plunger while you take the needle out of the skin at the same angle as inserted (See Figure I). Figure I • After the needle is removed completely from the skin, release the plunger, allowing the needle-shield to protect the needle (See Figure J). Figure J After the Injection • There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site. • Do not rub the injection site. • If needed, you may cover the injection site with a small bandage. Reference ID: 5493108 59 Step 4. Dispose of the syringe • The ACTEMRA prefilled syringe should not be reused. • Put the used syringe into your puncture resistant container (See “How do I throw away used syringes?”) • Do not put the needle cap back on the needle. • If your injection is given by another person, this person must also be careful when removing the syringe and disposing of the syringe to prevent accidental needle stick injury and passing infection. How do I throw away used syringes? • Put your used needles and syringes including ACTEMRA in a FDA-cleared sharps disposal container right away after use (See Figure K). Do not throw away (dispose of) loose needles and syringes in your household trash. Figure K • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out o upright stable during use o leak-resistant o properly labeled to warn of hazardous waste inside the container • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. • Keep ACTEMRA prefilled syringes and the disposal container out of the reach of children. Record your Injection • Write the date, time, and specific part of your body where you injected yourself. It may also be helpful to write any questions or concerns about the injection so you can ask your healthcare provider. If you have questions or concerns about your ACTEMRA prefilled syringe, please contact your healthcare provider familiar with ACTEMRA or call 1-800-ACTEMRA. This Medication Guide and Instructions for Use has been approved by the U.S. Food and Drug Administration. Medication Guide Revised: 09/2024 ACTEMRA is a registered trademark of Chugai Seiyaku Kabushiki Kaisha Corp., a member of the Roche Group. Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No.: 1048 © 2024 Genentech, Inc. All rights reserved. Reference ID: 5493108 60 Fi ureA Expiration date Before use t-- Green ~ activation button Window{ area I Needle-shield - ~Green cap -1 After use Purple indicator "injection complete" Needle-shield (extended -­ and locked) Instructions for Use ACTEMRA® (AC-TEM-RA) (tocilizumab) Injection, For Subcutaneous Use Single-dose Prefilled ACTPen® (AKT-PEN) Autoinjector Read and follow the Instructions for Use that come with your ACTEMRA ACTPen autoinjector before you start using it and each time you get a prescription refill. Before you use the ACTEMRA ACTPen autoinjector for the first time, make sure your healthcare provider shows you the right way to use it. Important: Keep your unused Autoinjectors in the original carton and keep in the refrigerator at 36˚F to 46˚F (2˚C to 8˚C). Do not freeze. Once removed from the refrigerator, your Autoinjector can be stored up to 2 weeks at or below 86°F (30°C). Your Autoinjector must always be kept in the original carton in order to protect from light and moisture. • Do not remove the Autoinjector cap until you are ready to inject ACTEMRA. • Do not try to take apart the Autoinjector at any time. • Do not reuse the same Autoinjector. • Do not use the Autoinjector through clothing. • Do not leave the Autoinjector unattended. • Do not use the Autoinjector if it appears to be damaged or if you have accidentally dropped the Autoinjector. • Keep out of the reach of children. Parts of your ACTEMRA ACTPen autoinjector (See Figure A). Supplies needed for an injection using your ACTEMRA ACTPen autoinjector (See Figure B): • 1 ACTEMRA ACTPen autoinjector • 1 Alcohol pad • 1 Sterile cotton ball or gauze • 1 Puncture-resistant container or sharps container for safe disposal of Autoinjector cap and used Autoinjector (See Step 4 “Dispose of the Autoinjector”) Reference ID: 5493108 61 Figure B Sharps container Sharps Disposal Alcohol pad [o] 0 Sterile cotton ball r h ACTEMRA ACTPen autoinjector Step 1. Preparing for an ACTEMRA Injection Find a comfortable space with a clean, flat, working surface. • Take the box containing the Autoinjector out of the refrigerator. • If you are opening the box for the first time, check to make sure that it is properly sealed. Do not use the Autoinjector if the box looks like it has already been opened. • Check that the Autoinjector box is not damaged. Do not use ACTEMRA ACTPen autoinjector if the box looks damaged. • Check the expiration date on the Autoinjector box. Do not use the Autoinjector if the expiration date has passed because it may not be safe to use. • Open the box, and remove 1 single-use ACTEMRA ACTPen autoinjector from the box. • Return any remaining autoinjectors in the box to the refrigerator. • Check the expiration date on the ACTEMRA ACTPen autoinjector (See Figure A). Do not use it if the expiration date has passed because it may not be safe to use. If the expiration date has passed, safely dispose of the Autoinjector in a sharps container and get a new one. • Check the Autoinjector to make sure it is not damaged. Do not use the Autoinjector if it appears to be damaged or if you have accidentally dropped the Autoinjector. • Place the Autoinjector on a clean, flat surface and let the Autoinjector warm up for 45 minutes to allow it to reach room temperature. If the Autoinjector does not reach room temperature, this could cause your injection to feel uncomfortable and it could take longer to inject. - Do not speed up the warming process in any way, such as using the microwave or placing the Autoinjector in warm water. - Do not leave the Autoinjector to warm up in direct sunlight. - Do not remove the green cap while allowing your ACTEMRA ACTPen autoinjector to reach room temperature. • Hold your ACTEMRA ACTPen autoinjector with the green cap pointing down (See Figure C). • Look in the clear Window area. Check the liquid in the ACTEMRA ACTPen autoinjector (See Figure C). It should be clear and colorless to pale yellow. Do not inject ACTEMRA if the liquid is cloudy, discolored, or has lumps or particles in it because it may not be safe to use. Safely dispose of the Autoinjector in a sharps container and get a new one. Reference ID: 5493108 62 Figure C Front Back ■ = injection sites • Wash your hands well with soap and water. Step 2. Choose and Prepare an Injection Site Choose an Injection Site • The front of your thigh or your abdomen except for the 2-inch (5cm) area around your navel are the recommended injection sites (See Figure D). • The outer area of the upper arms may also be used only if the injection is being given by a caregiver. Do not attempt to use the upper arm area by yourself (See Figure D). Rotate Injection Site • Choose a different injection site for each new injection at least 1 inch (2.5cm) from the last area you injected. • Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard or not intact. Prepare the Injection Site • Wipe the injection site with an alcohol pad in a circular motion and let it air dry to reduce the chance of getting an infection. Do not touch the injection site again before giving the injection. • Do not fan or blow on the clean area. Reference ID: 5493108 63 figure E Figure F (t Step 3. Inject ACTEMRA • Hold the ACTEMRA ACTPen autoinjector firmly with one hand. Twist and pull off the green cap with the other hand (See Figure E). The green cap contains a loose fitting metal tube. • If you cannot remove the green cap you should ask a caregiver for help or contact your healthcare provider. Important: Do not touch the needle shield which is located at the tip of the Autoinjector below the Window area (See Figure A), to avoid accidental needle stick injury. • Throw away the green cap in a sharps container. • After you remove the green cap, the Autoinjector is ready for use. If the Autoinjector is not used within 3 minutes of the cap removal, the Autoinjector should be disposed of in the sharps container and a new Autoinjector should be used. • Never reattach the green cap after removal. • Hold the Autoinjector comfortably in 1 hand by the upper part, so that you can see the Window area of the Autoinjector (See Figure F). • Use your other hand to gently pinch the area of skin you cleaned, to prepare a firm injection site (See Figure G). The Autoinjector requires a firm injection site to properly activate. Pinching the skin is important to make sure that you inject under the skin (into fatty tissue) but not any deeper (into muscle). Injection into muscle could cause the injection to feel uncomfortable. Reference ID: 5493108 64 Figure G Figure I • Do not press the green Activation button yet. Place the needle-shield of the Autoinjector against your pinched skin at a 90° angle (See Figure H). • It is important to use the correct angle to make sure the medicine is delivered under the skin (into fatty tissue), or the injection could be painful and the medicine may not work. • Continue to gently pinch throughout the injection procedure. • To use the Autoinjector, you first have to unlock the green Activation button. To unlock it, press the Autoinjector firmly against your pinched skin until the needle-shield is completely pushed in (See Figure I). • Continue to keep the needle-shield pushed in. If you do not keep the needle-shield completely pushed against the skin, the green Activation button will not work. Continue to pinch the skin while you keep the Autoinjector in place. Reference ID: 5493108 65 "click" at start Figure K hold+ watch 10 seconds Figure L Figure J • Press the green Activation button to start the injection. A “click” sound indicates the start of the injection. Keep the green button pressed in and continue holding the Autoinjector pressed firmly against your skin (See Figure J). If you cannot start the injection you should ask for help from a caregiver or contact your healthcare provider. • The purple indicator will move along the Window area during the injection (See Figure K). • Watch the purple indicator until it stops moving to be sure the full dose of medicine is injected. This may take up to 10 seconds. • You may hear a second “click” during the injection but you should continue to hold the Autoinjector firmly against your skin until the purple indicator stops moving. • When the purple indicator has stopped moving, release the green button. Lift the Autoinjector straight off of the injection site at a 90° angle to remove the needle from the skin. The needle-shield will then move out and lock into place covering the needle (See Figure L). Reference ID: 5493108 66 Figure M • Check the Window area to see that it is filled with the purple indicator (See Figure L). • If the Window area is not filled by the purple indicator then: o The needle-shield may not have locked. Do not touch the needle-shield of the Autoinjector, because you may stick yourself with the needle. If the needle is not covered, carefully place the Autoinjector into the sharps container to avoid any injury with the needle. o You may not have received your full dose of ACTEMRA. Do not try to re-use the Autoinjector. Do not repeat the injection with another Autoinjector. Call your healthcare provider for help. After the Injection • There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site. • Do not rub the injection site. • If needed, you may cover the injection site with a small bandage. Step 4. Dispose of the Autoinjector • The ACTEMRA ACTPen autoinjector should not be reused. • Put the used Autoinjector into your sharps container (See “How do I dispose of used Autoinjectors?”). • Do not put the cap back on the Autoinjector. • If your injection is given by another person, this person must also be careful when removing the Autoinjector and disposing of it to prevent accidental needle stick injury and passing infection. How do I dispose of used Autoinjectors? • Put your used ACTEMRA ACTPen autoinjector and green cap in a FDA-cleared sharps disposal container right away after use (See Figure M). • Do not throw away (dispose of) the Autoinjector and the green cap in your household trash. • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out o upright stable during use o leak-resistant o properly labeled to warn of hazardous waste inside the container • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should dispose of used Autoinjectors. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Reference ID: 5493108 67 Keep the ACTEMRA ACTPen autoinjector and disposal container out of the reach of children. Record your Injection • Write the date, time, and specific part of your body where you injected yourself. It may also be helpful to write any questions or concerns about the injection so you can ask your healthcare provider. If you have any questions or concerns about your ACTEMRA ACTPen autoinjector, talk to your healthcare provider familiar with ACTEMRA or call 1-800-ACTEMRA. This Medication Guide and Instructions for Use has been approved by the U.S. Food and Drug Administration. Medication Guide Revised: 09/2024 ACTEMRA is a registered trademark of Chugai Seiyaku Kabushiki Kaisha Corp., a member of the Roche Group. ACTPen is a registered trademark of Chugai Seiyaku Kabushiki Kaisha Corp., a member of the Roche Group. Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No.: 1048 © 2024 Genentech, Inc. All rights reserved. Reference ID: 5493108 68 Push against skin to 1 unlock. Do not push The green button yet. Then press green 2 button to inject Refer to Instructions for Use www.actemra.com Reference ID: 5493108
custom-source
2025-02-12T15:47:39.771590
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CRENESSITY safely and effectively. See full prescribing information for CRENESSITY. CRENESSITY™ (crinecerfont) capsules, for oral use CRENESSITY™ (crinecerfont) oral solution Initial U.S. Approval: 2024 -----------------------------INDICATIONS AND USAGE-------------------------- CRENESSITY is a corticotropin-releasing factor type 1 receptor antagonist indicated as adjunctive treatment to glucocorticoid replacement to control androgens in adults and pediatric patients 4 years of age and older with classic congenital adrenal hyperplasia (CAH). ------------------------DOSAGE AND ADMINISTRATION---------------------- x Continue glucocorticoid replacement therapy for adrenal insufficiency associated with CAH. (2.1) x Adults: 100 mg orally, twice daily with a meal in the morning and evening. (2.2) x Pediatric Patients (4 years of age and older): Weight-based dosage orally, twice daily with a meal in the morning and evening. (2.2) x See Full Prescribing Information for complete dosage and administration information. ----------------------DOSAGE FORMS AND STRENGTHS--------------------- x Capsules: 25 mg, 50 mg, 100 mg (3) x Oral Solution: 50 mg/mL (3) -------------------------------CONTRAINDICATIONS-----------------------------­ Hypersensitivity to crinecerfont or any excipients of CRENESSITY. (4) ------------------------WARNINGS AND PRECAUTIONS----------------------- x Hypersensitivity Reactions: Include throat tightness, angioedema, and generalized rash. If clinically significant hypersensitivity occurs, initiate appropriate therapy and discontinue CRENESSITY. (5.1) x Risk of Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy: Continue glucocorticoids upon initiation of and during treatment with CRENESSITY. Do not reduce the glucocorticoid dose below the dose required for cortisol replacement. Any adjustment of daily glucocorticoid dosage after initiation of CRENESSITY should be performed under the supervision of a health care provider. Use glucocorticoid stress doses in cases of increased cortisol need (e.g., acute intercurrent illness, serious trauma, surgical procedures). (5.2) -------------------------------ADVERSE REACTIONS-----------------------------­ Adults: Most common adverse reactions (at least 4% for CRENESSITY and greater than placebo) are fatigue, headache, dizziness, arthralgia, back pain, decreased appetite, and myalgia. (6.1) Pediatric Patients: Most common adverse reactions (at least 4% for CRENESSITY and greater than placebo) are headache, abdominal pain, fatigue, nasal congestion, and epistaxis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Neurocrine Biosciences, Inc. at 877-641-3461 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------­ Strong CYP3A4 Inducers: Increase CRENESSITY morning and evening dosage 2-fold. (Section 2.3, 7.1) Moderate CYP3A4 Inducers: Increase CRENESSITY evening dosage 2-fold. (2.4, 7.1) See for 17 PATIENT COUNSELING INFORMATION Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Information 2.2 Recommended Dosage and Administration 2.3 Dosage Modifications for Concomitant Use with Strong CYP3A4 Inducers 2.4 Dosage Modifications for Concomitant Use with Moderate CYP3A4 Inducers 2.5 Administration Instructions 2.6 Missed Doses 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Risk of Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on CRENESSITY 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Adults with Congenital Adrenal Hyperplasia 14.2 Pediatric Patients with Congenital Adrenal Hyperplasia 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 5495978 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE CRENESSITY is indicated as adjunctive treatment to glucocorticoid replacement to control androgens in adults and pediatric patients 4 years of age and older with classic congenital adrenal hyperplasia (CAH). 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Information Patients receiving CRENESSITY should continue glucocorticoid replacement therapy for the adrenal insufficiency associated with congenital adrenal hyperplasia (see Warning and Precautions (5.2). Androstenedione levels can be assessed beginning four weeks after CRENESSITY initiation to inform reduction in glucocorticoid dosage as clinically indicated. Do not reduce the glucocorticoid dosage below that required for replacement therapy. 2.2 Recommended Dosage and Administration Recommended Dosage for Adults The recommended CRENESSITY dosage for adults is 100 mg orally, twice daily with a meal in the morning and evening [see Clinical Pharmacology (12.3)]. Recommended Dosage for Pediatric Patients 4 Years of Age and Older The recommended CRENESSITY dosage for pediatric patients 4 years of age and older is weight-based and administered orally, twice daily with a meal in the morning and evening (see Table 1) [see Clinical Pharmacology (12.3)]. Table 1. Recommended CRENESSITY Weight-Based Dosage for Pediatric Patients 4 Years of Age and Older Weight Dosage Regimen with a Meal 10 kg to less than 20 kg 25 mg orally twice daily 20 kg to less than 55 kg 50 mg orally twice daily Greater than or equal to 55 kg 100 mg orally twice daily 2.3 Dosage Modifications for Concomitant Use with Strong CYP3A4 Inducers Adults In adults, increase the CRENESSITY dosage to 200 mg orally, twice daily with a meal in the morning and evening when used concomitantly with strong CYP3A4 inducers [see Drug Interactions (7.1)]. Pediatric Patients 4 Years of Age and Older In pediatric patients, increase the CRENESSITY dosage with a meal in the morning and evening when used concomitantly with strong CYP3A4 inducers as shown in Table 2 [see Drug Interactions (7.1)]. 2 Reference ID: 5495978 Table 2. Dosage Increase of CRENESSITY for Use with Strong CYP3A4 Inducers in Pediatric Patients 4 Years of Age and Older Weight Dosage Regimen with a Meal 10 kg to less than 20 kg 50 mg orally twice daily 20 kg to less than 55 kg 100 mg orally twice daily Greater than or equal to 55 kg 200 mg orally twice daily 2.4 Dosage Modifications for Concomitant Use with Moderate CYP3A4 Inducers Adults In adults, increase the CRENESSITY dosage to 200 mg orally with the evening meal when used concomitantly with moderate CYP3A4 inducers. The CRENESSITY dosage of 100 mg with the morning meal remains unchanged [see Drug Interactions (7.1)]. Pediatric Patients 4 Years of Age and Older In pediatric patients, increase the CRENESSITY dosage with the evening meal when used concomitantly with moderate CYP3A4 inducers as shown in Table 3 [see Drug Interactions (7.1)]. Table 3. Dosage Increase of CRENESSITY for Use with Moderate CYP3A4 Inducers in Pediatric Patients 4 Years of Age and Older Dosage Regimen with a Meal Weight Morning Dose Evening Dose 10 kg to less than 20 kg 25 mg orally 50 mg orally 20 kg to less than 55 kg 50 mg orally 100 mg orally Greater than or equal to 55 kg 100 mg orally 200 mg orally 2.5 Administration Instructions Administer CRENESSITY orally, twice daily, with a meal in the morning and evening [see Clinical Pharmacology (12.3)]. CRENESSITY Capsules Take CRENESSITY capsules orally and swallow whole with liquid. CRENESSITY Oral Solution Refer patients and/or caregivers to the Instructions for Use (IFU) for complete administration instructions. Discard any unused CRENESSITY oral solution after 30 days of first opening the bottle [see How Supplied/Storage and Handling (16.2)]. 2.6 Missed Doses If a dose or doses are missed, advise the patient to take one dose of CRENESSITY as soon as possible (even if it is soon before the next scheduled dose) and then to resume the regular dosing schedule. 3 DOSAGE FORMS AND STRENGTHS CRENESSITY is available as: Capsules: o 25 mg oval, orange soft gelatin capsule printed with ‘WWV 25’ in black ink 3 Reference ID: 5495978 x o 50 mg oval, two-toned orange and gold soft gelatin capsule printed with ‘WWV 50’ in black ink o 100 mg oblong, gold soft gelatin capsule printed with ‘WWV 100’ in black ink x Oral Solution: 50 mg/mL in a light yellow to orange, clear to slightly opalescent oral solution 4 CONTRAINDICATIONS CRENESSITY is contraindicated in patients with hypersensitivity to crinecerfont or any excipients of CRENESSITY. Reactions have included throat tightness, angioedema, and generalized rash [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions A hypersensitivity reaction, including throat tightness, angioedema, and generalized rash, occurred in a subject after 3 days of treatment with CRENESSITY. If a clinically significant hypersensitivity reaction occurs, initiate appropriate therapy and discontinue CRENESSITY. 5.2 Risk of Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy Continue glucocorticoids upon initiation of and during treatment with CRENESSITY. Do not reduce the glucocorticoid dose below the dose required for cortisol replacement. Acute adrenal insufficiency or adrenal crisis, which can potentially be fatal or life-threatening, can occur in patients with underlying adrenal insufficiency who are on inadequate daily glucocorticoid doses, especially in situations associated with increased cortisol need, such as acute intercurrent illness, serious trauma, or surgical procedures. Any adjustment of daily glucocorticoid dosage after initiation of CRENESSITY should be performed under the supervision of a health care provider. Use glucocorticoid stress doses in case of increased cortisol need (e.g., acute intercurrent illness, serious trauma, surgical procedures). In the placebo-controlled clinical study of adults with classic CAH, the incidence of adrenal crisis was 1.6% in subjects treated with CRENESSITY and 0% in subjects treated with placebo. In the placebo-controlled clinical study of pediatric subjects with classic CAH, there were no events of adrenal crisis. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: x Hypersensitivity Reactions [see Warnings and Precautions (5.1)] x Risk of Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy [see Warnings and Precautions (5.2)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 4 Reference ID: 5495978 Adults with Congenital Adrenal Hyperplasia (CAH) The safety of CRENESSITY in adults was assessed in Study 1, a randomized, double-blind, placebo-controlled study of 182 adults aged 18 to 58 years with classic CAH due to 21-hydroxylase deficiency. A total of 122 subjects received CRENESSITY 100 mg twice daily and 59 subjects received placebo twice daily for up to 24 weeks [see Clinical Studies (14.1)]. Adverse Reactions Leading to Discontinuation of Treatment A total of 3% of CRENESSITY-treated subjects and no placebo-treated subjects discontinued treatment because of adverse reactions of restlessness, apathy, dyspepsia, nausea, and vomiting. Commonly Observed Adverse Reactions Adverse reactions that occurred in ≥4% of CRENESSITY-treated subjects and more frequently than in placebo-treated subjects are presented in Table 4. Table 4. Adverse Reactions (≥4%) in Adults with Congenital Adrenal Hyperplasia Treated with CRENESSITY and Occurring More Frequently Than in Placebo-Treated Subjects Adverse Reactions CRENESSITY (N=122) % Placebo (N=59) % Fatigue 25 15 Headache 16 15 Dizziness 8 3 Arthralgia 7 0 Back pain 6 3 Decreased appetite 4 2 Myalgia 4 3 Suicidal Ideation and Behavior Study 1 excluded subjects with active suicidal ideation with intent or plan within the six months prior to screening and those with a history of suicidal behavior within the past year, based on the Columbia-Suicide Severity Rating Scale (C-SSRS) administered at screening. The C-SSRS was administered to subjects at regular intervals during the study. Three of 122 (2.5%) CRENESSITY-treated subjects reported suicidal ideation without method, intent or plan on the C-SSRS during the 24-week double-blind treatment period compared to 1 of 59 (1.7%) placebo-treated subjects. One of the three subjects receiving CRENESSITY and the placebo-treated subject reported a lifetime history of suicidal ideation. One CRENESSITY-treated subject without a history of suicidal ideation or behavior attempted suicide during the open-label period after 320 days of treatment. Laboratory Findings Neutrophil count less than 2 x 103 cells/mcL occurred in 14% (17 of 120) of CRENESSITY-treated subjects, compared to 5% (3 of 58) of subjects in the placebo group. Neutrophil count less than 1 x 103 cells/mcL occurred in 0.8% (1 of 120) of CRENESSITY-treated subjects, compared to 1.7% subjects (1 of 58) in the placebo group. Pediatric Patients with Congenital Adrenal Hyperplasia The safety of CRENESSITY in pediatric patients was evaluated in Study 2, a randomized, double-blind placebo-controlled study of 103 pediatric subjects aged 4 to 17 years with classic CAH due to 21-hydroxylase deficiency. Pediatric subjects were randomized to receive CRENESSITY twice daily (N=69) or placebo (N=34) 5 Reference ID: 5495978 for 28 weeks, using weight-based dosing (50 mg twice daily via oral solution for subjects 20 to <55 kg, or 100 mg twice daily via oral capsules for subjects ≥55 kg) [see Clinical Studies (14.2)]. Adverse Reactions Leading to Discontinuation of Treatment A total of 3% of CRENESSITY-treated subjects and no placebo-treated subjects discontinued treatment because of adverse reactions of abdominal pain, myalgia, and dizziness. Commonly Observed Adverse Reactions Adverse reactions that occurred at an incidence of ≥4% in CRENESSITY-treated pediatric subjects (50 mg twice daily or 100 mg twice daily) and greater than placebo are presented in Table 5. Table 5. Adverse Reactions (≥ 4%) in Pediatric Subjects with Congenital Adrenal Hyperplasia Treated with CRENESSITY and Occurring More Frequently Than in Placebo-Treated Subjects Adverse Reactions CRENESSITY (N=69) % Placebo (N=33) % Headache 25 6 Abdominal pain1 13 0 Fatigue 7 0 Nasal congestion 7 3 Epistaxis 4 0 1Abdominal pain includes: abdominal pain, abdominal pain upper and abdominal pain lower Suicidal Ideation and Behavior Study 2 excluded subjects with active suicidal ideation with intent or plan within six months prior to screening or those with a lifetime history of suicidal behavior based on the C-SSRS administered at screening. Four of 67 (6%) CRENESSITY-treated subjects and 0 of the 31 (0%) placebo-treated subjects reported suicidal ideation without method, intent or plan on the C-SSRS during the 28-week double-blind treatment period. Two of the four CRENESSITY-treated subjects reported a lifetime history of suicidal ideation. There were no completed suicides or suicide attempts. Laboratory Findings Neutrophil count less than 2 x 103 cells/mcL occurred in 37% (25 of 68) of CRENESSITY-treated subjects, compared to 16% (5 of 32) of subjects in the placebo group. Neutrophil count less than 1 x 103 cells/mcL occurred in 4% (3 of 68) of CRENESSITY-treated subjects, compared to no subjects (0 of 32) in the placebo group. 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on CRENESSITY Strong CYP3A4 Inducers Increase CRENESSITY morning and evening dosages 2-fold when CRENESSITY is used concomitantly with a strong CYP3A4 inducer [see Dosage and Administration (2.3)]. Moderate CYP3A4 Inducers Increase CRENESSITY evening dosage 2-fold when CRENESSITY is used concomitantly with a moderate CYP3A4 inducer. Do not increase the morning dosage [see Dosage and Administration (2.4)]. 6 Reference ID: 5495978 Mechanism of Drug Interaction and Clinical Effect CRENESSITY is a CYP3A4 substrate. Concomitant use of CRENESSITY with a strong or moderate CYP3A4 inducer decreases crinecerfont exposure [see Clinical Pharmacology (12.3)], which may reduce CRENESSITY efficacy. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from reports of pregnancy in clinical trials with CRENESSITY are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. No developmental toxicity was observed in rats at 4-fold higher than human exposure at the maximum recommended human dose (MRHD) based on area under the concentration-time curve (AUC). Crinecerfont was associated with a low incidence of poly-malformations (craniofacial defects) in rabbits at 2-fold higher than human exposure at the MRHD. In a pre- and postnatal developmental toxicity study, no developmental toxicity was observed in rats at 4-fold higher than human exposure at the MRHD (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. If CRENESSITY is administered during pregnancy, or if a patient becomes pregnant while receiving CRENESSITY, health care providers should report exposure to CRENESSITY by calling 1-855-CRNSITY (1-855-276-7489). Data Animal Data Crinecerfont was administered orally to pregnant rabbits at doses of 100, 500, and 1000 mg/kg/day, and to pregnant rats at doses of 150, 500, and 2000 mg/kg/day during the period of organogenesis. No crinecerfont-related malformations were observed in rats at 4-fold higher than human exposure at the MRHD based on AUC. Low incidence of poly-malformations (craniofacial defects) and slightly lower mean fetal weights were observed in rabbits treated with crinecerfont at 2-fold higher than human exposure at the MRHD based on AUC. In a pre- and postnatal developmental toxicity study, crinecerfont was administered orally to pregnant rats at doses of 15, 50, and 250 mg/kg/day during the period of organogenesis and lactation through Day 20 postpartum. No changes in pup mortality, growth, sexual maturation, behavior, mating and fertility, or ovarian and uterine parameters were observed. The exposure in dams at the No Observed Adverse Effect Level (NOAEL) of 250 mg/kg/day was approximately 4-fold higher than human exposure at the MRHD based on AUC. 8.2 Lactation Risk Summary There are no data on the presence of crinecerfont in human milk, the effects on the breastfed infant, or the effects on milk production. Crinecerfont is present in animal milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Infants exposed to CRENESSITY through breast 7 Reference ID: 5495978 milk should be monitored for signs of adrenal insufficiency such as weakness, decreased feeding and weight loss. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CRENESSITY and any potential adverse effects on the breastfed child from CRENESSITY or from the underlying maternal condition. Data Crinecerfont was excreted in the milk of rats, with milk-to-plasma concentration ratios ranging from 1.5 to 12. No effects on postnatal development were observed in a pre- and postnatal development study, in which female rats were treated orally with up to 250 mg/kg/day (4-fold higher than human exposure at the MRHD based on AUC) during organogenesis through lactation. 8.4 Pediatric Use The safety and effectiveness of CRENESSITY as adjunctive treatment to glucocorticoid replacement to control androgens have been established in pediatric patients 4 years of age and older with classic CAH. Use of CRENESSITY for this indication is supported by evidence from an adequate and well-controlled study of 103 pediatric subjects (Study 2), evidence from an adequate and well-controlled study in adults with CAH (Study 1), and pharmacokinetic data from adults and pediatric subjects [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. The safety and effectiveness of CRENESSITY in pediatric patients less than 4 years of age have not been established. 8.5 Geriatric Use The clinical trial of CRENESSITY in adults with classic CAH did not enroll subjects 65 years of age and older to determine whether they respond differently from younger subjects. 8.6 Renal Impairment CRENESSITY is not recommended in patients with severe renal impairment or end-stage renal disease [see Clinical Pharmacology (12.3)]. 11 DESCRIPTION CRENESSITY contains crinecerfont, a selective corticotropin-releasing factor type 1 receptor antagonist, present as crinecerfont free base, with the chemical name, 2-thiazolamine, 4-(2-chloro-4-methoxy-5­ methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl. Crinecerfont free base is the S-enantiomer with an enantiomeric excess of at least 99.7%. Its molecular formula is C27H28ClFN2OS, and its molecular weight is 483.04 g/mol with the following structure: 8 Reference ID: 5495978 CRENESSITY Capsules CRENESSITY capsules are intended for oral administration only. Each capsule contains 25 mg, 50 mg, or 100 mg of crinecerfont free base. Inactive ingredients include lauroyl polyoxyl-32 glycerides, medium chain triglycerides, propylene glycol dicaprylate/dicaprate, and Vitamin E polyethylene glycol succinate. The capsule shell contains gelatin, glycerin, red iron oxide, Sorbitol glycerin blend, titanium dioxide, and yellow iron oxide. CRENESSITY Oral Solution The oral solution formulation contains 50 mg/mL of crinecerfont free base. Inactive ingredients include butylated hydroxytoluene, medium-chain triglycerides, oleoyl polyoxyl glycerides, orange flavor, and saccharin. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Crinecerfont is a selective corticotropin-releasing factor (CRF) type 1 receptor antagonist. Crinecerfont blocks the binding of CRF to CRF type 1 receptors in the pituitary but not CRF type 2 receptors. Crinecerfont binding to CRF type 1 receptors inhibits adrenocorticotropic hormone (ACTH) secretion from the pituitary, thereby reducing ACTH-mediated adrenal androgen production. 12.2 Pharmacodynamics Exposure-Response Relationships Model based exposure-response analyses for adults and pediatric patients with CAH demonstrated that, within the studied exposures of CRENESSITY in Phase 3 trials, relatively flat exposure-response relationships were observed for androstenedione reduction from baseline to Week 4 for both adults and pediatric patients and percent glucocorticoid daily dose reduction from baseline to Week 24 for adults and to Week 28 for pediatric patients. Adrenocorticotropic Hormone (ACTH) Reduction In 8 adults with classic CAH (NCT0352886) who received the recommended CRENESSITY dosage for 2 weeks, the median percent reduction from baseline in ACTH was 62%. In the Phase 3 clinical trials of adults and pediatric patients with classic CAH, administration of the recommended CRENESSITY dosage for 4 weeks during the initial glucocorticoid stable period led to a reduction in ACTH levels. In Study 1, the median percent reduction from baseline to Week 4 in ACTH was 65%. In Study 2, the median percent reduction from baseline to Week 4 in ACTH was 72%. Cardiac Electrophysiology At a dose 4 times the maximum approved recommended dosage, CRENESSITY does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Crinecerfont maximum plasma concentration (Cmax) and area under the time concentration curve (AUC0-24 hours) increases dose-proportionally over the approved recommended dosage range. Upon twice daily dosing, steady state conditions are achieved in approximately 7 days with an accumulation ratio of 1.4. Absorption Crinecerfont median time to reach Cmax (Tmax) is 4 hours following oral administration of CRENESSITY. 9 Reference ID: 5495978 No clinically significant differences in crinecerfont Cmax or AUC were observed following administration of CRENESSITY oral capsules and oral solution. Steady state exposures for crinecerfont in adults and pediatric patients following oral administration of CRENESSITY are presented in Table 6. Table 6. Geometric Mean (CV%) for AUC24,ss and Cmax in Adults and Pediatric Patients with Classic Congenital Adrenal Hyperplasia Following Oral Administration of CRENESSITY Parameter Geometric Mean (CV%) Study 1 (adults) Study 2 (pediatrics) AUC24hr,ss (ng*h/mL) 72846 (51%) Dose 100 mg bid (≥ 55 kg) Dose 50 mg bid (≥ 20 to < 55 kg) 74693 (48%) 47062 (51%) Cmax (ng/mL) Dose: 100 mg bid 4231 (46%) Dose 100 mg bid (≥ 55 kg) Dose 50 mg bid (≥ 20 to < 55 kg) 4555 (43%) 2887 (48%) CV%, coefficient of variation expressed as a percentage; bid, twice daily; steady-state exposure parameters are generated from simulation of 500 subjects based on population pharmacokinetic modeling and weight band appropriate formulation Effect of Food Following administration of CRENESSITY capsule, crinecerfont Cmax increased 4.9-fold and AUC increased 3.3-fold with a high-fat meal (800 to 1000 calories, 50% fat), compared to fasted conditions [see Dosage and Administration (2.2)]. Following administration of CRENESSITY oral solution, crinecerfont Cmax increased 8.6-fold and AUC increased 8.3-fold with a high-fat meal (800 to 1000 calories, 50% fat), compared to fasted conditions [see Dosage and Administration (2.2)]. Distribution Mean apparent volume of distribution (CV%) of crinecerfont in adults with CAH is 852 L (31%). Crinecerfont plasma protein binding is greater than or equal to 99.9%. Elimination Crinecerfont’s effective half-life is approximately 14 hours with a mean (CV%) apparent clearance of 3.5 L/h (37%). Metabolism Crinecerfont is metabolized primarily by CYP3A4 and to a lesser extent by CYP2B6 in vitro. Additionally, CYP2C8 and CYP2C19 may also have minor contributions to crinecerfont metabolism. Excretion Following a single oral 100 mg dose of radiolabeled crinecerfont, approximately 47.3% (2.7% as unchanged) of the dose was recovered in feces and 2% (amount as unchanged is undetectable) in urine. Specific Populations No clinically significant differences in the pharmacokinetics of crinecerfont were observed based on age (range: 5 to 54 years), sex (58.7% male), race (4.8% Asian, 9.7% Black, 77.5% White), mild to severe hepatic impairment (Child Pugh Class A to C), or mild to moderate renal impairment (estimated glomerular filtration rate: equal to or greater than 44 mL/min/1.73 m2; CKD-EPI 2009 formula for adults and bedside Schwartz formula for pediatric patients). Crinecerfont has not been studied in patients with severe renal impairment or end-stage renal disease. 10 Reference ID: 5495978 Drug Interaction Studies Clinical Studies Effect of Strong CYP3A4 Inducers on Crinecerfont: Crinecerfont Cmax decreased by 23% and AUC decreased by 62% following concomitant use with rifampin (strong CYP3A4 inducer) [see Dosage and Administration (2.3) and Drug Interactions (7.1)]. Effect of Strong CYP3A4 Inhibitors on Crinecerfont: Crinecerfont Cmax and AUC increased by 25% and 45%, respectively, when used concomitantly with ketoconazole (strong CYP3A4 inhibitor). Effect of Crinecerfont on CYP3A Substrates: No clinically significant differences in the pharmacokinetics of midazolam (CYP3A4 substrate) were observed when co-administered with crinecerfont. Concomitant use of crinecerfont did not affect the pharmacokinetics of oral contraceptives containing ethinyl estradiol and levonorgestrel. In Vitro Studies Cytochrome P450 Enzymes: Crinecerfont does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. Crinecerfont does not induce CYP2C8, CYP3A4, CYP1A2 and CYP2B6. Transporter Systems: Crinecerfont does not inhibit P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), bile salt export pump (BSEP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion protein (MATE)1, or MATE2-K. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 2-year carcinogenicity study, rats were administered daily crinecerfont doses of 5, 15, and 100 mg/kg/day via oral gavage. An increased incidence of thyroid follicular cell combined adenomas and carcinomas was observed in female rats at the 100 mg/kg/day dose level (approximately 4-fold higher than human exposure at the MRHD based on AUC). Thyroid follicular cell tumors can occur in rats from excessive thyroid stimulating hormone (TSH) secondary to liver enzyme induction, which is not thought to commonly occur in humans. No evidence of increased tumorigenicity was seen in male rats up to approximately 5-fold higher than human exposure at the MRHD based on AUC or in female rats up to approximately 2-fold higher than human exposure at the MRHD based on AUC. In a 6-month study in Tg.rasH2 mice, daily crinecerfont doses of 15, 50, 500, and 1500 mg/kg/day were administered via oral gavage. Crinecerfont did not increase the incidence of tumors in male or female transgenic mice (approximately 4-fold higher than human exposure at the MRHD based on AUC). Mutagenesis Crinecerfont was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay. Impairment of Fertility There were no crinecerfont-related effects on male or female fertility or female reproductive performance in rats treated orally with up to 1000 mg/kg/day crinecerfont at 2-fold higher than human exposure at the MRHD by AUC exposure. 11 Reference ID: 5495978 14 CLINICAL STUDIES 14.1 Adults with Classic Congenital Adrenal Hyperplasia The efficacy of CRENESSITY to reduce androgen levels and enable a reduced glucocorticoid dose while maintaining androgen control in adults with classic CAH was evaluated in a randomized, double-blind, placebo- controlled study (Study 1; NCT#04490915). This study enrolled 182 adults with classic CAH due to 21-hydroxylase deficiency on supraphysiological glucocorticoid doses and with androgen concentrations in the normal range or with inadequate androgen control. Subjects were randomized to receive CRENESSITY 100 mg twice daily (N=122) or placebo (N=60) for 24 weeks. During the first 4 weeks of CRENESSITY treatment, subjects maintained a stable glucocorticoid regimen except for stress dosing as needed. During Weeks 4 to 12, the glucocorticoid dose was reduced as frequently as every 2 weeks without regard to androstenedione levels, with the goal to achieve a glucocorticoid dose of 8 to 10 mg/m2/day in hydrocortisone dose equivalents adjusted for body surface area by Week 12. From Weeks 12 to 20, the glucocorticoid dose was further adjusted, if needed, to achieve androstenedione control by Week 24. The mean (range) age was 31 (18 to 58) years, 51% were male, 90% were White, and 8% were Hispanic or Latino. At baseline, the mean (SD) glucocorticoid total daily dose in hydrocortisone equivalents was 32 (9) mg/day (18 [5] mg/m2/day), with mean (SD) androstenedione levels of 620 (729) ng/dL prior to the morning glucocorticoid dose. The efficacy of CRENESSITY was assessed by the least-squares (LS) mean (SEM) percent change from baseline in the total glucocorticoid daily dose while androstenedione was controlled (≤120% of baseline or ≤upper limit of normal [ULN]) after 24 weeks. The LS mean percent change from baseline in daily glucocorticoid dose was statistically significantly greater in the CRENESSITY group at -27% compared to -10% in the placebo group, as shown in Table 7. Table 7. Percent Change From Baseline in Glucocorticoid Daily Dose While Maintaining Androstenedione Control at Week 24 in Adults with Classic Congenital Adrenal Hyperplasia (Study 1) Treatment Group Mean (SD) Baseline (mg/m2/day) LS Mean (SEM) Percent Change From Baseline (%) Placebo-Subtracted LS Mean Difference (95% CI) (%) Glucocorticoid CRENESSITY N=122 18 (5) -27 (2) -17 (-24, -10) p<0.0001 Daily Dose* Placebo N=60 18 (6) -10 (3) CI=confidence interval; LS mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean * In hydrocortisone equivalents (4x equivalency factor for (methyl)predniso(lo)ne, 60x for dexamethasone) adjusted for body surface area. At Week 24, there was a statistically significantly greater percentage of subjects achieving a reduction to a physiologic glucocorticoid daily dose (≤11 mg/m2/day hydrocortisone equivalents) while androstenedione was controlled (≤120% of baseline or ≤ULN) with CRENESSITY compared to placebo (63% vs 18%, p<0.0001). At Week 4, following a treatment period at a stable glucocorticoid dose regimen, the LS mean change from baseline in serum androstenedione in the CRENESSITY group was statistically significantly different at -299 ng/dL compared to the LS mean increase from baseline in the placebo group of 46 ng/dL, as shown in Table 8. 12 Reference ID: 5495978 Table 8. Change From Baseline in Serum Androstenedione (ng/dL) at Week 4* in Adults with Classic Congenital Adrenal Hyperplasia (Study 1) Treatment Group Mean (SD) Baseline LS Mean (SEM) Change from Baseline Placebo-subtracted LS Mean Difference (95% CI) Serum Androstenedione CRENESSITY N=122 634 (72) -299 (38) -345 (-457, -232) p<0.0001 (ng/dL)† Placebo N=60 590 (74) 46 (51) CI=confidence interval; LS mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean * End of glucocorticoid stable period. † Obtained prior to the morning glucocorticoid dose. 14.2 Pediatric Patients with Classic Congenital Adrenal Hyperplasia The efficacy of CRENESSITY to improve androgen control and enable a reduced glucocorticoid dose while maintaining androgen control in pediatric patients with classic CAH was evaluated in a Phase 3 randomized, double-blind, placebo-controlled study (Study 2; NCT#04806451). This study enrolled 103 pediatric subjects 4 to 17 years of age with classic CAH due to 21-hydroxylase deficiency and inadequate androgen control on supraphysiological glucocorticoid doses. Subjects were randomized to receive either CRENESSITY twice daily (N=69) or placebo (N=34) for 28 weeks, using weight-based dosing (50 mg twice daily via oral solution for subjects 20 to <55 kg [CRENESSITY N=37; placebo N=14 ], or 100 mg twice daily via oral capsules for subjects ≥55 kg [CRENESSITY N=32; placebo N=20]). During the first 4 weeks of CRENESSITY treatment, subjects were maintained on a stable glucocorticoid regimen except for stress dosing, as needed. The primary efficacy endpoint was the change from baseline in serum androstenedione at Week 4. From Weeks 4 to 20, the glucocorticoid dose could be reduced as frequently as every 4 weeks provided androstenedione levels were controlled. The goal was to achieve a glucocorticoid dose of 8 to 10 mg/m2/day (hydrocortisone dose equivalents adjusted for body surface area) by Week 28 while maintaining androstenedione control. The mean (range) age was 12 (4 to 17) years, 41% were Tanner Stage 1 or 2, 52% were male, 63% were White, and 11% were Hispanic or Latino. With respect to concurrent glucocorticoid use at baseline, 92% of patients were receiving hydrocortisone alone and 8% were receiving prednisone [or equivalent] (with or without hydrocortisone). At baseline, subjects were receiving a mean (SD) glucocorticoid total daily dose in hydrocortisone equivalents of 16 (4) mg/m2/day, and had a mean (SD) androstenedione level of 431 (461) ng/dL and mean (SD) serum 17-hydroxyprogesterone level of 8682 (6847) ng/dL prior to the morning glucocorticoid dose. At Week 4, following a treatment period at a stable glucocorticoid dose regimen, the LS mean reduction from baseline in serum androstenedione in the CRENESSITY group was statistically significantly different at -197 ng/dL compared to the increase of 71 ng/dL in the placebo group, as shown in Table 9. 13 Reference ID: 5495978 Table 9. Change From Baseline in Serum Androstenedione (ng/dL) at Week 4* in Pediatric Subjects with Classic Congenital Adrenal Hyperplasia (Study 2) Treatment Group Mean (SD) Baseline LS Mean (SEM) Change from Baseline Placebo-Subtracted LS Mean Difference (95% CI) Serum Androstenedione (ng/dL) † CRENESSITY N=69 405 (464) -197 (40) -268 (-403, -132) p=0.0002 Placebo N=34 483 (456) 71 (56) CI=confidence interval; LS mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean * End of glucocorticoid stable period. †Obtained prior to the morning glucocorticoid dose. At Week 4, following a treatment period at a stable glucocorticoid regimen, the LS mean reduction (SEM) from baseline in serum 17-hydroxyprogesterone in the CRENESSITY group was statistically significantly different at -5865 (572) ng/dL compared to the increase of 556 (818) ng/dL in the placebo group (LS Mean Treatment Difference -6421, 95% CI -8387, -4454, p<0.0001). The LS mean percent change from baseline in the total glucocorticoid daily dose while androstenedione was controlled (≤120% of baseline or ≤ULN) at Week 28 in the CRENESSITY group was statistically significantly different at -18% compared to the increase of 6% in the placebo group, as shown in Table 10. Table 10. Percent Change From Baseline in Glucocorticoid Daily Dose While Maintaining Androstenedione Control at Week 28 in Pediatric Subjects with Classic Congenital Adrenal Hyperplasia (Study 2) Treatment Group Mean (SD) Baseline (mg/m2/day) LS Mean (SEM) Percent Change from Baseline (%) Placebo-subtracted LS Mean Difference (95% CI) (%) Glucocorticoid CRENESSITY N=69 17 (4) -18 (2) -24 (-30, -17) p<0.0001 Daily Dose* Placebo N=34 16 (3) 6 (3) CI=confidence interval; LS mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean *In hydrocortisone equivalents (4x equivalency factor for (methyl)predniso(lo)ne) adjusted for body surface area. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied CRENESSITY Capsules CRENESSITY (crinecerfont) capsules are available in the doses shown in Table 11. 14 Reference ID: 5495978 Table 11. CRENESSITY Capsule Information Capsule Strength Capsule Color/Shape Capsule Marking Quantity in bottle NDC Number 25 mg Oval, orange soft gelatin capsules Printed with ‘WWV 25’ in black ink 60 70370-5025-1 50 mg Oval, two-toned orange and gold soft gelatin capsules Printed with ‘WWV 50’ in black ink 60 70370-5050-1 100 mg Oblong, gold soft gelatin capsules Printed with ‘WWV 100’ in black ink 30 70370-5100-1 CRENESSITY Oral Solution 50 mg/mL is a light yellow to orange, orange-flavored liquid. It is supplied in a 30 mL amber polyethylene terephthalate (PET) bottle (NDC 70370-5250-1). 16.2 Storage and Handling CRENESSITY Capsules Store at 15°C to 25°C (59°F to 77°F). Packaged in child-resistant HDPE bottles. Do not freeze. CRENESSITY Oral Solution Store and dispense in original container. Store CRENESSITY Oral Solution in an upright position. Store unopened bottles under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. Once a bottle is opened for use, it may be stored under refrigeration at 2°C to 8°C (36°F to 46°F) or at room temperature (15°C to 25°C [59°F to 77°F]) for up to 30 days. Discard any unused oral solution after 30 days of first opening the bottle. Packaged in child-resistant PET bottles. 17 PATIENT COUNSELING INFORMATION Advise patients and/or caregivers to read the FDA-approved patient labeling (Patient Information leaflet and CRENESSITY oral solution IFU, if applicable). Administration Information Counsel patients that CRENESSITY must be taken with a meal, without regard to fat or caloric content [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Drug Interactions Inform patients that the CRENESSITY dosage will need to be increased if they are taking strong or moderate CYP3A4 inducers [see Dosage and Administration (2.3, 2.4), Drug Interactions (7.1)]. Hypersensitivity Reactions Advise patients to seek prompt medical attention if signs or symptoms of hypersensitivity reactions occur. Advise patients who have had signs or symptoms of systemic hypersensitivity reactions to CRENESSITY that they should not receive CRENESSITY [see Contraindications (4) and Warnings and Precautions (5.1)]. Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy Inform patients that they should continue glucocorticoids when taking CRENESSITY. Counsel patients that any adjustment of glucocorticoid doses should be done under the guidance of their health care provider. 15 Reference ID: 5495978 Counsel patients about the continued need for stress dose glucocorticoids during times of increased cortisol need (e.g., during illness) [see Warnings and Precautions (5.2)]. Pregnancy Advise women who are exposed to CRENESSITY during pregnancy that there is a pregnancy safety study [see Use in Specific Populations (8.1)]. For information on CRENESSITY, visit www.CRENESSITY.com or call 1-855-CRNSITY (1-855-276-7489). Distributed by: Neurocrine Biosciences, Inc., San Diego, CA 92130, U.S.A. CRENESSITY is a trademark of Neurocrine Biosciences, Inc. 16 Reference ID: 5495978 PATIENT INFORMATION CRENESSITYTM (kreh NEH sih tee) (crinecerfont) capsules and oral solution What is CRENESSITY? CRENESSITY is a prescription medicine used together with glucocorticoids (steroids) to control androgen (testosterone-like hormone) levels in adults and children 4 years of age and older with classic congenital adrenal hyperplasia (CAH). It is not known if CRENESSITY is safe and effective in children younger than 4 years of age. Do not take CRENESSITY if you: x are allergic to crinecerfont, or any of the ingredients in CRENESSITY. See the end of this Patient Information leaflet for a complete list of ingredients in CRENESSITY. Before taking CRENESSITY, tell your health care provider about all of your medical conditions, including if you: x are pregnant or plan to become pregnant. It is not known if CRENESSITY will harm your unborn baby. If you become pregnant while taking CRENESSITY, tell your health care provider right away. There is a pregnancy safety study for women who become pregnant during treatment with CRENESSITY. x are breastfeeding or plan to breastfeed. It is not known if CRENESSITY passes into your breast milk. Talk to your health care provider about the best way to feed your baby during treatment with CRENESSITY. Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking CRENESSITY with certain other medicines may cause your CRENESSITY to not work as well. Do not start any new medicines while taking CRENESSITY without talking to your health care provider first. How should I take CRENESSITY? x Take CRENESSITY exactly as your health care provider tells you to. Your health care provider will tell you how much CRENESSITY to take and when to take it. x Do not stop taking CRENESSITY without talking to your health care provider first. x While your health care provider may lower your glucocorticoids (steroids), you should continue to take glucocorticoids (steroids) to treat adrenal insufficiency, including stress dose steroids (such as when your body may be under stress from fever, infection or surgery). Do not change your daily glucocorticoid (steroid) dose without talking to your health care provider. See “What are the possible side effects of CRENESSITY?” x Take CRENESSITY by mouth 2 times each day, in the morning and evening with a meal. x Swallow CRENESSITY capsules whole with liquid. Tell your health care provider if you cannot swallow the capsule whole. Your healthcare provider may need to switch you to CRENESSITY oral solution. x If your health care provider prescribes CRENESSITY oral solution, you should use the oral dosing syringe that your pharmacist will give you to measure and take the correct dose. See the Instructions for Use for CRENESSITY oral solution for more information. x If you miss a dose of CRENESSITY, take it as soon as you remember (even if it is almost time for your next dose). Take the next dose at your regular time. What are the possible side effects of CRENESSITY? CRENESSITY may cause serious side effects, including: x Allergic reactions. Symptoms of an allergic reaction include tightness of the throat, trouble breathing or swallowing, swelling of the lips, tongue, or face, and rash. If you have an allergic reaction to CRENESSITY, get emergency medical help right away and stop taking CRENESSITY. x Risk of Sudden Adrenal Insufficiency or Adrenal Crisis with Too Little Glucocorticoid (Steroid) Medicine. Sudden adrenal insufficiency or adrenal crisis can happen in people with congenital adrenal hyperplasia who are not taking enough glucocorticoid (steroid) medicine. You should continue taking your glucocorticoid (steroid) medicine during treatment with CRENESSITY. Certain conditions such as infection, severe injury, or shock may increase your risk for sudden adrenal insufficiency or adrenal crisis. Tell your health care provider if you get a severe injury, infection, illness, or have any planned surgery during treatment with CRENESSITY. Your health care provider may need to change your dose of glucocorticoid (steroid) medicine. The most common side effects of CRENESSITY in adults include: x tiredness x back pain x headache x decreased appetite x dizziness x muscle pain x joint pain The most common side effects of CRENESSITY in children include: x headache x nasal congestion x stomach pain x nose bleeds Reference ID: 5495978 x tiredness These are not all the possible side effects of CRENESSITY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store CRENESSITY? x Store CRENESSITY capsules at room temperature between 59°F to 77°F (15°C to 25°C). Do not freeze. x Store unopened CRENESSITY oral solution in the refrigerator between 36°F to 46°F (2°C to 8°C). Do not freeze. o Store in the original container in an upright position. o After opening the bottle, CRENESSITY oral solution may be stored in the refrigerator or at room temperature between 59°F to 77°F (15°C to 25°C) for up to 30 days. o Use CRENESSITY oral solution within 30 days of first opening the bottle. Throw away (dispose of) any unused medicine after 30 days. Keep CRENESSITY and all medicines out of the reach of children. General information about the safe and effective use of CRENESSITY. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CRENESSITY for a condition for which it was not prescribed. Do not give CRENESSITY to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or health care provider for information about CRENESSITY that is written for health professionals. What are the ingredients in CRENESSITY? Active ingredient: crinecerfont Inactive ingredients: x CRENESSITY capsules: lauroyl polyoxyl-32 glycerides, medium chain triglycerides, propylene glycol dicaprylate/dicaprate, and Vitamin E polyethylene glycol succinate. The capsule shell contains gelatin, glycerin, red iron oxide, Sorbitol glycerin blend, titanium dioxide, yellow iron oxide. x CRENESSITY oral solution: butylated hydroxytoluene, medium-chain triglycerides, oleoyl polyoxyl glycerides, orange flavor, and saccharin. Distributed by: Neurocrine Biosciences, Inc., San Diego, CA 92130, U.S.A For more information, go to www.CRENESSITY.com or call 1-855-CRNSITY (1 855-276-7489). This Patient Information has been approved by the U.S. Food and Drug Administration Issued: 12/2024 Reference ID: 5495978 INSTRUCTIONS FOR USE CRENESSITYTM (kreh NEH sih tee) (crinecerfont) oral solution 50 mg/mL Read this Instructions for Use for important information you need to know before taking CRENESSITY oral solution for the first time and each time you get a refill. There may be new information. This information does not take the place of talking to your health care provider about your medical condition or treatment. Important information: x Take CRENESSITY oral solution exactly as your health care provider tells you to. Your health care provider will tell you how much CRENESSITY oral solution to take and when to take it. x CRENESSITY oral solution should be taken with a meal in the morning and evening. x Always use the oral syringe provided by your pharmacist to make sure you measure the right amount of CRENESSITY oral solution. x Use CRENESSITY oral solution within 30 days of first opening the bottle. After 30 days of first opening the bottle, throw away (dispose of) any CRENESSITY oral solution that has not been used. x Do not stop taking CRENESSITY oral solution without talking to your health care provider first. x See the Patient Information leaflet that comes with CRENESSITY for more information. Supplies not included in the package: x Press-in bottle adapter x Oral syringes You must get a press-in bottle adapter and oral syringe from your pharmacist. Your pharmacist can help you choose the right press-in bottle adapter and oral syringe to use with CRENESSITY oral solution. Call your pharmacist right away if you do not have a press-in bottle adapter and the right oral syringe to use with your CRENESSITY oral solution. Reference ID: 5495978 CRENESSITY Oral Solution Bottle Oral Syringe Syringe­ Cap (if applicable) Tip - Barrel Press-in Bottle Adapter - Plunger How should I prepare and take CRENESSITY oral solution? 1. Gather the supplies (see Figure A): x CRENESSITY oral solution bottle x Press-in bottle adapter x Oral syringe Figure A 2. Inspect CRENESSITY. a. Check the pharmacy label to make sure the medicine name and dose are correct. b. Check the oral solution bottle, oral syringe, and press-in bottle adapter for signs of damage. Do not use the CRENESSITY oral solution bottle, oral syringe, or press-in bottle adapter if it appears to be damaged or tampered with. Contact your pharmacist or health care provider. Reference ID: 5495978 3. Prepare CRENESSITY oral solution. a. Remove the child-resistant cap by pressing it down while twisting it to the left (counterclockwise) (See Figure B). Figure B b. Carefully puncture and peel off the seal from the bottle (See Figure C). Figure C c. First time use of the bottle only. While holding the bottle firmly with one hand, use the thumb on your other hand to push the press-in bottle adapter into the bottle as far as it will go using constant pressure (see Figure D). Do not remove the press-in bottle adapter after it has been inserted. Figure D Reference ID: 5495978 4. Prepare the dose. a. Push in the plunger of the oral syringe as far as it will go (see Figure E). If the oral syringe comes with a cap, pull off the syringe cap. b. Insert the tip of the oral syringe into the press-in bottle adapter, then with the oral syringe still inserted, turn the bottle upside down (see Figure F). Figure E Figure F c. Slowly pull the plunger of the oral syringe until the part of the plunger that is touching the liquid is even with the marking of your prescribed dose (see Figure G). Note: Slowly push the plunger to return any large air bubbles back to the bottle and repeat the prior step until the air bubbles are gone. Figure G d. When you have measured the correct amount of CRENESSITY, keep the oral syringe inserted in the bottle and turn the bottle and oral syringe right side up. Hold the oral syringe from the middle, then carefully remove it from the bottle (see Figure H). Do not touch the plunger to avoid oral solution accidentally coming out of the syringe before you are ready to give the medicine. Figure H Reference ID: 5495978 5. Give a dose of CRENESSITY oral solution. a. Place the tip of the oral syringe inside your mouth and point it towards the inside of the cheek. b. Slowly push the plunger all the way down to give the full dose (see Figure I). c. Put the child-resistant cap back on the bottle with the press-in bottle adapter still inserted by turning the cap to the right (clockwise). Do not remove the press-in bottle adapter. The child-resistant cap will fit over it. 6. Rinse and store the oral syringe. a. Remove the plunger from the oral syringe. b. Rinse both parts with water (see Figure J). c. Push plunger back into the oral syringe to remove any large droplets of water. d. Remove the plunger from the oral syringe and allow these separated parts to air dry thoroughly on a clean surface. e. Push the dried plunger back into the dried oral syringe. f. Store the oral syringe in a clean, dry place. How should I store CRENESSITY oral solution? x Store CRENESSITY oral solution in the original container in an upright position. x Store unopened CRENESSITY oral solution in the refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze. x After opening the bottle, CRENESSITY oral solution can be stored in the refrigerator or at room temperature between 59°F to 77°F (15°C to 25°C) for up to 30 days. x Use CRENESSITY oral solution within 30 days of first opening the bottle. Throw away (dispose of) any unused medicine after 30 days. x Keep CRENESSITY oral solution and all medicines out of the reach of children. Figure I Figure J Reference ID: 5495978 Distributed by: Neurocrine Biosciences, Inc., San Diego, CA 92130, U.S.A For information, visit www.CRENESSITY.com or call 1-855-CRNSITY (1 855-276-7489). This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 12/2024 Reference ID: 5495978
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2025-02-12T15:47:40.695788
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CRENESSITY safely and effectively. See full prescribing information for CRENESSITY. CRENESSITY™ (crinecerfont) capsules, for oral use CRENESSITY™ (crinecerfont) oral solution Initial U.S. Approval: 2024 -----------------------------INDICATIONS AND USAGE-------------------------- CRENESSITY is a corticotropin-releasing factor type 1 receptor antagonist indicated as adjunctive treatment to glucocorticoid replacement to control androgens in adults and pediatric patients 4 years of age and older with classic congenital adrenal hyperplasia (CAH). ------------------------DOSAGE AND ADMINISTRATION---------------------- x Continue glucocorticoid replacement therapy for adrenal insufficiency associated with CAH. (2.1) x Adults: 100 mg orally, twice daily with a meal in the morning and evening. (2.2) x Pediatric Patients (4 years of age and older): Weight-based dosage orally, twice daily with a meal in the morning and evening. (2.2) x See Full Prescribing Information for complete dosage and administration information. ----------------------DOSAGE FORMS AND STRENGTHS--------------------- x Capsules: 25 mg, 50 mg, 100 mg (3) x Oral Solution: 50 mg/mL (3) -------------------------------CONTRAINDICATIONS-----------------------------­ Hypersensitivity to crinecerfont or any excipients of CRENESSITY. (4) ------------------------WARNINGS AND PRECAUTIONS----------------------- x Hypersensitivity Reactions: Include throat tightness, angioedema, and generalized rash. If clinically significant hypersensitivity occurs, initiate appropriate therapy and discontinue CRENESSITY. (5.1) x Risk of Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy: Continue glucocorticoids upon initiation of and during treatment with CRENESSITY. Do not reduce the glucocorticoid dose below the dose required for cortisol replacement. Any adjustment of daily glucocorticoid dosage after initiation of CRENESSITY should be performed under the supervision of a health care provider. Use glucocorticoid stress doses in cases of increased cortisol need (e.g., acute intercurrent illness, serious trauma, surgical procedures). (5.2) -------------------------------ADVERSE REACTIONS-----------------------------­ Adults: Most common adverse reactions (at least 4% for CRENESSITY and greater than placebo) are fatigue, headache, dizziness, arthralgia, back pain, decreased appetite, and myalgia. (6.1) Pediatric Patients: Most common adverse reactions (at least 4% for CRENESSITY and greater than placebo) are headache, abdominal pain, fatigue, nasal congestion, and epistaxis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Neurocrine Biosciences, Inc. at 877-641-3461 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------­ Strong CYP3A4 Inducers: Increase CRENESSITY morning and evening dosage 2-fold. (Section 2.3, 7.1) Moderate CYP3A4 Inducers: Increase CRENESSITY evening dosage 2-fold. (2.4, 7.1) See for 17 PATIENT COUNSELING INFORMATION Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Information 2.2 Recommended Dosage and Administration 2.3 Dosage Modifications for Concomitant Use with Strong CYP3A4 Inducers 2.4 Dosage Modifications for Concomitant Use with Moderate CYP3A4 Inducers 2.5 Administration Instructions 2.6 Missed Doses 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Risk of Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on CRENESSITY 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Adults with Congenital Adrenal Hyperplasia 14.2 Pediatric Patients with Congenital Adrenal Hyperplasia 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 5495978 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE CRENESSITY is indicated as adjunctive treatment to glucocorticoid replacement to control androgens in adults and pediatric patients 4 years of age and older with classic congenital adrenal hyperplasia (CAH). 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Information Patients receiving CRENESSITY should continue glucocorticoid replacement therapy for the adrenal insufficiency associated with congenital adrenal hyperplasia (see Warning and Precautions (5.2). Androstenedione levels can be assessed beginning four weeks after CRENESSITY initiation to inform reduction in glucocorticoid dosage as clinically indicated. Do not reduce the glucocorticoid dosage below that required for replacement therapy. 2.2 Recommended Dosage and Administration Recommended Dosage for Adults The recommended CRENESSITY dosage for adults is 100 mg orally, twice daily with a meal in the morning and evening [see Clinical Pharmacology (12.3)]. Recommended Dosage for Pediatric Patients 4 Years of Age and Older The recommended CRENESSITY dosage for pediatric patients 4 years of age and older is weight-based and administered orally, twice daily with a meal in the morning and evening (see Table 1) [see Clinical Pharmacology (12.3)]. Table 1. Recommended CRENESSITY Weight-Based Dosage for Pediatric Patients 4 Years of Age and Older Weight Dosage Regimen with a Meal 10 kg to less than 20 kg 25 mg orally twice daily 20 kg to less than 55 kg 50 mg orally twice daily Greater than or equal to 55 kg 100 mg orally twice daily 2.3 Dosage Modifications for Concomitant Use with Strong CYP3A4 Inducers Adults In adults, increase the CRENESSITY dosage to 200 mg orally, twice daily with a meal in the morning and evening when used concomitantly with strong CYP3A4 inducers [see Drug Interactions (7.1)]. Pediatric Patients 4 Years of Age and Older In pediatric patients, increase the CRENESSITY dosage with a meal in the morning and evening when used concomitantly with strong CYP3A4 inducers as shown in Table 2 [see Drug Interactions (7.1)]. 2 Reference ID: 5495978 Table 2. Dosage Increase of CRENESSITY for Use with Strong CYP3A4 Inducers in Pediatric Patients 4 Years of Age and Older Weight Dosage Regimen with a Meal 10 kg to less than 20 kg 50 mg orally twice daily 20 kg to less than 55 kg 100 mg orally twice daily Greater than or equal to 55 kg 200 mg orally twice daily 2.4 Dosage Modifications for Concomitant Use with Moderate CYP3A4 Inducers Adults In adults, increase the CRENESSITY dosage to 200 mg orally with the evening meal when used concomitantly with moderate CYP3A4 inducers. The CRENESSITY dosage of 100 mg with the morning meal remains unchanged [see Drug Interactions (7.1)]. Pediatric Patients 4 Years of Age and Older In pediatric patients, increase the CRENESSITY dosage with the evening meal when used concomitantly with moderate CYP3A4 inducers as shown in Table 3 [see Drug Interactions (7.1)]. Table 3. Dosage Increase of CRENESSITY for Use with Moderate CYP3A4 Inducers in Pediatric Patients 4 Years of Age and Older Dosage Regimen with a Meal Weight Morning Dose Evening Dose 10 kg to less than 20 kg 25 mg orally 50 mg orally 20 kg to less than 55 kg 50 mg orally 100 mg orally Greater than or equal to 55 kg 100 mg orally 200 mg orally 2.5 Administration Instructions Administer CRENESSITY orally, twice daily, with a meal in the morning and evening [see Clinical Pharmacology (12.3)]. CRENESSITY Capsules Take CRENESSITY capsules orally and swallow whole with liquid. CRENESSITY Oral Solution Refer patients and/or caregivers to the Instructions for Use (IFU) for complete administration instructions. Discard any unused CRENESSITY oral solution after 30 days of first opening the bottle [see How Supplied/Storage and Handling (16.2)]. 2.6 Missed Doses If a dose or doses are missed, advise the patient to take one dose of CRENESSITY as soon as possible (even if it is soon before the next scheduled dose) and then to resume the regular dosing schedule. 3 DOSAGE FORMS AND STRENGTHS CRENESSITY is available as: Capsules: o 25 mg oval, orange soft gelatin capsule printed with ‘WWV 25’ in black ink 3 Reference ID: 5495978 x o 50 mg oval, two-toned orange and gold soft gelatin capsule printed with ‘WWV 50’ in black ink o 100 mg oblong, gold soft gelatin capsule printed with ‘WWV 100’ in black ink x Oral Solution: 50 mg/mL in a light yellow to orange, clear to slightly opalescent oral solution 4 CONTRAINDICATIONS CRENESSITY is contraindicated in patients with hypersensitivity to crinecerfont or any excipients of CRENESSITY. Reactions have included throat tightness, angioedema, and generalized rash [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions A hypersensitivity reaction, including throat tightness, angioedema, and generalized rash, occurred in a subject after 3 days of treatment with CRENESSITY. If a clinically significant hypersensitivity reaction occurs, initiate appropriate therapy and discontinue CRENESSITY. 5.2 Risk of Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy Continue glucocorticoids upon initiation of and during treatment with CRENESSITY. Do not reduce the glucocorticoid dose below the dose required for cortisol replacement. Acute adrenal insufficiency or adrenal crisis, which can potentially be fatal or life-threatening, can occur in patients with underlying adrenal insufficiency who are on inadequate daily glucocorticoid doses, especially in situations associated with increased cortisol need, such as acute intercurrent illness, serious trauma, or surgical procedures. Any adjustment of daily glucocorticoid dosage after initiation of CRENESSITY should be performed under the supervision of a health care provider. Use glucocorticoid stress doses in case of increased cortisol need (e.g., acute intercurrent illness, serious trauma, surgical procedures). In the placebo-controlled clinical study of adults with classic CAH, the incidence of adrenal crisis was 1.6% in subjects treated with CRENESSITY and 0% in subjects treated with placebo. In the placebo-controlled clinical study of pediatric subjects with classic CAH, there were no events of adrenal crisis. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: x Hypersensitivity Reactions [see Warnings and Precautions (5.1)] x Risk of Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy [see Warnings and Precautions (5.2)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 4 Reference ID: 5495978 Adults with Congenital Adrenal Hyperplasia (CAH) The safety of CRENESSITY in adults was assessed in Study 1, a randomized, double-blind, placebo-controlled study of 182 adults aged 18 to 58 years with classic CAH due to 21-hydroxylase deficiency. A total of 122 subjects received CRENESSITY 100 mg twice daily and 59 subjects received placebo twice daily for up to 24 weeks [see Clinical Studies (14.1)]. Adverse Reactions Leading to Discontinuation of Treatment A total of 3% of CRENESSITY-treated subjects and no placebo-treated subjects discontinued treatment because of adverse reactions of restlessness, apathy, dyspepsia, nausea, and vomiting. Commonly Observed Adverse Reactions Adverse reactions that occurred in ≥4% of CRENESSITY-treated subjects and more frequently than in placebo-treated subjects are presented in Table 4. Table 4. Adverse Reactions (≥4%) in Adults with Congenital Adrenal Hyperplasia Treated with CRENESSITY and Occurring More Frequently Than in Placebo-Treated Subjects Adverse Reactions CRENESSITY (N=122) % Placebo (N=59) % Fatigue 25 15 Headache 16 15 Dizziness 8 3 Arthralgia 7 0 Back pain 6 3 Decreased appetite 4 2 Myalgia 4 3 Suicidal Ideation and Behavior Study 1 excluded subjects with active suicidal ideation with intent or plan within the six months prior to screening and those with a history of suicidal behavior within the past year, based on the Columbia-Suicide Severity Rating Scale (C-SSRS) administered at screening. The C-SSRS was administered to subjects at regular intervals during the study. Three of 122 (2.5%) CRENESSITY-treated subjects reported suicidal ideation without method, intent or plan on the C-SSRS during the 24-week double-blind treatment period compared to 1 of 59 (1.7%) placebo-treated subjects. One of the three subjects receiving CRENESSITY and the placebo-treated subject reported a lifetime history of suicidal ideation. One CRENESSITY-treated subject without a history of suicidal ideation or behavior attempted suicide during the open-label period after 320 days of treatment. Laboratory Findings Neutrophil count less than 2 x 103 cells/mcL occurred in 14% (17 of 120) of CRENESSITY-treated subjects, compared to 5% (3 of 58) of subjects in the placebo group. Neutrophil count less than 1 x 103 cells/mcL occurred in 0.8% (1 of 120) of CRENESSITY-treated subjects, compared to 1.7% subjects (1 of 58) in the placebo group. Pediatric Patients with Congenital Adrenal Hyperplasia The safety of CRENESSITY in pediatric patients was evaluated in Study 2, a randomized, double-blind placebo-controlled study of 103 pediatric subjects aged 4 to 17 years with classic CAH due to 21-hydroxylase deficiency. Pediatric subjects were randomized to receive CRENESSITY twice daily (N=69) or placebo (N=34) 5 Reference ID: 5495978 for 28 weeks, using weight-based dosing (50 mg twice daily via oral solution for subjects 20 to <55 kg, or 100 mg twice daily via oral capsules for subjects ≥55 kg) [see Clinical Studies (14.2)]. Adverse Reactions Leading to Discontinuation of Treatment A total of 3% of CRENESSITY-treated subjects and no placebo-treated subjects discontinued treatment because of adverse reactions of abdominal pain, myalgia, and dizziness. Commonly Observed Adverse Reactions Adverse reactions that occurred at an incidence of ≥4% in CRENESSITY-treated pediatric subjects (50 mg twice daily or 100 mg twice daily) and greater than placebo are presented in Table 5. Table 5. Adverse Reactions (≥ 4%) in Pediatric Subjects with Congenital Adrenal Hyperplasia Treated with CRENESSITY and Occurring More Frequently Than in Placebo-Treated Subjects Adverse Reactions CRENESSITY (N=69) % Placebo (N=33) % Headache 25 6 Abdominal pain1 13 0 Fatigue 7 0 Nasal congestion 7 3 Epistaxis 4 0 1Abdominal pain includes: abdominal pain, abdominal pain upper and abdominal pain lower Suicidal Ideation and Behavior Study 2 excluded subjects with active suicidal ideation with intent or plan within six months prior to screening or those with a lifetime history of suicidal behavior based on the C-SSRS administered at screening. Four of 67 (6%) CRENESSITY-treated subjects and 0 of the 31 (0%) placebo-treated subjects reported suicidal ideation without method, intent or plan on the C-SSRS during the 28-week double-blind treatment period. Two of the four CRENESSITY-treated subjects reported a lifetime history of suicidal ideation. There were no completed suicides or suicide attempts. Laboratory Findings Neutrophil count less than 2 x 103 cells/mcL occurred in 37% (25 of 68) of CRENESSITY-treated subjects, compared to 16% (5 of 32) of subjects in the placebo group. Neutrophil count less than 1 x 103 cells/mcL occurred in 4% (3 of 68) of CRENESSITY-treated subjects, compared to no subjects (0 of 32) in the placebo group. 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on CRENESSITY Strong CYP3A4 Inducers Increase CRENESSITY morning and evening dosages 2-fold when CRENESSITY is used concomitantly with a strong CYP3A4 inducer [see Dosage and Administration (2.3)]. Moderate CYP3A4 Inducers Increase CRENESSITY evening dosage 2-fold when CRENESSITY is used concomitantly with a moderate CYP3A4 inducer. Do not increase the morning dosage [see Dosage and Administration (2.4)]. 6 Reference ID: 5495978 Mechanism of Drug Interaction and Clinical Effect CRENESSITY is a CYP3A4 substrate. Concomitant use of CRENESSITY with a strong or moderate CYP3A4 inducer decreases crinecerfont exposure [see Clinical Pharmacology (12.3)], which may reduce CRENESSITY efficacy. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from reports of pregnancy in clinical trials with CRENESSITY are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. No developmental toxicity was observed in rats at 4-fold higher than human exposure at the maximum recommended human dose (MRHD) based on area under the concentration-time curve (AUC). Crinecerfont was associated with a low incidence of poly-malformations (craniofacial defects) in rabbits at 2-fold higher than human exposure at the MRHD. In a pre- and postnatal developmental toxicity study, no developmental toxicity was observed in rats at 4-fold higher than human exposure at the MRHD (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. If CRENESSITY is administered during pregnancy, or if a patient becomes pregnant while receiving CRENESSITY, health care providers should report exposure to CRENESSITY by calling 1-855-CRNSITY (1-855-276-7489). Data Animal Data Crinecerfont was administered orally to pregnant rabbits at doses of 100, 500, and 1000 mg/kg/day, and to pregnant rats at doses of 150, 500, and 2000 mg/kg/day during the period of organogenesis. No crinecerfont-related malformations were observed in rats at 4-fold higher than human exposure at the MRHD based on AUC. Low incidence of poly-malformations (craniofacial defects) and slightly lower mean fetal weights were observed in rabbits treated with crinecerfont at 2-fold higher than human exposure at the MRHD based on AUC. In a pre- and postnatal developmental toxicity study, crinecerfont was administered orally to pregnant rats at doses of 15, 50, and 250 mg/kg/day during the period of organogenesis and lactation through Day 20 postpartum. No changes in pup mortality, growth, sexual maturation, behavior, mating and fertility, or ovarian and uterine parameters were observed. The exposure in dams at the No Observed Adverse Effect Level (NOAEL) of 250 mg/kg/day was approximately 4-fold higher than human exposure at the MRHD based on AUC. 8.2 Lactation Risk Summary There are no data on the presence of crinecerfont in human milk, the effects on the breastfed infant, or the effects on milk production. Crinecerfont is present in animal milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Infants exposed to CRENESSITY through breast 7 Reference ID: 5495978 milk should be monitored for signs of adrenal insufficiency such as weakness, decreased feeding and weight loss. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CRENESSITY and any potential adverse effects on the breastfed child from CRENESSITY or from the underlying maternal condition. Data Crinecerfont was excreted in the milk of rats, with milk-to-plasma concentration ratios ranging from 1.5 to 12. No effects on postnatal development were observed in a pre- and postnatal development study, in which female rats were treated orally with up to 250 mg/kg/day (4-fold higher than human exposure at the MRHD based on AUC) during organogenesis through lactation. 8.4 Pediatric Use The safety and effectiveness of CRENESSITY as adjunctive treatment to glucocorticoid replacement to control androgens have been established in pediatric patients 4 years of age and older with classic CAH. Use of CRENESSITY for this indication is supported by evidence from an adequate and well-controlled study of 103 pediatric subjects (Study 2), evidence from an adequate and well-controlled study in adults with CAH (Study 1), and pharmacokinetic data from adults and pediatric subjects [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. The safety and effectiveness of CRENESSITY in pediatric patients less than 4 years of age have not been established. 8.5 Geriatric Use The clinical trial of CRENESSITY in adults with classic CAH did not enroll subjects 65 years of age and older to determine whether they respond differently from younger subjects. 8.6 Renal Impairment CRENESSITY is not recommended in patients with severe renal impairment or end-stage renal disease [see Clinical Pharmacology (12.3)]. 11 DESCRIPTION CRENESSITY contains crinecerfont, a selective corticotropin-releasing factor type 1 receptor antagonist, present as crinecerfont free base, with the chemical name, 2-thiazolamine, 4-(2-chloro-4-methoxy-5­ methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl. Crinecerfont free base is the S-enantiomer with an enantiomeric excess of at least 99.7%. Its molecular formula is C27H28ClFN2OS, and its molecular weight is 483.04 g/mol with the following structure: 8 Reference ID: 5495978 CRENESSITY Capsules CRENESSITY capsules are intended for oral administration only. Each capsule contains 25 mg, 50 mg, or 100 mg of crinecerfont free base. Inactive ingredients include lauroyl polyoxyl-32 glycerides, medium chain triglycerides, propylene glycol dicaprylate/dicaprate, and Vitamin E polyethylene glycol succinate. The capsule shell contains gelatin, glycerin, red iron oxide, Sorbitol glycerin blend, titanium dioxide, and yellow iron oxide. CRENESSITY Oral Solution The oral solution formulation contains 50 mg/mL of crinecerfont free base. Inactive ingredients include butylated hydroxytoluene, medium-chain triglycerides, oleoyl polyoxyl glycerides, orange flavor, and saccharin. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Crinecerfont is a selective corticotropin-releasing factor (CRF) type 1 receptor antagonist. Crinecerfont blocks the binding of CRF to CRF type 1 receptors in the pituitary but not CRF type 2 receptors. Crinecerfont binding to CRF type 1 receptors inhibits adrenocorticotropic hormone (ACTH) secretion from the pituitary, thereby reducing ACTH-mediated adrenal androgen production. 12.2 Pharmacodynamics Exposure-Response Relationships Model based exposure-response analyses for adults and pediatric patients with CAH demonstrated that, within the studied exposures of CRENESSITY in Phase 3 trials, relatively flat exposure-response relationships were observed for androstenedione reduction from baseline to Week 4 for both adults and pediatric patients and percent glucocorticoid daily dose reduction from baseline to Week 24 for adults and to Week 28 for pediatric patients. Adrenocorticotropic Hormone (ACTH) Reduction In 8 adults with classic CAH (NCT0352886) who received the recommended CRENESSITY dosage for 2 weeks, the median percent reduction from baseline in ACTH was 62%. In the Phase 3 clinical trials of adults and pediatric patients with classic CAH, administration of the recommended CRENESSITY dosage for 4 weeks during the initial glucocorticoid stable period led to a reduction in ACTH levels. In Study 1, the median percent reduction from baseline to Week 4 in ACTH was 65%. In Study 2, the median percent reduction from baseline to Week 4 in ACTH was 72%. Cardiac Electrophysiology At a dose 4 times the maximum approved recommended dosage, CRENESSITY does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Crinecerfont maximum plasma concentration (Cmax) and area under the time concentration curve (AUC0-24 hours) increases dose-proportionally over the approved recommended dosage range. Upon twice daily dosing, steady state conditions are achieved in approximately 7 days with an accumulation ratio of 1.4. Absorption Crinecerfont median time to reach Cmax (Tmax) is 4 hours following oral administration of CRENESSITY. 9 Reference ID: 5495978 No clinically significant differences in crinecerfont Cmax or AUC were observed following administration of CRENESSITY oral capsules and oral solution. Steady state exposures for crinecerfont in adults and pediatric patients following oral administration of CRENESSITY are presented in Table 6. Table 6. Geometric Mean (CV%) for AUC24,ss and Cmax in Adults and Pediatric Patients with Classic Congenital Adrenal Hyperplasia Following Oral Administration of CRENESSITY Parameter Geometric Mean (CV%) Study 1 (adults) Study 2 (pediatrics) AUC24hr,ss (ng*h/mL) 72846 (51%) Dose 100 mg bid (≥ 55 kg) Dose 50 mg bid (≥ 20 to < 55 kg) 74693 (48%) 47062 (51%) Cmax (ng/mL) Dose: 100 mg bid 4231 (46%) Dose 100 mg bid (≥ 55 kg) Dose 50 mg bid (≥ 20 to < 55 kg) 4555 (43%) 2887 (48%) CV%, coefficient of variation expressed as a percentage; bid, twice daily; steady-state exposure parameters are generated from simulation of 500 subjects based on population pharmacokinetic modeling and weight band appropriate formulation Effect of Food Following administration of CRENESSITY capsule, crinecerfont Cmax increased 4.9-fold and AUC increased 3.3-fold with a high-fat meal (800 to 1000 calories, 50% fat), compared to fasted conditions [see Dosage and Administration (2.2)]. Following administration of CRENESSITY oral solution, crinecerfont Cmax increased 8.6-fold and AUC increased 8.3-fold with a high-fat meal (800 to 1000 calories, 50% fat), compared to fasted conditions [see Dosage and Administration (2.2)]. Distribution Mean apparent volume of distribution (CV%) of crinecerfont in adults with CAH is 852 L (31%). Crinecerfont plasma protein binding is greater than or equal to 99.9%. Elimination Crinecerfont’s effective half-life is approximately 14 hours with a mean (CV%) apparent clearance of 3.5 L/h (37%). Metabolism Crinecerfont is metabolized primarily by CYP3A4 and to a lesser extent by CYP2B6 in vitro. Additionally, CYP2C8 and CYP2C19 may also have minor contributions to crinecerfont metabolism. Excretion Following a single oral 100 mg dose of radiolabeled crinecerfont, approximately 47.3% (2.7% as unchanged) of the dose was recovered in feces and 2% (amount as unchanged is undetectable) in urine. Specific Populations No clinically significant differences in the pharmacokinetics of crinecerfont were observed based on age (range: 5 to 54 years), sex (58.7% male), race (4.8% Asian, 9.7% Black, 77.5% White), mild to severe hepatic impairment (Child Pugh Class A to C), or mild to moderate renal impairment (estimated glomerular filtration rate: equal to or greater than 44 mL/min/1.73 m2; CKD-EPI 2009 formula for adults and bedside Schwartz formula for pediatric patients). Crinecerfont has not been studied in patients with severe renal impairment or end-stage renal disease. 10 Reference ID: 5495978 Drug Interaction Studies Clinical Studies Effect of Strong CYP3A4 Inducers on Crinecerfont: Crinecerfont Cmax decreased by 23% and AUC decreased by 62% following concomitant use with rifampin (strong CYP3A4 inducer) [see Dosage and Administration (2.3) and Drug Interactions (7.1)]. Effect of Strong CYP3A4 Inhibitors on Crinecerfont: Crinecerfont Cmax and AUC increased by 25% and 45%, respectively, when used concomitantly with ketoconazole (strong CYP3A4 inhibitor). Effect of Crinecerfont on CYP3A Substrates: No clinically significant differences in the pharmacokinetics of midazolam (CYP3A4 substrate) were observed when co-administered with crinecerfont. Concomitant use of crinecerfont did not affect the pharmacokinetics of oral contraceptives containing ethinyl estradiol and levonorgestrel. In Vitro Studies Cytochrome P450 Enzymes: Crinecerfont does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. Crinecerfont does not induce CYP2C8, CYP3A4, CYP1A2 and CYP2B6. Transporter Systems: Crinecerfont does not inhibit P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), bile salt export pump (BSEP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion protein (MATE)1, or MATE2-K. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 2-year carcinogenicity study, rats were administered daily crinecerfont doses of 5, 15, and 100 mg/kg/day via oral gavage. An increased incidence of thyroid follicular cell combined adenomas and carcinomas was observed in female rats at the 100 mg/kg/day dose level (approximately 4-fold higher than human exposure at the MRHD based on AUC). Thyroid follicular cell tumors can occur in rats from excessive thyroid stimulating hormone (TSH) secondary to liver enzyme induction, which is not thought to commonly occur in humans. No evidence of increased tumorigenicity was seen in male rats up to approximately 5-fold higher than human exposure at the MRHD based on AUC or in female rats up to approximately 2-fold higher than human exposure at the MRHD based on AUC. In a 6-month study in Tg.rasH2 mice, daily crinecerfont doses of 15, 50, 500, and 1500 mg/kg/day were administered via oral gavage. Crinecerfont did not increase the incidence of tumors in male or female transgenic mice (approximately 4-fold higher than human exposure at the MRHD based on AUC). Mutagenesis Crinecerfont was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay. Impairment of Fertility There were no crinecerfont-related effects on male or female fertility or female reproductive performance in rats treated orally with up to 1000 mg/kg/day crinecerfont at 2-fold higher than human exposure at the MRHD by AUC exposure. 11 Reference ID: 5495978 14 CLINICAL STUDIES 14.1 Adults with Classic Congenital Adrenal Hyperplasia The efficacy of CRENESSITY to reduce androgen levels and enable a reduced glucocorticoid dose while maintaining androgen control in adults with classic CAH was evaluated in a randomized, double-blind, placebo- controlled study (Study 1; NCT#04490915). This study enrolled 182 adults with classic CAH due to 21-hydroxylase deficiency on supraphysiological glucocorticoid doses and with androgen concentrations in the normal range or with inadequate androgen control. Subjects were randomized to receive CRENESSITY 100 mg twice daily (N=122) or placebo (N=60) for 24 weeks. During the first 4 weeks of CRENESSITY treatment, subjects maintained a stable glucocorticoid regimen except for stress dosing as needed. During Weeks 4 to 12, the glucocorticoid dose was reduced as frequently as every 2 weeks without regard to androstenedione levels, with the goal to achieve a glucocorticoid dose of 8 to 10 mg/m2/day in hydrocortisone dose equivalents adjusted for body surface area by Week 12. From Weeks 12 to 20, the glucocorticoid dose was further adjusted, if needed, to achieve androstenedione control by Week 24. The mean (range) age was 31 (18 to 58) years, 51% were male, 90% were White, and 8% were Hispanic or Latino. At baseline, the mean (SD) glucocorticoid total daily dose in hydrocortisone equivalents was 32 (9) mg/day (18 [5] mg/m2/day), with mean (SD) androstenedione levels of 620 (729) ng/dL prior to the morning glucocorticoid dose. The efficacy of CRENESSITY was assessed by the least-squares (LS) mean (SEM) percent change from baseline in the total glucocorticoid daily dose while androstenedione was controlled (≤120% of baseline or ≤upper limit of normal [ULN]) after 24 weeks. The LS mean percent change from baseline in daily glucocorticoid dose was statistically significantly greater in the CRENESSITY group at -27% compared to -10% in the placebo group, as shown in Table 7. Table 7. Percent Change From Baseline in Glucocorticoid Daily Dose While Maintaining Androstenedione Control at Week 24 in Adults with Classic Congenital Adrenal Hyperplasia (Study 1) Treatment Group Mean (SD) Baseline (mg/m2/day) LS Mean (SEM) Percent Change From Baseline (%) Placebo-Subtracted LS Mean Difference (95% CI) (%) Glucocorticoid CRENESSITY N=122 18 (5) -27 (2) -17 (-24, -10) p<0.0001 Daily Dose* Placebo N=60 18 (6) -10 (3) CI=confidence interval; LS mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean * In hydrocortisone equivalents (4x equivalency factor for (methyl)predniso(lo)ne, 60x for dexamethasone) adjusted for body surface area. At Week 24, there was a statistically significantly greater percentage of subjects achieving a reduction to a physiologic glucocorticoid daily dose (≤11 mg/m2/day hydrocortisone equivalents) while androstenedione was controlled (≤120% of baseline or ≤ULN) with CRENESSITY compared to placebo (63% vs 18%, p<0.0001). At Week 4, following a treatment period at a stable glucocorticoid dose regimen, the LS mean change from baseline in serum androstenedione in the CRENESSITY group was statistically significantly different at -299 ng/dL compared to the LS mean increase from baseline in the placebo group of 46 ng/dL, as shown in Table 8. 12 Reference ID: 5495978 Table 8. Change From Baseline in Serum Androstenedione (ng/dL) at Week 4* in Adults with Classic Congenital Adrenal Hyperplasia (Study 1) Treatment Group Mean (SD) Baseline LS Mean (SEM) Change from Baseline Placebo-subtracted LS Mean Difference (95% CI) Serum Androstenedione CRENESSITY N=122 634 (72) -299 (38) -345 (-457, -232) p<0.0001 (ng/dL)† Placebo N=60 590 (74) 46 (51) CI=confidence interval; LS mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean * End of glucocorticoid stable period. † Obtained prior to the morning glucocorticoid dose. 14.2 Pediatric Patients with Classic Congenital Adrenal Hyperplasia The efficacy of CRENESSITY to improve androgen control and enable a reduced glucocorticoid dose while maintaining androgen control in pediatric patients with classic CAH was evaluated in a Phase 3 randomized, double-blind, placebo-controlled study (Study 2; NCT#04806451). This study enrolled 103 pediatric subjects 4 to 17 years of age with classic CAH due to 21-hydroxylase deficiency and inadequate androgen control on supraphysiological glucocorticoid doses. Subjects were randomized to receive either CRENESSITY twice daily (N=69) or placebo (N=34) for 28 weeks, using weight-based dosing (50 mg twice daily via oral solution for subjects 20 to <55 kg [CRENESSITY N=37; placebo N=14 ], or 100 mg twice daily via oral capsules for subjects ≥55 kg [CRENESSITY N=32; placebo N=20]). During the first 4 weeks of CRENESSITY treatment, subjects were maintained on a stable glucocorticoid regimen except for stress dosing, as needed. The primary efficacy endpoint was the change from baseline in serum androstenedione at Week 4. From Weeks 4 to 20, the glucocorticoid dose could be reduced as frequently as every 4 weeks provided androstenedione levels were controlled. The goal was to achieve a glucocorticoid dose of 8 to 10 mg/m2/day (hydrocortisone dose equivalents adjusted for body surface area) by Week 28 while maintaining androstenedione control. The mean (range) age was 12 (4 to 17) years, 41% were Tanner Stage 1 or 2, 52% were male, 63% were White, and 11% were Hispanic or Latino. With respect to concurrent glucocorticoid use at baseline, 92% of patients were receiving hydrocortisone alone and 8% were receiving prednisone [or equivalent] (with or without hydrocortisone). At baseline, subjects were receiving a mean (SD) glucocorticoid total daily dose in hydrocortisone equivalents of 16 (4) mg/m2/day, and had a mean (SD) androstenedione level of 431 (461) ng/dL and mean (SD) serum 17-hydroxyprogesterone level of 8682 (6847) ng/dL prior to the morning glucocorticoid dose. At Week 4, following a treatment period at a stable glucocorticoid dose regimen, the LS mean reduction from baseline in serum androstenedione in the CRENESSITY group was statistically significantly different at -197 ng/dL compared to the increase of 71 ng/dL in the placebo group, as shown in Table 9. 13 Reference ID: 5495978 Table 9. Change From Baseline in Serum Androstenedione (ng/dL) at Week 4* in Pediatric Subjects with Classic Congenital Adrenal Hyperplasia (Study 2) Treatment Group Mean (SD) Baseline LS Mean (SEM) Change from Baseline Placebo-Subtracted LS Mean Difference (95% CI) Serum Androstenedione (ng/dL) † CRENESSITY N=69 405 (464) -197 (40) -268 (-403, -132) p=0.0002 Placebo N=34 483 (456) 71 (56) CI=confidence interval; LS mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean * End of glucocorticoid stable period. †Obtained prior to the morning glucocorticoid dose. At Week 4, following a treatment period at a stable glucocorticoid regimen, the LS mean reduction (SEM) from baseline in serum 17-hydroxyprogesterone in the CRENESSITY group was statistically significantly different at -5865 (572) ng/dL compared to the increase of 556 (818) ng/dL in the placebo group (LS Mean Treatment Difference -6421, 95% CI -8387, -4454, p<0.0001). The LS mean percent change from baseline in the total glucocorticoid daily dose while androstenedione was controlled (≤120% of baseline or ≤ULN) at Week 28 in the CRENESSITY group was statistically significantly different at -18% compared to the increase of 6% in the placebo group, as shown in Table 10. Table 10. Percent Change From Baseline in Glucocorticoid Daily Dose While Maintaining Androstenedione Control at Week 28 in Pediatric Subjects with Classic Congenital Adrenal Hyperplasia (Study 2) Treatment Group Mean (SD) Baseline (mg/m2/day) LS Mean (SEM) Percent Change from Baseline (%) Placebo-subtracted LS Mean Difference (95% CI) (%) Glucocorticoid CRENESSITY N=69 17 (4) -18 (2) -24 (-30, -17) p<0.0001 Daily Dose* Placebo N=34 16 (3) 6 (3) CI=confidence interval; LS mean=least-squares mean; SD=standard deviation; SEM=standard error of the mean *In hydrocortisone equivalents (4x equivalency factor for (methyl)predniso(lo)ne) adjusted for body surface area. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied CRENESSITY Capsules CRENESSITY (crinecerfont) capsules are available in the doses shown in Table 11. 14 Reference ID: 5495978 Table 11. CRENESSITY Capsule Information Capsule Strength Capsule Color/Shape Capsule Marking Quantity in bottle NDC Number 25 mg Oval, orange soft gelatin capsules Printed with ‘WWV 25’ in black ink 60 70370-5025-1 50 mg Oval, two-toned orange and gold soft gelatin capsules Printed with ‘WWV 50’ in black ink 60 70370-5050-1 100 mg Oblong, gold soft gelatin capsules Printed with ‘WWV 100’ in black ink 30 70370-5100-1 CRENESSITY Oral Solution 50 mg/mL is a light yellow to orange, orange-flavored liquid. It is supplied in a 30 mL amber polyethylene terephthalate (PET) bottle (NDC 70370-5250-1). 16.2 Storage and Handling CRENESSITY Capsules Store at 15°C to 25°C (59°F to 77°F). Packaged in child-resistant HDPE bottles. Do not freeze. CRENESSITY Oral Solution Store and dispense in original container. Store CRENESSITY Oral Solution in an upright position. Store unopened bottles under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. Once a bottle is opened for use, it may be stored under refrigeration at 2°C to 8°C (36°F to 46°F) or at room temperature (15°C to 25°C [59°F to 77°F]) for up to 30 days. Discard any unused oral solution after 30 days of first opening the bottle. Packaged in child-resistant PET bottles. 17 PATIENT COUNSELING INFORMATION Advise patients and/or caregivers to read the FDA-approved patient labeling (Patient Information leaflet and CRENESSITY oral solution IFU, if applicable). Administration Information Counsel patients that CRENESSITY must be taken with a meal, without regard to fat or caloric content [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Drug Interactions Inform patients that the CRENESSITY dosage will need to be increased if they are taking strong or moderate CYP3A4 inducers [see Dosage and Administration (2.3, 2.4), Drug Interactions (7.1)]. Hypersensitivity Reactions Advise patients to seek prompt medical attention if signs or symptoms of hypersensitivity reactions occur. Advise patients who have had signs or symptoms of systemic hypersensitivity reactions to CRENESSITY that they should not receive CRENESSITY [see Contraindications (4) and Warnings and Precautions (5.1)]. Acute Adrenal Insufficiency or Adrenal Crisis with Inadequate Concomitant Glucocorticoid Therapy Inform patients that they should continue glucocorticoids when taking CRENESSITY. Counsel patients that any adjustment of glucocorticoid doses should be done under the guidance of their health care provider. 15 Reference ID: 5495978 Counsel patients about the continued need for stress dose glucocorticoids during times of increased cortisol need (e.g., during illness) [see Warnings and Precautions (5.2)]. Pregnancy Advise women who are exposed to CRENESSITY during pregnancy that there is a pregnancy safety study [see Use in Specific Populations (8.1)]. For information on CRENESSITY, visit www.CRENESSITY.com or call 1-855-CRNSITY (1-855-276-7489). Distributed by: Neurocrine Biosciences, Inc., San Diego, CA 92130, U.S.A. CRENESSITY is a trademark of Neurocrine Biosciences, Inc. 16 Reference ID: 5495978 PATIENT INFORMATION CRENESSITYTM (kreh NEH sih tee) (crinecerfont) capsules and oral solution What is CRENESSITY? CRENESSITY is a prescription medicine used together with glucocorticoids (steroids) to control androgen (testosterone-like hormone) levels in adults and children 4 years of age and older with classic congenital adrenal hyperplasia (CAH). It is not known if CRENESSITY is safe and effective in children younger than 4 years of age. Do not take CRENESSITY if you: x are allergic to crinecerfont, or any of the ingredients in CRENESSITY. See the end of this Patient Information leaflet for a complete list of ingredients in CRENESSITY. Before taking CRENESSITY, tell your health care provider about all of your medical conditions, including if you: x are pregnant or plan to become pregnant. It is not known if CRENESSITY will harm your unborn baby. If you become pregnant while taking CRENESSITY, tell your health care provider right away. There is a pregnancy safety study for women who become pregnant during treatment with CRENESSITY. x are breastfeeding or plan to breastfeed. It is not known if CRENESSITY passes into your breast milk. Talk to your health care provider about the best way to feed your baby during treatment with CRENESSITY. Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking CRENESSITY with certain other medicines may cause your CRENESSITY to not work as well. Do not start any new medicines while taking CRENESSITY without talking to your health care provider first. How should I take CRENESSITY? x Take CRENESSITY exactly as your health care provider tells you to. Your health care provider will tell you how much CRENESSITY to take and when to take it. x Do not stop taking CRENESSITY without talking to your health care provider first. x While your health care provider may lower your glucocorticoids (steroids), you should continue to take glucocorticoids (steroids) to treat adrenal insufficiency, including stress dose steroids (such as when your body may be under stress from fever, infection or surgery). Do not change your daily glucocorticoid (steroid) dose without talking to your health care provider. See “What are the possible side effects of CRENESSITY?” x Take CRENESSITY by mouth 2 times each day, in the morning and evening with a meal. x Swallow CRENESSITY capsules whole with liquid. Tell your health care provider if you cannot swallow the capsule whole. Your healthcare provider may need to switch you to CRENESSITY oral solution. x If your health care provider prescribes CRENESSITY oral solution, you should use the oral dosing syringe that your pharmacist will give you to measure and take the correct dose. See the Instructions for Use for CRENESSITY oral solution for more information. x If you miss a dose of CRENESSITY, take it as soon as you remember (even if it is almost time for your next dose). Take the next dose at your regular time. What are the possible side effects of CRENESSITY? CRENESSITY may cause serious side effects, including: x Allergic reactions. Symptoms of an allergic reaction include tightness of the throat, trouble breathing or swallowing, swelling of the lips, tongue, or face, and rash. If you have an allergic reaction to CRENESSITY, get emergency medical help right away and stop taking CRENESSITY. x Risk of Sudden Adrenal Insufficiency or Adrenal Crisis with Too Little Glucocorticoid (Steroid) Medicine. Sudden adrenal insufficiency or adrenal crisis can happen in people with congenital adrenal hyperplasia who are not taking enough glucocorticoid (steroid) medicine. You should continue taking your glucocorticoid (steroid) medicine during treatment with CRENESSITY. Certain conditions such as infection, severe injury, or shock may increase your risk for sudden adrenal insufficiency or adrenal crisis. Tell your health care provider if you get a severe injury, infection, illness, or have any planned surgery during treatment with CRENESSITY. Your health care provider may need to change your dose of glucocorticoid (steroid) medicine. The most common side effects of CRENESSITY in adults include: x tiredness x back pain x headache x decreased appetite x dizziness x muscle pain x joint pain The most common side effects of CRENESSITY in children include: x headache x nasal congestion x stomach pain x nose bleeds Reference ID: 5495978 x tiredness These are not all the possible side effects of CRENESSITY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store CRENESSITY? x Store CRENESSITY capsules at room temperature between 59°F to 77°F (15°C to 25°C). Do not freeze. x Store unopened CRENESSITY oral solution in the refrigerator between 36°F to 46°F (2°C to 8°C). Do not freeze. o Store in the original container in an upright position. o After opening the bottle, CRENESSITY oral solution may be stored in the refrigerator or at room temperature between 59°F to 77°F (15°C to 25°C) for up to 30 days. o Use CRENESSITY oral solution within 30 days of first opening the bottle. Throw away (dispose of) any unused medicine after 30 days. Keep CRENESSITY and all medicines out of the reach of children. General information about the safe and effective use of CRENESSITY. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CRENESSITY for a condition for which it was not prescribed. Do not give CRENESSITY to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or health care provider for information about CRENESSITY that is written for health professionals. What are the ingredients in CRENESSITY? Active ingredient: crinecerfont Inactive ingredients: x CRENESSITY capsules: lauroyl polyoxyl-32 glycerides, medium chain triglycerides, propylene glycol dicaprylate/dicaprate, and Vitamin E polyethylene glycol succinate. The capsule shell contains gelatin, glycerin, red iron oxide, Sorbitol glycerin blend, titanium dioxide, yellow iron oxide. x CRENESSITY oral solution: butylated hydroxytoluene, medium-chain triglycerides, oleoyl polyoxyl glycerides, orange flavor, and saccharin. Distributed by: Neurocrine Biosciences, Inc., San Diego, CA 92130, U.S.A For more information, go to www.CRENESSITY.com or call 1-855-CRNSITY (1 855-276-7489). This Patient Information has been approved by the U.S. Food and Drug Administration Issued: 12/2024 Reference ID: 5495978 INSTRUCTIONS FOR USE CRENESSITYTM (kreh NEH sih tee) (crinecerfont) oral solution 50 mg/mL Read this Instructions for Use for important information you need to know before taking CRENESSITY oral solution for the first time and each time you get a refill. There may be new information. This information does not take the place of talking to your health care provider about your medical condition or treatment. Important information: x Take CRENESSITY oral solution exactly as your health care provider tells you to. Your health care provider will tell you how much CRENESSITY oral solution to take and when to take it. x CRENESSITY oral solution should be taken with a meal in the morning and evening. x Always use the oral syringe provided by your pharmacist to make sure you measure the right amount of CRENESSITY oral solution. x Use CRENESSITY oral solution within 30 days of first opening the bottle. After 30 days of first opening the bottle, throw away (dispose of) any CRENESSITY oral solution that has not been used. x Do not stop taking CRENESSITY oral solution without talking to your health care provider first. x See the Patient Information leaflet that comes with CRENESSITY for more information. Supplies not included in the package: x Press-in bottle adapter x Oral syringes You must get a press-in bottle adapter and oral syringe from your pharmacist. Your pharmacist can help you choose the right press-in bottle adapter and oral syringe to use with CRENESSITY oral solution. Call your pharmacist right away if you do not have a press-in bottle adapter and the right oral syringe to use with your CRENESSITY oral solution. Reference ID: 5495978 CRENESSITY Oral Solution Bottle Oral Syringe Syringe­ Cap (if applicable) Tip - Barrel Press-in Bottle Adapter - Plunger How should I prepare and take CRENESSITY oral solution? 1. Gather the supplies (see Figure A): x CRENESSITY oral solution bottle x Press-in bottle adapter x Oral syringe Figure A 2. Inspect CRENESSITY. a. Check the pharmacy label to make sure the medicine name and dose are correct. b. Check the oral solution bottle, oral syringe, and press-in bottle adapter for signs of damage. Do not use the CRENESSITY oral solution bottle, oral syringe, or press-in bottle adapter if it appears to be damaged or tampered with. Contact your pharmacist or health care provider. Reference ID: 5495978 3. Prepare CRENESSITY oral solution. a. Remove the child-resistant cap by pressing it down while twisting it to the left (counterclockwise) (See Figure B). Figure B b. Carefully puncture and peel off the seal from the bottle (See Figure C). Figure C c. First time use of the bottle only. While holding the bottle firmly with one hand, use the thumb on your other hand to push the press-in bottle adapter into the bottle as far as it will go using constant pressure (see Figure D). Do not remove the press-in bottle adapter after it has been inserted. Figure D Reference ID: 5495978 4. Prepare the dose. a. Push in the plunger of the oral syringe as far as it will go (see Figure E). If the oral syringe comes with a cap, pull off the syringe cap. b. Insert the tip of the oral syringe into the press-in bottle adapter, then with the oral syringe still inserted, turn the bottle upside down (see Figure F). Figure E Figure F c. Slowly pull the plunger of the oral syringe until the part of the plunger that is touching the liquid is even with the marking of your prescribed dose (see Figure G). Note: Slowly push the plunger to return any large air bubbles back to the bottle and repeat the prior step until the air bubbles are gone. Figure G d. When you have measured the correct amount of CRENESSITY, keep the oral syringe inserted in the bottle and turn the bottle and oral syringe right side up. Hold the oral syringe from the middle, then carefully remove it from the bottle (see Figure H). Do not touch the plunger to avoid oral solution accidentally coming out of the syringe before you are ready to give the medicine. Figure H Reference ID: 5495978 5. Give a dose of CRENESSITY oral solution. a. Place the tip of the oral syringe inside your mouth and point it towards the inside of the cheek. b. Slowly push the plunger all the way down to give the full dose (see Figure I). c. Put the child-resistant cap back on the bottle with the press-in bottle adapter still inserted by turning the cap to the right (clockwise). Do not remove the press-in bottle adapter. The child-resistant cap will fit over it. 6. Rinse and store the oral syringe. a. Remove the plunger from the oral syringe. b. Rinse both parts with water (see Figure J). c. Push plunger back into the oral syringe to remove any large droplets of water. d. Remove the plunger from the oral syringe and allow these separated parts to air dry thoroughly on a clean surface. e. Push the dried plunger back into the dried oral syringe. f. Store the oral syringe in a clean, dry place. How should I store CRENESSITY oral solution? x Store CRENESSITY oral solution in the original container in an upright position. x Store unopened CRENESSITY oral solution in the refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze. x After opening the bottle, CRENESSITY oral solution can be stored in the refrigerator or at room temperature between 59°F to 77°F (15°C to 25°C) for up to 30 days. x Use CRENESSITY oral solution within 30 days of first opening the bottle. Throw away (dispose of) any unused medicine after 30 days. x Keep CRENESSITY oral solution and all medicines out of the reach of children. Figure I Figure J Reference ID: 5495978 Distributed by: Neurocrine Biosciences, Inc., San Diego, CA 92130, U.S.A For information, visit www.CRENESSITY.com or call 1-855-CRNSITY (1 855-276-7489). This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 12/2024 Reference ID: 5495978
custom-source
2025-02-12T15:47:41.686545
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use NEMLUVIO safely and effectively. See full prescribing information for NEMLUVIO. NEMLUVIO® (nemolizumab-ilto) for injection, for subcutaneous use Initial U.S. Approval: 2024 ----------------------INDICATIONS AND USAGE---------------------­ NEMLUVIO is an interleukin-31 receptor antagonist indicated for the treatment of adults and pediatric patients 12 years of age and older with moderate-to-severe atopic dermatitis in combination with topical corticosteroids and/or calcineurin inhibitors when the disease is not adequately controlled with topical prescription therapies. (1) ------------------DOSAGE AND ADMINISTRATION-----------------­ • Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to treatment with NEMLUVIO. (2.1) • The recommended dosage is an initial dose of 60 mg (two 30 mg injections), followed by 30 mg given every 4 weeks. (2.2) • After 16 weeks of treatment, for patients who achieve clear or almost clear skin, a dosage of 30 mg every 8 weeks is recommended. (2.2) • Use NEMLUVIO with topical corticosteroids and/or topical calcineurin inhibitors. When the disease has sufficiently improved, discontinue use of topical therapies. (2.2) • Administer NEMLUVIO by subcutaneous injection. (2.4) • NEMLUVIO must be reconstituted prior to administration. (2.5) -----------------DOSAGE FORMS AND STRENGTHS---------------­ For injection: single-dose pre-filled dual-chamber pen containing 30 mg of nemolizumab-ilto lyophilized powder and diluent, water for injection. (3) -------------------------CONTRAINDICATIONS------------------------­ Known hypersensitivity to nemolizumab-ilto or to any of the excipients in NEMLUVIO. (4) ------------------WARNINGS AND PRECAUTIONS------------------­ • Hypersensitivity: Hypersensitivity reactions have been reported with NEMLUVIO use. If a clinically significant hypersensitivity reaction occurs, immediately institute appropriate therapy and discontinue NEMLUVIO. (5.1) • Vaccinations: Avoid use of live vaccines during treatment with NEMLUVIO. (5.2) -------------------------ADVERSE REACTIONS-------------------------­ Most common adverse reaction (incidence ≥1%) headache (including migraine), arthralgia, urticaria, and myalgia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P at 1-866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Vaccination Prior to Treatment 2.2 Recommended Dosage for Atopic Dermatitis 2.3 Missed Dose 2.4 Important Administration Instructions 2.5 Preparation for Use of NEMLUVIO 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity 5.2 Vaccinations 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Atopic Dermatitis 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5495566 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE NEMLUVIO is indicated for the treatment of adults and pediatric patients 12 years of age and older with moderate-to-severe atopic dermatitis in combination with topical corticosteroids and/or calcineurin inhibitors when the disease is not adequately controlled with topical prescription therapies. 2 DOSAGE AND ADMINISTRATION 2.1 Vaccination Prior to Treatment Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to treatment with NEMLUVIO [see Warnings and Precautions (5.2)]. 2.2 Recommended Dosage for Atopic Dermatitis The recommended subcutaneous dosage of NEMLUVIO in adults and pediatric patients 12 years of age and older is an initial dose of 60 mg (two 30 mg injections), followed by 30 mg given every 4 weeks. After 16 weeks of treatment, for patients who achieve clear or almost clear skin, a subcutaneous dosage of 30 mg every 8 weeks is recommended. Concomitant Topical Therapies: Use NEMLUVIO with topical corticosteroids and/or topical calcineurin inhibitors. When the disease has sufficiently improved, discontinue use of topical therapies. 2.3 Missed Dose If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time. 2.4 Important Administration Instructions • NEMLUVIO is administered by subcutaneous injection. • NEMLUVIO is intended for use under the guidance of a healthcare provider. Prior to the first injection, provide patients and/or caregivers with proper training on the preparation and administration of NEMLUVIO. Patients may self-inject NEMLUVIO after receiving training on subcutaneous injection techniques. In pediatric patients 12 years of age and older, administer NEMLUVIO by or under the supervision of a trained adult or caregiver. Reference ID: 5495566 • For the initial dose, administer each of the two NEMLUVIO injections at different injection sites. • Administer subcutaneous injection into the front upper thighs or abdomen except for the 2 inches (5 cm) around the navel. Injection in upper arm should only be performed by a caregiver or healthcare professional. • Alternate the injection site with each injection. Do not inject NEMLUVIO into skin that is tender, inflamed, swollen, damaged or has bruises or scars or open wounds. • Refer to the Instructions for Use for complete administration instructions with illustrations [see Instructions for Use]. 2.5 Preparation for Use of NEMLUVIO • Before injection, remove NEMLUVIO carton from the refrigerator and allow to reach room temperature (30-45 minutes). • Inspect NEMLUVIO visually prior to reconstitution. NEMLUVIO is supplied in a single- dose prefilled dual-chamber pen with white powder in one chamber and a clear diluent in the other chamber. Do not use if powder is not white, or if diluent is cloudy or contains visible particles. • NEMLUVIO must be reconstituted prior to administration. • Following reconstitution, each prefilled pen delivers 30 mg/0.49 mL as a clear and colorless to slightly yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the reconstituted solution has discoloration or contains particles. • Use NEMLUVIO pens within 4 hours after reconstitution. Discard unused reconstituted NEMLUVIO pens after 4 hours. • Discard any unused portions after administration. • Refer to the Instructions for Use for complete administration instructions with illustrations [see Instructions for Use]. 3 DOSAGE FORMS AND STRENGTHS For injection: single-dose prefilled dual-chamber pen containing 30 mg of nemolizumab-ilto as a white lyophilized powder in one chamber and diluent, water for injection, in the other chamber. 4 CONTRAINDICATIONS Reference ID: 5495566 NEMLUVIO is contraindicated in patients who have known hypersensitivity to nemolizumab­ ilto or to any of the excipients in NEMLUVIO [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Hypersensitivity reactions, such as facial angioedema, have been reported with use of NEMLUVIO. NEMLUVIO is contraindicated in patients with a known hypersensitivity to nemolizumab-ilto or to any of the excipients in NEMLUVIO. If a clinically significant hypersensitivity reaction occurs, immediately institute appropriate therapy and discontinue NEMLUVIO [see Contraindications (4), Adverse Reactions (6.1)]. 5.2 Vaccinations Complete all age-appropriate vaccinations as recommended by current immunization guidelines prior to treatment with NEMLUVIO. Avoid use of live vaccines in patients during treatment with NEMLUVIO. It is unknown if administration of live vaccines during NEMLUVIO treatment will impact the safety or effectiveness of these vaccines. No data are available on the response to non-live vaccines. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail elsewhere in the labeling: • Hypersensitivity [see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 1148 subjects, including 180 subjects 12 to 17 years of age, with moderate-to-severe atopic dermatitis were treated with NEMLUVIO for at least 1 year during the development program. The safety of NEMLUVIO was evaluated in a pool of two randomized, double-blind, placebo- controlled, multicenter phase 3 trials (ARCADIA 1, ARCADIA 2). In these two trials, 1135 adult and pediatric subjects 12 years of age and older with moderate-to-severe AD were treated with subcutaneous injections of NEMLUVIO, with concomitant topical corticosteroids (TCS) and/or topical calcineurin inhibitors (TCI) for up to 16 weeks (Initial Treatment Period) [see Clinical Studies (14)]. After the Initial Treatment Period, subjects that responded to NEMLUVIO were re-randomized to every 4 weeks, every 8 weeks, or placebo dosing for the Maintenance Treatment Period (Week 16 through Week 48). The safety population during the Maintenance Treatment Period Reference ID: 5495566 had a mean age of 31 to 33 years (median age of 26 to 29 years) for the NEMLUVIO cohorts. Week 0 to Week 16 In ARCADIA 1 and ARCADIA 2 trials through Week 16, the proportion of subjects who discontinued treatment because of adverse events was 2.3% in the NEMLUVIO 30 mg every 4 weeks group and 2.2% in the placebo groups. Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% in the NEMLUVIO group, and for which the rate exceeds the rate in the placebo group during the first 16 weeks of treatment. Table 1: Adverse Reactions Occurring in ≥1% of Adult and Pediatric Subjects 12 Years of Age and Older with Atopic Dermatitis in the NEMLUVIO Group and Greater than Placebo in ARCADIA 1 and ARCADIA 2 Trials through Week 16 Adverse reactions NEMLUVIO (N = 1135) n (%) Placebo (N=584) n (%) Headache (incl. migraine) 52 (5) 22 (4) Arthralgia 12 (1) 1 (0.2) Urticaria 12 (1) 2 (0.3) Myalgia 11 (1) 1 (0.2) Assessment of the safety profile of NEMLUVIO in 505 subjects up through Week 48 in the ARCADIA 1 and ARCADIA 2 trials was generally consistent with the safety profile observed at Week 16. Specific Adverse Reactions Hypersensitivity reactions Type 1 hypersensitivity reactions (Ig-E mediated reactions) were reported in subjects treated with NEMLUVIO. This included occurrence of mild urticaria that did not lead to discontinuation of treatment. Injection site reactions The incidence of injection site reactions during initial period was reported for 1.2% of subjects treated with NEMLUVIO and 0.9% of subjects receiving placebo; during the maintenance period, the incidence was 0.6% with NEMLUVIO every 4 weeks, 0% with NEMLUVIO every 8 weeks, and 0% with placebo. None of these reactions led to discontinuation of treatment. Herpes Zoster During the initial treatment period herpes zoster infections were reported in 5 subjects (0.4%) treated with NEMLUVIO (including 1 case of ophthalmic herpes zoster) and no subjects receiving placebo. Cases of herpes zoster were mild to moderate in severity and did not lead to discontinuation of treatment. Pediatric Subjects 12 Years of Age and Older with Atopic Dermatitis The safety of NEMLUVIO was assessed in 176 subjects 12 to 17 years of age with moderate-to­ severe atopic dermatitis enrolled in the ARCADIA 1 or ARCADIA 2 trials who received at least Reference ID: 5495566 one dose of NEMLUVIO from Week 0 to Week 16 in the primary safety population. The safety profile of NEMLUVIO in these subjects through Week 16 was consistent with the safety profile observed in adults with atopic dermatitis. The safety profile of NEMLUVIO in 98 subjects 12 to 17 years of age followed through Week 48 was consistent with the safety profile observed at Week 16. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data on NEMLUVIO use in pregnant women exposed during clinical trials are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Transport of human IgG antibody across the placenta increases as pregnancy progresses and peaks during the third trimester; therefore, NEMLUVIO may be transferred from the mother to the developing fetus (see Clinical Considerations). In an enhanced pre- and postnatal development study in cynomolgus monkeys, when nemolizumab­ ilto was administered subcutaneously during organogenesis to parturition, an increase in early postnatal death was observed at a dose 50 times the maximum recommended human dose (MRHD) (see Data). The clinical significance of this nonclinical finding is unknown. The background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. It is unclear whether nemolizumab-ilto may interfere with an infant’s immune response to infections. Therefore, monitoring for the development of serious infection during the first 3 months of life in infants exposed in utero is recommended. Data Animal Data In an enhanced pre- and postnatal development study, subcutaneous doses up to 25 mg/kg nemolizumab-ilto were administered to pregnant cynomolgus monkeys once every two weeks during organogenesis to parturition. No maternal or embryofetal toxicities were observed at doses up to 25 mg/kg (50 times the MRHD, based on AUC comparison). Early postnatal death occurred in the offspring of one control monkey and 3 monkeys at 25 mg/kg (50 times the MRHD, based on AUC comparison). The clinical significance of this nonclinical finding is unknown. Nemolizumab-ilto was administered subcutaneously to the offspring at doses up to 25 mg/kg (168 times the MRHD, based on AUC comparison), once every 2 weeks for 6 months, Reference ID: 5495566 starting from postnatal day 35. No adverse effects were noted in the remaining offspring. 8.2 Lactation Risk Summary There are no data on the presence of nemolizumab-ilto in human milk, the effects on the breastfed infant, or the effects on milk production. Nemolizumab-ilto was detected in breast milk of monkeys (see Data). Endogenous maternal IgG and monoclonal antibodies are transferred in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to nemolizumab-ilto are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NEMLUVIO and any potential adverse effects on the breastfed child from NEMLUVIO or from the underlying maternal condition. Data Nemolizumab-ilto was detected in breast milk of monkeys in the enhanced pre- and postnatal development study following subcutaneous doses up to 25 mg/kg once every two weeks during organogenesis to parturition. The mean nemolizumab-ilto concentrations in milk were approximately 0.3 – 0.5% of the maternal plasma levels from lactation day 7 to 63. The concentration of nemolizumab-ilto in animal milk does not necessarily predict the concentration of drug in human milk. 8.4 Pediatric Use The safety and effectiveness of NEMLUVIO for the treatment of moderate-to-severe atopic dermatitis in combination with topical corticosteroids and/or calcineurin inhibitors have been established in pediatric patients 12 years of age and older whose disease is not adequately controlled with topical prescription therapies. Use of NEMLUVIO for this indication is supported by evidence from two randomized, double-blind, placebo-controlled trials. The safety and effectiveness were generally consistent between pediatric and adult subjects [See Adverse Reactions (6.1) and Clinical Studies (14.1)]. The safety and effectiveness of NEMLUVIO have not been established in pediatric patients younger than 12 years of age. 8.5 Geriatric Use Of the 1192 subjects with atopic dermatitis exposed to NEMLUVIO in the primary safety population, 72 (6.0%) subjects were 65 years of age or older. The long-term safety of NEMLUVIO was assessed in 78 (4.5%) subjects 65 years of age or older. Clinical studies of NEMLUVIO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger adult subjects [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Reference ID: 5495566 There is no specific treatment for NEMLUVIO overdose. In the event of overdosage, contact Poison Control (1-800-222-1222) for the latest recommendations and monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately. 11 DESCRIPTION Nemolizumab-ilto, an interleukin-31 receptor alpha (IL-31RA) antagonist, is a humanized monoclonal modified immunoglobulin G (IgG) antibody with a molecular weight of approximately 144 kDa. Nemolizumab-ilto is produced by recombinant DNA technology in Chinese Hamster Ovary cells. NEMLUVIO (nemolizumab-ilto) for injection is a sterile, preservative-free, white lyophilized powder in a dual-chamber single-dose, prefilled pen. One chamber contains 30 mg of nemolizumab-ilto with inactive ingredients arginine hydrochloride (9.5 mg), poloxamer 188 (0.15 mg), sucrose (25.8 mg), trometamol (0.10 mg), and tris hydrochloride for pH adjustment. The diluent, water for injection, is in the other chamber. Following reconstitution, each prefilled pen delivers 30 mg/0.49 mL of nemolizumab-ilto with a pH of 6.7 to 7.3. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Nemolizumab-ilto is a humanized IgG2 monoclonal antibody that inhibits IL-31 signaling by binding selectively to IL-31 RA. IL-31 is a naturally occurring cytokine that is involved in pruritus, inflammation, epidermal dysregulation, and fibrosis. Nemolizumab-ilto inhibited IL-31­ induced responses including the release of proinflammatory cytokines and chemokines. 12.3 Pharmacokinetics After a single dose, nemolizumab-ilto exposure increased dose proportionally over a dose range of 0.03 and 3 mg/kg following subcutaneous administration. After multiple doses, nemolizumab­ ilto systemic exposure increased in an approximately dose-proportional manner across the subcutaneous dose range up to 30 mg. There was a decrease in bioavailability by 9% with the 60 mg subcutaneous dose and by 15% with the 90 mg subcutaneous dose. Following multiple doses of NEMLUVIO in subjects with atopic dermatitis, the estimated mean (SD) steady-state trough concentrations of nemolizumab-ilto were 2.63 (1.27) µg/mL for 30 mg administered every 4 weeks and 0.74 (0.44) µg/mL for 30 mg administered every 8 weeks. Steady-state nemolizumab concentrations were achieved 4 weeks after the initial 60 mg loading dose. Absorption Following an initial subcutaneous dose of 60 mg, nemolizumab-ilto reached peak mean (SD) concentrations (Cmax) of 7.5 (2.31) µg/mL by approximately 6 days post dose. Reference ID: 5495566 Distribution The volume of distribution of nemolizumab-ilto was estimated to be 7.67 L. Elimination Nemolizumab-ilto is expected to be degraded in the same manner as endogenous IgG. The terminal elimination half-life (SD) of nemolizumab-ilto was estimated to be 18.9 (4.96) days and systemic clearance was estimated to be 0.263 L/day. Metabolism The metabolic pathway of nemolizumab-ilto has not been characterized. Nemolizumab-ilto is expected to be degraded into small peptides by catabolic pathways. Specific Populations Geriatric Populations No clinically significant difference in the pharmacokinetics of nemolizumab-ilto was estimated based on age (subjects 18 to 65 years of age and older than 65 years of age). Dose adjustment in this population is not needed. Pediatric Populations No clinically significant difference in the pharmacokinetics of nemolizumab-ilto was estimated in pediatric subjects 12 to 17 years of age compared to adults. Dose adjustment in this population is not needed. Renal or Hepatic Impairment No clinically significant differences in the pharmacokinetics of nemolizumab-ilto were estimated based on mild to moderate renal or hepatic impairments. The effect of severe renal and severe hepatic impairments on the pharmacokinetics of nemolizumab-ilto is unknown. Body Weight The exposure of nemolizumab-ilto decreases with increasing body weight. With the recommended dose, the steady state mean exposure parameters (AUCss, Cmaxss and Ctrough) of subjects with body weight of above 87 kg is expected to be 1.7-fold lower than that of subjects weighing below 62 kg. The difference in systemic exposure due to body weight had no clinically meaningful impact on efficacy in subjects with atopic dermatitis. Dose adjustment based on body weight is not needed. Drug Interaction Studies The effects of nemolizumab on the pharmacokinetics of midazolam (CYP3A4/5 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), metoprolol (CYP2D6 substrate), and caffeine (CYP1A2 substrate) were evaluated in a study in 14 subjects with Reference ID: 5495566 moderate to severe AD receiving an initial SC dose of 60 mg followed by 30 mg SC every four weeks for 12 weeks. No clinically significant changes in the exposure of CYP450 substrates before and after multiple nemolizumab injections were observed, with Cmax and AUC ratios ranging from 88.2 to 107.8%. The concomitant use of nemolizumab-ilto is unlikely to influence the PK profiles of CYP substrates. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the trials described below with the incidence of anti-drug antibodies in other trials, including those of nemolizumab-ilto or other nemolizumab products. In the phase 3 trials (ARCADIA 1, ARCADIA 2) up to 16 weeks, the incidence of treatment- emergent ADAs was 5.6% (33/593) and 6.8% (34/499), respectively. Among subjects who continued treatment from week 16 through week 48 in the two studies, the ADA incidence was 11.2% (10/89) and 16.9% (13/77) for those received 30 mg every 4 weeks, and 12.8% (11/86) and 8% (6/75) for those received 30 mg every 8 weeks. Neutralizing antibody incidence was 6% (2/33) and 2.9% (1/34) among the ADA+ subjects throughout 48 weeks in ARCADIA 1 and ARCADIA 2, respectively. Antibodies to nemolizumab-ilto were associated with reduced serum nemolizumab-ilto concentrations beyond Week 16. In the phase 3 trials, NEMLUVIO treated subjects who developed ADAs had nemolizumab-ilto concentrations that were 20% to 70% lower compared to subjects who did not develop ADAs. There was no clinically significant effect of anti-drug antibodies on safety or efficacy of nemolizumab-ilto over the treatment duration of 48 weeks. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of NEMLUVIO. No effects on fertility parameters as reproductive organ morphology, menstrual cycle length, or sperm/testicular analysis were observed in male or female sexually mature cynomolgus monkeys that were administered nemolizumab-ilto at subcutaneous doses up to 25 mg/kg once every two weeks for 6 months (72 times the MRHD, based on AUC comparison). The monkeys were not mated to evaluate fertility. 14 CLINICAL STUDIES 14.1 Atopic Dermatitis Two randomized, double-blind, placebo-controlled trials (ARCADIA 1 [NCT03985943] and Reference ID: 5495566 ARCADIA 2 [NCT03989349]) enrolled a total of 1728 subjects 12 years of age and older with moderate-to-severe atopic dermatitis not adequately controlled by topical treatments. Disease severity was defined by an Investigator’s Global Assessment (IGA) score of 3 (moderate) and 4 (severe) in the overall assessment of atopic dermatitis, an Eczema Area and Severity Index (EASI) score of ≥16, a minimum body surface area (BSA) involvement of ≥10%, and a Peak Pruritus Numeric Rating Scale (PP-NRS) score of ≥ 4. Subjects in the NEMLUVIO group received initial subcutaneous injections of NEMLUVIO 60 mg, followed by 30 mg injections every 4 weeks. Concomitant low and/or medium potency TCS and/or TCI were administered for at least 14 days prior to baseline and continued during the trial. Based on disease activity, these concomitant therapies could be tapered and/or discontinued at investigator discretion. After 16 weeks, subjects achieving either EASI-75 or IGA success continued into the trial maintenance period for another 32 weeks to evaluate the maintenance of response achieved at Week 16. NEMLUVIO responders were re-randomized to either NEMLUVIO 30 mg every 4 weeks, NEMLUVIO 30 mg every 8 weeks, or placebo every 4 weeks (all groups continued background TCS/TCI). Subjects randomized to placebo in the initial treatment period who achieved the same clinical response at Week 16 continued to receive placebo every 4 weeks. In these trials, at baseline, 51% of subjects were male, 80% were White, 13% were Asian, and 6% were Black or African American; for ethnicity, 9% of subjects identified as Hispanic or Latino. Fifteen (15)% of subjects were 12-17 years of age. Seventy (70)% of subjects had a baseline IGA score of 3 (moderate AD), and 30% of subjects had a baseline IGA score of 4 (severe AD). The baseline mean EASI score was 27.5 and the baseline mean weekly average PP­ NRS was 7.1. Overall, 63% of subjects received other previous systemic treatments for AD. The IGA is a 5-category scale, including “0 = clear”, “1 = almost clear”, “2 = mild”, “3 = moderate” or “4 = severe” indicating the investigator’s overall assessment of the AD. EASI scores range from 0 to 72 points and reflect the severity and extent of AD. EASI-75 indicates at least a 75% improvement in EASI score from baseline. The PP-NRS score is a weekly average of daily PP NRS scores on an 11-point scale from 0-10 that assesses the maximal intensity of pruritus in the last 24 hours with 0 being no itch and 10 being worst itch imaginable. Both ARCADIA 1 and ARCADIA 2 assessed the co-primary endpoints of: • Proportion of subjects with an IGA success (defined as an IGA of 0 [clear] or 1 [almost clear] and a ≥2-point reduction from baseline) at Week 16 • Proportion of subjects with EASI-75 (≥75% improvement in EASI from baseline) at Week 16 PP-NRS improvement ≥ 4 from baseline at Week 16 was a key secondary outcome in both trials. Clinical Response at Week 16 (ARCADIA 1 and ARCADIA 2) The efficacy results for ARCADIA 1 and ARCADIA 2 evaluating the initial treatment period with NEMLUVIO over 16 weeks are presented in Table 2. Reference ID: 5495566 Table 2: Efficacy Results of NEMLUVIO (30 mg Every 4 Weeks) with Concomitant TCS/TCI at Week 16 in Adult and Pediatric Subjects 12 Years of Age and Older with Moderate to Severe AD in ARCADIA 1 and ARCADIA 2 ARCADIA 1 ARCADIA 2 Difference Difference from from NEMLUVIO Placebo + Placebo NEMLUVIO Placebo + Placebo + TCS/TCI TCS/TCI (95% CI) + TCS/TCI TCS/TCI (95% CI) Number of subjects randomized 620 321 522 265 Proportion of subjects with IGA 0 or 1a 36% 25% 12% (6%, 17%) 38% 26% 12% (6%, 19%) Proportion of subjects with EASI-75a 44% 29% 15% (9%, 21%) 42% 30% 12% (6%, 19%) Proportion of subjects with an improvement (reduction) of ≥4 from baseline in PP-NRSa 33% 15% 18% (13%, 23%) 36% 15% 21% (15%, 27%) a Subjects who received rescue treatment or had missing data (fewer than 4 PP-NRS daily diary entries in a 7-day period) were considered non-responders. Examination of weight, age, gender, race, and prior treatment did not identify meaningful difference in response to NEMLUVIO among these subgroups at Week 16. Maintenance and Durability of Response (Week 16 to Week 48) The clinical response in NEMLUVIO responders (IGA 0/1 or EASI-75 at Week 16) was evaluated between Week 16 and Week 48 in ARCADIA 1 and ARCADIA 2 trials. For the maintenance treatment period, NEMLUVIO responders were re-randomized to NEMLUVIO 30 mg every 4 weeks, NEMLUVIO 30 mg every 8 weeks or placebo every 4 weeks (NEMLUVIO withdrawal) with concomitant TCS/TCI. The results are presented in Table 3. Table 3: Efficacy Results of NEMLUVIO with Concomitant TCS/TCI at Week 48 in Adult and Pediatric Subjects 12 Years of Age and Older with Moderate to Severe AD in ARCADIA 1 and ARCADIA 2 NEMLUVIO Every 4 Weeks + TCS/TCI NEMLUVIO Every 8 Weeks + TCS/TCI Placebo + TCS/TCI Number of subjects who were IGA Respondersa at Week 16 142 142 131 Proportion of subjects with IGA 0 or 1b at Week 48 63% 64% 55% Number of subjects who were EASI-75 Responders at Week 16 163 163 157 Proportion of subjects with EASI-75b at Week 48 75% 77% 65% a Responder was defined as a subject with an IGA of 0 (clear) or 1 (almost clear) and a ≥2-point reduction from baseline. b Subjects who received rescue treatment or with missing data were considered non-responders. 16 HOW SUPPLIED/STORAGE AND HANDLING Reference ID: 5495566 How Supplied NEMLUVIO (nemolizumab-ilto) for injection is a sterile, preservative-free, white lyophilized powder available in single-dose, dual-chamber prefilled pen containing 30 mg of nemolizumab­ ilto in one chamber and the diluent, water for injection, in the other chamber. Following reconstitution, each prefilled pen delivers 30 mg/0.49 mL of nemolizumab-ilto. Each carton contains 1 single-dose prefilled pen. Presentation Pack size NDC # Pre-filled Pen Pack of 1 pen 0299-6220-15 Storage and Handling Store the NEMLUVIO dual chamber prefilled pen in a refrigerator at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light until the expiration date. Do not freeze. Do NOT expose to heat or direct sunlight. Alternatively, the NEMLUVIO carton containing the unused dual chamber prefilled pen may be stored at room temperature [up to 77°F (25°C)] for up to 90 days. Write the date the NEMLUVIO dual chamber prefilled pen is first removed from the refrigerator in the space provided on the inner partition for the pen. Do not use the NEMLUVIO dual chamber prefilled pen beyond the expiration date or 90 days after the date it was first removed from the refrigerator (whichever is earlier). 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Hypersensitivity Advise patients to seek immediate medical attention and discontinue NEMLUVIO if they experience any symptoms of hypersensitivity reactions [see Warnings and Precautions (5.1)]. Vaccinations Instruct patients to inform their healthcare provider that they are taking NEMLUVIO prior to a potential vaccination [see Warnings and Precautions (5.2)]. Administration Instructions: • Instruct patients and/or caregivers to receive proper training in subcutaneous injection technique prior to self-injection [see Dosage and Administration (2.4)]. Inform patients and/or caregivers that Galderma Customer Support may be called for assistance at 1-866-735-4137. • Inform patients that NEMLUVIO must be reconstituted prior to administration. Advise patients/caregivers to refer to the Instructions for Use that accompany the NEMLUVIO pen Reference ID: 5495566 for complete mixing and administration instructions with illustrations [see Dosage and Administration (2.4, 2.5), Instructions for Use]. • Inform patients and/or caregivers of proper pen disposal and caution against any reuse of needles. Instruct patients and/or caregivers to discard used pens in an appropriate sharps disposal container following safe needle disposal practices [see Instructions for Use]. • Advise patients and/or caregivers of the importance of complying with dosing schedule. If a dose is missed, instruct patients/caregivers to administer the injection as soon as possible, and thereafter, resume dosing at the regular scheduled time. [see Dosage and Administration (2.3)]. Manufactured by: Galderma Laboratories, L.P., Dallas, TX 75201 U.S. License No. 2289 NEMLUVIO® is a trademark of Galderma. © 2024 Galderma Laboratories, L.P. All rights reserved. Reference ID: 5495566 PATIENT INFORMATION NEMLUVIO® [Nem LOO vee oh] (nemolizumab-ilto) for injection, for subcutaneous use What is NEMLUVIO? • NEMLUVIO is a prescription medicine used to treat adults and children 12 years of age and older with moderate-to-severe eczema (atopic dermatitis) that is not well controlled with prescription therapies used on the skin (topical). NEMLUVIO can be used with certain prescription topical medicines. It is not known if NEMLUVIO is safe and effective in children under 12 years of age. Do not use NEMLUVIO if you are allergic to nemolizumab-ilto or to any ingredients in NEMLUVIO. See the end of this Patient Information leaflet for a complete list of ingredients in NEMLUVIO. Before taking NEMLUVIO, tell your healthcare provider about all of your medical conditions, including if you: • are scheduled to receive any vaccination. You should not receive a live vaccine right before or during treatment with NEMLUVIO. • are pregnant or plan to become pregnant. It is not known whether NEMLUVIO will harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known whether NEMLUVIO passes into your breast milk and if it can harm your baby. Tell your healthcare provider about all of the medicines you take, including prescription and over-the­ counter medicines, vitamins, and herbal supplements. How should I take NEMLUVIO? • See the detailed Instructions for Use that comes with NEMLUVIO for information on how to prepare and inject NEMLUVIO and how to properly store and throw away (dispose of) used NEMLUVIO prefilled pens. • Use NEMLUVIO exactly as prescribed by your healthcare provider. • Use NEMLUVIO with prescription topical therapies. When your eczema has improved, your healthcare provider may stop topical therapies. • Your healthcare provider will tell you how much NEMLUVIO to inject and how often to inject it. • NEMLUVIO comes as a single-dose pre-filled pen with a needle guard. • NEMLUVIO is given as an injection under the skin (subcutaneous injection). • If your healthcare provider decides that you or your caregiver can give the injections of NEMLUVIO, you or your caregiver should receive training on the right way to prepare and inject NEMLUVIO. Do not try to inject NEMLUVIO until you have been shown the right way by your healthcare provider. • If you miss a dose, inject the missed dose as soon as possible, then continue with your next dose at your regular scheduled time. • If you inject too much NEMLUVIO, call your healthcare provider or the Poison Help line at 1-800-222­ 1222 or go to the nearest hospital emergency room right away. • Your healthcare provider may prescribe other medicines to use with NEMLUVIO. Use the other prescribed medicines exactly as your healthcare provider tells you to. What should I avoid while taking NEMLUVIO? You should not receive live vaccines while taking NEMLUVIO. What are the possible side effects of NEMLUVIO? NEMLUVIO may cause serious side effects including: • allergic reactions (hypersensitivity). NEMLUVIO can cause allergic reactions that can sometimes be serious. Stop using NEMLUVIO and tell your healthcare provider or get emergency help right away if you get any of the following symptoms: o breathing problems o swelling of the face, lips, mouth, o fainting, dizziness, feeling or wheezing tongue, or throat lightheaded Reference ID: 5495566 o fast pulse o swollen lymph nodes o joint pain o fever o skin rash (red or rough skin) o nausea or vomiting o general ill feeling o cramps in your stomach area The most common side effects of NEMLUVIO include: • headache • joint pain • hives (itchy red rash or wheals) • muscle aches These are not all of the possible side effects of NEMLUVIO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA­ 1088. How should I store NEMLUVIO? • Store the NEMLUVIO pen in the refrigerator between 36°F to 46°F (2°C to 8°C) until the expiration date. • Store the NEMLUVIO pen in the original carton to protect it from light. • The NEMLUVIO pen can be stored at room temperature (up to 77°F or 25°C) for a single period up to 90 days. Throw away (dispose of) the NEMLUVIO pen after the expiration date and any NEMLUVIO pen that has been left at room temperature longer than 90 days. • After the NEMLUVIO pen lyophilized powder and water for injection are mixed (reconstituted), the NEMLUVIO pen must be used within 4 hours or thrown away (discarded). • Do not heat or put the NEMLUVIO pen in direct sunlight. • Do not freeze the NEMLUVIO pen. • If the NEMLUVIO pen was heated or frozen, throw it away (dispose of it). Keep the NEMLUVIO pen and all medicines out of the reach of children. General information about the safe and effective use of NEMLUVIO. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use NEMLUVIO for a condition for which it was not prescribed. Do not give NEMLUVIO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about NEMLUVIO that is written for healthcare professionals. What are the ingredients in NEMLUVIO? Active ingredients: nemolizumab-ilto Inactive ingredients: arginine hydrochloride, poloxamer 188, sucrose, trometamol, and tris hydrochloride Manufactured by: Galderma Laboratories, L.P., Dallas, TX 75201 U.S License No. 2289 NEMLUVIO® is a trademark of Galderma. ©2024 Galderma Laboratories, L.P. All rights reserved. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 12/2024 Reference ID: 5495566 Device Overview NEMLUVIO Single-Dose Pre-Filled Dual-Chamber Pen Before use Gray cap Inspection window Lyophilized powder (medicine) Water for disso(v!ng~fll the medicine :~ (in a separate ., chamber, not visible) Activation knob (arrow on locked icon) - After use !l , Needle cover i"- Orange needle guard Gray rod Orange rod It is normal that orange rod does not cover the full window at the end of t he injection i.: Activation knob al.ll!Mlli--- Jll (arrow on unlocked icon) INSTRUCTIONS FOR USE NEMLUVIO® [Nem LOO vee oh] (nemolizumab-ilto) for injection, for subcutaneous use This Instructions for Use contains information on how to inject NEMLUVIO. Read and understand these instructions before using the NEMLUVIO pen. Do not inject yourself or someone else until you have been instructed how to inject NEMLUVIO. In adolescents (ages 12 to 17 years old), it is recommended that NEMLUVIO be given by or under supervision of a trained adult or caregiver. Your healthcare provider will instruct you or your caregiver how to prepare and inject a dose of NEMLUVIO before you try to do it yourself the first time. Call your healthcare provider if you have any questions. NEMLUVIO is supplied as a single-dose pen (called NEMLUVIO pen or pen in these instructions). It contains medicine (30 mg of lyophilized powder) in one chamber and water for dissolving the medicine in the other chamber. Before you can inject it, you must mix the lyophilized powder with the water for dissolving the medicine. Important Information What you need to know before using the NEMLUVIO pen: • Read all the instructions carefully before using the NEMLUVIO pen. • Mark your calendar ahead of time to remember when to take NEMLUVIO. • Follow all steps exactly as described. This makes sure that you get the correct dose of medicine. • Make sure that the lyophilized powder is completely dissolved before injecting (Step 9). • After dissolving, proceed right away with the injection to avoid any contamination or break down of medicine (degradation). • Do not use the NEMLUVIO pen if it has been dropped on a hard surface or is damaged, cracked or broken. • In some cases, your healthcare provider may prescribe 2 pens for a full dose. Use 1 NEMLUVIO pen after the other. • To reduce the risk of accidental needle stick injury, each NEMLUVIO pen has an orange needle guard. After injecting the medicine, as you lift the pen from your skin, the orange needle guard locks into place to cover the needle (Step 16). • When preparing the pen for injection, do not pull the gray cap. Instead, twist the gray cap until the orange needle guard pops up. Then, gently pull the cap off the orange needle guard (Step 12). • Throw away (dispose of) the used NEMLUVIO pen right away after use in a sharps disposal container. See Section C: Throwing away (Disposing of) NEMLUVIO below. Reference ID: 5495566 Figure A i Let NEMLUVIO come to room temperature. Figure B 0 Storage Information • Store the NEMLUVIO pen in the refrigerator between 36°Fto46°F (2°C to 8°C) until the expiration date. • Store the NEMLUVIO pen in the original carton to protect it from light. • The NEMLUVIO pen can be stored at room temperature up to 77°F (25°C) for a single period up to 90 days. Throw away (dispose of) the NEMLUVIO pen after the expiration date and any NEMLUVIO pen that has been left at room temperature longer than 90 days. • After the NEMLUVIO pen lyophilized powder and water for injection are mixed (reconstituted), the NEMLUVIO pen must be used within 4 hours or thrown away (discarded). • Do not heat or put the NEMLUVIO pen into direct sunlight. • Do not freeze the NEMLUVIO pen. • If the NEMLUVIO pen was heated or frozen, throw it away (dispose of it). Keep the NEMLUVIO pen and all medicines out of the reach of children. Traveling Information: • Generally, you are allowed to carry pens with you on an airplane. Be sure to carry the NEMLUVIO pens with you in your carry-on luggage. If you have any other questions refer to the Frequently asked questions (FAQs) on the back of this leaflet. A. Preparing to inject NEMLUVIO Step 1: Let NEMLUVIO reach room temperature Injecting cold medicine might result in pain at the injection site. Take the NEMLUVIO carton out of the refrigerator and let it come to room temperature for 30 to 45 minutes before starting Step 2 (see Figure A). Do not: • warm the pen with any heat source (such as microwave or direct sunlight). This might damage NEMLUVIO. • directly expose the pen to liquids. Step 2: Wash your hands a. b. To avoid contamination and infection, wash your hands with soap (see Figure B). Dry them properly. Reference ID: 5495566 Figure C 1. 2. [tk ~ 1o=i • DJ B, 4. 0 Figure D B Lyophilized powder If.] Expiration ~ date Unlock Icon EB Figure E Figure F Gray 0 rod n-a Before After Step 3: Gather supplies (see Figure C) a. Remove the pen from the carton. b. Gather the following supplies on a clean, flat and well-lit surface: 1. Pen 2. Alcohol wipes* 3. Sharps disposal container* 4. Gauze pads or cotton balls* *Items not included in the carton. Note: In some cases, your healthcare provider may prescribe 2 pens. Use 1 pen after the other. Step 4: Check the NEMLUVIO pen for the following: a. Expiration date has not passed. b. The lyophilized powder is white and not dissolved (see Figure D). c. The pen has not been dropped and is not damaged or cracked. Do not use the pen unless all conditions above are met. If any condition is not met, call: 1-866-735­ 4137. Throw away (dispose of) the pen and use a new one (see Section C: Throwing away (Disposing of) NEMLUVIO). Step 5: Activate the NEMLUVIO pen Hold the pen upright and turn the activation knob to the right until it stops (see Figure E). This starts the process of transferring water to the powder chamber. Step 6: Wait until the gray rod stops moving Watch the inspection window until the gray rod has stopped moving (see Figure F). Do not shake the pen. Shaking the pen before the gray rod has completely stopped can affect the medicine dose. Reference ID: 5495566 Qi) Not dissolved 2 i Shake for 30 seconds Figure G Figure H @ Dissolved Figure i ~ ~ .. . Step 7: Dissolve the medicine When the gray rod has completely stopped, shake the pen up and down for 30 seconds (see Figure G). Step 8: Wait 5 minutes for bubbles to decrease Wait for bubbles to decrease and the lyophilized powder to dissolve completely. This will take about 5 minutes (see Figure H). Note: If the medicine has not dissolved completely, shake the pen up and down again for 30 seconds and then wait 5 minutes. Note: It is normal for a small foam layer or a few small air bubbles to remain in the dissolved medicine. Step 9: Check the medicine in the inspection window Check to see if the dissolved medicine: a. is clear and colorless to slightly yellow, b. does not contain particles (see Figure i). Do not use the pen if the dissolved medicine is cloudy or contains any particles. Throw away (dispose of) the pen and use a new one (see Section C: Throwing away (Disposing of) NEMLUVIO). Note: After the medicine has dissolved, it must be used within 4 hours. During this time, it should be kept at room temperature (up to 77°F (25°C)). If you have not used it within 4 hours, throw it away (dispose of it). Reference ID: 5495566 Self-Injection • • Abdomen 2 inches away from navel • Upper t high Injection by • Caregiver • Abdomen 2 inches away from navel • Upper t high • Out er, upper arm ,,-­ Figure K \ Alcohol Wipe FigureJ B. Injecting NEMLUVIO Step 10: Select one injection site (see Figure J) Note: When using a second pen, select a different injection site at least 1 inch away from the first injection site. Select the injection site using the following chart: Where not to inject: • near your waistline or about 2 inches around the navel. • into tender, bruised, red skin, or areas with scars or stretch marks. • twice into the same site (for example, within 1 inch). Step 11: Clean the injection site (see Figure K) a. b. Always use a new alcohol wipe to clean the injection site. This avoids contamination and infection. Let the skin air dry. Do not: • touch the injection site after cleaning. • fan or blow air on the cleaned injection site. • reuse the alcohol wipe. Reference ID: 5495566 ~ Do not pull ~ the gray cap @ @ @ ~~\JI ~l ~ Hold Twist Pull off upright cap cap Figure L (a,b,c) Figure M .. I lnJect1on site Orange needle guard Step 12: Twist the gray cap Do not: • pull the gray cap when twisting to avoid damaging the device. • touch the orange needle guard. a. Hold the pen upright (see Figure L, a). b. Twist the gray cap until the orange needle guard pops up (see Figure L, b). c. Gently pull the cap off the orange needle guard (see Figure L, c). d. After cap removal, please throw away (dispose of) the cap in a sharps disposal container (see Step 17). Note: If the cap cannot be removed, refer back to Step 5 and make sure the activation knob is turned completely to the right until it stops. Step 13: Place the NEMLUVIO pen Read Steps 13-16 before starting Step 13. Note: Always inject the way your healthcare provider showed you. Place the pen on the injection site vertically so that the orange needle guard is flat against the skin (see Figure M). Note: Make sure you can easily see the inspection window during injection. Reference ID: 5495566 Gray rod Push down on the orange needle guard Figure 0 Gray rod Orange needle guard locked Hold and slowly count to 15. Figure P A Lift lf straight up Turn over to read about ~ '1!!11 pen disposal and FAQs ..., Step 14: Start injection and hold the NEMLUVIO pen on the skin Gently push the pen down until the orange needle guard is completely pushed in. The injection starts right away with a click (see Figure N). The orange rod will begin to move down the injection window. Do not lift the pen yet and keep pushing down. Step 15: Inject for 15 seconds Hold slowly and count to 15. Check the inspection window to make sure the orange rod and gray rod have stopped (see Figure O). This means the injection has been completed. Note: It is normal that the orange rod does not cover the whole inspection window at the end of injection. Do not lift the pen until the orange rod and gray rod have stopped moving. If the orange rod is not visible, please call: 1-866­ 735-4137. Throw away (dispose of) the pen and use a new one (see Section C for disposal details). Step 16: Lift the NEMLUVIO pen up a. b. Lift the pen straight up from your skin. The orange needle guard locks into place to cover the needle (see Figure P). If there is bleeding, press a cotton ball or gauze over the injection site. Do not rub the injection site. Reference ID: 5495566 ~----1 Pen .-- ~Gray ,ca.p Figure, Q C. Throwing away (disposing of) NEMLUVIO Step 17: Throw away (dispose of) NEMLUVIO in a sharps disposal container Avoid contact with the needle. Throw away (dispose of) the used pen and the gray cap in a FDA cleared sharps disposal container right away after use (see Figure Q). Do not: • recap the pen after use, • dispose of the NEMLUVIO pen and cap in your household trash, • dispose of your used sharps disposal container in your household trash unless your community guidelines permit this, • recycle your used sharps disposal container. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: • made of a heavy-duty plastic, • can be closed with a tight-fitting, puncture- resistant lid, without sharps being able to come out, • upright and stable during use, • leak-resistant and • properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should dispose of used pens. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal FAQs (Frequently asked questions) Needle Injecting the medicine Where is the needle? Why do I need to hold the pen upright while removing the gray cap? The needle is attached to the NEMLUVIO pen and covered by the gray cap. When you twist the gray cap, the orange needle guard pops up and keeps the needle covered until you inject. Holding the NEMLUVIO pen with the gray cap upright helps prevent the medicine from leaking. It is normal to see a few drops of medicine inside the gray cap even when you hold the pen upright and remove the gray cap. Reference ID: 5495566 For more information, please see the figures in Step 12 in this Instructions for Use. Dissolving the medicine How do I know I injected myself the full dose of medicine in the pen? How do I know if the medicine is fully dissolved? To be sure you get the full dose of medicine, press and hold the NEMLUVIO pen against your skin. To dissolve, shake the NEMLUVIO pen up and down until the white particles are no longer on the bottom, top, or sides. The You will feel the needle go into your skin. dissolved medicine should look clear. Hold the NEMLUVIO pen against your skin for 15 Please refer to Step 9 in this Instructions seconds. This will allow enough time for all the for Use. medicine to go from the pen to under your skin. After shaking the NEMLUVIO pen, look Only remove the NEMLUVIO pen when the through both sides of the inspection orange rod and the gray rod have stopped window. You should not see any white moving. particles along the bottom, top, or sides. After removing the NEMLUVIO pen, look for the It is acceptable to have small air bubbles orange rod in the window as a way to tell that the or a small foam layer on top of the dose has been given. If the orange rod does not medicine. It does not harm you. appear, contact 1-866-735-4137. If you see white particles in the medicine, it For details please refer to Step 15 in this is not fully dissolved. Instructions for Use. Storage General Information How should I store the NEMLUVIO pen? Is it necessary to receive instructions on how to use the NEMLUVIO pen from a healthcare provider? The NEMLUVIO pen should be stored in Yes. the refrigerator in its original carton to protect it from light. It can be stored at Do not inject the medicine if you did not receive a room temperature for up to 77°F (25°C) for demonstration by your healthcare provider. a single period up to 90 days. You should contact your healthcare provider right The device should not come in contact away to receive the information on how to use the with liquids. NEMLUVIO pen. Where do I find the expiration date? Where can I get more information about using NEMLUVIO: You can find the expiration date on the If you have other questions about how to use the NEMLUVIO pen, it is labeled EXP YYYY­ NEMLUVIO pen: MM. - Call your healthcare provider - Call 1-866-735-4137 Do not use the NEMLUVIO pen past the expiration date. What should I do if the medicine has been frozen? Do not use the NEMLUVIO pen if it has been frozen. Throw away (dispose of) the NEMLUVIO pen and use a new one. Manufactured by: Galderma Laboratories, L.P. Dallas, TX 75201 US License number: 2289 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 12/2024 Reference ID: 5495566
custom-source
2025-02-12T15:47:41.758349
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use KEYTRUDA safely and effectively. See full prescribing information for KEYTRUDA. KEYTRUDA® (pembrolizumab) injection, for intravenous use Initial U.S. Approval: 2014 ---------------------------RECENT MAJOR CHANGES --------------------------­ Indications and Usage (1) 09/2024 Dosage and Administration (2) 09/2024 Warnings and Precautions (5) 03/2024 ----------------------------INDICATIONS AND USAGE---------------------------­ KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated: Melanoma • for the treatment of patients with unresectable or metastatic melanoma. (1.1) • for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. (1.1) Non-Small Cell Lung Cancer (NSCLC) • in combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations. (1.2) • in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of patients with metastatic squamous NSCLC. (1.2) • as a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is: o Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or o metastatic. (1.2, 2.1) • as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. (1.2, 2.1) • for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. (1.2) • as a single agent, for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. (1.2) Malignant Pleural Mesothelioma (MPM) • in combination with pemetrexed and platinum chemotherapy, as first-line treatment of adult patients with unresectable advanced or metastatic MPM. (1.3) Head and Neck Squamous Cell Cancer (HNSCC) • in combination with platinum and FU for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC. (1.4) • as a single agent for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test. (1.4, 2.1) • as a single agent for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. (1.4) Classical Hodgkin Lymphoma (cHL) • for the treatment of adult patients with relapsed or refractory cHL. (1.5) • for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. (1.5) Primary Mediastinal Large B-Cell Lymphoma (PMBCL) • for the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after 2 or more prior lines of therapy. (1.6) • Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. Urothelial Cancer • in combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial cancer. (1.7) • as a single agent for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: o are not eligible for any platinum-containing chemotherapy, or o who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum- containing chemotherapy. (1.7) • as a single agent for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. (1.7) Microsatellite Instability-High or Mismatch Repair Deficient Cancer • for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. (1.8, 2.1) Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer (CRC) • for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test. (1.9, 2.1) Gastric Cancer • in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.1 (1.10) • in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. (1.10) Esophageal Cancer • for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: o in combination with platinum- and fluoropyrimidine-based chemotherapy, or o as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test. (1.11, 2.1) Cervical Cancer • in combination with chemoradiotherapy, for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. (1.12) • in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. (1.12, 2.1) • as a single agent for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. (1.12, 2.1) Hepatocellular Carcinoma (HCC) • for the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD- 1/PD-L1-containing regimen. (1.13) Biliary Tract Cancer (BTC) • in combination with gemcitabine and cisplatin, for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer. (1.14) Reference ID: 5493485 Merkel Cell Carcinoma (MCC) • for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. (1.15) Renal Cell Carcinoma (RCC) • in combination with axitinib, for the first-line treatment of adult patients with advanced RCC. (1.16) • in combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC. (1.16) • for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. (1.16) Endometrial Carcinoma • in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. (1.17) • in combination with lenvatinib, for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA- approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (1.17, 2.1) • as a single agent, for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (1.17, 2.1) Tumor Mutational Burden-High (TMB-H) Cancer • for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.1 (1.18, 2.1) • Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established. Cutaneous Squamous Cell Carcinoma (cSCC) • for the treatment of patients with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation. (1.19) Triple-Negative Breast Cancer (TNBC) • for the treatment of patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. (1.20) • in combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA approved test. (1.20, 2.1) Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks • for use at an additional recommended dosage of 400 mg every 6 weeks for Classical Hodgkin Lymphoma and Primary Mediastinal Large B-Cell Lymphoma in adults.2 (1.21, 2.2) 1 This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 2 This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety. Continued approval for this dosing may be contingent upon verification and description of clinical benefit in the confirmatory trials. ----------------------- DOSAGE AND ADMINISTRATION ----------------------­ • Melanoma: 200 mg every 3 weeks or 400 mg every 6 weeks; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) • NSCLC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • MPM: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • HNSCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • cHL or PMBCL: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) • Urothelial Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • MSI-H or dMMR Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) • MSI-H or dMMR CRC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • Gastric Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • Esophageal Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • Cervical Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • HCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • BTC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • MCC: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) • RCC: 200 mg every 3 weeks or 400 mg every 6 weeks as a single agent in the adjuvant setting, or in the advanced setting with either: o axitinib 5 mg orally twice daily or o lenvatinib 20 mg orally once daily. (2.2) • Endometrial Carcinoma: 200 mg every 3 weeks or 400 mg every 6 weeks o in combination with carboplatin and paclitaxel regardless of MMR or MSI status, or o in combination with lenvatinib 20 mg orally once daily for pMMR or not MSI-H tumors, or o as a single agent for MSI-H or dMMR tumors. (2.2) • TMB-H Cancer: 200 mg every 3 weeks or 400 mg every 6 weeks for adults; 2 mg/kg (up to 200 mg) every 3 weeks for pediatrics. (2.2) • cSCC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • TNBC: 200 mg every 3 weeks or 400 mg every 6 weeks. (2.2) • Administer KEYTRUDA as an intravenous infusion over 30 minutes after dilution. (2.4) • See Full Prescribing Information for dosage modifications for adverse reactions and preparation and administration instructions. (2.3, 2.4) --------------------- DOSAGE FORMS AND STRENGTHS --------------------­ • Injection: 100 mg/4 mL (25 mg/mL) solution in a single-dose vial (3) -------------------------------CONTRAINDICATIONS------------------------------­ None. (4) ----------------------- WARNINGS AND PRECAUTIONS ----------------------­ • Immune-Mediated Adverse Reactions (5.1) o Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune- mediated colitis, immune-mediated hepatitis, immune- mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and solid organ transplant rejection. o Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. o Withhold or permanently discontinue based on severity and type of reaction. • Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue KEYTRUDA based on the severity of reaction. (5.2) • Complications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. (5.3) • Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. (5.4) Reference ID: 5493485 • Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective method of contraception. (5.5, 8.1, 8.3) ------------------------------ ADVERSE REACTIONS -----------------------------­ Most common adverse reactions (reported in ≥20% of patients) were: • KEYTRUDA as a single agent: fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism. (6.1) • KEYTRUDA in combination with chemotherapy or chemoradiotherapy: fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism. (6.1) • KEYTRUDA in combination with chemotherapy and bevacizumab: peripheral neuropathy, alopecia, anemia, fatigue/asthenia, nausea, neutropenia, diarrhea, hypertension, thrombocytopenia, constipation, arthralgia, vomiting, urinary tract infection, rash, leukopenia, hypothyroidism, and decreased appetite. (6.1) • KEYTRUDA in combination with axitinib: diarrhea, fatigue/asthenia, hypertension, hepatotoxicity, hypothyroidism, decreased appetite, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. (6.1) • KEYTRUDA in combination with lenvatinib: hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight loss, abdominal pain, urinary tract infection, proteinuria, constipation, headache, hemorrhagic events, palmar-plantar erythrodysesthesia, dysphonia, rash, hepatotoxicity, and acute kidney injury. (6.1) • KEYTRUDA in combination with enfortumab vedotin: rash, peripheral neuropathy, fatigue, pruritus, diarrhea, alopecia, weight loss, decreased appetite, dry eye, nausea, constipation, dysgeusia, and urinary tract infection. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ----------------------- USE IN SPECIFIC POPULATIONS ----------------------­ Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Melanoma 1.2 Non-Small Cell Lung Cancer 1.3 Malignant Pleural Mesothelioma 1.4 Head and Neck Squamous Cell Cancer 1.5 Classical Hodgkin Lymphoma 1.6 Primary Mediastinal Large B-Cell Lymphoma 1.7 Urothelial Cancer 1.8 Microsatellite Instability-High or Mismatch Repair Deficient Cancer 1.9 Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer 1.10 Gastric Cancer 1.11 Esophageal Cancer 1.12 Cervical Cancer 1.13 Hepatocellular Carcinoma 1.14 Biliary Tract Cancer 1.15 Merkel Cell Carcinoma 1.16 Renal Cell Carcinoma 1.17 Endometrial Carcinoma 1.18 Tumor Mutational Burden-High Cancer 1.19 Cutaneous Squamous Cell Carcinoma 1.20 Triple-Negative Breast Cancer 1.21 Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Recommended Dosage 2.3 Dose Modifications 2.4 Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Severe and Fatal Immune-Mediated Adverse Reactions 5.2 Infusion-Related Reactions 5.3 Complications of Allogeneic HSCT 5.4 Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to a Thalidomide Analogue and Dexamethasone 5.5 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Melanoma 14.2 Non-Small Cell Lung Cancer 14.3 Malignant Pleural Mesothelioma 14.4 Head and Neck Squamous Cell Cancer 14.5 Classical Hodgkin Lymphoma 14.6 Primary Mediastinal Large B-Cell Lymphoma 14.7 Urothelial Cancer 14.8 Microsatellite Instability-High or Mismatch Repair Deficient Cancer 14.9 Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer 14.10 Gastric Cancer 14.11 Esophageal Cancer 14.12 Cervical Cancer 14.13 Hepatocellular Carcinoma 14.14 Biliary Tract Cancer 14.15 Merkel Cell Carcinoma 14.16 Renal Cell Carcinoma 14.17 Endometrial Carcinoma 14.18 Tumor Mutational Burden-High Cancer 14.19 Cutaneous Squamous Cell Carcinoma 14.20 Triple-Negative Breast Cancer 14.21 Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5493485 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Melanoma KEYTRUDA® is indicated for the treatment of patients with unresectable or metastatic melanoma. KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. 1.2 Non-Small Cell Lung Cancer KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC. KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥1%] as determined by an FDA-approved test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations, and is: • Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or • metastatic. KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. KEYTRUDA is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. 1.3 Malignant Pleural Mesothelioma KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM). 1.4 Head and Neck Squamous Cell Cancer KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test [see Dosage and Administration (2.1)]. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. 1.5 Classical Hodgkin Lymphoma KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL). 4 Reference ID: 5493485 KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. 1.6 Primary Mediastinal Large B-Cell Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. 1.7 Urothelial Cancer KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer. KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma: • who are not eligible for any platinum-containing chemotherapy, or • who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. 1.8 Microsatellite Instability-High or Mismatch Repair Deficient Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options [see Dosage and Administration (2.1)]. 1.9 Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. 1.10 Gastric Cancer KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.10)]. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. KEYTRUDA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. 1.11 Esophageal Cancer KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: • in combination with platinum- and fluoropyrimidine-based chemotherapy, or • as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. 5 Reference ID: 5493485 1.12 Cervical Cancer KEYTRUDA, in combination with chemoradiotherapy (CRT), is indicated for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. 1.13 Hepatocellular Carcinoma KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. 1.14 Biliary Tract Cancer KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). 1.15 Merkel Cell Carcinoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). 1.16 Renal Cell Carcinoma KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC. KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions [see Clinical Studies (14.16)]. 1.17 Endometrial Carcinoma KEYTRUDA, in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA-approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration (2.1)]. KEYTRUDA, as a single agent, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration (2.1)]. 1.18 Tumor Mutational Burden-High Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test [see Dosage and Administration (2.1)], that have progressed following prior treatment and who have no satisfactory alternative treatment options. 6 Reference ID: 5493485 This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.18)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Limitations of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established. 1.19 Cutaneous Squamous Cell Carcinoma KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. 1.20 Triple-Negative Breast Cancer KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test [see Dosage and Administration (2.1)]. 1.21 Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks KEYTRUDA is indicated for use at an additional recommended dosage of 400 mg every 6 weeks for classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma in adults [see Indications and Usage (1.5, 1.6), Dosage and Administration (2.2)]. This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety [see Clinical Pharmacology (12.2), Clinical Studies (14.21)]. Continued approval for this dosage may be contingent upon verification and description of clinical benefit in the confirmatory trials. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Information on FDA-approved tests for patient selection is available at: http://www.fda.gov/CompanionDiagnostics. Patient Selection for Single-Agent Treatment Select patients for treatment with KEYTRUDA as a single agent based on the presence of positive PD-L1 expression in: • Stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.2)]. • metastatic NSCLC [see Clinical Studies (14.2)]. • first-line treatment of metastatic or unresectable, recurrent HNSCC [see Clinical Studies (14.4)]. • previously treated recurrent locally advanced or metastatic esophageal cancer [see Clinical Studies (14.11)]. • recurrent or metastatic cervical cancer with disease progression on or after chemotherapy [see Clinical Studies (14.12)]. For the MSI-H/dMMR indications, select patients for treatment with KEYTRUDA as a single agent based on MSI-H/dMMR status in tumor specimens [see Clinical Studies (14.8, 14.9)]. For the TMB-H indication, select patients for treatment with KEYTRUDA as a single agent based on TMB-H status in tumor specimens [see Clinical Studies (14.18)]. Because subclonal dMMR mutations and microsatellite instability may arise in high-grade gliomas during temozolomide therapy, it is recommended to test for TMB-H, MSI-H, and dMMR in the primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas. 7 Reference ID: 5493485 Additional Patient Selection Information for MSI-H or dMMR in Patients with non-CRC Solid Tumors Due to discordance between local tests and FDA-approved tests, confirmation of MSI-H or dMMR status is recommended by an FDA-approved test in patients with MSI-H or dMMR solid tumors, if feasible. If unable to perform confirmatory MSI-H/dMMR testing, the presence of TMB ≥10 mut/Mb, as determined by an FDA-approved test, may be used to select patients for treatment [see Clinical Studies (14.8)]. Patient Selection for Combination Therapy For use of KEYTRUDA in combination with chemotherapy and trastuzumab, select patients based on the presence of positive PD-L1 expression (CPS ≥1) in locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma [see Clinical Studies (14.10)]. For use of KEYTRUDA in combination with chemotherapy, with or without bevacizumab, select patients based on the presence of positive PD-L1 expression in persistent, recurrent, or metastatic cervical cancer [see Clinical Studies (14.12)]. For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with KEYTRUDA in combination with lenvatinib based on MSI or MMR status in tumor specimens [see Clinical Studies (14.17)]. For use of KEYTRUDA in combination with chemotherapy, select patients based on the presence of positive PD-L1 expression in locally recurrent unresectable or metastatic TNBC [see Clinical Studies (14.20)]. Additional Patient Selection Information • An FDA-approved test for the detection of not MSI-H is currently unavailable for the selection of patients with not MSI-H endometrial carcinoma for treatment with KEYTRUDA in combination with lenvatinib [see Clinical Studies (14.17)]. 2.2 Recommended Dosage Table 1: Recommended Dosage Indication Recommended Dosage of KEYTRUDA Duration/Timing of Treatment Monotherapy Adult patients with unresectable or metastatic melanoma 200 mg every 3 weeks* or 400 mg every 6 weeks* Until disease progression or unacceptable toxicity Adjuvant treatment of adult patients with melanoma, NSCLC, or RCC 200 mg every 3 weeks* or 400 mg every 6 weeks* Until disease recurrence, unacceptable toxicity, or up to 12 months Adult patients with NSCLC, HNSCC, cHL, PMBCL, locally advanced or metastatic Urothelial Carcinoma, MSI-H or dMMR Cancer, MSI-H or dMMR CRC, MSI-H or dMMR Endometrial Carcinoma, Esophageal Cancer, Cervical Cancer, HCC, MCC, TMB-H Cancer, or cSCC 200 mg every 3 weeks* or 400 mg every 6 weeks* Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with high-risk BCG- unresponsive NMIBC 200 mg every 3 weeks* or 400 mg every 6 weeks* Until persistent or recurrent high-risk NMIBC, disease progression, unacceptable toxicity, or up to 24 months Pediatric patients with cHL, PMBCL, MSI-H or dMMR Cancer, MCC, or TMB­ H Cancer 2 mg/kg every 3 weeks (up to a maximum of 200 mg)* Until disease progression, unacceptable toxicity, or up to 24 months Pediatric patients (12 years and older) for adjuvant treatment of melanoma 2 mg/kg every 3 weeks (up to a maximum of 200 mg)* Until disease recurrence, unacceptable toxicity, or up to 12 months Combination Therapy† 8 Reference ID: 5493485 Indication Recommended Dosage of KEYTRUDA Duration/Timing of Treatment Adult patients with resectable NSCLC 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to chemotherapy when given on the same day. Neoadjuvant treatment in combination with chemotherapy for 12 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as a single agent after surgery for 39 weeks or until disease recurrence or unacceptable toxicity Adult patients with NSCLC, MPM, HNSCC, HER2-negative Gastric Cancer, Esophageal Cancer, or BTC 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with locally advanced or metastatic urothelial cancer 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA after enfortumab vedotin when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with HER2-positive Gastric Cancer 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to trastuzumab and chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with Cervical Cancer 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to chemoradiotherapy or prior to chemotherapy with or without bevacizumab when given on the same day. Until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months Adult patients with RCC 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA in combination with axitinib 5 mg orally twice daily‡ Until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months or Administer KEYTRUDA in combination with lenvatinib 20 mg orally once daily. Adult patients with Endometrial Carcinoma 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to carboplatin and paclitaxel when given on the same day. Until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months or Administer KEYTRUDA in combination with lenvatinib 20 mg orally once daily. Adult patients with high-risk early-stage TNBC 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to chemotherapy when given on the same day. Neoadjuvant treatment in combination with chemotherapy for 24 weeks (8 doses of 200 mg every 3 weeks or 4 doses of 400 mg every 6 weeks) or until disease progression or unacceptable toxicity, followed by adjuvant treatment with KEYTRUDA as a single agent for up to 9 Reference ID: 5493485 Indication Recommended Dosage of KEYTRUDA Duration/Timing of Treatment 27 weeks (9 doses of 200 mg every 3 weeks or 5 doses of 400 mg every 6 weeks) or until disease recurrence or unacceptable toxicity§ Adult patients with locally recurrent unresectable or metastatic TNBC 200 mg every 3 weeks* or 400 mg every 6 weeks* Administer KEYTRUDA prior to chemotherapy when given on the same day. Until disease progression, unacceptable toxicity, or up to 24 months * 30-minute intravenous infusion † Refer to the Prescribing Information for the agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate. ‡ When axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer. § Patients who experience disease progression or unacceptable toxicity related to KEYTRUDA with neoadjuvant treatment in combination with chemotherapy should not receive adjuvant single agent KEYTRUDA. 2.3 Dose Modifications No dose reduction for KEYTRUDA is recommended. In general, withhold KEYTRUDA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue KEYTRUDA for Life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids. Dosage modifications for KEYTRUDA for adverse reactions that require management different from these general guidelines are summarized in Table 2. Table 2: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity* Dosage Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] Pneumonitis Grade 2 Withhold† Grade 3 or 4 Permanently discontinue Colitis Grade 2 or 3 Withhold† Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy with axitinib, see Table 3. AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN Withhold† AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Hepatitis with tumor involvement of the liver‡ Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN Withhold† ALT or AST increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue 10 Reference ID: 5493485 Adverse Reaction Severity* Dosage Modification Endocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold† Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold† Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grade 2, 3, or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold† Grade 3 or 4 Permanently discontinue Hematologic toxicity in patients with cHL or PMBCL Grade 4 Withhold until resolution to Grades 0 or 1 Other Adverse Reactions Infusion-related reactions [see Warnings and Precautions (5.2)] Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue * Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 † Resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids. ‡ If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue KEYTRUDA based on recommendations for hepatitis with no liver involvement. ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal The following table represents dosage modifications that are different from those described above for KEYTRUDA or in the Full Prescribing Information for the drug administered in combination. Table 3: Recommended Specific Dosage Modifications for Adverse Reactions for KEYTRUDA in Combination with Axitinib Treatment Adverse Reaction Severity Dosage Modification KEYTRUDA in combination with Liver enzyme elevations* ALT or AST increases to at least 3 times but less than 10 times ULN without concurrent total bilirubin at least 2 times ULN Withhold both KEYTRUDA and axitinib until resolution to Grades 0 or 1† axitinib ALT or AST increases to more than 3 times ULN with concurrent total bilirubin at least 2 times ULN or ALT or AST ≥10 times ULN Permanently discontinue both KEYTRUDA and axitinib * Consider corticosteroid therapy † Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Consider rechallenge with a single drug or sequential rechallenge with both drugs after recovery. If rechallenging with axitinib, consider dose reduction as per the axitinib Prescribing Information. ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal Recommended Dose Modifications for Adverse Reactions for KEYTRUDA in Combination with Lenvatinib When administering KEYTRUDA in combination with lenvatinib, modify the dosage of one or both drugs. Withhold or discontinue KEYTRUDA as shown in Table 2. Refer to lenvatinib prescribing information for additional dose modification information. 2.4 Preparation and Administration Preparation for Intravenous Infusion • Visually inspect the solution for particulate matter and discoloration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed. 11 Reference ID: 5493485 • Dilute KEYTRUDA injection (solution) prior to intravenous administration. • Withdraw the required volume from the vial(s) of KEYTRUDA and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL. • Discard any unused portion left in the vial. Storage of Diluted Solution The product does not contain a preservative. Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either: • At room temperature for no more than 6 hours from the time of dilution. This includes room temperature storage of the diluted solution, and the duration of infusion. • Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 96 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Do not shake. Discard after 6 hours at room temperature or after 96 hours under refrigeration. Do not freeze. Administration • Administer diluted solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter. • Do not co-administer other drugs through the same infusion line. 3 DOSAGE FORMS AND STRENGTHS • Injection: 100 mg/4 mL (25 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Severe and Fatal Immune-Mediated Adverse Reactions KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune- mediated adverse reactions. Important immune-mediated adverse reactions listed under WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune- mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. 12 Reference ID: 5493485 Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune- mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis KEYTRUDA can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) adverse reactions. Systemic corticosteroids were required in 67% (63/94) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) of patients and withholding of KEYTRUDA in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of pneumonitis. Pneumonitis resolved in 59% of the 94 patients. In clinical studies enrolling 389 adult patients with cHL who received KEYTRUDA as a single agent, pneumonitis occurred in 31 (8%) patients, including Grades 3-4 pneumonitis in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 21 (5.4%) patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution. In a clinical study enrolling 580 adult patients with resected NSCLC (KEYNOTE-091) who received KEYTRUDA as a single agent for adjuvant treatment, pneumonitis occurred in 41 (7%) patients, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution. Immune-Mediated Colitis KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) adverse reactions. Systemic corticosteroids were required in 69% (33/48) of patients with colitis. Additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) of patients and withholding of KEYTRUDA in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence of colitis. Colitis resolved in 85% of the 48 patients. Hepatotoxicity and Immune-Mediated Hepatitis KEYTRUDA as a Single Agent KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 68% (13/19) of patients with hepatitis. Eleven percent of these patients required additional immunosuppressant therapy. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) of patients and withholding of KEYTRUDA in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of hepatitis. Hepatitis resolved in 79% of the 19 patients. 13 Reference ID: 5493485 KEYTRUDA with Axitinib KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed [see Dosage and Administration (2.3)]. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both KEYTRUDA and axitinib. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event. Immune-Mediated Endocrinopathies Adrenal Insufficiency KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypophysitis KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) adverse reactions. Systemic corticosteroids were required in 94% (16/17) of patients with hypophysitis; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) of patients and withholding of KEYTRUDA in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Thyroid Disorders KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). No patients discontinued KEYTRUDA due to thyroiditis. KEYTRUDA was withheld in <0.1% (1) of patients. Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). Hyperthyroidism led to permanent discontinuation of KEYTRUDA in <0.1% (2) of patients and withholding of KEYTRUDA in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. 14 Reference ID: 5493485 The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.2%) hyperthyroidism. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). Hypothyroidism led to permanent discontinuation of KEYTRUDA in <0.1% (1) of patients and withholding of KEYTRUDA in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism. Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Type 1 diabetes mellitus occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. Type 1 diabetes mellitus led to permanent discontinuation in <0.1% (1) of patients and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. All patients with Type 1 diabetes mellitus required long-term insulin therapy. Immune-Mediated Nephritis with Renal Dysfunction KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 89% (8/9) of patients with nephritis. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) of patients and withholding of KEYTRUDA in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence of nephritis. Nephritis resolved in 56% of the 9 patients. Immune-Mediated Dermatologic Adverse Reactions KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome, DRESS, and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity [see Dosage and Administration (2.3)]. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 40% (15/38) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of KEYTRUDA in 0.1% (2) of patients and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence of immune- mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 79% of the 38 patients. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other PD­ 15 Reference ID: 5493485 1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada­ like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica Endocrine: Hypoparathyroidism Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection 5.2 Infusion-Related Reactions KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion- related reactions, stop infusion and permanently discontinue KEYTRUDA [see Dosage and Administration (2.3)]. 5.3 Complications of Allogeneic HSCT Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid- requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT. 5.4 Increased Mortality in Patients with Multiple Myeloma when KEYTRUDA is Added to a Thalidomide Analogue and Dexamethasone In two randomized trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled trials. 5.5 Embryo-Fetal Toxicity Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. Advise women of the potential risk to a fetus. 16 Reference ID: 5493485 Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. • Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)]. • Infusion-related reactions [see Warnings and Precautions (5.2)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS reflect exposure to KEYTRUDA as a single agent in 2799 patients in three randomized, open-label, active-controlled trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001), which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition to the 2799 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to KEYTRUDA as a single agent in a randomized, placebo-controlled trial (KEYNOTE-091), which enrolled 580 patients with resected NSCLC, a non-randomized, open-label, multi-cohort trial (KEYNOTE-012), a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and two randomized, open-label, active-controlled trials (KEYNOTE­ 040 and KEYNOTE-048 single agent arms), which enrolled 909 patients with HNSCC; in two non- randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087) and one randomized, open-label, active-controlled trial (KEYNOTE-204), which enrolled 389 patients with cHL; in a randomized, open- label, active-controlled trial (KEYNOTE-048 combination arm), which enrolled 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE-426), which enrolled 429 patients with RCC; and in post-marketing use. Across all trials, KEYTRUDA was administered at doses of 2 mg/kg intravenously every 3 weeks, 10 mg/kg intravenously every 2 weeks, 10 mg/kg intravenously every 3 weeks, or 200 mg intravenously every 3 weeks. Among the 2799 patients, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more. Melanoma Ipilimumab-Naive Melanoma The safety of KEYTRUDA for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received KEYTRUDA 10 mg/kg every 2 weeks (n=278) or KEYTRUDA 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies (14.1)]. Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible. The median duration of exposure was 5.6 months (range: 1 day to 11.0 months) for KEYTRUDA and similar in both treatment arms. Fifty-one and 46% of patients received KEYTRUDA 10 mg/kg every 2 or 3 weeks, respectively, for ≥6 months. No patients in either arm received treatment for more than one year. The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 32% had an elevated lactate dehydrogenase (LDH) value at baseline; 65% had M1c stage disease; 9% with history of brain metastasis; and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%). In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both 17 Reference ID: 5493485 I I I I I I I I I I I I I I I I I I I I KEYTRUDA arms. Adverse reactions leading to permanent discontinuation of KEYTRUDA occurred in 9% of patients. Adverse reactions leading to discontinuation of KEYTRUDA in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). Tables 4 and 5 summarize selected adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-006. Table 4: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-006 Adverse Reaction KEYTRUDA 10 mg/kg every 2 or 3 weeks n=555 Ipilimumab n=256 All Grades† (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue 28 0.9 28 3.1 Skin and Subcutaneous Tissue Rash‡ 24 0.2 23 1.2 Vitiligo§ 13 0 2 0 Musculoskeletal and Connective Tissue Arthralgia 18 0.4 10 1.2 Back pain 12 0.9 7 0.8 Respiratory, Thoracic and Mediastinal Cough 17 0 7 0.4 Dyspnea 11 0.9 7 0.8 Metabolism and Nutrition Decreased appetite 16 0.5 14 0.8 Nervous System Headache 14 0.2 14 0.8 * Adverse reactions occurring at same or higher incidence than in the ipilimumab arm † Graded per NCI CTCAE v4.0 ‡ Includes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo­ papular, rash papular, rash pruritic, and exfoliative rash. § Includes skin hypopigmentation Other clinically important adverse reactions occurring in ≥10% of patients receiving KEYTRUDA were diarrhea (26%), nausea (21%), and pruritus (17%). Table 5: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-006 Laboratory Test† KEYTRUDA 10 mg/kg every 2 or 3 weeks Ipilimumab All Grades‡ % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 45 4.2 45 3.8 Hypertriglyceridemia 43 2.6 31 1.1 Hyponatremia 28 4.6 26 7 Increased AST 27 2.6 25 2.5 Hypercholesterolemia 20 1.2 13 0 Hematology Anemia 35 3.8 33 4.0 Lymphopenia 33 7 25 6 * Laboratory abnormalities occurring at same or higher incidence than in ipilimumab arm † Each test incidence is based on the number of patients who had both baseline and at least one on- study laboratory measurement available: KEYTRUDA (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: KEYTRUDA n=429 and ipilimumab n=183; hypercholesterolemia: KEYTRUDA n=484 and ipilimumab n=205. ‡ Graded per NCI CTCAE v4.0 18 Reference ID: 5493485 Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3­ 4), and increased alkaline phosphatase (21% all Grades, 2% Grades 3-4). Ipilimumab-Refractory Melanoma The safety of KEYTRUDA in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was investigated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (KEYTRUDA dose), randomized (1:1:1), active-controlled trial in which 528 patients received KEYTRUDA 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator’s choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%) [see Clinical Studies (14.1)]. Patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C, were ineligible. The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). In the KEYTRUDA 2 mg/kg arm, 36% of patients were exposed to KEYTRUDA for ≥6 months and 4% were exposed for ≥12 months. In the KEYTRUDA 10 mg/kg arm, 41% of patients were exposed to KEYTRUDA for ≥6 months and 6% of patients were exposed to KEYTRUDA for ≥12 months. The study population characteristics were: median age of 62 years (range: 15 to 89); 61% male; 98% White; 41% had an elevated LDH value at baseline; 83% had M1c stage disease; 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor); and 15% with history of brain metastasis. In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both KEYTRUDA arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving KEYTRUDA; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). Tables 6 and 7 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-002. 19 Reference ID: 5493485 Table 6: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-002 Adverse Reaction KEYTRUDA 2 mg/kg or 10 mg/kg every 3 weeks n=357 Chemotherapy† n=171 All Grades‡ (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Pruritus 28 0 8 0 Rash§ 24 0.6 8 0 Gastrointestinal Constipation 22 0.3 20 2.3 Diarrhea 20 0.8 20 2.3 Abdominal pain 13 1.7 8 1.2 Respiratory, Thoracic and Mediastinal Cough 18 0 16 0 General Pyrexia 14 0.3 9 0.6 Asthenia 10 2.0 9 1.8 Musculoskeletal and Connective Tissue Arthralgia 14 0.6 10 1.2 * Adverse reactions occurring at same or higher incidence than in chemotherapy arm † Chemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin ‡ Graded per NCI CTCAE v4.0 § Includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%). Table 7: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-002 Laboratory Test† KEYTRUDA 2 mg/kg or 10 mg/kg every 3 weeks Chemotherapy All Grades‡ % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 49 6 44 6 Hypoalbuminemia 37 1.9 33 0.6 Hyponatremia 37 7 24 3.8 Hypertriglyceridemia 33 0 32 0.9 Increased alkaline phosphatase 26 3.1 18 1.9 Increased AST 24 2.2 16 0.6 Decreased bicarbonate 22 0.4 13 0 Hypocalcemia 21 0.3 18 1.9 Increased ALT 21 1.8 16 0.6 * Laboratory abnormalities occurring at same or higher incidence than in chemotherapy arm. † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: KEYTRUDA n=247 and chemotherapy n=116; decreased bicarbonate: KEYTRUDA n=263 and chemotherapy n=123. ‡ Graded per NCI CTCAE v4.0 Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4). Adjuvant Treatment of Resected Stage IIB or IIC Melanoma Among the 969 patients with Stage IIB or IIC melanoma enrolled in KEYNOTE-716 [see Clinical Studies (14.1)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 9.9 months (range: 0 to 15.4 months). Patients with autoimmune disease or a medical condition that required 20 Reference ID: 5493485 I I I I I I I I I I I I I I I I I I I I I I I I immunosuppression or mucosal or ocular melanoma were ineligible. Adverse reactions occurring in patients with Stage IIB or IIC melanoma were similar to those occurring in 1011 patients with Stage III melanoma from KEYNOTE-054 or the 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Adjuvant Treatment of Stage III Resected Melanoma The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-054, a randomized (1:1) double-blind trial in which 1019 patients with completely resected Stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=509) or placebo (n=502) for up to one year [see Clinical Studies (14.1)]. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Seventy-six percent of patients received KEYTRUDA for 6 months or longer. The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had Stage IIIA, 46% had Stage IIIB, 18% had Stage IIIC (1-3 positive lymph nodes), and 20% had Stage IIIC (≥4 positive lymph nodes). Two patients treated with KEYTRUDA died from causes other than disease progression; causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. Adverse reactions leading to permanent discontinuation occurred in 14% of patients receiving KEYTRUDA; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 19% of patients; the most common (≥1%) were diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST (1.4%), dyspnea (1%), and fatigue (1%). Tables 8 and 9 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-054. Table 8: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-054 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=509 Placebo n=502 All Grades† (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Diarrhea 28 1.2 26 1.2 Nausea 17 0.2 15 0 Skin and Subcutaneous Tissue Pruritus 19 0 12 0 Rash 13 0.2 9 0 Musculoskeletal and Connective Tissue Arthralgia 16 1.2 14 0 Endocrine Hypothyroidism 15 0 2.8 0 Hyperthyroidism 10 0.2 1.2 0 Respiratory, Thoracic and Mediastinal Cough 14 0 11 0 General Asthenia 11 0.2 8 0 Influenza like illness 11 0 8 0 Investigations Weight loss 11 0 8 0 * Adverse reactions occurring at same or higher incidence than in placebo arm † Graded per NCI CTCAE v4.03 21 Reference ID: 5493485 I I I I I I I I Table 9: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving KEYTRUDA in KEYNOTE-054 Laboratory Test† KEYTRUDA 200 mg every 3 weeks Placebo All Grades‡ % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Increased ALT 25 2.4 15 0.2 Increased AST 22 1.8 14 0.4 Hematology Lymphopenia 22 1 15 1.2 * Laboratory abnormalities occurring at same or higher incidence than placebo. † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 502 to 505 patients) and placebo (range: 491 to 497 patients). ‡ Graded per NCI CTCAE v4.03 NSCLC First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy The safety of KEYTRUDA in combination with pemetrexed and investigator’s choice of platinum (either carboplatin or cisplatin) was investigated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.2)]. A total of 607 patients received KEYTRUDA 200 mg, pemetrexed and platinum every 3 weeks for 4 cycles followed by KEYTRUDA and pemetrexed (n=405) or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). Sixty percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; and 18% with history of brain metastases at baseline. KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 53% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased ALT (2%), and pyrexia (2%). Tables 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE­ 189. 22 Reference ID: 5493485 Table 10: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189 Adverse Reaction KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy n=405 Placebo Pemetrexed Platinum Chemotherapy n=202 All Grades* (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Nausea 56 3.5 52 3.5 Constipation 35 1.0 32 0.5 Diarrhea 31 5 21 3.0 Vomiting 24 3.7 23 3.0 General Fatigue† 56 12 58 6 Pyrexia 20 0.2 15 0 Metabolism and Nutrition Decreased appetite 28 1.5 30 0.5 Skin and Subcutaneous Tissue Rash‡ 25 2.0 17 2.5 Respiratory, Thoracic and Mediastinal Cough 21 0 28 0 Dyspnea 21 3.7 26 5 * Graded per NCI CTCAE v4.03 † Includes asthenia and fatigue ‡ Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. Table 11: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-189 Laboratory Test* KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy Placebo Pemetrexed Platinum Chemotherapy All Grades† % Grades 3-4 % All Grades % Grades 3-4 % Hematology Anemia 85 17 81 18 Lymphopenia 65 22 64 25 Neutropenia 50 21 41 19 Thrombocytopenia 30 12 29 8 Chemistry Hyperglycemia 63 9 60 7 Increased ALT 47 3.8 42 2.6 Increased AST 47 2.8 40 1.0 Hypoalbuminemia 39 2.8 39 1.1 Increased creatinine 37 4.2 25 1.0 Hyponatremia 32 7 23 6 Hypophosphatemia 30 10 28 14 Increased alkaline phosphatase 26 1.8 29 2.1 Hypocalcemia 24 2.8 17 0.5 Hyperkalemia 24 2.8 19 3.1 Hypokalemia 21 5 20 5 * Each test incidence is based on the number of patients who had both baseline and at least one on- study laboratory measurement available: KEYTRUDA/pemetrexed/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients). † Graded per NCI CTCAE v4.03 First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy The safety of KEYTRUDA in combination with carboplatin and investigator’s choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in 558 patients with previously untreated, metastatic squamous NSCLC [see 23 Reference ID: 5493485 Clinical Studies (14.2)]. Safety data are available for the first 203 patients who received KEYTRUDA and chemotherapy (n=101) or placebo and chemotherapy (n=102). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA was 7 months (range: 1 day to 12 months). Sixty-one percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. A total of 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received paclitaxel protein-bound in combination with carboplatin. The study population characteristics were: median age of 65 years (range: 40 to 83), 52% age 65 or older; 78% male; 83% White; and 9% with history of brain metastases. KEYTRUDA was discontinued for adverse reactions in 15% of patients, with no single type of adverse reaction accounting for the majority. Adverse reactions leading to interruption of KEYTRUDA occurred in 43% of patients; the most common (≥2%) were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most frequent (≥2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%). The adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs. 36%) and peripheral neuropathy (31% vs. 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407. Previously Untreated NSCLC The safety of KEYTRUDA was investigated in KEYNOTE-042, a multicenter, open-label, randomized (1:1), active-controlled trial in 1251 patients with PD-L1 expressing, previously untreated Stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC [see Clinical Studies (14.2)]. Patients received KEYTRUDA 200 mg every 3 weeks (n=636) or investigator’s choice of chemotherapy (n=615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n=312) or paclitaxel and carboplatin followed by optional pemetrexed (n=303) every 3 weeks. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA was 5.6 months (range: 1 day to 27.3 months). Forty- eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA 200 mg for ≥6 months. The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Eighty-seven percent had metastatic disease (Stage IV), 13% had Stage III disease (2% Stage IIIA and 11% Stage IIIB), and 5% had treated brain metastases at baseline. KEYTRUDA was discontinued for adverse reactions in 19% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3.0%), death due to unknown cause (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were pneumonitis (3.1%), pneumonia (3.0%), hypothyroidism (2.2%), and increased ALT (2.0%). The most frequent (≥2%) serious adverse reactions were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-042. 24 Reference ID: 5493485 Table 12: Adverse Reactions Occurring in ≥10% of Patients in KEYNOTE-042 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=636 Chemotherapy n=615 All Grades* (%) Grades 3-5 (%) All Grades (%) Grades 3-5 (%) General Fatigue† 25 3.1 33 3.9 Pyrexia 10 0.3 8 0 Metabolism and Nutrition Decreased appetite 17 1.7 21 1.5 Respiratory, Thoracic and Mediastinal Dyspnea 17 2.0 11 0.8 Cough 16 0.2 11 0.3 Skin and Subcutaneous Tissue Rash‡ 15 1.3 8 0.2 Gastrointestinal Constipation 12 0 21 0.2 Diarrhea 12 0.8 12 0.5 Nausea 12 0.5 32 1.1 Endocrine Hypothyroidism 12 0.2 1.5 0 Infections Pneumonia 12 7 9 6 Investigations Weight loss 10 0.9 7 0.2 * Graded per NCI CTCAE v4.03 † Includes fatigue and asthenia ‡ Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. Table 13: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-042 Laboratory Test* KEYTRUDA 200 mg every 3 weeks Chemotherapy All Grades† % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 52 4.7 51 5 Increased ALT 33 4.8 34 2.9 Hypoalbuminemia 33 2.2 29 1.0 Increased AST 31 3.6 32 1.7 Hyponatremia 31 9 32 8 Increased alkaline phosphatase 29 2.3 29 0.3 Hypocalcemia 25 2.5 19 0.7 Hyperkalemia 23 3.0 20 2.2 Increased prothrombin INR 21 2.0 15 2.9 Hypophosphatemia 20 4.7 17 4.3 Hematology Anemia 43 4.4 79 19 Lymphopenia 30 7 42 13 * Each test incidence is based on the number of patients who had both baseline and at least one on- study laboratory measurement available: KEYTRUDA (range: 598 to 610 patients) and chemotherapy (range: 585 to 598 patients); increased prothrombin INR: KEYTRUDA n=203 and chemotherapy n=173. † Graded per NCI CTCAE v4.03 Previously Treated NSCLC The safety of KEYTRUDA was investigated in KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations [see Clinical Studies (14.2)]. A total of 991 patients received KEYTRUDA 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m2 every 3 weeks. Patients with autoimmune disease, medical conditions that required systemic 25 Reference ID: 5493485 corticosteroids or other immunosuppressive medication, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The median duration of exposure to KEYTRUDA 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to KEYTRUDA 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to KEYTRUDA 2 mg/kg in 31% of patients exposed to KEYTRUDA for ≥6 months. In the KEYTRUDA 10 mg/kg arm, 34% of patients were exposed to KEYTRUDA for ≥6 months. The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; and 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases. Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease. In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682). Treatment was discontinued for adverse reactions in 8% of patients receiving KEYTRUDA. The most common adverse events resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). Tables 14 and 15 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-010. Table 14: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-010 Adverse Reaction KEYTRUDA 2 or 10 mg/kg every 3 weeks n=682 Docetaxel 75 mg/m2 every 3 weeks n=309 All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%) Metabolism and Nutrition Decreased appetite 25 1.5 23 2.6 Respiratory, Thoracic and Mediastinal Dyspnea 23 3.7 20 2.6 Cough 19 0.6 14 0 Gastrointestinal Nausea 20 1.3 18 0.6 Constipation 15 0.6 12 0.6 Vomiting 13 0.9 10 0.6 Skin and Subcutaneous Tissue Rash‡ 17 0.4 8 0 Pruritus 11 0 3 0.3 Musculoskeletal and Connective Tissue Arthralgia 11 1.0 9 0.3 Back pain 11 1.5 8 0.3 * Adverse reactions occurring at same or higher incidence than in docetaxel arm † Graded per NCI CTCAE v4.0 ‡ Includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%). 26 Reference ID: 5493485 Table 15: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of NSCLC Patients Receiving KEYTRUDA in KEYNOTE-010 Laboratory Test† KEYTRUDA 2 or 10 mg/kg every 3 weeks Docetaxel 75 mg/m2 every 3 weeks All Grades‡ % Grades 3-4 % All Grades‡ % Grades 3-4 % Chemistry Hyponatremia 32 8 27 2.9 Increased alkaline phosphatase 28 3.0 16 0.7 Increased AST 26 1.6 12 0.7 Increased ALT 22 2.7 9 0.4 Hypocalcemia 20 0.9 20 1.8 * Laboratory abnormalities occurring at same or higher incidence than in docetaxel arm. † Each test incidence is based on the number of patients who had both baseline and at least one on- study laboratory measurement available: KEYTRUDA (range: 631 to 638 patients) and docetaxel (range: 271 to 277 patients). ‡ Graded per NCI CTCAE v4.0 Other laboratory abnormalities occurring in ≥20% of patients receiving KEYTRUDA were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% Grades 3-4), hypertriglyceridemia (36% all Grades; 1.8% Grades 3-4), lymphopenia (32% all Grades; 9% Grades 3-4), hypoalbuminemia (34% all Grades; 1.6% Grades 3-4), and hypercholesterolemia (20% all Grades; 0.7% Grades 3-4). Neoadjuvant and Adjuvant Treatment of Resectable NSCLC The safety of KEYTRUDA in combination with neoadjuvant platinum-containing chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent after surgery was investigated in KEYNOTE-671, a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition [see Clinical Studies (14.2)]. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 10.9 months (range: 1 day to 18.6 months). The study population characteristics were: median age of 64 years (range: 26 to 83), 45% age 65 or older, 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino. Adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum containing chemotherapy, given as neoadjuvant treatment and continued as single agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy. Neoadjuvant Phase of KEYNOTE-671 A total of 396 patients received at least 1 dose of KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment and 399 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment. Serious adverse reactions occurred in 34% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%). Of the 396 KEYTRUDA-treated patients and 399 placebo-treated patients who received neoadjuvant treatment, 6% (n=25) and 4.3% (n=17), respectively, did not receive surgery due to adverse reactions. 27 Reference ID: 5493485 The most frequent (≥1%) adverse reactions that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%). Of the 325 KEYTRUDA-treated patients who received surgery, 3.1% (n=10) experienced delay of surgery (surgery more than 8 weeks from last neoadjuvant treatment if patient received less than 4 cycles of neoadjuvant therapy or more than 20 weeks after first dose of neoadjuvant treatment if patient received 4 cycles of neoadjuvant therapy) due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 2.5% (n=8) experienced delay of surgery due to adverse reactions. Of the 325 KEYTRUDA-treated patients who received surgery, 7% (n=22) did not receive adjuvant treatment due to adverse reactions. Of the 317 placebo-treated patients who received surgery, 3.2% (n=10) did not receive adjuvant treatment due to adverse reactions. Adjuvant Phase of KEYNOTE-671 A total of 290 patients in the KEYTRUDA arm and 267 patients in the placebo arm received at least 1 dose of adjuvant treatment. Of the patients who received single agent KEYTRUDA as adjuvant treatment, 14% experienced serious adverse reactions; the most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of adjuvant KEYTRUDA due to an adverse reaction occurred in 12% of patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), AST increased (1%), and musculoskeletal pain (1%). Adjuvant Treatment of Resected NSCLC The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-091, a multicenter, randomized (1:1), triple-blind, placebo-controlled trial in patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC; adjuvant chemotherapy up to 4 cycles was optional [see Clinical Studies (14.2)]. A total of 1161 patients received KEYTRUDA 200 mg (n=580) or placebo (n=581) every 3 weeks. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents, or had a history of interstitial lung disease or pneumonitis. The median duration of exposure to KEYTRUDA was 11.7 months (range: 1 day to 18.9 months). Sixty- eight percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. The adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred. Malignant Pleural Mesothelioma (MPM) First-line treatment of unresectable advanced or metastatic MPM with pemetrexed and platinum chemotherapy The safety of KEYTRUDA in combination with pemetrexed and platinum chemotherapy (either carboplatin or cisplatin) was investigated in KEYNOTE-483, a multicenter, open-label, randomized (1:1), active- controlled trial in patients with previously untreated, unresectable advanced or metastatic MPM [see Clinical Studies (14.3)]. A total of 473 patients received KEYTRUDA 200 mg, pemetrexed, and platinum every 3 weeks for up to 6 cycles followed by KEYTRUDA (n=241), or pemetrexed and platinum chemotherapy every 3 weeks for up to 6 cycles (n=232). Patients with autoimmune disease that required systemic therapy within 3 years of treatment or a medical condition that required immunosuppression were ineligible. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 6.9 months (range: 1 day to 25.2 months). Sixty-one percent of patients in the KEYTRUDA arm were exposed to KEYTRUDA for ≥6 months. Adverse reactions occurring in patients with MPM were generally similar to those in other patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. 28 Reference ID: 5493485 HNSCC First-line treatment of metastatic or unresectable, recurrent HNSCC The safety of KEYTRUDA, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in KEYNOTE-048, a multicenter, open-label, randomized (1:1:1), active-controlled trial in patients with previously untreated, recurrent or metastatic HNSCC [see Clinical Studies (14.4)]. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576 patients received KEYTRUDA 200 mg every 3 weeks either as a single agent (n=300) or in combination with platinum and FU (n=276) every 3 weeks for 6 cycles followed by KEYTRUDA, compared to 287 patients who received cetuximab weekly in combination with platinum and FU every 3 weeks for 6 cycles followed by cetuximab. The median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 24.2 months) in the KEYTRUDA single agent arm and was 5.8 months (range: 3 days to 24.2 months) in the combination arm. Seventeen percent of patients in the KEYTRUDA single agent arm and 18% of patients in the combination arm were exposed to KEYTRUDA for ≥12 months. Fifty-seven percent of patients receiving KEYTRUDA in combination with chemotherapy started treatment with carboplatin. KEYTRUDA was discontinued for adverse reactions in 12% of patients in the KEYTRUDA single agent arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 31% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%). KEYTRUDA was discontinued for adverse reactions in 16% of patients in the combination arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 45% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%). Tables 16 and 17 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-048. 29 Reference ID: 5493485 Table 16: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-048 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=300 KEYTRUDA 200 mg every 3 weeks Platinum FU n=276 Cetuximab Platinum FU n=287 All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) General Fatigue† 33 4 49 11 48 8 Pyrexia 13 0.7 16 0.7 12 0 Mucosal inflammation 4.3 1.3 31 10 28 5 Gastrointestinal Constipation 20 0.3 37 0 33 1.4 Nausea 17 0 51 6 51 6 Diarrhea‡ 16 0.7 29 3.3 35 3.1 Vomiting 11 0.3 32 3.6 28 2.8 Dysphagia 8 2.3 12 2.9 10 2.1 Stomatitis 3 0 26 8 28 3.5 Skin Rash§ 20 2.3 17 0.7 70 8 Pruritus 11 0 8 0 10 0.3 Respiratory, Thoracic and Mediastinal Cough¶ 18 0.3 22 0 15 0 Dyspnea# 14 2.0 10 1.8 8 1.0 Endocrine Hypothyroidism 18 0 15 0 6 0 Metabolism and Nutrition Decreased appetite 15 1.0 29 4.7 30 3.5 Weight loss 15 2 16 2.9 21 1.4 Infections PneumoniaÞ 12 7 19 11 13 6 Nervous System Headache 12 0.3 11 0.7 8 0.3 Dizziness 5 0.3 10 0.4 13 0.3 Peripheral sensory neuropathyβ 1 0 14 1.1 7 1 Musculoskeletal Myalgiaà 12 1.0 13 0.4 11 0.3 Neck pain 6 0.7 10 1.1 7 0.7 Psychiatric Insomnia 7 0.7 10 0 8 0 * Graded per NCI CTCAE v4.0 † Includes fatigue, asthenia ‡ Includes diarrhea, colitis, hemorrhagic diarrhea, microscopic colitis § Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, drug eruption, erythema, erythema multiforme, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, pruritic rash, seborrheic dermatitis ¶ Includes cough, productive cough # Includes dyspnea, exertional dyspnea Þ Includes pneumonia, atypical pneumonia, bacterial pneumonia, staphylococcal pneumonia, aspiration pneumonia, lower respiratory tract infection, lung infection, lung infection pseudomonal β Includes peripheral sensory neuropathy, peripheral neuropathy, hypoesthesia, dysesthesia à Includes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia 30 Reference ID: 5493485 Table 17: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-048 Laboratory Test* KEYTRUDA 200 mg every 3 weeks KEYTRUDA 200 mg every 3 weeks Platinum FU Cetuximab Platinum FU All Grades† (%) Grades 3­ 4 (%) All Grades† (%) Grades 3­ 4 (%) All Grades† (%) Grades 3-4 (%) Hematology Lymphopenia 54 25 70 35 75 46 Anemia 52 7 89 29 79 20 Thrombocytopenia 12 3.8 73 18 76 18 Neutropenia 8 1.4 68 37 73 43 Chemistry Hyperglycemia 47 3.8 54 6 65 4.7 Hyponatremia 46 18 55 20 59 20 Hypoalbuminemia 44 3.5 46 3.9 49 1.1 Increased AST 28 3.1 25 1.9 37 3.6 Increased ALT 25 2.1 22 1.5 38 1.8 Increased alkaline phosphatase 25 2.1 26 1.1 33 1.1 Hypercalcemia 22 4.5 16 4.2 13 2.5 Hypocalcemia 22 1.0 32 3.8 58 6 Hyperkalemia 21 2.8 28 4.2 29 4.6 Hypophosphatemia 20 5 34 12 49 20 Hypokalemia 19 5 33 12 47 15 Increased creatinine 17 1.0 36 2.3 27 2.1 Hypomagnesemia 15 0.4 40 1.7 76 9 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/chemotherapy (range: 240 to 267 patients), KEYTRUDA (range: 245 to 292 patients), cetuximab/chemotherapy (range: 249 to 282 patients). † Graded per NCI CTCAE v4.0 Previously treated recurrent or metastatic HNSCC Among the 192 patients with HNSCC enrolled in KEYNOTE-012 [see Clinical Studies (14.4)], the median duration of exposure to KEYTRUDA was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for KEYNOTE-012. The study population characteristics were: median age of 60 years (range: 20 to 84), 35% age 65 or older; 83% male; and 77% White, 15% Asian, and 5% Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease. KEYTRUDA was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, summary safety results are provided in a pooled analysis. The most common adverse reactions (occurring in ≥20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism [see Warnings and Precautions (5.1)]. Relapsed or Refractory cHL KEYNOTE-204 The safety of KEYTRUDA was evaluated in KEYNOTE-204 [see Clinical Studies (14.5)]. Adults with relapsed or refractory cHL received KEYTRUDA 200 mg intravenously every 3 weeks (n=148) or 31 Reference ID: 5493485 brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks (n=152). The trial required an ANC ≥1000/µL, platelet count ≥75,000/µL, hepatic transaminases ≤2.5 times the upper limit of normal (ULN), bilirubin ≤1.5 times ULN, and ECOG performance status of 0 or 1. The trial excluded patients with active non-infectious pneumonitis, prior pneumonitis requiring steroids, active autoimmune disease, a medical condition requiring immunosuppression, or allogeneic HSCT within the past 5 years. The median duration of exposure to KEYTRUDA was 10 months (range: 1 day to 2.2 years), with 68% receiving at least 6 months of treatment and 48% receiving at least 1 year of treatment. Serious adverse reactions occurred in 30% of patients who received KEYTRUDA. Serious adverse reactions in ≥1% included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients (2%) died from causes other than disease progression: two from complications after allogeneic HSCT and one from unknown cause. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 14% of patients; 7% of patients discontinued treatment due to pneumonitis. Dosage interruption of KEYTRUDA due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dosage interruption in ≥3% of patients were upper respiratory tract infection, pneumonitis, transaminase increase, and pneumonia. Thirty-eight percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Table 18 summarizes adverse reactions in KEYNOTE-204. 32 Reference ID: 5493485 Table 18: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-204 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=148 Brentuximab Vedotin 1.8 mg/kg every 3 weeks N=152 All Grades* (%) Grades 3- 4 (%) All Grades* (%) Grades 3- 4† (%) Infections Upper respiratory tract infection‡ 41 1.4 24 0 Urinary tract infection 11 0 3 0.7 Musculoskeletal and Connective Tissue Musculoskeletal pain§ 32 0 29 1.3 Gastrointestinal Diarrhea¶ 22 2.7 17 1.3 Nausea 14 0 24 0.7 Vomiting 14 1.4 20 0 Abdominal pain# 11 0.7 13 1.3 General Pyrexia 20 0.7 13 0.7 FatigueÞ 20 0 22 0.7 Skin and Subcutaneous Tissue Rashβ 20 0 19 0.7 Pruritus 18 0 12 0 Respiratory, Thoracic and Mediastinal Coughà 20 0.7 14 0.7 Pneumonitisè 11 5 3 1.3 Dyspneað 11 0.7 7 0.7 Endocrine Hypothyroidism 19 0 3 0 Nervous System Peripheral neuropathyø 11 0.7 43 7 Headacheý 11 0 11 0 * Graded per NCI CTCAE v4.0 † Adverse reactions in BV arm were Grade 3 only. ‡ Includes acute sinusitis, nasopharyngitis, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, upper respiratory tract infection, viral upper respiratory tract infection § Includes arthralgia, back pain, bone pain, musculoskeletal discomfort, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity ¶ Includes diarrhea, gastroenteritis, colitis, enterocolitis # Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper Þ Includes fatigue, asthenia β Includes dermatitis acneiform, dermatitis atopic, dermatitis allergic, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, eczema, rash, rash erythematous, rash follicular‚ rash maculo-papular, rash papular, rash pruritic, toxic skin eruption à Includes cough, productive cough è Includes pneumonitis, interstitial lung disease ð Includes dyspnea, dyspnea exertional, wheezing ø Includes dysesthesia, hypoesthesia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy ý Includes headache, migraine, tension headache Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included herpes virus infection (9%), pneumonia (8%), oropharyngeal pain (8%), hyperthyroidism (5%), hypersensitivity (4.1%), infusion reactions (3.4%), altered mental state (2.7%), and in 1.4% each, uveitis, myocarditis, thyroiditis, febrile neutropenia, sepsis, and tumor flare. Table 19 summarizes laboratory abnormalities in KEYNOTE-204. 33 Reference ID: 5493485 Table 19: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL in KEYNOTE-204 Laboratory Abnormality* KEYTRUDA 200 mg every 3 weeks Brentuximab Vedotin 1.8 mg/kg every 3 weeks All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%) Chemistry Hyperglycemia 45 4.1 36 2.0 Increased AST 38 4.7 38 2.0 Increased ALT 31 5 43 2.6 Hypophosphatemia 31 4.9 17 2.8 Increased creatinine 26 3.4 13 2.6 Hypomagnesemia 23 0 13 0 Hyponatremia 24 4.1 20 3.3 Hypocalcemia 21 2.0 15 0 Increased alkaline phosphatase 19 2.1 21 2.0 Hypoalbuminemia 16 0.7 18 0.7 Hyperbilirubinemia 15 1.4 8 0.7 Hematology Lymphopenia 34 8 32 13 Thrombocytopenia 32 9 24 4.0 Neutropenia 27 8 42 16 Anemia 22 4.1 32 7 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 143 to 148 patients) and BV (range: 145 to 152 patients); hypomagnesemia: KEYTRUDA n=52 and BV n=47. † Graded per NCI CTCAE v4.0 KEYNOTE-087 Among the 210 patients with cHL who received KEYTRUDA in KEYNOTE-087 [see Clinical Studies (14.5)], the median duration of exposure to KEYTRUDA was 8.4 months (range: 1 day to 15.2 months). Serious adverse reactions occurred in 16% of patients who received KEYTRUDA. Serious adverse reactions that occurred in ≥1% of patients included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease (GVHD) and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 5% of patients and dosage interruption due to an adverse reaction occurred in 26%. Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-087. 34 Reference ID: 5493485 Table 20: Adverse Reactions (≥10%) in Patients with cHL who Received KEYTRUDA in KEYNOTE-087 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=210 All Grades* (%) Grade 3 (%) General Fatigue† 26 1.0 Pyrexia 24 1.0 Respiratory, Thoracic and Mediastinal Cough‡ 24 0.5 Dyspnea§ 11 1.0 Musculoskeletal and Connective Tissue Musculoskeletal pain¶ 21 1.0 Arthralgia 10 0.5 Gastrointestinal Diarrhea# 20 1.4 Vomiting 15 0 Nausea 13 0 Skin and Subcutaneous Tissue Rash Þ 20 0.5 Pruritus 11 0 Endocrine Hypothyroidism 14 0.5 Infections Upper respiratory tract infection 13 0 Nervous System Headache 11 0.5 Peripheral neuropathyβ 10 0 * Graded per NCI CTCAE v4.0 † Includes fatigue, asthenia ‡ Includes cough, productive cough § Includes dyspnea, dyspnea exertional, wheezing ¶ Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain # Includes diarrhea, gastroenteritis, colitis, enterocolitis Þ Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, dermatitis acneiform, dermatitis contact, rash erythematous, rash macular, rash papular, rash pruritic, seborrheic dermatitis, dermatitis psoriasiform β Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each). 35 Reference ID: 5493485 Table 21: Select Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with cHL who Received KEYTRUDA in KEYNOTE-087 Laboratory Abnormality* KEYTRUDA 200 mg every 3 weeks All Grades† (%) Grades 3-4 (%) Chemistry Hypertransaminasemia‡ 35 2.4 Increased alkaline phosphatase 17 0 Increased creatinine 15 0.5 Hematology Anemia 30 6 Thrombocytopenia 27 4.3 Neutropenia 25 7 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 208 to 209 patients) † Graded per NCI CTCAE v4.0 ‡ Includes elevation of AST or ALT Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087 (10% all Grades, 2.4% Grade 3-4). PMBCL Among the 53 patients with PMBCL who received KEYTRUDA in KEYNOTE-170 [see Clinical Studies (14.6)], the median duration of exposure to KEYTRUDA was 3.5 months (range: 1 day to 22.8 months). Serious adverse reactions occurred in 26% of patients. Serious adverse reactions that occurred in >2% of patients included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 8% of patients and dosage interruption due to an adverse reaction occurred in 15%. Twenty-five percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-170. 36 Reference ID: 5493485 Table 22: Adverse Reactions (≥10%) in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=53 All Grades* (%) Grades 3-4 (%) Musculoskeletal and Connective Tissue Musculoskeletal pain† 30 0 Infections Upper respiratory tract infection‡ 28 0 General Pyrexia 28 0 Fatigue§ 23 2 Respiratory, Thoracic and Mediastinal Cough¶ 26 2 Dyspnea 21 11 Gastrointestinal Diarrhea# 13 2 Abdominal pain Þ 13 0 Nausea 11 0 Cardiac Arrhythmia β 11 4 Nervous System Headache 11 0 * Graded per NCI CTCAE v4.0 † Includes arthralgia, back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, bone pain, neck pain, non-cardiac chest pain ‡ Includes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection § Includes fatigue, asthenia ¶ Includes allergic cough, cough, productive cough # Includes diarrhea, gastroenteritis Þ Includes abdominal pain, abdominal pain upper β Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia Clinically relevant adverse reactions in <10% of patients who received KEYTRUDA included hypothyroidism (8%), hyperthyroidism and pericarditis (4% each), and thyroiditis, pericardial effusion, pneumonitis, arthritis and acute kidney injury (2% each). Table 23: Laboratory Abnormalities (≥15%) That Worsened from Baseline in Patients with PMBCL who Received KEYTRUDA in KEYNOTE-170 Laboratory Abnormality* KEYTRUDA 200 mg every 3 weeks All Grades† (%) Grades 3-4 (%) Hematology Anemia 23 0 Leukopenia 47 12 Lymphopenia 27 10 Neutropenia 39 15 Chemistry Hyperglycemia 33 2.2 Hypophosphatemia 24 11 Hypertransaminasemia‡ 24 4.4 Hypoglycemia 20 0 Increased creatinine 16 0 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 41 to 45 patients) † Graded per NCI CTCAE v4.0 ‡ Includes elevation of AST or ALT 37 Reference ID: 5493485 Urothelial Cancer Patients with urothelial cancer in combination with enfortumab vedotin The safety of KEYTRUDA in combination with enfortumab vedotin was investigated in KEYNOTE-A39 in patients with locally advanced or metastatic urothelial cancer [see Clinical Studies (14.7)]. A total of 440 patients received KEYTRUDA 200 mg on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle compared to 433 patients who received gemcitabine on Days 1 and 8 and investigator’s choice of cisplatin or carboplatin on Day 1 of each 21-day cycle. Among patients who received KEYTRUDA and enfortumab vedotin, the median duration of exposure to KEYTRUDA was 8.5 months (range: 9 days to 28.5 months). Fatal adverse reactions occurred in 3.9% of patients treated with KEYTRUDA in combination with enfortumab vedotin including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin. Serious adverse reactions in ≥2% of patients receiving KEYTRUDA in combination with enfortumab vedotin were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). Dose interruptions of KEYTRUDA occurred in 61% of patients. The most common adverse reactions (≥2%) resulting in interruption of KEYTRUDA were rash (17%), peripheral neuropathy (7%), COVID-19 (5%), diarrhea (4.3%), pneumonitis/ILD (3.6%), neutropenia (3.4%), fatigue (3%), alanine aminotransferase increased (2.7%), hyperglycemia (2.5%), pneumonia (2%), and pruritus (2%). Tables 24 and 25 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with enfortumab vedotin in KEYNOTE-A39. 38 Reference ID: 5493485 Table 24: Adverse Reactions ≥20% (All Grades) in Patients Treated with KEYTRUDA in Combination with Enfortumab Vedotin in KEYNOTE-A39 Adverse Reaction KEYTRUDA in combination with Enfortumab Vedotin n=440 Chemotherapy n=433 All Grades* % Grades 3-4 % All Grades* % Grades 3-4 % Skin and subcutaneous tissue disorders Rash† 68 15 15 0 Pruritus 41 1.1 7 0 Alopecia 35 0.5 8 0.2 General disorders and administration site conditions Fatigue† 51 6 57 7 Nervous system disorders Peripheral neuropathy† 67 8 14 0 Dysgeusia 21 0 9 0 Metabolism and nutrition disorders Decreased appetite 33 1.8 26 1.8 Gastrointestinal disorders Diarrhea 38 4.5 16 1.4 Nausea 26 1.6 41 2.8 Constipation 26 0 34 0.7 Investigations Weight loss 33 3.6 9 0.2 Eye disorders Dry eye† 24 0 2.1 0 Infections and infestations Urinary tract infection 21 5 19 8 * Graded per NCI CTCAE v4.03 † Includes multiple terms Clinically relevant adverse reactions (<20%) include pyrexia (18%), dry skin (17%), vomiting (12%), pneumonitis/ILD (10%), hypothyroidism (10%), blurred vision (6%), infusion site extravasation (2%), and myositis (0.5%). 39 Reference ID: 5493485 Table 25: Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-A39 Laboratory Test* KEYTRUDA 200 mg every 3 weeks and Enfortumab Vedotin Chemotherapy All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Chemistry Increased aspartate aminotransferase 75 4.6 39 3.3 Increased creatinine 71 3.2 68 2.6 Hyperglycemia 66 14 54 4.7 Increased alanine aminotransferase 59 5 49 3.3 Hyponatremia 46 13 47 13 Hypophosphatemia 44 9 36 9 Hypoalbuminemia 39 1.8 35 0.5 Hypokalemia 26 5 16 3.1 Hyperkalemia 24 1.4 36 4.0 Hypercalcemia 21 1.2 14 0.2 Hematology Lymphopenia 58 15 59 17 Anemia 53 7 89 33 Neutropenia 30 9 80 50 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 407 to 439 patients) † Graded per NCI CTCAE v4.03 Cisplatin-ineligible patients with urothelial cancer in combination with enfortumab vedotin The safety of KEYTRUDA in combination with enfortumab vedotin was investigated in KEYNOTE-869 in patients with locally advanced or metastatic urothelial cancer and who are not eligible for cisplatin-based chemotherapy [see Clinical Studies (14.7)]. A total of 121 patients received KEYTRUDA 200 mg on Day 1, and enfortumab vedotin 1.25 mg/kg on days 1 and 8 of each 21-day cycle. The median duration of exposure to KEYTRUDA was 6.9 months (range 1 day to 29.6 months). Fatal adverse reactions occurred in 5% of patients treated with KEYTRUDA in combination with enfortumab vedotin, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis (0.8%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA and enfortumab vedotin. Serious adverse reactions in ≥2% of patients receiving KEYTRUDA in combination with enfortumab vedotin were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), hematuria (3.3%), pneumonia (3.3%), pneumonitis (3.3%), sepsis (3.3%), anemia (2.5%), diarrhea (2.5%), hypotension (2.5%), myasthenia gravis (2.5%), myositis (2.5%), and urinary retention (2.5%). Permanent discontinuation of KEYTRUDA occurred in 32% of patients. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis (5%), peripheral neuropathy (5%), rash (3.3%), and myasthenia gravis (2.5%). Dose interruptions of KEYTRUDA occurred in 69% of patients. The most common adverse reactions (≥2%) resulting in interruption of KEYTRUDA were peripheral neuropathy (22%), rash (17%), neutropenia (7%), fatigue (6%), diarrhea (5%), lipase increased (5%), acute kidney injury (3.3%), ALT increased (2.5%), and COVID-19 (2.5%). Tables 26 and 27 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with enfortumab vedotin in KEYNOTE-869. 40 Reference ID: 5493485 Table 26: Adverse Reactions Occurring in ≥20% of Patients Treated with KEYTRUDA in Combination with Enfortumab Vedotin in KEYNOTE-869 Adverse Reaction KEYTRUDA in combination with Enfortumab Vedotin n=121 All Grades* % Grade 3-4 % Skin and subcutaneous tissue disorders Rash† 71 21 Alopecia 52 0 Pruritus 40 3.3 Dry skin 21 0.8 Nervous system disorders Peripheral neuropathy‡ 65 3.3 Dysgeusia 35 0 Dizziness 23 0 General disorders and administration site conditions Fatigue 60 11 Peripheral edema 26 0 Investigations Weight loss 48 5 Gastrointestinal disorders Diarrhea 45 7 Nausea 36 0.8 Constipation 27 0 Metabolism and nutrition disorders Decreased appetite 38 0.8 Infections and infestations Urinary tract infection 30 12 Eye disorders Dry eye 25 0 Musculoskeletal and connective tissue disorders Arthralgia 23 1.7 * Graded per NCI CTCAE v4.03 † Includes: blister, conjunctivitis, dermatitis, dermatitis bullous, dermatitis exfoliative generalized, erythema, erythema multiforme, exfoliative rash, palmar-plantar erythrodysesthesia syndrome, pemphigoid, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular, skin exfoliation, and stomatitis ‡ Includes: dysesthesia, hypoesthesia, muscular weakness, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, and gait disturbance Clinically relevant adverse reactions (<20%) include vomiting (19.8%), fever (18%), hypothyroidism (11%), pneumonitis/ILD (10%), myositis (3.3%), myasthenia gravis (2.5%), and infusion site extravasation (0.8%). 41 Reference ID: 5493485 Table 27: Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients in KEYNOTE-869 Laboratory Test* KEYTRUDA 200 mg every 3 weeks and Enfortumab Vedotin All Grades† % Grades 3-4 % Chemistry Hyperglycemia 74 13 Increased aspartate aminotransferase 73 9 Increased creatinine 69 3.3 Hyponatremia 60 19 Increased alanine aminotransferase 60 7 Increased lipase 59 32 Hypoalbuminemia 59 4.2 Hypophosphatemia 51 15 Hypokalemia 35 8 Increased potassium 27 1.7 Increased calcium 27 4.2 Hematology Anemia 69 15 Lymphopenia 64 17 Neutropenia 32 12 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 114 to 121 patients) † Graded per NCI CTCAE v4.03 Platinum-Ineligible Patients with Urothelial Carcinoma The safety of KEYTRUDA was investigated in KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible [see Clinical Studies (14.7)]. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression. The median duration of exposure to KEYTRUDA was 2.8 months (range: 1 day to 15.8 months). KEYTRUDA was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients, and 5% of patients required at least one steroid dose ≥40 mg oral prednisone equivalent. Table 28 summarizes adverse reactions in patients on KEYTRUDA in KEYNOTE-052. 42 Reference ID: 5493485 Table 28: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-052 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=370 All Grades* (%) Grades 3–4 (%) General Fatigue† 38 6 Pyrexia 11 0.5 Weight loss 10 0 Musculoskeletal and Connective Tissue Musculoskeletal pain‡ 24 4.9 Arthralgia 10 1.1 Metabolism and Nutrition Decreased appetite 22 1.6 Hyponatremia 10 4.1 Gastrointestinal Constipation 21 1.1 Diarrhea§ 20 2.4 Nausea 18 1.1 Abdominal pain¶ 18 2.7 Elevated LFTs# 13 3.5 Vomiting 12 0 Skin and Subcutaneous Tissue RashÞ 21 0.5 Pruritus 19 0.3 Edema peripheralβ 14 1.1 Infections Urinary tract infection 19 9 Blood and Lymphatic System Anemia 17 7 Respiratory, Thoracic, and Mediastinal Cough 14 0 Dyspnea 11 0.5 Renal and Urinary Increased blood creatinine 11 1.1 Hematuria 13 3.0 * Graded per NCI CTCAE v4.0 † Includes fatigue, asthenia ‡ Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity, spinal pain § Includes diarrhea, colitis, enterocolitis, gastroenteritis, frequent bowel movements ¶ Includes abdominal pain, pelvic pain, flank pain, abdominal pain lower, tumor pain, bladder pain, hepatic pain, suprapubic pain, abdominal discomfort, abdominal pain upper # Includes autoimmune hepatitis, hepatitis, hepatitis toxic, liver injury, increased transaminases, hyperbilirubinemia, increased blood bilirubin, increased alanine aminotransferase, increased aspartate aminotransferase, increased hepatic enzymes, increased liver function tests Þ Includes dermatitis, dermatitis bullous, eczema, erythema, rash, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin reaction, dermatitis acneiform, seborrheic dermatitis, palmar-plantar erythrodysesthesia syndrome, rash generalized β Includes edema peripheral, peripheral swelling Previously Treated Urothelial Carcinoma The safety of KEYTRUDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma with disease progression following platinum-containing chemotherapy was investigated in KEYNOTE-045. KEYNOTE-045 was a multicenter, open-label, randomized (1:1), active-controlled trial in which 266 patients received KEYTRUDA 200 mg every 3 weeks or investigator’s choice of chemotherapy (n=255), consisting of paclitaxel (n=84), docetaxel (n=84) or vinflunine (n=87) [see Clinical Studies (14.7)]. Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. 43 Reference ID: 5493485 The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients who received KEYTRUDA and 1.5 months (range: 1 day to 14 months) in patients who received chemotherapy. KEYTRUDA was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis. Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-045. Table 29: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-045 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=266 Chemotherapy* n=255 All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%) General Fatigue‡ 38 4.5 56 11 Pyrexia 14 0.8 13 1.2 Musculoskeletal and Connective Tissue Musculoskeletal pain§ 32 3.0 27 2.0 Skin and Subcutaneous Tissue Pruritus 23 0 6 0.4 Rash¶ 20 0.4 13 0.4 Gastrointestinal Nausea 21 1.1 29 1.6 Constipation 19 1.1 32 3.1 Diarrhea# 18 2.3 19 1.6 Vomiting 15 0.4 13 0.4 Abdominal pain 13 1.1 13 2.7 Metabolism and Nutrition Decreased appetite 21 3.8 21 1.2 Infections Urinary tract infection 15 4.9 14 4.3 Respiratory, Thoracic and Mediastinal CoughÞ 15 0.4 9 0 Dyspneaß 14 1.9 12 1.2 Renal and Urinary Hematuria à 12 2.3 8 1.6 * Chemotherapy: paclitaxel, docetaxel, or vinflunine † Graded per NCI CTCAE v4.0 ‡ Includes asthenia, fatigue, malaise, lethargy § Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain ¶ Includes rash maculo-papular, rash, genital rash, rash erythematous, rash papular, rash pruritic, rash pustular, erythema, drug eruption, eczema, eczema asteatotic, dermatitis contact, dermatitis acneiform, dermatitis, seborrheic keratosis, lichenoid keratosis # Includes diarrhea, gastroenteritis, colitis, enterocolitis Þ Includes cough, productive cough ß Includes dyspnea, dyspnea exertional, wheezing à Includes blood urine present, hematuria, chromaturia 44 Reference ID: 5493485 Table 30: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Urothelial Carcinoma Patients Receiving KEYTRUDA in KEYNOTE-045 Laboratory Test* KEYTRUDA 200 mg every 3 weeks Chemotherapy All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Chemistry Hyperglycemia 52 8 60 7 Anemia 52 13 68 18 Lymphopenia 45 15 55 26 Hypoalbuminemia 43 1.7 50 3.8 Hyponatremia 37 9 47 13 Increased alkaline phosphatase 37 7 33 4.9 Increased creatinine 35 4.4 28 2.9 Hypophosphatemia 29 8 34 14 Increased AST 28 4.1 20 2.5 Hyperkalemia 28 0.8 27 6 Hypocalcemia 26 1.6 34 2.1 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 240 to 248 patients) and chemotherapy (range: 238 to 244 patients); phosphate decreased: KEYTRUDA n=232 and chemotherapy n=222. † Graded per NCI CTCAE v4.0 BCG-unresponsive High-risk NMIBC The safety of KEYTRUDA was investigated in KEYNOTE-057, a multicenter, open-label, single-arm trial that enrolled 148 patients with high-risk non-muscle invasive bladder cancer (NMIBC), 96 of whom had BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression. The median duration of exposure to KEYTRUDA was 4.3 months (range: 1 day to 25.6 months). KEYTRUDA was discontinued due to adverse reactions in 11% of patients. The most common adverse (>1%) reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of KEYTRUDA-treated patients. The most frequent serious adverse reactions (≥2%) in KEYTRUDA-treated patients were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-057. 45 Reference ID: 5493485 Table 31: Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-057 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=148 All Grades* (%) Grades 3–4 (%) General Fatigue† 29 0.7 Peripheral edema‡ 11 0 Gastrointestinal Diarrhea§ 24 2.0 Nausea 13 0 Constipation 12 0 Skin and Subcutaneous Tissue Rash¶ 24 0.7 Pruritus 19 0.7 Musculoskeletal and Connective Tissue Musculoskeletal pain# 19 0 Arthralgia 14 1.4 Renal and Urinary Hematuria 19 1.4 Respiratory, Thoracic, and Mediastinal CoughÞ 19 0 Infections Urinary tract infection 12 2.0 Nasopharyngitis 10 0 Endocrine Hypothyroidism 11 0 * Graded per NCI CTCAE v4.03 † Includes asthenia, fatigue, malaise ‡ Includes edema peripheral, peripheral swelling § Includes diarrhea, gastroenteritis, colitis ¶ Includes rash maculo-papular, rash, rash erythematous, rash pruritic, rash pustular, erythema, eczema, eczema asteatotic, lichenoid keratosis, urticaria, dermatitis # Includes back pain, myalgia, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, neck pain Þ Includes cough, productive cough Table 32: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of BCG-unresponsive NMIBC Patients Receiving KEYTRUDA in KEYNOTE-057 Laboratory Test* KEYTRUDA 200 mg every 3 weeks All Grades† (%) Grades 3-4 (%) Chemistry Hyperglycemia 59 7 Increased ALT 25 2.7 Hyponatremia 24 7 Hypophosphatemia 24 6 Hypoalbuminemia 24 1.4 Hyperkalemia 23 1.4 Hypocalcemia 22 0.7 Increased AST 20 2.7 Increased creatinine 20 0.7 Hematology Anemia 35 1.4 Lymphopenia 29 1.6 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 124 to 147 patients) † Graded per NCI CTCAE v4.03 46 Reference ID: 5493485 Microsatellite Instability-High or Mismatch Repair Deficient Cancer The safety of KEYTRUDA was investigated in 504 patients with MSI-H or dMMR cancer enrolled in KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051 [see Clinical Studies (14.8)]. The median duration of exposure to KEYTRUDA was 6.2 months (range: 1 day to 53.5 months). Adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer Among the 153 patients with MSI-H or dMMR CRC enrolled in KEYNOTE-177 [see Clinical Studies (14.9)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 30.6 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Gastric Cancer First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma The safety of KEYTRUDA was evaluated in 433 patients with HER2-positive gastric or GEJ cancer enrolled in KEYNOTE-811, which included 217 patients treated with KEYTRUDA 200 mg, trastuzumab, and CAPOX (n=189) or FP (n=28) every 3 weeks, compared to 216 patients treated with placebo, trastuzumab, and CAPOX (n=187) or FP (n=29) every 3 weeks [see Clinical Studies (14.10)]. The median duration of exposure to KEYTRUDA was 5.8 months (range: 1 day to 17.7 months). The study population characteristics were: median age of 63 years (range: 19 to 84), 43% age 65 or older; 81% male; 58% White, 35% Asian, and 0.9% Black; 44% ECOG PS of 0 and 56% ECOG PS of 1. KEYTRUDA and placebo were discontinued due to adverse reactions in 6% of patients in each arm. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 58% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (18%), thrombocytopenia (12%), diarrhea (6%), anemia (3.7%), hypokalemia (3.7%), fatigue/asthenia (3.2%), decreased appetite (3.2%), increased AST (2.8%), increased blood bilirubin (2.8%), pneumonia (2.8%), increased ALT (2.3%), and vomiting (2.3%). In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. There was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for increased creatinine (20% vs 10%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction Adenocarcinoma The safety of KEYTRUDA was evaluated in 1572 patients with HER2-negative gastric or GEJ cancer enrolled in KEYNOTE-859, which included 785 patients treated with KEYTRUDA 200 mg and FP (n=106) or CAPOX (n=674) every 3 weeks, compared to 787 patients who received placebo and FP (n=107) or CAPOX (n=679) every 3 weeks [see Clinical Studies (14.10)]. The median duration of exposure to KEYTRUDA was 6.2 months (range: 1 day to 33.7 months). Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA, including infection (2.3%) and thromboembolism (1.3%). 47 Reference ID: 5493485 Permanent discontinuation of KEYTRUDA due to adverse reactions occurred in 15% of patients. Adverse reaction resulting in permanent discontinuation of KEYTRUDA in ≥1% were infections (1.8%) and diarrhea (1.0%). Dosage interruptions of KEYTRUDA due to an adverse reaction occurred in 65% of patients. Adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (21%), thrombocytopenia (13%), diarrhea (5.5%), fatigue (4.8%), infection (4.8%), anemia (4.5%), increased AST (4.3%), increased ALT (3.8%), increased blood bilirubin (3.3%), white blood cell count decreased (2.2%), nausea (2%), palmar-plantar erythrodysesthesia syndrome (2%), and vomiting (2%). Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-859. Table 33: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-859 Adverse Reaction KEYTRUDA 200 mg every 3 weeks and FP or CAPOX n=785 Placebo and FP or CAPOX n=787 All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) Nervous System Peripheral neuropathy† 47 5 48 6 Gastrointestinal Nausea 46 3.7 46 4.4 Diarrhea 36 6 32 5 Vomiting 34 5 27 5 Abdominal Pain‡ 26 2.8 24 2.9 Constipation 22 0.5 21 0.8 General Fatigue§ 40 8 39 9 Metabolism and Nutrition Decreased appetite 29 3.3 29 2.5 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 25 3.1 22 1.8 Investigations Weight loss 20 2.8 19 2.7 * Graded per NCI CTCAE v4.03 † Includes dysesthesia, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy ‡ Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal tenderness, abdominal pain upper, epigastric discomfort, gastrointestinal pain § Includes asthenia, fatigue 48 Reference ID: 5493485 Table 34: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-859 Laboratory Test* KEYTRUDA 200 mg every 3 weeks and FP or CAPOX Placebo and FP or CAPOX All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Hematology Anemia 65 15 69 13 Thrombocytopenia 64 12 62 10 Neutropenia 63 25 58 20 Leukopenia 59 7 56 6 Lymphopenia 57 20 51 16 Chemistry Increased AST 57 4.7 48 3.6 Hypoalbuminemia 55 4.1 52 2.9 Hyperglycemia 53 6 52 4.6 Hypocalcemia 49 3.6 45 3.3 Increased alkaline phosphatase 48 6 41 5 Hyponatremia 40 13 40 12 Increased ALT 40 4.2 29 2.9 Hypokalemia 35 10 27 9 Bilirubin increased 32 5 30 5 Hypophosphatemia 30 10 27 8 Hypomagnesemia 29 0.3 22 0.7 Increased creatinine 21 3.5 18 1.7 Hyperkalemia 20 3.7 18 2.9 Increased INR 20 1.4 22 0 * Each test incidence is based on the number of patients who had both baseline and at least one on- study laboratory measurement available: KEYTRUDA/FP or CAPOX (range: 210 to 766 patients) and placebo/FP or CAPOX (range: 190 to 762 patients) † Graded per NCI CTCAE v4.03 Esophageal Cancer First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal Cancer/Gastroesophageal Junction The safety of KEYTRUDA, in combination with cisplatin and FU chemotherapy was investigated in KEYNOTE-590, a multicenter, double-blind, randomized (1:1), placebo-controlled trial for the first-line treatment in patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation [see Clinical Studies (14.11)]. A total of 740 patients received either KEYTRUDA 200 mg (n=370) or placebo (n=370) every 3 weeks for up to 35 cycles, both in combination with up to 6 cycles of cisplatin and up to 35 cycles of FU. The median duration of exposure was 5.7 months (range: 1 day to 26 months) in the KEYTRUDA combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm. KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 67% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (19%), fatigue/asthenia (8%), decreased white blood cell count (5%), pneumonia (5%), decreased appetite (4.3%), anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%), malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%), and nausea (2.2%). Tables 35 and 36 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-590. 49 Reference ID: 5493485 Table 35: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-590 Adverse Reaction KEYTRUDA 200 mg every 3 weeks Cisplatin FU n=370 Placebo Cisplatin FU n=370 All Grades* (%) Grades 3-4† (%) All Grades* (%) Grades 3-4† (%) Gastrointestinal Nausea 67 7 63 7 Constipation 40 0 40 0 Diarrhea 36 4.1 33 3 Vomiting 34 7 32 5 Stomatitis 27 6 26 3.8 General Fatigue‡ 57 12 46 9 Metabolism and Nutrition Decreased appetite 44 4.1 38 5 Investigations Weight loss 24 3.0 24 5 * Graded per NCI CTCAE v4.03 † One fatal event of diarrhea was reported in each arm. ‡ Includes asthenia, fatigue Table 36: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Esophageal Cancer Patients Receiving KEYTRUDA in KEYNOTE-590 Laboratory Test* KEYTRUDA 200 mg every 3 weeks Cisplatin FU Chemotherapy (Cisplatin and FU) All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Hematology Anemia 84 21 87 25 Neutropenia 77 44 73 41 Leukopenia 73 21 73 17 Lymphopenia 57 23 53 18 Thrombocytopenia 43 5 46 8 Chemistry Hyperglycemia 56 7 55 6 Hyponatremia 53 19 53 19 Hypoalbuminemia 53 2.8 52 2.3 Increased creatinine 45 2.5 42 2.5 Hypocalcemia 44 3.9 37 2 Hypophosphatemia 37 9 31 10 Hypokalemia 30 12 34 15 Increased alkaline phosphatase 29 1.9 29 1.7 Hyperkalemia 28 3.6 28 2.5 Increased AST 25 4.4 22 2.8 Increased ALT 23 3.6 18 1.7 * Each test incidence is based on the number of patients who had both baseline and at least one on- study laboratory measurement available: KEYTRUDA/cisplatin/FU (range: 353 to 365 patients) and placebo/cisplatin/FU (range: 347 to 359 patients) † Graded per NCI CTCAE v4.03 Previously Treated Recurrent Locally Advanced or Metastatic Esophageal Cancer Among the 314 patients with esophageal cancer enrolled in KEYNOTE-181 [see Clinical Studies (14.11)] treated with KEYTRUDA, the median duration of exposure to KEYTRUDA was 2.1 months (range: 1 day to 24.4 months). Patients with autoimmune disease or a medical condition that required 50 Reference ID: 5493485 immunosuppression were ineligible. Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Cervical Cancer FIGO 2014 Stage III-IVA Cervical Cancer with Chemoradiotherapy The safety of KEYTRUDA in combination with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) was investigated in KEYNOTE-A18, a placebo-controlled, randomized (1:1), multicenter, double-blind trial including 594 patients with FIGO 2014 Stage III-IVA cervical cancer [see Clinical Studies (14.12)]. Two hundred ninety-two patients received KEYTRUDA in combination with chemoradiotherapy and 302 patients received placebo in combination with chemoradiotherapy. The median duration of exposure to KEYTRUDA was 12.1 months (range: 1 day to 27 months). Fatal adverse reactions occurred in 1.4% of patients receiving KEYTRUDA in combination with chemoradiotherapy, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemoradiotherapy. Serious adverse reactions occurring in ≥1% of patients included urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 7% of patients. The most common adverse reaction (≥1%) resulting in permanent discontinuation was diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 43% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were anemia (8%), COVID-19 (6%), SARS-CoV-2 test positive (3.1%), decreased neutrophil count (2.7%), diarrhea (2.7%), urinary tract infection (2.7%), and increased ALT (2.4%). Table 37 and Table 38 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-A18. Table 37: Adverse Reactions Occurring in ≥10% of Patients with FIGO 2014 Stage III-IVA Cervical Cancer Receiving KEYTRUDA in KEYNOTE-A18 Adverse Reaction KEYTRUDA 200 mg every 3 weeks and 400 mg every 6 weeks with chemoradiotherapy n=292 Placebo with chemoradiotherapy n=302 All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) Gastrointestinal Nausea 56 0 61 2.3 Diarrhea 50 3.8 50 4.3 Vomiting 33 1 34 1.7 Constipation 18 0 18 0.7 Abdominal pain 12 0.7 12 1.7 Infections Urinary tract infection† 32 4.1 31 4.6 General Fatigue‡ 26 1 27 1.3 Pyrexia 12 0.3 13 0 Endocrine Hypothyroidism§ 20 0.7 5 0 Hyperthyroidism 11 0.3 2.6 0 Metabolism and Nutrition Decreased appetite 17 0.7 17 0.3 Investigations Weight loss 17 1.4 18 1 51 Reference ID: 5493485 I I I I I I I I I I I I Renal and Urinary Dysuria 11 0.3 12 0 Skin and Subcutaneous Tissue Disorders Rash¶ 11 0.7 7 0.3 Reproductive System Pelvic pain 10 1 13 1.3 * Graded per NCI CTCAE v5.0 † Includes urinary tract infection, urinary tract infection pseudomonal, pyelonephritis acute, cystitis, Escherichia urinary tract infection ‡ Includes fatigue, asthenia § Includes hypothyroidism, autoimmune hypothyroidism ¶ Includes erythema multiforme, dermatitis, drug eruption, eczema, rash, skin exfoliation, dermatitis bullous, rash maculo-papular, lichen planus, dyshidrotic eczema, dermatitis acneiform Table 38: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with FIGO 2014 Stage III-IVA Cervical Cancer Receiving KEYTRUDA in KEYNOTE-A18 Laboratory Test* KEYTRUDA 200 mg every 3 weeks and 400 mg every 6 weeks with chemoradiotherapy Placebo with chemoradiotherapy All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%) Hematology Lymphopenia 99 96 99 92 Leukopenia 96 46 94 49 Anemia 88 31 81 25 Neutropenia 75 32 74 33 Thrombocytopenia 65 8 61 6 Chemistry Hypomagnesemia 59 4.2 63 3.4 Hyponatremia 54 3.8 47 4 Increased AST 45 1 39 1.7 Increased ALT 44 2.1 44 1 Hypocalcemia 43 4.8 40 4.3 Hypokalemia 42 14 38 10 Increased creatinine 41 6 43 6 Hypoalbuminemia 37 0.7 35 1.7 Increased alkaline phosphatase 34 0.3 33 0.3 * Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: KEYTRUDA + chemoradiotherapy (range: 286 to 291 patients) and placebo + chemoradiotherapy (range: 298 to 300 patients) † Graded per NCI CTCAE v5.0 Persistent, Recurrent, or Metastatic Cervical Cancer The safety of KEYTRUDA in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826, a multicenter, double-blind, randomized (1:1), placebo-controlled trial in patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent [see Clinical Studies (14.12)]. A total of 616 patients, regardless of tumor PD-L1 expression, received KEYTRUDA 200 mg and chemotherapy with or without bevacizumab (n=307) every 3 weeks or placebo and chemotherapy with or without bevacizumab (n=309) every 3 weeks. The median duration of exposure to KEYTRUDA was 9.9 months (range: 1 day to 26 months). Fatal adverse reactions occurred in 4.6% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab, including 3 cases of hemorrhage, 2 cases of sepsis, 2 cases 52 Reference ID: 5493485 due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab. Serious adverse reactions in ≥3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), acute kidney injury (3.3%), and sepsis (3.3%). KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was colitis (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 66% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were thrombocytopenia (15%), neutropenia (14%), anemia (11%), increased ALT (6%), leukopenia (5%), fatigue/asthenia (4.2%), urinary tract infection (3.6%), increased AST (3.3%), pyrexia (3.3%), diarrhea (2.6%), acute kidney injury (2.6%), increased blood creatinine (2.6%), colitis (2.3%), decreased appetite (2%), and cough (2%). For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common (≥20%) adverse reactions were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea (41%), neutropenia (41%), diarrhea (39%), hypertension (35%), thrombocytopenia (35%), constipation (31%), arthralgia (31%), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%). Table 39 and Table 40 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-826. Table 39: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-826 Adverse Reaction KEYTRUDA 200 mg every 3 weeks and chemotherapy* with or without bevacizumab n=307 Placebo and chemotherapy* with or without bevacizumab n=309 All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%) Nervous System Peripheral neuropathy‡ 58 4.2 57 6 Skin and Subcutaneous Tissue Alopecia 56 0 58 0 Rash§ 22 3.6 15 0.3 General Fatigue¶ 47 7 46 6 Gastrointestinal Nausea 40 2 44 1.6 Diarrhea 36 2 30 2.6 Constipation 28 0.3 33 1 Vomiting 26 2.6 27 1.9 Musculoskeletal and Connective Tissue Arthralgia 27 0.7 26 1.3 Vascular Hypertension 24 9 23 11 Infections Urinary tract infection 24 9 26 8 * Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) † Graded per NCI CTCAE v4.0 ‡ Includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia § Includes rash, rash maculo-papular, rash erythematous, rash macular, rash papular, rash pruritic, rash pustular ¶ Includes fatigue, asthenia 53 Reference ID: 5493485 Table 40: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-826 Laboratory Test* KEYTRUDA 200 mg every 3 weeks and chemotherapy† with or without bevacizumab n=307 Placebo and chemotherapy† with or without bevacizumab n=309 All Grades‡ (%) Grades 3-4 (%) All Grades‡ (%) Grades 3-4 (%) Hematology Anemia 80 35 77 33 Leukopenia 76 27 69 19 Neutropenia 73 43 62 32 Lymphopenia 64 35 59 35 Thrombocytopenia 57 19 53 15 Chemistry Hyperglycemia 51 4.7 46 2.3 Hypoalbuminemia 46 1.4 37 5 Hyponatremia 39 14 38 11 Increased ALT 40 7 38 6 Increased AST 40 6 36 3.0 Increased alkaline phosphatase 38 3.4 40 2.3 Hypocalcemia 37 4.1 31 5 Increased creatinine 34 5 32 6 Hypokalemia 29 7 26 7 Hyperkalemia 23 3.7 27 4.7 Hypercalcemia 21 1.0 20 1.3 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA plus chemotherapy (range: 296 to 301 patients) and placebo plus chemotherapy (range: 299 to 302 patients) † Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) ‡ Graded per NCI CTCAE v4.0 Previously Treated Recurrent or Metastatic Cervical Cancer Among the 98 patients with cervical cancer enrolled in Cohort E of KEYNOTE-158 [see Clinical Studies (14.12)], the median duration of exposure to KEYTRUDA was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. KEYTRUDA was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%). Tables 41 and 42 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-158. 54 Reference ID: 5493485 Table 41: Adverse Reactions Occurring in ≥10% of Patients with Cervical Cancer in KEYNOTE-158 Adverse Reaction KEYTRUDA 200 mg every 3 weeks N=98 All Grades* (%) Grades 3–4 (%) General Fatigue† 43 5 Pain‡ 22 2.0 Pyrexia 19 1.0 Edema peripheral§ 15 2.0 Musculoskeletal and Connective Tissue Musculoskeletal pain¶ 27 5 Gastrointestinal Diarrhea# 23 2.0 Abdominal painÞ 22 3.1 Nausea 19 0 Vomiting 19 1.0 Constipation 14 0 Metabolism and Nutrition Decreased appetite 21 0 Vascular Hemorrhageß 19 5 Infections UTIà 18 6 Infection (except UTI)è 16 4.1 Skin and Subcutaneous Tissue Rashð 17 2.0 Endocrine Hypothyroidism 11 0 Nervous System Headache 11 2.0 Respiratory, Thoracic and Mediastinal Dyspnea 10 1.0 * Graded per NCI CTCAE v4.0 † Includes asthenia, fatigue, lethargy, malaise ‡ Includes breast pain, cancer pain, dysesthesia, dysuria, ear pain, gingival pain, groin pain, lymph node pain, oropharyngeal pain, pain, pain of skin, pelvic pain, radicular pain, stoma site pain, toothache § Includes edema peripheral, peripheral swelling ¶ Includes arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, pain in extremity # Includes colitis, diarrhea, gastroenteritis Þ Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper ß Includes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal hemorrhage, uterine hemorrhage, vaginal hemorrhage à Includes bacterial pyelonephritis, pyelonephritis acute, urinary tract infection, urinary tract infection bacterial, urinary tract infection pseudomonal, urosepsis è Includes cellulitis, clostridium difficile infection, device-related infection, empyema, erysipelas, herpes virus infection, infected neoplasm, infection, influenza, lower respiratory tract congestion, lung infection, oral candidiasis, oral fungal infection, osteomyelitis, pseudomonas infection, respiratory tract infection, tooth abscess, upper respiratory tract infection, uterine abscess, vulvovaginal candidiasis ð Includes dermatitis, drug eruption, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash, rash generalized, rash maculo-papular 55 Reference ID: 5493485 Table 42: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with Cervical Cancer in KEYNOTE-158 Laboratory Test* KEYTRUDA 200 mg every 3 weeks All Grades† (%) Grades 3-4 (%) Hematology Anemia 54 24 Lymphopenia 45 9 Chemistry Hypoalbuminemia 44 5 Increased alkaline phosphatase 40 1.3 Hyponatremia 38 13 Hyperglycemia 38 1.3 Increased AST 34 3.9 Increased creatinine 32 5 Hypocalcemia 27 0 Increased ALT 21 3.9 Hypokalemia 20 6 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 76 to 79 patients) † Graded per NCI CTCAE v4.0 Other laboratory abnormalities occurring in ≥10% of patients receiving KEYTRUDA were hypophosphatemia (19% all Grades; 6% Grades 3-4), increased INR (17% all Grades; 0% Grades 3-4), hypercalcemia (14% all Grades; 2.6% Grades 3-4), platelet count decreased (14% all Grades; 1.3% Grades 3-4), activated partial thromboplastin time prolonged (10% all Grades; 0% Grades 3-4), hypoglycemia (13% all Grades; 1.3% Grades 3-4), white blood cell decreased (13% all Grades; 2.6% Grades 3-4), and hyperkalemia (13% all Grades; 1.3% Grades 3-4). HCC Previously Treated HCC The safety of KEYTRUDA was investigated in KEYNOTE-394, a multicenter, double-blind, randomized, placebo-controlled trial that enrolled patients with previously treated HCC. Patients were randomized (2:1) and received KEYTRUDA 200 mg (n=299) or placebo (n=153) intravenously every 3 weeks for up to 35 cycles [see Clinical Studies (14.13)]. The median duration of exposure was 3.3 months (range: 1 day to 27.3 months) in the KEYTRUDA arm and 2.2 months (range: 1 day to 15.5 months) in the placebo arm. KEYTRUDA was discontinued due to adverse reactions in 13% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). Adverse reactions leading to interruption of KEYTRUDA occurred in 26% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were increased blood bilirubin (9%), increased AST (5%), and increased ALT (2%). Tables 43 and 44 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-394. 56 Reference ID: 5493485 Table 43: Adverse Reactions Occurring in ≥10% of Patients with HCC Receiving KEYTRUDA in KEYNOTE-394 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=299 Placebo n=153 All Grades* (%) Grades 3-5 (%) All Grades* (%) Grades 3-5 (%) General Pyrexia 18 0.7 14 0 Skin and Subcutaneous Tissue Rash† 18 0.7 7 0 Pruritus 12 0 4 0 Gastrointestinal Diarrhea 16 1.7 9 0 Metabolism and Nutrition Decreased appetite 15 0.3 9 0 Infections Upper respiratory tract infection 11 1.0 7 0.7 Respiratory, Thoracic, and Mediastinal Cough 11 0 9 0 Endocrine Hypothyroidism 10 0 7 0 * Graded per NCI CTCAE v4.03 † Includes dermatitis, dermatitis allergic, dermatitis bullous, rash, rash erythematous, rash maculo-papular, rash pustular, and blister. Table 44: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients with HCC Receiving KEYTRUDA in KEYNOTE-394 Laboratory Test* KEYTRUDA Placebo All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Chemistry Increased AST 54 14 44 12 Increased bilirubin 47 11 36 7 Increased ALT 47 7 32 4.6 Increased gamma-glutamyl transferase (GGT) 40 20 39 15 Hypoalbuminemia 40 0.7 20 0.7 Increased alkaline phosphatase 39 4.1 34 4 Hyperglycemia 36 3.3 26 1.4 Hyponatremia 36 11 28 5 Hypophosphatemia 30 6 17 4 Hypocalcemia 24 1.4 15 0.7 Hematology Lymphopenia 44 11 34 4.6 Anemia 36 7 30 3.3 Decreased platelets 32 4.7 29 2 Leukopenia 30 1.3 21 0.7 Neutropenia 25 4.4 21 2 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 223 to 297 patients) and placebo (range: 144 to 151 patients). † Graded per NCI CTCAE v4.03 BTC The safety of KEYTRUDA in combination with gemcitabine and cisplatin, was investigated in KEYNOTE-966, a multicenter, double-blind, randomized, placebo-controlled trial in patients with locally advanced unresectable or metastatic BTC who had not received prior systemic therapy in the advanced disease setting [see Clinical Studies (14.14)]. A total of 1063 patients received either KEYTRUDA 200 mg plus gemcitabine and cisplatin chemotherapy (n=529) or placebo plus gemcitabine and cisplatin chemotherapy (n=534) every 3 weeks. 57 Reference ID: 5493485 The median duration of exposure to KEYTRUDA was 6 months (range: 1 day to 28 months). KEYTRUDA was discontinued for adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%). In the KEYTRUDA plus chemotherapy versus placebo plus chemotherapy arms, there was a difference of ≥5% incidence in adverse reactions between patients treated with KEYTRUDA versus placebo for pyrexia (26% vs 20%), rash (21% vs 13%), pruritus (15% vs 10%), and hypothyroidism (9% vs. 2.6%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. There was a difference of ≥5% incidence in laboratory abnormalities between patients treated with KEYTRUDA plus chemotherapy versus placebo plus chemotherapy for decreased lymphocytes (69% vs 61%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms. MCC Among the 105 patients with MCC enrolled in KEYNOTE-017 and KEYNOTE-913 [see Clinical Studies (14.15)], the median duration of exposure to KEYTRUDA was 6.3 months (range 1 day to 28 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Adverse reactions occurring in patients with MCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included increased lipase (17%). RCC In combination with axitinib in the first-line treatment of advanced RCC (KEYNOTE-426) The safety of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 [see Clinical Studies (14.16)]. Patients with medical conditions that required systemic corticosteroids or other immunosuppressive medications or had a history of severe autoimmune disease other than type 1 diabetes, vitiligo, Sjogren’s syndrome, and hypothyroidism stable on hormone replacement were ineligible. Patients received KEYTRUDA 200 mg intravenously every 3 weeks and axitinib 5 mg orally twice daily, or sunitinib 50 mg once daily for 4 weeks and then off treatment for 2 weeks. The median duration of exposure to the combination therapy of KEYTRUDA and axitinib was 10.4 months (range: 1 day to 21.2 months). The study population characteristics were: median age of 62 years (range: 30 to 89), 40% age 65 or older; 71% male; 80% White; and 80% Karnofsky Performance Status (KPS) of 90-100 and 20% KPS of 70-80. Fatal adverse reactions occurred in 3.3% of patients receiving KEYTRUDA in combination with axitinib. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier’s gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure. Serious adverse reactions occurred in 40% of patients receiving KEYTRUDA in combination with axitinib. Serious adverse reactions in ≥1% of patients receiving KEYTRUDA in combination with axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction of either KEYTRUDA or axitinib occurred in 31% of patients; 13% KEYTRUDA only, 13% axitinib only, and 8% both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of KEYTRUDA, axitinib, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of KEYTRUDA infusions due to infusion-related reactions, occurred in 76% of patients receiving 58 Reference ID: 5493485 KEYTRUDA in combination with axitinib. This includes interruption of KEYTRUDA in 50% of patients. Axitinib was interrupted in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (>10%) resulting in interruption of KEYTRUDA were hepatotoxicity (14%) and diarrhea (11%), and the most common adverse reactions (>10%) resulting in either interruption or reduction of axitinib were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA and axitinib were diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. Twenty-seven percent (27%) of patients treated with KEYTRUDA in combination with axitinib received an oral prednisone dose equivalent to ≥40 mg daily for an immune-mediated adverse reaction. Tables 45 and 46 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in at least 20% of patients treated with KEYTRUDA and axitinib in KEYNOTE-426. Table 45: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426 Adverse Reaction KEYTRUDA 200 mg every 3 weeks and Axitinib n=429 Sunitinib n=425 All Grades* (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Diarrhea† 56 11 45 5 Nausea 28 0.9 32 0.9 Constipation 21 0 15 0.2 General Fatigue/Asthenia 52 5 51 10 Vascular Hypertension‡ 48 24 48 20 Hepatobiliary Hepatotoxicity§ 39 20 25 4.9 Endocrine Hypothyroidism 35 0.2 32 0.2 Metabolism and Nutrition Decreased appetite 30 2.8 29 0.7 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 28 5 40 3.8 Stomatitis/Mucosal inflammation 27 1.6 41 4 Rash¶ 25 1.4 21 0.7 Respiratory, Thoracic and Mediastinal Dysphonia 25 0.2 3.3 0 Cough 21 0.2 14 0.5 * Graded per NCI CTCAE v4.03 † Includes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, enterocolitis hemorrhagic ‡ Includes hypertension, blood pressure increased, hypertensive crisis, labile hypertension § Includes ALT increased, AST increased, autoimmune hepatitis, blood bilirubin increased, drug- induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased ¶ Includes rash, butterfly rash, dermatitis, dermatitis acneform, dermatitis atopic, dermatitis bullous, dermatitis contact, exfoliative rash, genital rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, seborrheic dermatitis, skin discoloration, skin exfoliation, perineal rash 59 Reference ID: 5493485 Table 46: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Axitinib in KEYNOTE-426 Laboratory Test* KEYTRUDA 200 mg every 3 weeks and Axitinib Sunitinib All Grades† % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 62 9 54 3.2 Increased ALT 60 20 44 5 Increased AST 57 13 56 5 Increased creatinine 43 4.3 40 2.4 Hyponatremia 35 8 29 8 Hyperkalemia 34 6 22 1.7 Hypoalbuminemia 32 0.5 34 1.7 Hypercalcemia 27 0.7 15 1.9 Hypophosphatemia 26 6 49 17 Increased alkaline phosphatase 26 1.7 30 2.7 Hypocalcemia‡ 22 0.2 29 0.7 Blood bilirubin increased 22 2.1 21 1.9 Activated partial thromboplastin time prolonged§ 22 1.2 14 0 Hematology Lymphopenia 33 11 47 9 Anemia 29 2.1 65 8 Thrombocytopenia 27 1.4 78 14 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA/axitinib (range: 342 to 425 patients) and sunitinib (range: 345 to 421 patients). † Graded per NCI CTCAE v4.03 ‡ Corrected for albumin § Two patients with a Grade 3 elevated activated partial thromboplastin time prolonged (aPTT) were also reported as having an adverse reaction of hepatotoxicity. In combination with lenvatinib in the first-line treatment of advanced RCC (KEYNOTE-581) The safety of KEYTRUDA was evaluated in KEYNOTE-581 [see Clinical Studies (14.16)]. Patients received KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily (n=352), or lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340). The median duration of exposure to the combination therapy of KEYTRUDA and lenvatinib was 17 months (range: 0.1 to 39). Fatal adverse reactions occurred in 4.3% of patients treated with KEYTRUDA in combination with lenvatinib, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm, and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of either of KEYTRUDA, lenvatinib or both due to an adverse reaction occurred in 37% of patients receiving KEYTRUDA in combination with lenvatinib; 29% KEYTRUDA only, 26% lenvatinib only, and 13% both. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA, lenvatinib, or the combination were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of KEYTRUDA, lenvatinib, or both due to an adverse reaction occurred in 78% of patients receiving KEYTRUDA in combination with lenvatinib. KEYTRUDA was interrupted in 55% of 60 Reference ID: 5493485 patients and both drugs were interrupted in 39% of patients. The most common adverse reactions (≥3%) resulting in interruption of KEYTRUDA were diarrhea (10%), hepatotoxicity (8%), fatigue (7%), lipase increased (5%), amylase increased (4%), musculoskeletal pain (3%), hypertension (3%), rash (3%), acute kidney injury (3%), and decreased appetite (3%). Fifteen percent (15%) of patients treated with KEYTRUDA in combination with lenvatinib received an oral prednisone equivalent to ≥40 mg daily for an immune-mediated adverse reaction. Tables 47 and 48 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in ≥20% of patients treated with KEYTRUDA and lenvatinib in KEYNOTE-581. Table 47: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Lenvatinib in KEYNOTE-581 Adverse Reaction KEYTRUDA 200 mg every 3 weeks with Lenvatinib N=352 Sunitinib 50 mg N=340 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue* 63 9 56 8 Gastrointestinal Diarrhea† 62 10 50 6 Stomatitis‡ 43 2 43 2 Nausea 36 3 33 1 Abdominal pain§ 27 2 18 1 Vomiting 26 3 20 1 Constipation 25 1 19 0 Musculoskeletal and Connective Tissue Musculoskeletal disorders¶ 58 4 41 3 Endocrine Hypothyroidism# 57 1 32 0 Vascular HypertensionÞ 56 29 43 20 Hemorrhagic eventsß 27 5 26 4 Metabolism Decreased appetiteà 41 4 31 1 Skin and Subcutaneous Tissue Rashè 37 5 17 1 Palmar-plantar erythrodysesthesia syndromeð 29 4 38 4 Investigations Weight loss 30 8 9 0.3 Respiratory, Thoracic and Mediastinal Dysphonia 30 0 4 0 Renal and Urinary Proteinuriaø 30 8 13 3 Acute kidney injuryý 21 5 16 2 Hepatobiliary Hepatotoxicity£ 25 9 21 5 Nervous System Headache 23 1 16 1 * Includes asthenia, fatigue, lethargy, malaise † Includes diarrhea, gastroenteritis ‡ Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, stomatitis § Includes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastric discomfort, lower abdominal pain, upper abdominal pain ¶ Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, pain in jaw 61 Reference ID: 5493485 # Includes hypothyroidism, increased blood thyroid stimulating hormone, secondary hypothyroidism Þ Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, labile blood pressure ß Includes all hemorrhage terms. Hemorrhage terms that occurred in 1 or more subjects in either treatment group include Anal hemorrhage, aneurysm ruptured, blood blister, blood loss anemia, blood urine present, catheter site hematoma, cerebral microhemorrhage, conjunctival hemorrhage, contusion, diarrhea hemorrhagic, disseminated intravascular coagulation, ecchymosis, epistaxis, eye hemorrhage, gastric hemorrhage, gastritis hemorrhagic, gingival bleeding, hemorrhage urinary tract, hemothorax, hematemesis, hematoma, hematochezia, hematuria, hemoptysis, hemorrhoidal hemorrhage, increased tendency to bruise, injection site hematoma, injection site hemorrhage, intra-abdominal hemorrhage, lower gastrointestinal hemorrhage, Mallory-Weiss syndrome, melaena, petechiae, rectal hemorrhage, renal hemorrhage, retroperitoneal hemorrhage, small intestinal hemorrhage, splinter hemorrhages, subcutaneous hematoma, subdural hematoma, subarachnoid hemorrhage, thrombotic thrombocytopenic purpura, tumor hemorrhage, traumatic hematoma, upper gastrointestinal hemorrhage à Includes decreased appetite, early satiety è Includes genital rash, infusion site rash, penile rash, perineal rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular ð Includes palmar erythema, palmar-plantar erythrodysesthesia syndrome, plantar erythema ø Includes hemoglobinuria, nephrotic syndrome, proteinuria ý Includes acute kidney injury, azotemia, blood creatinine increased, creatinine renal clearance decreased, hypercreatininemia, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, and nephropathy toxic £ Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased, gamma-glutamyltransferase increased Clinically relevant adverse reactions (<20%) that occurred in patients receiving KEYTRUDA with lenvatinib were myocardial infarction (3%) and angina pectoris (1%). 62 Reference ID: 5493485 Table 48: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% (All Grades) of Patients Receiving KEYTRUDA with Lenvatinib in KEYNOTE-581 Laboratory Test* KEYTRUDA 200 mg every 3 weeks with Lenvatinib Sunitinib 50 mg All Grades %† Grade 3-4 %† All Grades %† Grade 3-4 %† Chemistry Hypertriglyceridemia 80 15 71 15 Hypercholesterolemia 64 5 43 1 Increased lipase 61 34 59 28 Increased creatinine 61 5 61 2 Increased amylase 59 17 41 9 Increased AST 58 7 57 3 Hyperglycemia 55 7 48 3 Increased ALT 52 7 49 4 Hyperkalemia 44 9 28 6 Hypoglycemia 44 2 27 1 Hyponatremia 41 12 28 9 Decreased albumin 34 0.3 22 0 Increased alkaline phosphatase 32 4 32 1 Hypocalcemia 30 2 22 1 Hypophosphatemia 29 7 50 8 Hypomagnesemia 25 2 15 3 Increased creatine phosphokinase 24 6 36 5 Hypermagnesemia 23 2 22 3 Hypercalcemia 21 1 11 1 Hematology Lymphopenia 54 9 66 15 Thrombocytopenia 39 2 73 13 Anemia 38 3 66 8 Leukopenia 34 1 77 8 Neutropenia 31 4 72 16 * With at least one Grade increase from baseline † Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post- baseline laboratory measurement for each parameter: KEYTRUDA with lenvatinib (range: 343 to 349 patients) and sunitinib (range: 329 to 335 patients). Grade 3 and 4 increased ALT or AST was seen in 9% of patients. Grade ≥2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg daily oral prednisone equivalent. Recurrence of Grade ≥2 increased ALT or AST was observed on rechallenge in 10 patients receiving both KEYTRUDA and lenvatinib (n=38) and was not observed on rechallenge with KEYTRUDA alone (n=3). Adjuvant treatment of RCC The safety of KEYTRUDA as a single agent was investigated in KEYNOTE-564, a randomized (1:1) double-blind placebo-controlled trial in which 984 patients who had undergone nephrectomy for RCC received 200 mg of KEYTRUDA by intravenous infusion every 3 weeks (n=488) or placebo (n=496) for up to one year [see Clinical Studies (14.16)]. The median duration of exposure to KEYTRUDA was 11.1 months (range: 1 day to 14.3 months). Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Serious adverse reactions occurred in 20% of these patients receiving KEYTRUDA. Serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% of those treated with KEYTRUDA, including one case of pneumonia. Discontinuation of KEYTRUDA due to an adverse reaction occurred in 21% of patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 26% of patients; the most common (≥1%) were increased AST (2.3%), arthralgia (1.6%), hypothyroidism (1.6%), diarrhea (1.4%), 63 Reference ID: 5493485 increased ALT (1.4%), fatigue (1.4%), rash, decreased appetite, and vomiting (1% each). Tables 49 and 50 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in KEYNOTE-564. Table 49: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving KEYTRUDA in KEYNOTE-564 Adverse Reaction KEYTRUDA 200 mg every 3 weeks n=488 Placebo n=496 All Grades† (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Musculoskeletal and Connective Tissue Musculoskeletal pain‡ 41 1.2 36 0.6 General Fatigue§ 40 1.2 31 0.2 Skin and Subcutaneous Tissue Rash¶ 30 1.4 15 0.4 Pruritus 23 0.2 13 0 Gastrointestinal Diarrhea# 27 2.7 23 0.2 Nausea 16 0.4 10 0 Abdominal painÞ 11 0.4 13 0.2 Endocrine Hypothyroidism 21 0.2 3.6 0 Hyperthyroidism 12 0.2 0.2 0 Respiratory, Thoracic and Mediastinal Cough ß 17 0 12 0 Nervous System Headacheà 15 0.2 13 0 Hepatobiliary Hepatotoxicityè 14 3.7 7 0.6 Renal and Urinary Acute kidney injuryð 13 1.2 10 0.2 * Adverse reactions occurring at same or higher incidence than in placebo arm † Graded per NCI CTCAE v4.0 ‡ Includes arthralgia, back pain, myalgia, arthritis, pain in extremity, neck pain, musculoskeletal pain, musculoskeletal stiffness, spinal pain, musculoskeletal chest pain, bone pain, musculoskeletal discomfort § Includes asthenia, fatigue ¶ Includes rash, rash maculo-papular, rash papular, skin exfoliation, lichen planus, rash erythematous, eczema, rash macular, dermatitis acneiform, dermatitis, rash pruritic, Stevens-Johnson Syndrome, eczema asteatotic, palmar-plantar erythrodysesthesia syndrome # Includes diarrhea, colitis, enterocolitis, frequent bowel movements, enteritis Þ Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort, gastrointestinal pain ß Includes upper-airway cough syndrome, productive cough, cough à Includes tension headache, headache, sinus headache, migraine with aura è Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, transaminases increased, gamma-glutamyltransferase increased, bilirubin conjugated increased ð Includes acute kidney injury, blood creatinine increased, renal failure, renal impairment, oliguria, glomerular filtration rate decreased, nephropathy toxic 64 Reference ID: 5493485 Table 50: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-564 Laboratory Test† KEYTRUDA 200 mg every 3 weeks Placebo All Grades‡ % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 48 8 45 4.5 Increased creatinine 39 1.1 28 0.2 Increased INR 29 1.0 20 0.9 Hyponatremia 21 3.3 13 1.9 Increased ALT 20 3.6 11 0.2 Hematology Anemia 28 0.5 20 0.4 * Laboratory abnormalities occurring at same or higher incidence than placebo † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA (range: 440 to 449 patients) and placebo (range: 461 to 469 patients); increased INR: KEYTRUDA n=199 and placebo n=224. ‡ Graded per NCI CTCAE v4.03 Endometrial Carcinoma Primary Advanced or Recurrent Endometrial Carcinoma The safety of KEYTRUDA in combination with chemotherapy (paclitaxel and carboplatin) was investigated in KEYNOTE-868, a randomized (1:1), multicenter, double-blind, placebo-controlled trial that enrolled patients with advanced or recurrent endometrial carcinoma [see Clinical Studies (14.17)]. A total of 759 patients received KEYTRUDA 200 mg every 3 weeks and chemotherapy for 6 cycles followed by KEYTRUDA 400 mg every 6 weeks for up to 14 cycles (n=382) or placebo and chemotherapy for 6 cycles followed by placebo for up to 14 cycles (n=377). The median duration of exposure to KEYTRUDA was 5.6 months (range: 1 day to 24.0 months). Serious adverse reactions occurred in 35% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 19% of patients receiving placebo in combination with chemotherapy. Fatal adverse reactions occurred in 1.6% of patients receiving KEYTRUDA in combination with chemotherapy, including COVID-19 (0.5%), and cardiac arrest (0.3%). KEYTRUDA was discontinued for an adverse reaction in 14% of patients. Chemotherapy dose reduction was required in 29% of patients receiving KEYTRUDA in combination with chemotherapy, compared to 23% of patients receiving placebo in combination with chemotherapy. There were no clinically meaningful differences in chemotherapy discontinuations or interruptions between arms. Adverse reactions occurring in patients treated with KEYTRUDA and chemotherapy were generally similar to those observed with KEYTRUDA alone or chemotherapy alone with the exception of rash (33% all Grades; 2.9% Grades 3-4). In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That Is pMMR or Not MSI-H. The safety of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775, a multicenter, open-label, randomized (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings [see Clinical Studies (14.17)]. Patients with endometrial carcinoma that is pMMR or not MSI-H received KEYTRUDA 200 mg every 3 weeks in combination with lenvatinib 20mg orally once daily (n=342) or received doxorubicin or paclitaxel (n=325). For patients with pMMR or not MSI-H tumor status, the median duration of study treatment was 7.2 months (range 1 day to 26.8 months) and the median duration of exposure to KEYTRUDA was 6.8 months (range: 1 day to 25.8 months). 65 Reference ID: 5493485 Fatal adverse reactions among these patients occurred in 4.7% of those treated with KEYTRUDA and lenvatinib, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of these patients receiving KEYTRUDA and lenvatinib. Serious adverse reactions (≥3%) were hypertension (4.4%) and urinary tract infections (3.2%). Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (≥1%) was increased ALT (1.2%). Dose interruptions of KEYTRUDA due to an adverse reaction occurred in 48% of these patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥3%) were diarrhea (8%), increased ALT (4.4%), increased AST (3.8%), and hypertension (3.5%). Tables 51 and 52 summarize adverse reactions and laboratory abnormalities, respectively, in patients on KEYTRUDA in combination with lenvatinib in KEYNOTE-775. Table 51: Adverse Reactions Occurring in ≥20% of Patients with Endometrial Carcinoma in KEYNOTE-775 Endometrial Carcinoma (pMMR or not MSI-H) Adverse Reaction KEYTRUDA 200 mg every 3 weeks and Lenvatinib n=342 Doxorubicin or Paclitaxel n=325 All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) Endocrine Hypothyroidism† 67 0.9 0.9 0 Vascular Hypertension‡ 67 39 6 2.5 Hemorrhagic events§ 25 2.6 15 0.9 General Fatigue¶ 58 11 54 6 Gastrointestinal Diarrhea# 55 8 20 2.8 Nausea 49 2.9 47 1.5 Vomiting 37 2.3 21 2.2 StomatitisÞ 35 2.6 26 1.2 Abdominal painß 34 2.6 21 1.2 Constipation 27 0 25 0.6 Musculoskeletal and Connective Tissue Musculoskeletal disordersà 53 5 27 0.6 Metabolism Decreased appetiteè 44 7 21 0 Investigations Weight loss 34 10 6 0.3 Renal and Urinary Proteinuriað 29 6 3.4 0.3 Infections Urinary tract infectionø 31 5 13 1.2 Nervous System Headache 26 0.6 9 0.3 Respiratory, Thoracic and Mediastinal Dysphonia 22 0 0.6 0 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesiaý 23 2.9 0.9 0 Rash£ 20 2.3 4.9 0 * Graded per NCI CTCAE v4.03 † Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, secondary hypothyroidism 66 Reference ID: 5493485 ‡ Includes hypertension, blood pressure increased, secondary hypertension, blood pressure abnormal, hypertensive encephalopathy, blood pressure fluctuation § Includes epistaxis, vaginal hemorrhage, hematuria, gingival bleeding, metrorrhagia, rectal hemorrhage, contusion, hematochezia, cerebral hemorrhage, conjunctival hemorrhage, gastrointestinal hemorrhage, hemoptysis, hemorrhage urinary tract, lower gastrointestinal hemorrhage, mouth hemorrhage, petechiae, uterine hemorrhage, anal hemorrhage, blood blister, eye hemorrhage, hematoma, hemorrhage intracranial, hemorrhagic stroke, melena, stoma site hemorrhage, upper gastrointestinal hemorrhage, wound hemorrhage, blood urine present, ecchymosis, hematemesis, hemorrhage subcutaneous, hepatic hematoma, injection site bruising, intestinal hemorrhage, laryngeal hemorrhage, pulmonary hemorrhage, subdural hematoma, umbilical hemorrhage, vessel puncture site bruise ¶ Includes fatigue, asthenia, malaise, lethargy # Includes diarrhea, gastroenteritis Þ Includes stomatitis, mucosal inflammation, oropharyngeal pain, aphthous ulcer, mouth ulceration, cheilitis, oral mucosal erythema, tongue ulceration ß Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, gastrointestinal pain, abdominal tenderness, epigastric discomfort à Includes arthralgia, myalgia, back pain, pain in extremity, bone pain, neck pain, musculoskeletal pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, non-cardiac chest pain, pain in jaw è Includes decreased appetite, early satiety ð Includes proteinuria, protein urine present, hemoglobinuria ø Includes urinary tract infection, cystitis, pyelonephritis ý Includes palmar-plantar erythrodysesthesia syndrome, palmar erythema, plantar erythema £ Includes rash, rash maculo-papular, rash pruritic, rash erythematous, rash macular, rash pustular, rash papular, rash vesicular, application site rash 67 Reference ID: 5493485 Table 52: Laboratory Abnormalities Worsened from Baseline* Occurring in ≥20% (All Grades) or ≥3% (Grades 3-4) of Patients with Endometrial Carcinoma in KEYNOTE-775 Endometrial Carcinoma (pMMR or not MSI-H) Laboratory Test† KEYTRUDA 200 mg every 3 weeks and Lenvatinib Doxorubicin or Paclitaxel All Grades‡ % Grades 3-4 % All Grades‡ % Grades 3-4 % Chemistry Hypertriglyceridemia 70 6 45 1.7 Hypoalbuminemia 60 2.7 42 1.6 Increased aspartate aminotransferase 58 9 23 1.6 Hyperglycemia 58 8 45 4.4 Hypomagnesemia 46 0 27 1.3 Increased alanine aminotransferase 55 9 21 1.2 Hypercholesteremia 53 3.2 23 0.7 Hyponatremia 46 15 28 7 Increased alkaline phosphatase 43 4.7 18 0.9 Hypocalcemia 40 4.7 21 1.9 Increased lipase 36 14 13 3.9 Increased creatinine 35 4.7 18 1.9 Hypokalemia 34 10 24 5 Hypophosphatemia 26 8 17 3.2 Increased amylase 25 7 8 1 Hyperkalemia 23 2.4 12 1.2 Increased creatine kinase 19 3.7 7 0 Increased bilirubin 18 3.6 6 1.6 Hematology Lymphopenia 51 18 66 23 Thrombocytopenia 50 8 30 4.7 Anemia 49 8 84 14 Leukopenia 43 3.5 83 43 Neutropenia 34 8 80 60 * With at least one grade increase from baseline † Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one post- baseline laboratory measurement for each parameter: KEYTRUDA and lenvatinib (range: 263 to 340 patients) and doxorubicin or paclitaxel (range: 240 to 322 patients). ‡ Graded per NCI CTCAE v4.03 As a Single Agent for the Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma Among the 90 patients with MSI-H or dMMR endometrial carcinoma enrolled in KEYNOTE-158 [see Clinical Studies (14.17)] treated with KEYTRUDA as a single agent, the median duration of exposure to KEYTRUDA was 8.3 months (range: 1 day to 26.9 months). Adverse reactions occurring in patients with endometrial carcinoma were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. TMB-H Cancer The safety of KEYTRUDA was investigated in 105 patients with TMB-H cancer enrolled in KEYNOTE-158 [see Clinical Studies (14.18)]. The median duration of exposure to KEYTRUDA was 4.9 months (range: 0.03 to 35.2 months). Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent. 68 Reference ID: 5493485 cSCC Among the 159 patients with advanced cSCC (recurrent or metastatic or locally advanced disease) enrolled in KEYNOTE-629 [see Clinical Studies (14.19)], the median duration of exposure to KEYTRUDA was 6.9 months (range 1 day to 28.9 months). Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in 2799 patients with melanoma or NSCLC treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%) and decreased sodium (10%). TNBC Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC The safety of KEYTRUDA in combination with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-522, a randomized (2:1), multicenter, double-blind, placebo-controlled trial in patients with newly diagnosed, previously untreated, high-risk early-stage TNBC. A total of 778 patients on the KEYTRUDA arm received at least 1 dose of KEYTRUDA in combination with neoadjuvant chemotherapy followed by KEYTRUDA as adjuvant treatment after surgery, compared to 389 patients who received at least 1 dose of placebo in combination with neoadjuvant chemotherapy followed by placebo as adjuvant treatment after surgery [see Clinical Studies (14.20)]. The median duration of exposure to KEYTRUDA 200 mg every 3 weeks was 13.3 months (range: 1 day to 21.9 months). Fatal adverse reactions occurred in 0.9% of patients receiving KEYTRUDA, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA. Serious adverse reactions in ≥2% of patients who received KEYTRUDA included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued for adverse reactions in 20% of patients. The most common adverse reactions (≥1%) resulting in permanent discontinuation of KEYTRUDA were increased ALT (2.7%), increased AST (1.5%), and rash (1%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 57% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (26%), thrombocytopenia (6%), increased ALT (6%), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia (2.8%), leukopenia (2.8%), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%). 69 Reference ID: 5493485 Tables 53 and 54 summarize the adverse reactions and laboratory abnormalities, respectively, in patients treated with KEYTRUDA in KEYNOTE-522. Table 53: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-522 Adverse Reaction KEYTRUDA 200 mg every 3 weeks with chemotherapy*/KEYTRUDA n=778 Placebo with chemotherapy*/Placebo n=389 All Grades† (%) Grades 3-4 (%) All Grades† (%) Grades 3-4 (%) General Fatigue‡ 70 8 66 3.9 Pyrexia 28 1.3 19 0.3 Gastrointestinal Nausea 67 3.7 66 1.8 Constipation 42 0 39 0.3 Diarrhea 41 3.2 34 1.8 Stomatitis§ 34 2.7 29 1 Vomiting 31 2.7 28 1.5 Abdominal pain¶ 24 0.5 23 0.8 Skin and Subcutaneous Tissue Alopecia 61 0 58 0 Rash# 52 5 41 0.5 Nervous System Peripheral neuropathyÞ 41 3.3 42 2.3 Headache 30 0.5 29 1 Musculoskeletal and Connective Tissue Arthralgia 29 0.5 31 0.3 Myalgia 20 0.5 19 0 Respiratory, Thoracic and Mediastinal Coughß 26 0.1 24 0 Metabolism and Nutrition Decreased appetite 23 0.9 17 0.3 Psychiatric Insomnia 21 0.5 19 0 * Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide † Graded per NCI CTCAE v4.0 ‡ Includes asthenia, fatigue § Includes aphthous ulcer, cheilitis, lip pain, lip ulceration, mouth ulceration, mucosal inflammation, oral mucosal eruption, oral pain, stomatitis, tongue blistering, tongue ulceration ¶ Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness # Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis exfoliative generalized, drug eruption, eczema, incision site rash, injection site rash, rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash rubelliform, skin exfoliation, skin toxicity, toxic skin eruption, urticaria, vasculitic rash, viral rash Þ Includes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy ß Includes cough, productive cough, upper-airway cough syndrome 70 Reference ID: 5493485 Table 54: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA in KEYNOTE-522 Laboratory Test* KEYTRUDA 200 mg every 3 weeks with chemotherapy†/KEYTRUDA Placebo with chemotherapy†/Placebo All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Hematology Anemia 97 22 96 19 Leukopenia 93 41 91 32 Neutropenia 88 62 89 62 Lymphopenia 79 28 74 22 Thrombocytopenia 57 10 56 8 Chemistry Increased ALT 70 9 67 3.9 Increased AST 65 6 56 1.5 Hyperglycemia 63 4.3 61 2.8 Increased alkaline phosphatase 37 1 35 0.5 Hyponatremia 35 9 25 4.6 Hypoalbuminemia 34 1.0 30 1.3 Hypocalcemia 31 2.2 28 3.1 Hypokalemia 31 6 22 2.8 Hypophosphatemia 20 6 15 4.2 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA in combination with chemotherapy followed by KEYTRUDA as a single agent (range: 762 to 777 patients) and placebo in combination with chemotherapy followed by placebo (range: 381 to 389 patients). † Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide † Graded per NCI CTCAE v4.0 Locally Recurrent Unresectable or Metastatic TNBC The safety of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355, a multicenter, double-blind, randomized (2:1), placebo-controlled trial in patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting [see Clinical Studies (14.20)]. A total of 596 patients (including 34 patients from a safety run-in) received KEYTRUDA 200 mg every 3 weeks in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin. The median duration of exposure to KEYTRUDA was 5.7 months (range: 1 day to 33.0 months). Fatal adverse reactions occurred in 2.5% of patients receiving KEYTRUDA in combination with chemotherapy, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin. Serious adverse reactions in ≥2% of patients were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued for adverse reactions in 11% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 50% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (≥2%) were neutropenia (22%), thrombocytopenia (14%), anemia (7%), increased ALT (6%), leukopenia (5%), increased AST (5%), decreased white blood cell count (3.9%), and diarrhea (2%). Tables 55 and 56 summarize the adverse reactions and laboratory abnormalities in patients on KEYTRUDA in KEYNOTE-355. 71 Reference ID: 5493485 Table 55: Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA with Chemotherapy in KEYNOTE-355 Adverse Reaction KEYTRUDA 200 mg every 3 weeks with chemotherapy n=596 Placebo every 3 weeks with chemotherapy n=281 All Grades* (%) Grades 3-4 (%) All Grades* (%) Grades 3-4 (%) General Fatigue† 48 5 49 4.3 Gastrointestinal Nausea 44 1.7 47 1.8 Diarrhea 28 1.8 23 1.8 Constipation 28 0.5 27 0.4 Vomiting 26 2.7 22 3.2 Skin and Subcutaneous Tissue Alopecia 34 0.8 35 1.1 Rash‡ 26 2 16 0 Respiratory, Thoracic and Mediastinal Cough§ 23 0 20 0.4 Metabolism and Nutrition Decreased appetite 21 0.8 14 0.4 Nervous System Headache¶ 20 0.7 23 0.7 * Graded per NCI CTCAE v4.03 † Includes fatigue and asthenia ‡ Includes rash, rash maculo-papular, rash pruritic, rash pustular, rash macular, rash papular, butterfly rash, rash erythematous, eyelid rash § Includes cough, productive cough, upper-airway cough syndrome ¶ Includes headache, migraine, tension headache Table 56: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Patients Receiving KEYTRUDA with Chemotherapy in KEYNOTE-355 Laboratory Test* KEYTRUDA 200 mg every 3 weeks with chemotherapy Placebo every 3 weeks with chemotherapy All Grades† % Grades 3-4 % All Grades† % Grades 3-4 % Hematology Anemia 90 20 85 19 Leukopenia 85 39 86 39 Neutropenia 78 50 79 53 Lymphopenia 73 28 71 19 Thrombocytopenia 54 19 53 21 Chemistry Increased ALT 60 11 58 8 Increased AST 57 9 55 6 Hyperglycemia 52 4.4 51 2.2 Hypoalbuminemia 36 2.0 32 2.2 Increased alkaline phosphatase 35 3.9 39 2.2 Hypocalcemia 29 3.3 27 1.8 Hyponatremia 28 5 26 6 Hypophosphatemia 21 7 18 4.8 Hypokalemia 20 4.4 18 4.0 * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: KEYTRUDA + chemotherapy (range: 566 to 592 patients) and placebo + chemotherapy (range: 269 to 280 patients). † Graded per NCI CTCAE v4.03 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of KEYTRUDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 72 Reference ID: 5493485 Gastrointestinal: Exocrine pancreatic insufficiency Hepatobiliary: sclerosing cholangitis 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. There are no available human data informing the risk of embryo-fetal toxicity. In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue (see Data). Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects of the PD-1 pathway on reproduction demonstrated that a central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering KEYTRUDA during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or of altering the normal immune response. 8.2 Lactation Risk Summary There are no data on the presence of pembrolizumab in either animal or human milk or its effects on the breastfed child or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to KEYTRUDA are unknown. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating KEYTRUDA [see Use in Specific Populations (8.1)]. Contraception KEYTRUDA can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose. 8.4 Pediatric Use The safety and effectiveness of KEYTRUDA as a single agent have been established in pediatric patients with melanoma, cHL, PMBCL, MCC, MSI-H or dMMR cancer, and TMB-H cancer. Use of KEYTRUDA in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1, 14.5, 14.6, 14.8, 14.15, 14.18)]. 73 Reference ID: 5493485 In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 pediatric patients aged 12 to 17 years) with advanced melanoma, lymphoma, or PD-L1 positive or MSI-H solid tumors received KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 25 months). Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults included pyrexia (33%), vomiting (29%), headache (25%), abdominal pain (23%), decreased lymphocyte count (13%), and decreased white blood cell count (11%). Laboratory abnormalities that occurred at a ≥10% higher rate in pediatric patients when compared to adults were leukopenia (30%), neutropenia (28%), thrombocytopenia (22%), and Grade 3 anemia (17%). The safety and effectiveness of KEYTRUDA in pediatric patients have not been established in the other approved indications [see Indications and Usage (1)]. 8.5 Geriatric Use Of 3781 patients with melanoma, NSCLC, HNSCC, or urothelial carcinoma who were treated with KEYTRUDA in clinical studies, 48% were 65 years and over and 17% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of 389 adult patients with cHL who were treated with KEYTRUDA in clinical studies, 46 (12%) were 65 years and over. Patients aged 65 years and over had a higher incidence of serious adverse reactions (50%) than patients aged younger than 65 years (24%). Clinical studies of KEYTRUDA in cHL did not include sufficient numbers of patients aged 65 years and over to determine whether effectiveness differs from that in younger patients. Of 506 adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC following complete resection and platinum-based chemotherapy who were treated with KEYTRUDA in KEYNOTE-091, 242 (48%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of 596 adult patients with TNBC who were treated with KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin in KEYNOTE-355, 137 (23%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of 406 adult patients with endometrial carcinoma who were treated with KEYTRUDA in combination with lenvatinib in KEYNOTE-775, 201 (50%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older. Of the 432 patients randomized to KEYTRUDA in combination with axitinib in the KEYNOTE-426 trial, 40% were 65 years or older. No overall difference in safety or efficacy was reported between patients who were ≥65 years of age and younger. Of 292 adult patients with FIGO 2014 Stage III-IVA cervical cancer who were treated with KEYTRUDA in combination with CRT in KEYNOTE-A18, 42 (14%) were 65 years and over. No overall differences in safety or efficacy were observed between elderly and younger patients. 11 DESCRIPTION Pembrolizumab is a programmed death receptor-1 (PD 1)-blocking antibody. Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells. KEYTRUDA (pembrolizumab) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous use. Each vial contains 100 mg of pembrolizumab in 4 mL of 74 Reference ID: 5493485 solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. In syngeneic mouse tumor models, combination treatment of a PD-1 blocking antibody and kinase inhibitor lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and reduced tumor growth compared to either treatment alone. 12.2 Pharmacodynamics There are no clinically significant exposure-response relationships for efficacy or safety at pembrolizumab dosages of 200 mg or 2 mg/kg every 3 weeks regardless of cancer type. There are no clinically significant exposure-response relationships for efficacy or safety at pembrolizumab dosages of 200 mg or 2 mg/kg every 3 weeks and 400 mg every 6 weeks in patients with solid tumors based on observed data in adult patients with melanoma. The exposure-response relationships for efficacy or safety at pembrolizumab dosages of 400 mg every 6 weeks in patients with classical Hodgkin lymphoma or mediastinal large B-cell lymphoma have not been fully characterized. 12.3 Pharmacokinetics The pharmacokinetics (PK) of pembrolizumab was characterized using a population PK analysis with concentration data collected from 2993 patients with various cancers who received pembrolizumab doses of 1 to 10 mg/kg every 2 weeks, 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.1-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks. Distribution The geometric mean value (CV%) for volume of distribution at steady state is 6.0 L (20%). Elimination Pembrolizumab clearance (CV%) is approximately 23% lower [geometric mean, 195 mL/day (40%)] at steady state than that after the first dose [252 mL/day (37%)]; this decrease in clearance with time is not considered clinically important. The terminal half-life (t1/2) is 22 days (32%). Specific Populations The following factors had no clinically important effect on the CL of pembrolizumab: age (range: 15 to 94 years), sex, race (89% White), renal impairment (eGFR ≥15 mL/min/1.73 m2), mild to moderate hepatic impairment (total bilirubin ≤3 times ULN and any AST), or tumor burden. The impact of severe hepatic impairment (total bilirubin >3 times ULN and any AST) on the pharmacokinetics of pembrolizumab is unknown. Pediatric Patients: Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 3 weeks in pediatric patients (10 months to 17 years) are comparable to those of adults at the same dose. 12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence 75 Reference ID: 5493485 of ADA in the studies described in this section with the incidence of ADA in other studies, including those of KEYTRUDA or of other pembrolizumab products. Trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) assay results; therefore, a subset analysis was performed in the KEYTRUDA-treated patients with a pembrolizumab concentration below the drug tolerance level of the ADA assay. In clinical studies in patients treated with KEYTRUDA at a dosage of 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks, 27 (2.1%) of 1,289 evaluable patients tested positive for treatment-emergent anti-pembrolizumab antibodies of whom 6 (0.5%) patients had neutralizing antibodies against pembrolizumab. There were no identified clinically significant effects of ADA on pembrolizumab pharmacokinetics or on the risk of infusion reactions. Because of the low occurrence of ADA, the effect of these ADA on the effectiveness of KEYTRUDA is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been performed to test the potential of pembrolizumab for carcinogenicity or genotoxicity. Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature. 13.2 Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-1/PD-L1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade using a primate anti-PD-1 antibody was also shown to exacerbate M. tuberculosis infection in rhesus macaques. PD-1 and PD-L1 knockout mice and mice receiving PD-L1-blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus. Administration of pembrolizumab in chimpanzees with naturally occurring chronic hepatitis B infection resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT, which persisted for at least 1 month after discontinuation of pembrolizumab. 14 CLINICAL STUDIES 14.1 Melanoma Ipilimumab-Naive Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-006 (NCT01866319), a randomized (1:1:1), open-label, multicenter, active-controlled trial in 834 patients. Patients were randomized to receive KEYTRUDA at a dose of 10 mg/kg intravenously every 2 weeks or 10 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity or to ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity. Patients with disease progression could receive additional doses of treatment unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Randomization was stratified by line of therapy (0 vs. 1), ECOG PS (0 vs. 1), and PD-L1 expression (≥1% of tumor cells [positive] vs. <1% of tumor cells [negative]) according to an investigational use only (IUO) assay. Key eligibility criteria were unresectable or metastatic melanoma; no prior ipilimumab; and no more than one prior systemic treatment for metastatic melanoma. Patients with BRAF V600E mutation-positive melanoma were not required to have received prior BRAF inhibitor therapy. Patients with autoimmune disease; a medical condition that required immunosuppression; previous severe hypersensitivity to other monoclonal antibodies; and HIV, hepatitis B or hepatitis C infection, were ineligible. Assessment of tumor status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS; as assessed by blinded independent central review [BICR] using Response Evaluation Criteria in Solid 76 Reference ID: 5493485 Tumors [RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ]). Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DoR). The study population characteristics were: median age of 62 years (range: 18 to 89); 60% male; 98% White; 66% had no prior systemic therapy for metastatic disease; 69% ECOG PS of 0; 80% had PD-L1 positive melanoma, 18% had PD-L1 negative melanoma, and 2% had unknown PD-L1 status using the IUO assay; 65% had M1c stage disease; 68% with normal LDH; 36% with reported BRAF mutation- positive melanoma; and 9% with a history of brain metastases. Among patients with BRAF mutation- positive melanoma, 139 (46%) were previously treated with a BRAF inhibitor. The study demonstrated statistically significant improvements in OS and PFS for patients randomized to KEYTRUDA as compared to ipilimumab. Among the 91 patients randomized to KEYTRUDA 10 mg/kg every 3 weeks with an objective response, response durations ranged from 1.4+ to 8.1+ months. Among the 94 patients randomized to KEYTRUDA 10 mg/kg every 2 weeks with an objective response, response durations ranged from 1.4+ to 8.2 months. Efficacy results are summarized in Table 57 and Figure 1. Table 57: Efficacy Results in KEYNOTE-006 Endpoint KEYTRUDA 10 mg/kg every 3 weeks n=277 KEYTRUDA 10 mg/kg every 2 weeks n=279 Ipilimumab 3 mg/kg every 3 weeks n=278 OS Deaths (%) 92 (33%) 85 (30%) 112 (40%) Hazard ratio* (95% CI) 0.69 (0.52, 0.90) 0.63 (0.47, 0.83) --­ p-Value (stratified log-rank) 0.004 <0.001 --­ PFS by BICR Events (%) 157 (57%) 157 (56%) 188 (68%) Median in months (95% CI) 4.1 (2.9, 6.9) 5.5 (3.4, 6.9) 2.8 (2.8, 2.9) Hazard ratio* (95% CI) 0.58 (0.47, 0.72) 0.58 (0.46, 0.72) --­ p-Value (stratified log-rank) <0.001 <0.001 --­ Best objective response by BICR ORR (95% CI) 33% (27, 39) 34% (28, 40) 12% (8, 16) Complete response rate 6% 5% 1% Partial response rate 27% 29% 10% * Hazard ratio (KEYTRUDA compared to ipilimumab) based on the stratified Cox proportional hazard model 77 Reference ID: 5493485 Figure 1: Kaplan-Meier Curve for Overall Survival in KEYNOTE-006* 100 90 80 70 60 50 40 30 20 10 0 Treatment arm KEYTRUDA 10 mg/kg every 2 weeks KEYTRUDA 10 mg/kg every 3 weeks ipilimumab 0 4 8 12 16 20 24 28 Time in Months Overall Survival (%) Number at Risk KEYTRUDA 10 mg/kg every 2 weeks: 279 249 221 202 176 156 44 0 KEYTRUDA 10 mg/kg every 3 weeks: 277 251 215 184 174 156 43 0 ipilimumab: 278 213 170 145 122 110 28 0 *Based on the final analysis with an additional follow-up of 9 months (total of 383 deaths as pre-specified in the protocol) Ipilimumab-Refractory Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-002 (NCT01704287), a multicenter, randomized (1:1:1), active-controlled trial in 540 patients randomized to receive one of two doses of KEYTRUDA in a blinded fashion or investigator’s choice chemotherapy. The treatment arms consisted of KEYTRUDA 2 mg/kg or 10 mg/kg intravenously every 3 weeks or investigator’s choice of any of the following chemotherapy regimens: dacarbazine 1000 mg/m2 intravenously every 3 weeks (26%), temozolomide 200 mg/m2 orally once daily for 5 days every 28 days (25%), carboplatin AUC 6 mg/mL/min intravenously plus paclitaxel 225 mg/m2 intravenously every 3 weeks for four cycles then carboplatin AUC of 5 mg/mL/min plus paclitaxel 175 mg/m2 every 3 weeks (25%), paclitaxel 175 mg/m2 intravenously every 3 weeks (16%), or carboplatin AUC 5 or 6 mg/mL/min intravenously every 3 weeks (8%). Randomization was stratified by ECOG PS (0 vs. 1), LDH levels (normal vs. elevated [≥110% ULN]) and BRAF V600 mutation status (wild-type [WT] or V600E). The trial included patients with unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab. The trial excluded patients with uveal melanoma and active brain metastasis. Patients received KEYTRUDA until unacceptable toxicity; disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging; withdrawal of consent; or physician’s decision to stop therapy for the patient. Assessment of tumor status was performed at 12 weeks after randomization, then every 6 weeks through week 48, followed by every 12 weeks thereafter. Patients on chemotherapy who experienced progression of disease were offered KEYTRUDA. The major efficacy outcomes were PFS as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. Additional efficacy outcome measures were confirmed ORR as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR. 78 Reference ID: 5493485 The study population characteristics were: median age of 62 years (range: 15 to 89), 43% age 65 or older; 61% male; 98% White; and 55% ECOG PS of 0 and 45% ECOG PS of 1. Twenty-three percent of patients were BRAF V600 mutation positive, 40% had elevated LDH at baseline, 82% had M1c disease, and 73% had two or more prior therapies for advanced or metastatic disease. The study demonstrated a statistically significant improvement in PFS for patients randomized to KEYTRUDA as compared to control arm. There was no statistically significant difference between KEYTRUDA 2 mg/kg and chemotherapy or between KEYTRUDA 10 mg/kg and chemotherapy in the OS analysis in which 55% of the patients who had been randomized to receive chemotherapy had crossed over to receive KEYTRUDA. Among the 38 patients randomized to KEYTRUDA 2 mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months. Among the 46 patients randomized to KEYTRUDA 10 mg/kg with an objective response, response durations ranged from 1.1+ to 11.1+ months. Efficacy results are summarized in Table 58 and Figure 2. Table 58: Efficacy Results in KEYNOTE-002 Endpoint KEYTRUDA 2 mg/kg every 3 weeks n=180 KEYTRUDA 10 mg/kg every 3 weeks n=181 Chemotherapy n=179 PFS Number of Events, n (%) 129 (72%) 126 (70%) 155 (87%) Progression, n (%) 105 (58%) 107 (59%) 134 (75%) Death, n (%) 24 (13%) 19 (10%) 21 (12%) Median in months (95% CI) 2.9 (2.8, 3.8) 2.9 (2.8, 4.7) 2.7 (2.5, 2.8) p-Value (stratified log-rank) <0.001 <0.001 --­ Hazard ratio* (95% CI) 0.57 (0.45, 0.73) 0.50 (0.39, 0.64) --­ OS† Deaths (%) 123 (68%) 117 (65%) 128 (72%) Hazard ratio* (95% CI) 0.86 (0.67, 1.10) 0.74 (0.57, 0.96) --­ p-Value (stratified log-rank) 0.117 0.011‡ --­ Median in months (95% CI) 13.4 (11.0, 16.4) 14.7 (11.3, 19.5) 11.0 (8.9, 13.8) Objective Response Rate ORR (95% CI) 21% (15, 28) 25% (19, 32) 4% (2, 9) Complete response rate 2% 3% 0% Partial response rate 19% 23% 4% * Hazard ratio (KEYTRUDA compared to chemotherapy) based on the stratified Cox proportional hazard model † With additional follow-up of 18 months after the PFS analysis ‡ Not statistically significant compared to multiplicity adjusted significance level of 0.01 Figure 2: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-002 100 90 80 70 60 50 40 30 20 10 0 Progression-Free Survival (%) Treatment arm KEYTRUDA 10 mg/kg every 3 weeks KEYTRUDA 2 mg/kg every 3 weeks Chemotherapy 0 2 4 6 8 10 12 14 Time in Months Number at Risk KEYTRUDA 10 mg/kg: 181 158 82 55 39 15 5 1 KEYTRUDA 2 mg/kg: 180 153 74 53 26 9 4 2 Chemotherapy: 179 128 43 22 15 4 2 1 79 Reference ID: 5493485 I I I I I Adjuvant Treatment of Resected Stage IIB or IIC Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-716 (NCT03553836), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with completely resected Stage IIB or IIC melanoma. Patients were randomized to KEYTRUDA 200 mg or the pediatric (≥12 years old) dose of KEYTRUDA 2 mg/kg intravenously (up to a maximum of 200 mg) every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by AJCC 8th edition T Stage (>2.0-4.0 mm with ulceration vs. >4.0 mm without ulceration vs. >4.0 mm with ulceration). Patients must not have been previously treated for melanoma beyond complete surgical resection for their melanoma prior to study entry. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) (defined as the time between the date of randomization and the date of first recurrence [local, in-transit or regional lymph nodes or distant recurrence] or death, whichever occurred first). New primary melanomas were excluded from the definition of RFS. Distant metastasis- free survival (DMFS), defined as a spread of tumor to distant organs or distant lymph nodes, was an additional efficacy outcome measure. Patients underwent imaging every six months for one year from randomization, every 6 months from years 2 to 4, and then once in year 5 from randomization or until recurrence, whichever came first. The study population characteristics were: median age of 61 years (range: 16 to 87), 39% age 65 or older; 60% male; 98% White; and 93% ECOG PS of 0 and 7% ECOG PS of 1. Sixty-four percent had Stage IIB and 35% had Stage IIC. The trial demonstrated a statistically significant improvement in RFS and DMFS for patients randomized to the KEYTRUDA arm compared with placebo. Efficacy results are summarized in Table 59 and Figure 3. Table 59: Efficacy Results in KEYNOTE-716 Endpoint KEYTRUDA 200 mg every 3 weeks n=487 Placebo n=489 RFS Number (%) of patients with event 54 (11%) 82 (17%) Median in months (95% CI) NR (22.6, NR) NR (NR, NR) Hazard ratio*,† (95% CI) 0.65 (0.46, 0.92) p-Value† 0.0132‡ DMFS Number (%) of patients with event 63 (13%) 95 (19%) Median in months (95% CI) NR (NR, NR) NR (NR, NR) Hazard ratio*,† (95% CI) 0.64 (0.47, 0.88) p-Value† 0.0058§ * Based on the stratified Cox proportional hazard model † Based on a log-rank test stratified by American Joint Committee on Cancer 8th edition (AJCC) stage ‡ p-Value is compared with 0.0202 of the allocated alpha for this interim analysis. § p-Value is compared with 0.0256 of the allocated alpha for this interim analysis. NR = not reached 80 Reference ID: 5493485 100 90 80 ~ 70 "iii > -~ 60 ::, V> Cl) ~ so LL C1l u C 40 ~ ::, u Cl) 30 ll'. 20 10 Treatment arm KEYTRUDA - - - • Placebo 0 Number at Risk KEYTRUDA 487 Placebo 489 3 465 475 6 401 400 9 340 336 12 15 Time in Months 249 229 149 149 18 71 77 21 21 27 24 27 0 0 Figure 3: Kaplan-Meier Curve for Recurrence-Free Survival in KEYNOTE-716 Adjuvant Treatment of Stage III Resected Melanoma The efficacy of KEYTRUDA was investigated in KEYNOTE-054 (NCT02362594), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in patients with completely resected Stage IIIA (>1 mm lymph node metastasis), IIIB, or IIIC melanoma. Patients were randomized to KEYTRUDA 200 mg intravenously every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity. Randomization was stratified by American Joint Committee on Cancer 7th edition (AJCC) stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC ≥4 positive lymph nodes) and geographic region (North America, European countries, Australia, and other countries as designated). Patients must have undergone lymph node dissection and, if indicated, radiotherapy within 13 weeks prior to starting treatment. The major efficacy outcome measure was investigator-assessed recurrence-free survival (RFS) in the whole population and in the population with PD-L1 positive tumors where RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. New primary melanomas were excluded from the definition of RFS. DMFS in the whole population and in the population with PD-L1 positive tumors were additional efficacy outcome measures. DMFS was defined as a spread of tumor to distant organs or distant lymph nodes. Patients underwent imaging every 12 weeks after the first dose of KEYTRUDA for the first two years, then every 6 months from year 3 to 5, and then annually. The study population characteristics were: median age of 54 years (range: 19 to 88), 25% age 65 or older; 62% male; and 94% ECOG PS of 0 and 6% ECOG PS of 1. Sixteen percent had Stage IIIA, 46% had Stage IIIB, 18% had Stage IIIC (1-3 positive lymph nodes), and 20% had Stage IIIC (≥4 positive lymph nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type; and 84% had PD­ L1 positive melanoma with TPS ≥1% according to an IUO assay. The trial demonstrated a statistically significant improvement in RFS and DMFS for patients randomized to the KEYTRUDA arm compared with placebo. Efficacy results are summarized in Table 60 and Figure 4. 81 Reference ID: 5493485 Table 60: Efficacy Results in KEYNOTE-054 Endpoint KEYTRUDA 200 mg every 3 weeks n=514 Placebo n=505 RFS Number (%) of patients with event 135 (26%) 216 (43%) Median in months (95% CI) NR 20.4 (16.2, NR) Hazard ratio*,† (95% CI) 0.57 (0.46, 0.70) p-Value† (log-rank) <0.001± DMFS Number (%) of patients with event 173 (34%) 245 (49%) Median in months (95% CI) NR (49.6, NR) 40.0 (27.7, NR) Hazard ratio*,† (95% CI) 0.60 (0.49, 0.73) p-Value† (log-rank) <0.0001§ * Based on the stratified Cox proportional hazard model † Stratified by American Joint Committee on Cancer 7th edition (AJCC) stage ± p-Value is compared with 0.016 of the allocated alpha for this interim analysis. § p-Value is compared with 0.028 of the allocated alpha for this analysis. NR = not reached For patients with PD-L1 positive tumors, the RFS HR was 0.54 (95% CI: 0.42, 0.69); p<0.0001. For patients with PD-L1 positive tumors, the DMFS HR was 0.61 (95% CI: 0.49, 0.76); p<0.0001. The RFS and DMFS benefit for KEYTRUDA compared to placebo was observed regardless of tumor PD-L1 expression. Figure 4: Kaplan-Meier Curve for Recurrence-Free Survival in KEYNOTE-054 Recurrence-Free Survival (%) 100 90 80 70 60 50 40 30 20 10 0 Treatment arm KEYTRUDA Placebo 0 3 6 9 12 15 18 21 24 Time in Months Number at Risk KEYTRUDA: 514 438 413 392 313 182 73 15 0 Placebo: 505 415 363 323 264 157 60 15 0 14.2 Non-Small Cell Lung Cancer First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy The efficacy of KEYTRUDA in combination with pemetrexed and platinum chemotherapy was investigated in KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active- controlled trial conducted in 616 patients with metastatic nonsquamous NSCLC, regardless of PD-L1 82 Reference ID: 5493485 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by smoking status (never vs. former/current), choice of platinum (cisplatin vs. carboplatin), and tumor PD-L1 status (TPS <1% [negative] vs. TPS ≥1%). Patients were randomized (2:1) to one of the following treatment arms: • KEYTRUDA 200 mg, pemetrexed 500 mg/m2, and investigator’s choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by KEYTRUDA 200 mg and pemetrexed 500 mg/m2 intravenously every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1. • Placebo, pemetrexed 500 mg/m2, and investigator’s choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks. Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Patients randomized to placebo and chemotherapy were offered KEYTRUDA as a single agent at the time of disease progression. Assessment of tumor status was performed at Week 6, Week 12, and then every 9 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR and DoR, as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG PS of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1% [negative]. Seventy-two percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression. The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with pemetrexed and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy. Table 61 and Figure 5 summarize the efficacy results for KEYNOTE-189. 83 Reference ID: 5493485 Table 61: Efficacy Results in KEYNOTE-189 Endpoint KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy n=410 Placebo Pemetrexed Platinum Chemotherapy n=206 OS Number (%) of patients with event 127 (31%) 108 (52%) Median in months (95% CI) NR (NR, NR) 11.3 (8.7, 15.1) Hazard ratio* (95% CI) 0.49 (0.38, 0.64) p-Value† <0.0001 PFS Number of patients with event (%) 245 (60%) 166 (81%) Median in months (95% CI) 8.8 (7.6, 9.2) 4.9 (4.7, 5.5) Hazard ratio* (95% CI) 0.52 (0.43, 0.64) p-Value† <0.0001 Objective Response Rate ORR‡ (95% CI) 48% (43, 53) 19% (14, 25) Complete response 0.5% 0.5% Partial response 47% 18% p-Value§ <0.0001 Duration of Response Median in months (range) 11.2 (1.1+, 18.0+) 7.8 (2.1+, 16.4+) * Based on the stratified Cox proportional hazard model † Based on a stratified log-rank test ‡ Response: Best objective response as confirmed complete response or partial response § Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy, and smoking status NR = not reached At the protocol-specified final OS analysis, the median in the KEYTRUDA in combination with pemetrexed and platinum chemotherapy arm was 22.0 months (95% CI: 19.5, 24.5) compared to 10.6 months (95% CI: 8.7, 13.6) in the placebo with pemetrexed and platinum chemotherapy arm, with an HR of 0.56 (95% CI: 0.46, 0.69). 84 Reference ID: 5493485 100 90 80 70 # 60 ro > ~ ::::, 50 Cf) ro a, 40 > 0 30 20 10 0 0 Number at Risk KEYTRUDA: 410 Contro l: 206 ~ \ '\. \ \ \ '-., \ ' \ '\ ""l ......... ... ., Treatment arm KEYTRU DA Control 6 347 149 12 283 98 ........ ...... ..... "- ..... ... , 18 Ti me in Months 234 72 - ... ~ ..... ~ tt-t, ... ttt+ tt 24 184 55 30 86 25 36 12 5 42 0 0 Figure 5: Kaplan-Meier Curve for Overall Survival in KEYNOTE-189* *Based on the protocol-specified final OS analysis First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy The efficacy of KEYTRUDA in combination with carboplatin and investigator’s choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407 (NCT02775435), a randomized, multi- center, double-blind, placebo-controlled trial conducted in 559 patients with metastatic squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD­ L1 status (TPS <1% [negative] vs. TPS ≥1%), choice of paclitaxel or paclitaxel protein-bound, and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion: • KEYTRUDA 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles, and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by KEYTRUDA 200 mg every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1. • Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by placebo every 3 weeks. Treatment with KEYTRUDA and chemotherapy or placebo and chemotherapy continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Patients randomized to the placebo and chemotherapy arm were offered KEYTRUDA as a single agent at the time 85 Reference ID: 5493485 of disease progression. Assessment of tumor status was performed every 6 weeks through Week 18, every 9 weeks through Week 45 and every 12 weeks thereafter. The main efficacy outcome measures were PFS and ORR as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. An additional efficacy outcome measure was DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 65 years (range: 29 to 88), 55% age 65 or older; 81% male; 77% White; 71% ECOG PS of 1; and 8% with a history of brain metastases. Thirty-five percent had tumor PD-L1 expression TPS <1%; 19% were from the East Asian region; and 60% received paclitaxel. The trial demonstrated a statistically significant improvement in OS, PFS and ORR in patients randomized to KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy compared with patients randomized to placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy. Table 62 and Figure 6 summarize the efficacy results for KEYNOTE-407. Table 62: Efficacy Results in KEYNOTE-407 Endpoint KEYTRUDA 200 mg every 3 weeks Carboplatin Paclitaxel/Paclitaxel protein-bound n=278 Placebo Carboplatin Paclitaxel/Paclitaxel protein-bound n=281 OS Number of events (%) 85 (31%) 120 (43%) Median in months (95% CI) 15.9 (13.2, NE) 11.3 (9.5, 14.8) Hazard ratio* (95% CI) 0.64 (0.49, 0.85) p-Value† 0.0017 PFS Number of events (%) 152 (55%) 197 (70%) Median in months (95% CI) 6.4 (6.2, 8.3) 4.8 (4.2, 5.7) Hazard ratio* (95% CI) 0.56 (0.45, 0.70) p-Value† <0.0001 n=101 n=103 Objective Response Rate‡ ORR (95% CI) 58% (48, 68) 35% (26, 45) Difference (95% CI) 23.6% (9.9, 36.4) p-Value§ 0.0008 Duration of Response‡ Median duration of response in months (range) 7.2 (2.4, 12.4+) 4.9 (2.0, 12.4+) * Based on the stratified Cox proportional hazard model † Based on a stratified log-rank test ‡ ORR primary analysis and DoR analysis were conducted with the first 204 patients enrolled. § Based on a stratified Miettinen-Nurminen test NE = not estimable At the protocol-specified final OS analysis, the median in the KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy arm was 17.1 months (95% CI: 14.4, 19.9) compared to 11.6 months (95% CI: 10.1, 13.7) in the placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy arm, with an HR of 0.71 (95% CI: 0.58, 0.88). 86 Reference ID: 5493485 100 90 80 70 $ '::::: 60 "' > .2'. ::::, 50 Cl) ~ (!) 40 > 0 30 20 10 Treatment arm KEYTRUDA Control 0 0 3 6 9 12 15 18 21 24 27 30 33 Ti me in Months Number at Risk KEYTRUDA: 278 256 232 203 180 150 119 80 46 14 4 0 Control: 281 245 210 163 137 113 91 61 36 16 3 0 Figure 6: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407* *Based on the protocol-specified final OS analysis First-line treatment of metastatic NSCLC as a single agent KEYNOTE-042 The efficacy of KEYTRUDA was investigated in KEYNOTE-042 (NCT02220894), a randomized, multicenter, open-label, active-controlled trial conducted in 1274 patients with Stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or patients with metastatic NSCLC. Only patients whose tumors expressed PD-L1 (TPS ≥1%) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit and who had not received prior systemic treatment for metastatic NSCLC were eligible. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of radiation in the thoracic region within the prior 26 weeks of initiation of study were ineligible. Randomization was stratified by ECOG PS (0 vs. 1), histology (squamous vs. nonsquamous), geographic region (East Asia vs. non-East Asia), and PD-L1 expression (TPS ≥50% vs. TPS 1 to 49%). Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of either of the following platinum-containing chemotherapy regimens: • Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies; • Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies. Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST- defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Treatment with KEYTRUDA could be reinitiated at the time of subsequent disease 87 Reference ID: 5493485 progression and administered for up to 12 months. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measure was OS in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC. Additional efficacy outcome measures were PFS and ORR in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Sixty-nine percent had ECOG PS of 1; 39% with squamous and 61% with nonsquamous histology; 87% had M1 disease and 13% had Stage IIIA (2%) or Stage IIIB (11%) and who were not candidates for surgical resection or definitive chemoradiation per investigator assessment; and 5% with treated brain metastases at baseline. Forty-seven percent of patients had TPS ≥50% NSCLC and 53% had TPS 1 to 49% NSCLC. The trial demonstrated a statistically significant improvement in OS for patients (PD-L1 TPS ≥50%, TPS ≥20%, TPS ≥1%) randomized to KEYTRUDA as compared with chemotherapy. Table 63 and Figure 7 summarize the efficacy results in the subgroup of patients with TPS ≥50% and in all randomized patients with TPS ≥1%. Table 63: Efficacy Results of All Randomized Patients (TPS ≥1% and TPS ≥50%) in KEYNOTE-042 TPS ≥1% TPS ≥50% Endpoint KEYTRUDA 200 mg every 3 weeks n=637 Chemotherapy n=637 KEYTRUDA 200 mg every 3 weeks n=299 Chemotherapy n=300 OS Number of events (%) 371 (58%) 438 (69%) 157 (53%) 199 (66%) Median in months (95% CI) 16.7 (13.9, 19.7) 12.1 (11.3, 13.3) 20.0 (15.4, 24.9) 12.2 (10.4, 14.2) Hazard ratio* (95% CI) 0.81 (0.71, 0.93) 0.69 (0.56, 0.85) p-Value† 0.0036 0.0006 PFS Number of events (%) 507 (80%) 506 (79%) 221 (74%) 233 (78%) Median in months (95% CI) 5.4 (4.3, 6.2) 6.5 (6.3, 7.0) 6.9 (5.9, 9.0) 6.4 (6.1, 6.9) Hazard ratio*, ‡ (95% CI) 1.07 (0.94, 1.21) 0.82 (0.68, 0.99) p-Value† -‡ NS§ Objective Response Rate ORR‡ (95% CI) 27% (24, 31) 27% (23, 30) 39% (33.9, 45.3) 32% (26.8, 37.6) Complete response rate 0.5% 0.5% 0.7% 0.3% Partial response rate 27% 26% 39% 32% Duration of Response % with duration ≥12 months¶ 47% 16% 42% 17% % with duration ≥18 months¶ 26% 6% 25% 5% * Based on the stratified Cox proportional hazard model † Based on a stratified log-rank test; compared to a p-Value boundary of 0.0291 ‡ Not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints § Not significant compared to a p-Value boundary of 0.0291 ¶ Based on observed duration of response The results of all efficacy outcome measures in the subgroup of patients with PD-L1 TPS ≥20% NSCLC were intermediate between the results of those with PD-L1 TPS ≥1% and those with PD-L1 TPS ≥50%. In a pre-specified exploratory subgroup analysis for patients with TPS 1-49% NSCLC, the median OS was 13.4 months (95% CI: 10.7, 18.2) for the pembrolizumab group and 12.1 months (95% CI: 11.0, 14.0) in the chemotherapy group, with an HR of 0.92 (95% CI: 0.77, 1.11). 88 Reference ID: 5493485 '\ "\ \ \ \ \ Figure 7: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-042 (TPS ≥1%) 100 90 80 70 60 50 40 30 20 10 0 Overall Survival (%) Treatment arm KEYTRUDA Chemotherapy 0 6 12 18 24 30 36 42 Time in Months Number at Risk KEYTRUDA: 637 463 365 214 112 35 2 0 Chemotherapy: 637 485 316 166 88 24 1 0 KEYNOTE-024 The efficacy of KEYTRUDA was also investigated in KEYNOTE-024 (NCT02142738), a randomized, multicenter, open-label, active-controlled trial in 305 previously untreated patients with metastatic NSCLC. The study design was similar to that of KEYNOTE-042, except that only patients whose tumors had high PD-L1 expression (TPS of 50% or greater) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit were eligible. Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of any of the following platinum-containing chemotherapy regimens: • Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies; • Pemetrexed 500 mg/m2 every 3 weeks and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies; • Gemcitabine 1250 mg/m2 on days 1 and 8 and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles; • Gemcitabine 1250 mg/m2 on Days 1 and 8 and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles; • Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed maintenance (for nonsquamous histologies). Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression. 89 Reference ID: 5493485 The main efficacy outcome measure was PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were OS and ORR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 65 years (range: 33 to 90), 54% age 65 or older; 61% male; 82% White and 15% Asian; 65% with ECOG PS of 1; 18% with squamous and 82% with nonsquamous histology and 9% with history of brain metastases. A total of 66 patients in the chemotherapy arm received KEYTRUDA at the time of disease progression. The trial demonstrated a statistically significant improvement in both PFS and OS for patients randomized to KEYTRUDA as compared with chemotherapy. Table 64 and Figure 8 summarize the efficacy results for KEYNOTE-024. Table 64: Efficacy Results in KEYNOTE-024 Endpoint KEYTRUDA 200 mg every 3 weeks n=154 Chemotherapy n=151 PFS Number (%) of patients with event 73 (47%) 116 (77%) Median in months (95% CI) 10.3 (6.7, NR) 6.0 (4.2, 6.2) Hazard ratio* (95% CI) 0.50 (0.37, 0.68) p-Value (stratified log-rank) <0.001 OS Number (%) of patients with event 44 (29%) 64 (42%) Median in months (95% CI)† 30.0 (18.3, NR) 14.2 (9.8, 19.0) Hazard ratio* (95% CI) 0.60 (0.41, 0.89) p-Value (stratified log-rank) 0.005‡ Objective Response Rate ORR (95% CI) 45% (37, 53) 28% (21, 36) Complete response rate 4% 1% Partial response rate 41% 27% p-Value (Miettinen-Nurminen) 0.001 Median duration of response in months (range) NR (1.9+, 14.5+) 6.3 (2.1+, 12.6+) * Based on the stratified Cox proportional hazard model for the interim analysis † Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis. ‡ p-Value is compared with 0.0118 of the allocated alpha for the interim analysis NR = not reached 90 Reference ID: 5493485 Figure 8: Kaplan-Meier Curve for Overall Survival in KEYNOTE-024* 100 90 80 70 60 50 40 30 20 10 0 Treatment arm KEYTRUDA Chemotherapy 0 3 6 9 12 15 18 21 24 27 30 33 Time in Months Overall Survival (%) Number at Risk KEYTRUDA: 154 136 121 112 106 96 89 83 52 22 5 0 Chemotherapy: 151 123 107 88 80 70 61 55 31 16 5 0 *Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis. Previously treated NSCLC The efficacy of KEYTRUDA was investigated in KEYNOTE-010 (NCT01905657), a randomized, multicenter, open-label, active-controlled trial conducted in 1033 patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations. Eligible patients had PD-L1 expression TPS of 1% or greater by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit. Patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 expression (PD-L1 expression TPS ≥50% vs. PD-L1 expression TPS=1-49%), ECOG PS (0 vs. 1), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1:1) to receive KEYTRUDA 2 mg/kg intravenously every 3 weeks, KEYTRUDA 10 mg/kg intravenously every 3 weeks or docetaxel intravenously 75 mg/m2 every 3 weeks until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue until disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or confirmation of progression at 4 to 6 weeks with repeat imaging or for up to 24 months without disease progression. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%. Additional efficacy outcome measures were ORR and DoR in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%. The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; 66% ECOG PS of 1; 43% with high PD-L1 tumor expression; 21% with squamous, 70% with nonsquamous, and 8% with mixed, other or unknown histology; 91% metastatic (M1) disease; 15% with history of brain metastases; and 8% and 1% with EGFR and ALK genomic aberrations, respectively. All patients had received prior therapy with a platinum- doublet regimen, 29% received two or more prior therapies for their metastatic disease. 91 Reference ID: 5493485 Tables 65 and 66 and Figure 9 summarize efficacy results in the subgroup with TPS ≥50% population and in all patients, respectively. Table 65: Efficacy Results of the Subgroup of Patients with TPS ≥50% in KEYNOTE-010 Endpoint KEYTRUDA 2 mg/kg every 3 weeks n=139 KEYTRUDA 10 mg/kg every 3 weeks n=151 Docetaxel 75 mg/m2 every 3 weeks n=152 OS Deaths (%) 58 (42%) 60 (40%) 86 (57%) Median in months (95% CI) 14.9 (10.4, NR) 17.3 (11.8, NR) 8.2 (6.4, 10.7) Hazard ratio* (95% CI) 0.54 (0.38, 0.77) 0.50 (0.36, 0.70) --­ p-Value (stratified log-rank) <0.001 <0.001 --­ PFS Events (%) 89 (64%) 97 (64%) 118 (78%) Median in months (95% CI) 5.2 (4.0, 6.5) 5.2 (4.1, 8.1) 4.1 (3.6, 4.3) Hazard ratio* (95% CI) 0.58 (0.43, 0.77) 0.59 (0.45, 0.78) --­ p-Value (stratified log-rank) <0.001 <0.001 --­ Objective Response Rate ORR† (95% CI) 30% (23, 39) 29% (22, 37) 8% (4, 13) p-Value (Miettinen-Nurminen) <0.001 <0.001 --­ Median duration of response in months (range) NR (0.7+, 16.8+) NR (2.1+, 17.8+) 8.1 (2.1+, 8.8+) * Hazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model † All responses were partial responses NR = not reached Table 66: Efficacy Results of All Randomized Patients (TPS ≥1%) in KEYNOTE-010 Endpoint KEYTRUDA 2 mg/kg every 3 weeks n=344 KEYTRUDA 10 mg/kg every 3 weeks n=346 Docetaxel 75 mg/m2 every 3 weeks n=343 OS Deaths (%) 172 (50%) 156 (45%) 193 (56%) Median in months (95% CI) 10.4 (9.4, 11.9) 12.7 (10.0, 17.3) 8.5 (7.5, 9.8) Hazard ratio* (95% CI) 0.71 (0.58, 0.88) 0.61 (0.49, 0.75) --­ p-Value (stratified log-rank) <0.001 <0.001 --­ PFS Events (%) 266 (77%) 255 (74%) 257 (75%) Median in months (95% CI) 3.9 (3.1, 4.1) 4.0 (2.6, 4.3) 4.0 (3.1, 4.2) Hazard ratio* (95% CI) 0.88 (0.73, 1.04) 0.79 (0.66, 0.94) --­ p-Value (stratified log-rank) 0.068 0.005 --­ Objective Response Rate ORR† (95% CI) 18% (14, 23) 19% (15, 23) 9% (7, 13) p-Value (Miettinen-Nurminen) <0.001 <0.001 --­ Median duration of response in months (range) NR (0.7+, 20.1+) NR (2.1+, 17.8+) 6.2 (1.4+, 8.8+) * Hazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model † All responses were partial responses NR = not reached 92 Reference ID: 5493485 H!ll(~H\11• 11111 I I 11 ........ fftl II l■I II■ II I Figure 9: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-010 (TPS ≥1%) 100 90 80 70 60 50 40 30 20 10 0 Overall Survival (%) Treatment arm KEYTRUDA 2 mg/kg KEYTRUDA 10 mg/kg Docetaxel 0 5 10 15 20 25 Time in Months Number at Risk KEYTRUDA 2 mg/kg: 344 259 115 49 12 0 KEYTRUDA 10 mg/kg: 346 255 124 56 6 0 Docetaxel: 343 212 79 33 1 0 Neoadjuvant and adjuvant treatment of resectable NSCLC The efficacy of KEYTRUDA in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-671 (NCT03425643), a multicenter, randomized, double-blind, placebo-controlled trial conducted in 797 patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition. Patients were enrolled regardless of tumor PD-L1 expression. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment, a medical condition that required immunosuppression, or a history of interstitial lung disease or pneumonitis that required steroids were ineligible. Randomization was stratified by stage (II vs. III), tumor PD-L1 expression (TPS ≥50% or <50%), histology (squamous vs. nonsquamous), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to one of the following treatment arms: • Treatment Arm A: neoadjuvant KEYTRUDA 200 mg on Day 1 in combination with cisplatin 75 mg/m2 and either pemetrexed 500 mg/m2 on Day 1 or gemcitabine 1000 mg/m2 on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Within 4-12 weeks following surgery, KEYTRUDA 200 mg was administered every 3 weeks for up to 13 cycles. • Treatment Arm B: neoadjuvant placebo on Day 1 in combination with cisplatin 75 mg/m2 and either pemetrexed 500 mg/m2 on Day 1 or gemcitabine 1000 mg/m2 on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Within 4-12 weeks following surgery, placebo was administered every 3 weeks for up to 13 cycles. All study medications were administered via intravenous infusion. Treatment with KEYTRUDA or placebo continued until completion of the treatment (17 cycles), disease progression that precluded definitive surgery, disease recurrence in the adjuvant phase, disease progression for those who did not undergo surgery or had incomplete resection and entered the adjuvant phase, or unacceptable toxicity. Assessment of tumor status was performed at baseline, Week 7, and Week 13 in the neoadjuvant phase and within 4 weeks prior to the start of the adjuvant phase. Following the start of the adjuvant phase, assessment of tumor status was performed every 16 weeks through the end of Year 3, and then every 6 months thereafter. The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment. 93 Reference ID: 5493485 The major efficacy outcome measures were OS and investigator-assessed event-free survival (EFS). Additional efficacy outcome measures were pathological complete response (pCR) rate and major pathological response (mPR) rate as assessed by blinded independent pathology review. The study population characteristics were: median age of 64 years (range: 26 to 83); 45% age 65 or older and 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino; 63% ECOG PS of 0 and 37% ECOG PS of 1. Thirty percent had Stage II and 70% had Stage III disease; 33% had TPS ≥50% and 67% had TPS <50%; 43% had tumors with squamous histology and 57% had tumors with non-squamous histology; 31% were from the East Asian region. Eighty-one percent of patients in the KEYTRUDA in combination with platinum-containing chemotherapy arm received definitive surgery compared to 76% of patients in the placebo in combination with platinum-containing chemotherapy arm. The trial demonstrated statistically significant improvements in OS and EFS for patients randomized to KEYTRUDA in combination with platinum-containing chemotherapy followed by KEYTRUDA as a single agent compared with patients randomized to placebo in combination with platinum-containing chemotherapy followed by placebo alone. Table 67 and Figure 10 summarize the efficacy results for KEYNOTE-671. Table 67: Efficacy Results in KEYNOTE-671 Endpoint KEYTRUDA 200 mg every 3 weeks with chemotherapy/KEYTRUDA n=397 Placebo with chemotherapy/Placebo n=400 OS Number of patients with event (%) 110 (28%) 144 (36%) Median in months* (95% CI) NR (NR, NR) 52.4 (45.7, NR) Hazard ratio† (95% CI) 0.72 (0.56, 0.93) p-Value‡,§ 0.0103 EFS Number of patients with event (%) 139 (35%) 205 (51%) Median in months* (95% CI) NR (34.1, NR) 17.0 (14.3, 22.0) Hazard ratio† (95% CI) 0.58 (0.46, 0.72) p-Value‡,¶ <0.0001 * Based on Kaplan-Meier estimates † Based on Cox regression model with treatment as a covariate stratified by stage, tumor PD-L1 expression, histology, and geographic region ‡ Based on stratified log-rank test § Compared to a two-sided p-Value boundary of 0.0109 ¶ Compared to a two-sided p-Value boundary of 0.0092 NR = not reached 94 Reference ID: 5493485 100 ........---------------------------, 90 80 70 60 50 40 30 20 10 0 6 12 18 24 30 36 42 48 397 371 347 327 277 205 148 108 69 400 379 347 319 256 176 125 77 39 54 32 20 60 4 4 66 0 0 Figure 10: Kaplan-Meier Curve for Overall Survival in KEYNOTE-671 Treatment arm KEYTRUDA Control Overall Survival (%) Time in Months Number at Risk KEYTRUDA Control The trial demonstrated a statistically significant difference in pCR rate (18.1% vs. 4.0%; p<0.0001) and mPR rate (30.2% vs. 11.0%; p<0.0001). Adjuvant treatment of resected NSCLC The efficacy of KEYTRUDA was investigated in KEYNOTE-091 (NCT02504372), a multicenter, randomized, triple-blind, placebo-controlled trial conducted in 1177 patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC by AJCC 7th edition. Patients had not received neoadjuvant radiotherapy or chemotherapy. Adjuvant chemotherapy up to 4 cycles was optional. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents, or had a history of interstitial lung disease or pneumonitis. Randomization was stratified by stage (IB vs. II vs. IIIA), receipt of adjuvant chemotherapy (yes vs. no), PD-L1 status (TPS <1% [negative] vs. TPS 1-49% vs. TPS ≥50%), and geographic region (Western Europe vs. Eastern Europe vs. Asia vs. Rest of World). Patients were randomized (1:1) to receive KEYTRUDA 200 mg or placebo intravenously every 3 weeks. Treatment continued until RECIST v1.1-defined disease recurrence as determined by the investigator, unacceptable toxicity or up to one year. Tumor assessments were conducted every 12 weeks for the first year, then every 6 months for years 2 to 3, and then annually through year 5. After year 5, imaging was 95 Reference ID: 5493485 performed as per local standard of care. The major efficacy outcome measure was investigator-assessed disease-free survival (DFS). An additional efficacy outcome measure was OS. Of 1177 patients randomized, 1010 (86%) received adjuvant platinum-based chemotherapy following resection. Among these 1010 patients, the median age was 64 years (range: 35 to 84), 49% age 65 or older; 68% male; 77% White, 18% Asian; 86% current or former smokers; and 39% with ECOG PS of 1. Eleven percent had Stage IB, 57% had Stage II, and 31% had Stage IIIA disease. Thirty-nine percent had PD-L1 TPS <1% [negative], 33% had TPS 1-49%, and 28% had TPS ≥50%. Fifty-two percent were from Western Europe, 20% from Eastern Europe, 17% from Asia, and 11% from Rest of World. The trial met its primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population for patients randomized to the KEYTRUDA arm compared to patients randomized to the placebo arm. In an exploratory subgroup analysis of the 167 patients (14%) who did not receive adjuvant chemotherapy, the DFS HR was 1.25 (95% CI: 0.76, 2.05). OS results were not mature with only 42% of pre-specified OS events in the overall population. Table 68 and Figure 11 summarize the efficacy results for KEYNOTE-091 in patients who received adjuvant chemotherapy. Table 68: Efficacy Results in KEYNOTE-091 for Patients Who Received Adjuvant Chemotherapy Endpoint KEYTRUDA 200 mg every 3 weeks n=506 Placebo n=504 DFS Number (%) of patients with event 177 (35%) 231 (46%) Median in months (95% CI) 58.7 (39.2, NR) 34.9 (28.6, NR) Hazard ratio* (95% CI) 0.73 (0.60, 0.89) * Based on the unstratified univariate Cox regression model NR = not reached 96 Reference ID: 5493485 100 --rr------------------------------, 90 80 70 60 50 40 30 20 10 0 506 504 6 422 422 12 372 349 18 308 272 24 227 206 30 158 134 36 71 58 42 61 47 48 27 17 54 16 15 60 66 0 0 Figure 11: Kaplan-Meier Curve for Disease-Free Survival in KEYNOTE-091 for Patients Who Received Adjuvant Chemotherapy Treatment arm KEYTRUDA Placebo Disease-Free Survival (%) Time in Months Number at Risk KEYTRUDA Placebo 14.3 Malignant Pleural Mesothelioma First-line treatment of unresectable advanced or metastatic malignant pleural mesothelioma (MPM) with pemetrexed and platinum chemotherapy The efficacy of KEYTRUDA in combination with pemetrexed and platinum chemotherapy was investigated in KEYNOTE-483 (NCT02784171), a multicenter, randomized, open-label, active-controlled trial that enrolled 440 patients with unresectable advanced or metastatic MPM and no prior systemic therapy for advanced/metastatic disease. Patients were enrolled regardless of tumor PD-L1 expression. Patients with autoimmune disease that required systemic therapy within 3 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by histological subtype (epithelioid vs. non-epithelioid). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion: • KEYTRUDA 200 mg with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5-6 mg/mL/min on Day 1 of each 21-day cycle for up to 6 cycles, followed by KEYTRUDA 200 mg every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1. 97 Reference ID: 5493485 • Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 or carboplatin AUC 5-6 mg/mL/min on Day 1 of each 21-day cycle for up to 6 cycles. Treatment with KEYTRUDA continued until disease progression as determined by the investigator according to modified RECIST 1.1 for mesothelioma (mRECIST), unacceptable toxicity, or a maximum of 24 months. Assessment of tumor status was performed every 6 weeks for 18 weeks, followed by every 12 weeks thereafter. The main efficacy outcome measure was OS. Additional efficacy outcome measures were PFS, ORR, and DoR, as assessed by BICR according to mRECIST. The study population characteristics were: median age of 70 years (77% age 65 or older); 76% male; 79% White, 21% race not reported or unknown; 2% Hispanic or Latino; and 53% ECOG performance status of 1. Seventy-eight percent had epithelioid and 22% had non-epithelioid histology; 60% had tumors with PD-L1 CPS ≥1 and 30% had tumors with PD-L1 CPS <1. The trial demonstrated a statistically significant improvement in OS, PFS, and ORR in patients randomized to KEYTRUDA in combination with chemotherapy compared with patients randomized to chemotherapy alone. Table 69 and Figure 12 summarize the efficacy results for KEYNOTE-483. Table 69: Efficacy Results in KEYNOTE-483 Endpoint KEYTRUDA 200 mg every 3 weeks Pemetrexed Platinum Chemotherapy (n=222) Pemetrexed Platinum Chemotherapy (n=218) OS Number (%) of patients with event 167 (75%) 175 (80%) Median in months (95% CI) 17.3 (14.4, 21.3) 16.1 (13.1, 18.2) Hazard ratio* (95% CI) 0.79 (0.64, 0.98) p-Value† 0.0162 PFS Number (%) of patients with event 190 (86%) 166 (76%) Median in months (95% CI) 7.1 (6.9, 8.1) 7.1 (6.8, 7.7) Hazard ratio* (95% CI) 0.80 (0.65, 0.99) p-Value† 0.0194 Objective Response Rate ORR % (95% CI) 52% (45.5, 59.0) 29% (23.0, 35.4) Complete responses 1 (0.5%) 0 (0%) Partial responses 115 (52%) 63 (29%) p-Value‡ <0.00001 Duration of Response§ Median in months (95% CI) 6.9 (5.8, 8.3) 6.8 (5.5, 8.5) * Based on stratified Cox proportional hazard model † Based on stratified log-rank test ‡ Based on Miettinen and Nurminen method stratified by histological subtype at randomization (epithelioid vs. non-epithelioid) § Based on patients with a best overall response as confirmed complete or partial response; n=116 for patients in the KEYTRUDA combination arm; n=63 for patients in the chemotherapy arm 98 Reference ID: 5493485 100 90 80 70 60 so 40 30 20 10 0 \ L '- - - 7 0 6 12 18 24 30 36 42 48 54 60 66 72 222 196 143 109 86 218 176 128 92 68 54 40 25 16 13 12 6 2 4 0 0 0 0 0 Figure 12: Kaplan-Meier Curve for Overall Survival in KEYNOTE-483 Treatment arm KEYTRUDA + Chemotherapy Control Overall Survival (%) Time in Months Number at Risk KEYTRUDA + Chemotherapy Control In a pre-specified exploratory analysis based on histology, in the subgroup of patients with epithelioid histology (n=345), the hazard ratio (HR) for OS was 0.89 (95% CI: 0.70, 1.13), with median OS of 19.8 months in KEYTRUDA in combination with chemotherapy and 18.2 months in chemotherapy alone. In the subgroup of patients with non-epithelioid histology (n=95), the HR for OS was 0.57 (95% CI: 0.36, 0.89), with median OS of 12.3 months in KEYTRUDA in combination with chemotherapy and 8.2 months in chemotherapy alone. 14.4 Head and Neck Squamous Cell Cancer First-line treatment of metastatic or unresectable, recurrent HNSCC The efficacy of KEYTRUDA was investigated in KEYNOTE-048 (NCT02358031), a randomized, multicenter, open-label, active-controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy for metastatic disease or with recurrent disease who were considered incurable by local therapies. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by tumor PD-L1 expression (TPS ≥50% or <50%) according to the 99 Reference ID: 5493485 PD-L1 IHC 22C3 pharmDx kit, HPV status according to p16 IHC (positive or negative), and ECOG PS (0 vs. 1). Patients were randomized 1:1:1 to one of the following treatment arms: • KEYTRUDA 200 mg intravenously every 3 weeks • KEYTRUDA 200 mg intravenously every 3 weeks, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m2 intravenously every 3 weeks, and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU) • Cetuximab 400 mg/m2 intravenously as the initial dose then 250 mg/m2 intravenously once weekly, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m2 intravenously every 3 weeks, and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU) Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at Week 9 and then every 6 weeks for the first year, followed by every 9 weeks through 24 months. A retrospective re-classification of patients’ tumor PD-L1 status according to CPS using the PD-L1 IHC 22C3 pharmDx kit was conducted using the tumor specimens used for randomization. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) sequentially tested in the subgroup of patients with CPS ≥20, the subgroup of patients with CPS ≥1, and the overall population. The study population characteristics were: median age of 61 years (range: 20 to 94), 36% age 65 or older; 83% male; 73% White, 20% Asian and 2.4% Black; 61% had ECOG PS of 1; and 79% were former/current smokers. Twenty-two percent of patients’ tumors were HPV-positive, 23% had PD-L1 TPS ≥50%, and 95% had Stage IV disease (Stage IVA 19%, Stage IVB 6%, and Stage IVC 70%). Eighty-five percent of patients’ tumors had PD-L1 expression of CPS ≥1 and 43% had CPS ≥20. The trial demonstrated a statistically significant improvement in OS for patients randomized to KEYTRUDA in combination with chemotherapy compared to those randomized to cetuximab in combination with chemotherapy at a pre-specified interim analysis in the overall population. Table 70 and Figure 13 summarize efficacy results for KEYTRUDA in combination with chemotherapy. 100 Reference ID: 5493485 Table 70: Efficacy Results* for KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048 Endpoint KEYTRUDA 200 mg every 3 weeks Platinum FU n=281 Cetuximab Platinum FU n=278 OS Number (%) of patients with event 197 (70%) 223 (80%) Median in months (95% CI) 13.0 (10.9, 14.7) 10.7 (9.3, 11.7) Hazard ratio† (95% CI) 0.77 (0.63, 0.93) p-Value‡ 0.0067 PFS Number of patients with event (%) 244 (87%) 253 (91%) Median in months (95% CI) 4.9 (4.7, 6.0) 5.1 (4.9, 6.0) Hazard ratio† (95% CI) 0.92 (0.77, 1.10) p-Value‡ 0.3394 Objective Response Rate ORR§ (95% CI) 36% (30.0, 41.5) 36% (30.7, 42.3) Complete response rate 6% 3% Partial response rate 30% 33% Duration of Response Median in months (range) 6.7 (1.6+, 30.4+) 4.3 (1.2+, 27.9+) * Results at a pre-specified interim analysis † Based on the stratified Cox proportional hazard model ‡ Based on stratified log-rank test § Response: Best objective response as confirmed complete response or partial response At the pre-specified final OS analysis for the ITT population, the hazard ratio was 0.72 (95% CI: 0.60, 0.87). In addition, KEYNOTE-048 demonstrated a statistically significant improvement in OS for the subgroups of patients with PD-L1 CPS ≥1 (HR=0.65, 95% CI: 0.53, 0.80) and CPS ≥20 (HR=0.60, 95% CI: 0.45, 0.82). 101 Reference ID: 5493485 Figure 13: Kaplan-Meier Curve for Overall Survival for KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048* 100 90 80 70 60 50 40 30 20 10 0 Overall Survival (%) Treatment arm KEYTRUDA + Chemo Standard 0 5 10 15 20 25 30 35 40 45 Time in Months Number at Risk KEYTRUDA + Chemo: 281 227 169 122 94 77 55 29 5 0 0 Standard: 278 227 147 100 66 45 23 6 1 0 0 * At the time of the protocol-specified final analysis. The trial also demonstrated a statistically significant improvement in OS for the subgroup of patients with PD-L1 CPS ≥1 randomized to KEYTRUDA as a single agent compared to those randomized to cetuximab in combination with chemotherapy at a pre-specified interim analysis. At the time of the interim and final analyses, there was no significant difference in OS between the KEYTRUDA single agent arm and the control arm for the overall population. Table 71 summarizes efficacy results for KEYTRUDA as a single agent in the subgroups of patients with CPS ≥1 HNSCC and CPS ≥20 HNSCC. Figure 14 summarizes the OS results in the subgroup of patients with CPS ≥1 HNSCC. 102 Reference ID: 5493485 50 Table 71: Efficacy Results* for KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS ≥1 and CPS ≥20) Endpoint CPS ≥1 CPS ≥20 KEYTRUDA 200 mg every 3 weeks n=257 Cetuximab Platinum FU n=255 KEYTRUDA 200 mg every 3 weeks n=133 Cetuximab Platinum FU n=122 OS Number of events (%) 177 (69%) 206 (81%) 82 (62%) 95 (78%) Median in months (95% CI) 12.3 (10.8, 14.9) 10.3 (9.0, 11.5) 14.9 (11.6, 21.5) 10.7 (8.8, 12.8) Hazard ratio† (95% CI) 0.78 (0.64, 0.96) 0.61 (0.45, 0.83) p-Value‡ 0.0171 0.0015 PFS Number of events (%) 225 (88%) 231 (91%) 113 (85%) 111 (91%) Median in months (95% CI) 3.2 (2.2, 3.4) 5.0 (4.8, 5.8) 3.4 (3.2, 3.8) 5.0 (4.8, 6.2) Hazard ratio† (95% CI) 1.15 (0.95, 1.38) 0.97 (0.74, 1.27) Objective Response Rate ORR§ (95% CI) 19% (14.5, 24.4) 35% (29.1, 41.1) 23% (16.4, 31.4) 36% (27.6, 45.3) Complete response rate 5% 3% 8% 3% Partial response rate 14% 32% 16% 33% Duration of Response Median in months (range) 20.9 (1.5+, 34.8+) 4.5 (1.2+, 28.6+) 20.9 (2.7, 34.8+) 4.2 (1.2+, 22.3+) * Results at a pre-specified interim analysis † Based on the stratified Cox proportional hazard model ‡ Based on a stratified log-rank test § Response: Best objective response as confirmed complete response or partial response At the pre-specified final OS analysis comparing KEYTRUDA as a single agent to cetuximab in combination with chemotherapy, the hazard ratio for the subgroup of patients with CPS ≥1 was 0.74 (95% CI: 0.61, 0.90) and the hazard ratio for the subgroup of patients with CPS ≥20 was 0.58 (95% CI: 0.44, 0.78). In an exploratory subgroup analysis for patients with CPS 1-19 HNSCC at the time of the pre-specified final OS analysis, the median OS was 10.8 months (95% CI: 9.0, 12.6) for KEYTRUDA as a single agent and 10.1 months (95% CI: 8.7, 12.1) for cetuximab in combination with chemotherapy, with an HR of 0.86 (95% CI: 0.66, 1.12). 103 Reference ID: 5493485 Figure 14: Kaplan-Meier Curve for Overall Survival for KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS ≥1)* 100 90 80 70 60 50 40 30 20 10 0 Treatment arm KEYTRUDA Standard 0 5 10 15 20 25 30 35 40 45 50 Time in Months Overall Survival (%) Number at Risk KEYTRUDA: 257 197 152 110 91 70 43 21 13 1 0 Standard: 255 207 131 89 59 40 21 9 5 0 0 * At the time of the protocol-specified final analysis. Previously treated recurrent or metastatic HNSCC The efficacy of KEYTRUDA was investigated in KEYNOTE-012 (NCT01848834), a multicenter, non- randomized, open-label, multi-cohort study that enrolled 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy. Patients with active autoimmune disease, a medical condition that required immunosuppression, evidence of interstitial lung disease, or ECOG PS ≥2 were ineligible. Patients received KEYTRUDA 10 mg/kg every 2 weeks (n=53) or 200 mg every 3 weeks (n=121) until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR. The study population characteristics were median age of 60 years, 32% age 65 or older; 82% male; 75% White, 16% Asian, and 6% Black; 87% had M1 disease; 33% had HPV positive tumors; 63% had prior cetuximab; 29% had an ECOG PS of 0 and 71% had an ECOG PS of 1; and the median number of prior lines of therapy administered for the treatment of HNSCC was 2. 104 Reference ID: 5493485 The ORR was 16% (95% CI: 11, 22) with a complete response rate of 5%. The median follow-up time was 8.9 months. Among the 28 responding patients, the median DoR had not been reached (range: 2.4+ to 27.7+ months), with 23 patients having responses of 6 months or longer. The ORR and DoR were similar irrespective of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status. 14.5 Classical Hodgkin Lymphoma KEYNOTE-204 The efficacy of KEYTRUDA was investigated in KEYNOTE-204 (NCT02684292), a randomized, open- label, active controlled trial conducted in 304 patients with relapsed or refractory cHL. The trial enrolled adults with relapsed or refractory disease after at least one multi-agent chemotherapy regimen. Patients were randomized (1:1) to receive: • KEYTRUDA 200 mg intravenously every 3 weeks or • Brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks Treatment was continued until unacceptable toxicity, disease progression, or a maximum of 35 cycles (up to approximately 2 years). Disease assessment was performed every 12 weeks. Randomization was stratified by prior autologous HSCT (yes vs. no) and disease status after frontline therapy (primary refractory vs. relapse <12 months after completion vs. relapse ≥12 months after completion). The main efficacy measure was PFS as assessed by BICR using 2007 revised International Working Group criteria. The study population characteristics were: median age of 35 years (range: 18 to 84); 57% male; 77% White, 9% Asian, 3.9% Black. The median number of prior therapies was 2 (range: 1 to 10) in the KEYTRUDA arm and 3 (range: 1 to 11) in the BV arm, with 18% in both arms having 1 prior line. Forty- two percent of patients were refractory to the last prior therapy, 29% had primary refractory disease, 37% had prior autologous HSCT, 5% had received prior BV, and 39% had prior radiation therapy. Efficacy is summarized in Table 72 and Figure 15. Table 72: Efficacy Results in Patients with cHL in KEYNOTE-204 Endpoint KEYTRUDA 200 mg every 3 weeks n=151 Brentuximab Vedotin 1.8 mg/kg every 3 weeks n=153 PFS Number of patients with event (%) 81 (54%) 88 (58%) Median in months (95% CI)* 13.2 (10.9, 19.4) 8.3 (5.7, 8.8) Hazard ratio† (95% CI) 0.65 (0.48, 0.88) p-Value‡ 0.0027 Objective Response Rate ORR§ (95% CI) 66% (57, 73) 54% (46, 62) Complete response 25% 24% Partial response 41% 30% Duration of Response Median in months (range)* 20.7 (0.0+, 33.2+) 13.8 (0.0+, 33.9+) * Based on Kaplan-Meier estimates. † Based on the stratified Cox proportional hazard model. ‡ Based on a stratified log-rank test. One-sided p-Value, with a prespecified boundary of 0.0043. § Difference in ORR is not statistically significant. + Denotes a censored value. 105 Reference ID: 5493485 Number at Risk KEYTRUDA: e ro ·~ :::, CJ) <l) <l) u: C: 0 ·.; "' <l) a, 0 a:. 100 90 80 70 60 50 40 30 20 10 0 Brentuximab V edotin: T reabne-nt arm KEYTRUDA Brentuximab Vedotin 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Time in Months 151 116 96 74 65 55 44 35 18 15 153 103 63 41 32 26 19 14 10 7 9 5 4 2 0 0 0 0 Figure 15: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-204 KEYNOTE-087 The efficacy of KEYTRUDA was investigated in KEYNOTE-087 (NCT02453594), a multicenter, non- randomized, open-label trial in 210 patients with relapsed or refractory cHL. Patients with active, non­ infectious pneumonitis, an allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients who did not progress. Disease assessment was performed every 12 weeks. The major efficacy outcome measures (ORR, Complete Response Rate, and DoR) were assessed by BICR according to the 2007 revised International Working Group (IWG) criteria. The study population characteristics were: median age of 35 years (range: 18 to 76), 9% age 65 or older; 54% male; 88% White; and 49% ECOG PS of 0 and 51% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range: 1 to 12). Fifty-eight percent were refractory to the last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior regimens. Sixty-one percent of patients had undergone prior autologous HSCT, 83% had received prior brentuximab vedotin and 36% of patients had prior radiation therapy. Efficacy results for KEYNOTE-087 are summarized in Table 73. 106 Reference ID: 5493485 Table 73: Efficacy Results in Patients with cHL in KEYNOTE-087 Endpoint KEYTRUDA 200 mg every 3 weeks n=210* Objective Response Rate ORR (95% CI) 69% (62, 75) Complete response rate 22% Partial response rate 47% Duration of Response Median in months (range) 11.1 (0.0+, 11.1)† * Median follow-up time of 9.4 months † Based on patients (n=145) with a response by independent review 14.6 Primary Mediastinal Large B-Cell Lymphoma The efficacy of KEYTRUDA was investigated in KEYNOTE-170 (NCT02576990), a multicenter, open- label, single-arm trial in 53 patients with relapsed or refractory PMBCL. Patients were not eligible if they had active non-infectious pneumonitis, allogeneic HSCT within the past 5 years (or >5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy. Patients were treated with KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for patients who did not progress. Disease assessments were performed every 12 weeks and assessed by BICR according to the 2007 revised IWG criteria. The efficacy outcome measures were ORR and DoR. The study population characteristics were: median age of 33 years (range: 20 to 61 years); 43% male; 92% White; and 43% ECOG PS of 0 and 57% ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of PMBCL was 3 (range 2 to 8). Thirty-six percent had primary refractory disease, 49% had relapsed disease refractory to the last prior therapy, and 15% had untreated relapse. Twenty-six percent of patients had undergone prior autologous HSCT, and 32% of patients had prior radiation therapy. All patients had received rituximab as part of a prior line of therapy. For the 24 responders, the median time to first objective response (complete or partial response) was 2.8 months (range 2.1 to 8.5 months). Efficacy results for KEYNOTE-170 are summarized in Table 74. Table 74: Efficacy Results in Patients with PMBCL in KEYNOTE-170 Endpoint KEYTRUDA 200 mg every 3 weeks n=53* Objective Response Rate ORR (95% CI) 45% (32, 60) Complete response rate 11% Partial response rate 34% Duration of Response Median in months (range) NR (1.1+, 19.2+)† * Median follow-up time of 9.7 months † Based on patients (n=24) with a response by independent review NR = not reached 14.7 Urothelial Cancer In Combination with Enfortumab Vedotin for the Treatment of Patients with Urothelial Cancer The efficacy of KEYTRUDA in combination with enfortumab vedotin was evaluated in KEYNOTE-A39 (NCT04223856), an open-label, randomized, multicenter trial that enrolled 886 patients with locally advanced or metastatic urothelial cancer who received no prior systemic therapy for locally advanced or metastatic disease. Patients with active CNS metastases, ongoing sensory or motor neuropathy Grade ≥2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms were excluded. Patients were randomized 1:1 to receive either: 107 Reference ID: 5493485 • KEYTRUDA 200 mg over 30 minutes on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle. KEYTRUDA was given approximately 30 minutes after enfortumab vedotin. Treatment was continued until disease progression or unacceptable toxicity. In the absence of disease progression or unacceptable toxicity, KEYTRUDA was continued for up to 2 years. • Gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle with cisplatin 70 mg/m2 or carboplatin (AUC = 4.5 or 5) on Day 1 of a 21-day cycle. Treatment was continued until disease progression or unacceptable toxicity for up to 6 cycles. Randomization was stratified by cisplatin eligibility, PD-L1 expression, and presence of liver metastases. The median age was 69 years (range: 22 to 91); 77% were male; 67% were White, 22% were Asian, 1% were Black or African American, and 10% were unknown or other; 12% were Hispanic or Latino. Patients had a baseline ECOG performance status of 0 (49%), 1 (47%), or 2 (3%). Forty-seven percent of patients had a documented baseline HbA1c of <5.7%. At baseline, 95% of patients had metastatic urothelial cancer, including 72% with visceral and 22% with liver metastases, and 5% had locally advanced urothelial cancer. Eighty-five percent of patients had urothelial carcinoma (UC) histology including 6% with UC mixed squamous differentiation and 2% with UC mixed other histologic variants. Forty-six percent of patients were considered cisplatin-ineligible and 54% were considered cisplatin-eligible at time of randomization. The major efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1. Additional efficacy outcome measures included ORR as assessed by BICR. The trial demonstrated statistically significant improvements in OS, PFS, and ORR for patients randomized to KEYTRUDA in combination with enfortumab vedotin as compared to platinum-based chemotherapy. Efficacy results were consistent across all stratified patient subgroups. Table 75 and Figures 16 and 17 summarize the efficacy results for KEYNOTE-A39. Table 75: Efficacy Results in KEYNOTE-A39 Endpoint KEYTRUDA 200 mg every 3 weeks in combination with Enfortumab Vedotin n=442 Cisplatin or carboplatin with gemcitabine n=444 OS Number (%) of patients with event 133 (30%) 226 (51%) Median in months (95% CI) 31.5 (25.4, NR) 16.1 (13.9, 18.3) Hazard ratio* (95% CI) 0.47 (0.38, 0.58) p-Value† <0.0001 PFS Number (%) of patients with event 223 (50%) 307 (69%) Median in months (95% CI) 12.5 (10.4, 16.6) 6.3 (6.2, 6.5) Hazard ratio* (95% CI) 0.45 (0.38, 0.54) p-Value† <0.0001 Confirmed Objective Response Rate‡ ORR§ % (95% CI) 68% (63, 72) 44% (40, 49) p-Value¶ <0.0001 Complete response 29% 12% Partial response 39% 32% * Based on the stratified Cox proportional hazard regression model † Two-sided p-Value based on stratified log-rank test ‡ Includes only patients with measurable disease at baseline (n=437 for KEYTRUDA in combination with enfortumab vedotin, n=441 for chemotherapy). § Based on patients with a best overall response as confirmed complete or partial response ¶ Two-sided p-Value based on Cochran-Mantel-Haenszel test stratified by PD-L1 expression, cisplatin eligibility and liver metastases NR = not reached 108 Reference ID: 5493485 100 90 -·i 80 f, . ' 70 'f,' ·~\ 60 \ 50 "111,% '~\ 40 ~I~ 30 1 •HHIHH& t Hl1H +- -, I '-t+-+-1 20 10 0 0 2 4 6 8 10 12 14 1 6 18 20 22 24 26 28 30 32 34 36 38 442 426 409 394 376 331 270 222 182 141 108 67 36 22 12 8 0 444 423 393 356 317 263 209 164 125 90 60 37 25 18 12 7 6 2 0 Figure 16: Kaplan-Meier Curve for Overall Survival in KEYNOTE-A39 Treatment arm KEYTRUDA + EV Chemotherapy Overall Survival (%) Time in Months Number at Risk KEYTRUDA + EV Chemotherapy 109 Reference ID: 5493485 100~------------------------~ 90 80 70 60 50 40 30 20 10 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 442 409 361 303 253 204 167 132 102 73 45 33 17 6 3 0 444 380 297 213 124 78 56 41 30 19 8 6 5 3 2 0 Figure 17: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-A39 Treatment arm KEYTRUDA + EV Chemotherapy Progression-Free Survival (%) Time in Months Number at Risk KEYTRUDA + EV Chemotherapy In Combination with Enfortumab Vedotin for the Treatment of Cisplatin-Ineligible Patients with Urothelial Cancer The efficacy of KEYTRUDA in combination with enfortumab vedotin was evaluated in KEYNOTE-869 (NCT03288545), an open-label, multi-cohort (dose escalation cohort, Cohort A, Cohort K) study in patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-containing chemotherapy and received no prior systemic therapy for locally advanced or metastatic disease. Patients with active CNS metastases, ongoing sensory or motor neuropathy Grade ≥2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms were excluded from participating in the study. Patients in the dose escalation cohort (n=5), Cohort A (n=40), and Cohort K (n=76) received enfortumab vedotin 1.25 mg/kg as an IV infusion over 30 minutes on Days 1 and 8 of a 21-day cycle followed by KEYTRUDA 200 mg as an IV infusion on Day 1 of a 21-day cycle approximately 30 minutes after enfortumab vedotin. Patients were treated until disease progression or unacceptable toxicity. A total of 121 patients received KEYTRUDA in combination with enfortumab vedotin. The median age was 71 years (range: 51 to 91); 74% were male; 85% were White, 5% were Black, 4% were Asian and 6% were other, unknown or not reported. Ten percent of patients were Hispanic or Latino. Forty-five 110 Reference ID: 5493485 percent of patients had an ECOG performance status of 1 and 15% had an ECOG performance status of 2. Forty-seven percent of patients had a documented baseline HbA1c of <5.7%. Reasons for cisplatin-ineligibility included: 60% with baseline creatinine clearance of 30-59 mL/min, 10% with ECOG PS of 2, 13% with Grade 2 or greater hearing loss, and 16% with more than one cisplatin-ineligibility criteria. At baseline, 97.5% of patients had metastatic urothelial cancer and 2.5% of patients had locally advanced urothelial cancer. Thirty-seven percent of patients had upper tract disease. Eighty-four percent of patients had visceral metastasis at baseline, including 22% with liver metastases. Thirty-nine percent of patients had TCC histology; 13% had TCC with squamous differentiation, and 48% had TCC with other histologic variants. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1. The median follow-up time for the dose escalation cohort + Cohort A was 44.7 months (range 0.7 to 52.4) and for Cohort K was 14.8 months (range: 0.6 to 26.2). Efficacy results are presented in Table 76 below. Table 76: Efficacy Results in KEYNOTE-869, Combined Dose Escalation Cohort, Cohort A, and Cohort K Endpoint KEYTRUDA in combination with Enfortumab Vedotin n=121 Confirmed ORR (95% CI) 68% (58.7, 76.0) Complete response rate 12% Partial response rate 55% The median duration of response for the dose escalation cohort + Cohort A was 22.1 months (range: 1.0+ to 46.3+) and for Cohort K was not reached (range: 1.2 to 24.1+). Platinum-Ineligible Patients with Urothelial Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-052 (NCT02335424), a multicenter, open- label, single-arm trial in 370 patients with locally advanced or metastatic urothelial carcinoma who had one or more comorbidities, including patients who were not eligible for any platinum-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Tumor response assessments were performed at 9 weeks after the first dose, then every 6 weeks for the first year, and then every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study population characteristics were: median age of 74 years; 77% male; and 89% White. Eighty- seven percent had M1 disease, and 13% had M0 disease. Eighty-one percent had a primary tumor in the lower tract, and 19% of patients had a primary tumor in the upper tract. Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Fifty percent of patients had baseline creatinine clearance of <60 mL/min, 32% had ECOG PS of 2, 9% had ECOG PS of 2 and baseline creatinine clearance of <60 mL/min, and 9% had one or more of Class III heart failure, Grade 2 or greater peripheral neuropathy, and Grade 2 or greater hearing loss. Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy. The median follow-up time for 370 patients treated with KEYTRUDA was 11.4 months (range 0.1 to 63.8 months). Efficacy results are summarized in Table 77. 111 Reference ID: 5493485 Table 77: Efficacy Results in KEYNOTE-052 Endpoint KEYTRUDA 200 mg every 3 weeks All Subjects n=370 Objective Response Rate ORR (95% CI) 29% (24, 34) Complete response rate 10% Partial response rate 20% Duration of Response Median in months (range) 33.4 (1.4+, 60.7+) + Denotes ongoing response Platinum-Eligible Patients with Previously Untreated Urothelial Carcinoma The efficacy of KEYTRUDA for the first-line treatment of platinum-eligible patients with locally advanced or metastatic urothelial carcinoma was investigated in KEYNOTE-361 (NCT02853305), a multicenter, randomized, open-label, active-controlled study in 1010 previously untreated patients. The safety and efficacy of KEYTRUDA in combination with platinum-based chemotherapy for previously untreated patients with locally advanced or metastatic urothelial carcinoma has not been established. The study compared KEYTRUDA with or without platinum-based chemotherapy (i.e., cisplatin or carboplatin with gemcitabine) to platinum-based chemotherapy alone. Among the patients receiving KEYTRUDA plus platinum-based chemotherapy, 44% received cisplatin and 56% received carboplatin. The study did not meet its major efficacy outcome measures of improved PFS or OS in the KEYTRUDA plus chemotherapy arm compared to the chemotherapy-alone arm. Additional efficacy endpoints, including improvement of OS in the KEYTRUDA monotherapy arm, could not be formally tested. Previously Treated Urothelial Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-045 (NCT02256436), a multicenter, randomized (1:1), active-controlled trial in 542 patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients were randomized to receive either KEYTRUDA 200 mg every 3 weeks (n=270) or investigator’s choice of any of the following chemotherapy regimens all given intravenously every 3 weeks (n=272): paclitaxel 175 mg/m2 (n=90), docetaxel 75 mg/m2 (n=92), or vinflunine 320 mg/m2 (n=90). Treatment continued until unacceptable toxicity or disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed at 9 weeks after randomization, then every 6 weeks through the first year, followed by every 12 weeks thereafter. The major efficacy outcomes were OS and PFS as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR as assessed by BICR per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and DoR. The study population characteristics were: median age of 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 42% ECOG PS of 0 and 56% ECOG PS of 1; and 96% M1 disease and 4% M0 disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver metastases. Eighty-six percent had a primary tumor in the lower tract and 14% had a primary tumor in the upper tract. Fifteen percent of patients had disease progression following prior platinum- containing neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 or more prior systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior carboplatin, and 1% were treated with other platinum-based regimens. 112 Reference ID: 5493485 The study demonstrated statistically significant improvements in OS and ORR for patients randomized to KEYTRUDA as compared to chemotherapy. There was no statistically significant difference between KEYTRUDA and chemotherapy with respect to PFS. The median follow-up time for this trial was 9.0 months (range: 0.2 to 20.8 months). Table 78 and Figure 18 summarize the efficacy results for KEYNOTE-045. Table 78: Efficacy Results in KEYNOTE-045 KEYTRUDA 200 mg every 3 weeks n=270 Chemotherapy n=272 OS Deaths (%) 155 (57%) 179 (66%) Median in months (95% CI) 10.3 (8.0, 11.8) 7.4 (6.1, 8.3) Hazard ratio* (95% CI) 0.73 (0.59, 0.91) p-Value (stratified log-rank) 0.004 PFS by BICR Events (%) 218 (81%) 219 (81%) Median in months (95% CI) 2.1 (2.0, 2.2) 3.3 (2.3, 3.5) Hazard ratio* (95% CI) 0.98 (0.81, 1.19) p-Value (stratified log-rank) 0.833 Objective Response Rate ORR (95% CI) 21% (16, 27) 11% (8, 16) Complete response rate 7% 3% Partial response rate 14% 8% p-Value (Miettinen-Nurminen) 0.002 Median duration of response in months (range) NR (1.6+, 15.6+) 4.3 (1.4+, 15.4+) * Hazard ratio (KEYTRUDA compared to chemotherapy) based on the stratified Cox proportional hazard model + Denotes ongoing response NR = not reached Figure 18: Kaplan-Meier Curve for Overall Survival in KEYNOTE-045 100 90 80 70 60 50 40 30 20 10 0 Overall Survival (%) Treatment arm KEYTRUDA Chemotherapy 0 2 4 6 8 10 12 14 16 18 20 22 24 Time in Months Number at Risk KEYTRUDA: 270 226 194 169 147 131 87 54 27 13 4 0 0 Chemotherapy: 272 232 171 138 109 89 55 27 14 3 0 0 0 113 Reference ID: 5493485 BCG-unresponsive High-Risk Non-Muscle Invasive Bladder Cancer The efficacy of KEYTRUDA was investigated in KEYNOTE-057 (NCT02625961), a multicenter, open- label, single-arm trial in 96 patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non- muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. BCG-unresponsive high-risk NMIBC was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor- free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Adequate BCG therapy was defined as administration of at least five of six doses of an initial induction course plus either of: at least two of three doses of maintenance therapy or at least two of six doses of a second induction course. Prior to treatment, all patients had undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease (Ta and T1 components). Residual CIS (Tis components) not amenable to complete resection was allowed. The trial excluded patients with muscle invasive (i.e., T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma, concurrent extra-vesical (i.e., urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium, or autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease. Assessment of tumor status was performed every 12 weeks for two years and then every 24 weeks for three years, and patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and computed tomography urography [CTU] imaging) and duration of response. The study population characteristics were: median age of 73 years (range: 44 to 92); 44% age ≥75; 84% male; 67% White; and 73% and 27% with an ECOG performance status of 0 or 1, respectively. Tumor pattern at study entry was CIS with T1 (13%), CIS with high grade TA (25%), and CIS (63%). Baseline high-risk NMIBC disease status was 27% persistent and 73% recurrent. The median number of prior instillations of BCG was 12. The median follow-up time was 28.0 months (range: 4.6 to 40.5 months). Efficacy results are summarized in Table 79. Table 79: Efficacy Results in KEYNOTE-057 Endpoint KEYTRUDA 200 mg every 3 weeks n=96 Complete Response Rate (95% CI) 41% (31, 51) Duration of Response* Median in months (range) 16.2 (0.0+, 30.4+) % (n) with duration ≥12 months 46% (18) * Based on patients (n=39) that achieved a complete response; reflects period from the time complete response was achieved + Denotes ongoing response 14.8 Microsatellite Instability-High or Mismatch Repair Deficient Cancer The efficacy of KEYTRUDA was investigated in 504 patients with MSI-H or dMMR cancers enrolled in three multicenter, non-randomized, open-label, multi-cohort trials: KEYNOTE-164 (NCT02460198), KEYNOTE-158 (NCT02628067), and KEYNOTE-051 (NCT02332668). All trials excluded patients with autoimmune disease or a medical condition that required immunosuppression. Regardless of histology, MSI or MMR tumor status was determined using polymerase chain reaction (PCR; local or central) or immunohistochemistry (IHC; local or central), respectively. • KEYNOTE-164 enrolled 124 patients with advanced MSI-H or dMMR colorectal cancer (CRC) that progressed following treatment with fluoropyrimidine and either oxaliplatin or irinotecan +/- anti-VEGF/EGFR mAb-based therapy. • KEYNOTE-158 enrolled 373 patients with advanced MSI-H or dMMR non-colorectal cancers (non-CRC) who had disease progression following prior therapy. Patients were either prospectively 114 Reference ID: 5493485 enrolled with MSI-H/dMMR tumors (Cohort K) or retrospectively identified in one of 10 solid tumor cohorts (Cohorts A-J). • KEYNOTE-051 enrolled 7 pediatric patients with MSI-H or dMMR cancers. Adult patients received KEYTRUDA 200 mg every 3 weeks (pediatric patients received 2 mg/kg every 3 weeks) until unacceptable toxicity, disease progression, or a maximum of 24 months. In KEYNOTE-164 and KEYNOTE-158, assessment of tumor status was performed every 9 weeks through the first year, then every 12 weeks thereafter. In KEYNOTE-051, assessment of tumor status was performed every 8 weeks for 24 weeks, and then every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ in KEYNOTE-158) and as assessed by the investigator according to RECIST v1.1 in KEYNOTE-051. In KEYNOTE-164 and KEYNOTE-158, the study population characteristics were median age of 60 years, 36% age 65 or older; 44% male; 78% White, 14% Asian, 4% American Indian or Alaska Native, and 3% Black; and 45% ECOG PS of 0 and 55% ECOG PS of 1. Ninety-two percent of patients had metastatic disease and 4% had locally advanced, unresectable disease. Thirty-seven percent of patients received one prior line of therapy and 61% received two or more prior lines of therapy. In KEYNOTE-051, the study population characteristics were median age of 11 years (range: 3 to 16); 71% female; 86% White and 14% Asian; and 57% had a Lansky/Karnofsky Score of 100. Seventy-one percent of patients had Stage IV and 14% had Stage III disease. Fifty-seven percent of patients received one prior line of therapy and 29% received two prior lines of therapy. Discordant results were observed between local MSI-H or dMMR tests and central testing among patients enrolled in Cohort K of KEYNOTE-158. Among 104 tumor samples that were MSI-H or dMMR by local testing and also tested using the FoundationOne®CDx (F1CDx) test, 59 (56.7%) were MSI-H and 45 (43.3%) were not MSI-H. Among 169 tumor samples that were MSI-H or dMMR by local testing and also tested using the VENTANA MMR RxDx Panel, 105 (62.1%) were dMMR and 64 (37.9%) were pMMR. Efficacy results are summarized in Tables 80 and 81. Table 80: Efficacy Results for Patients with MSI-H/dMMR Cancer Endpoint KEYTRUDA n=504* Objective Response Rate ORR (95% CI)† 33.3% (29.2, 37.6) Complete response rate 10.3% Partial response rate 23.0% Duration of Response n=168 Median in months (range) 63.2 (1.9+, 63.9+) % with duration ≥12 months 77% % with duration ≥36 months 39% * Median follow-up time of 20.1 months (range 0.1 to 71.4 months) † Of the 7 pediatric patients from KEYNOTE-051, 1 patient had a radiographic complete response after initial growth of their tumor but is not reflected in the results. + Denotes ongoing response 115 Reference ID: 5493485 Table 81: Response by Tumor Type N Objective Response Rate n (%) 95% CI Duration of Response range (months) CRC 124 42 (34%) (26%, 43%) (4.4, 58.5+) Non-CRC* 380 126 (33%) (28%, 38%) (1.9+, 63.9+) Endometrial cancer 94 47 (50%) (40%, 61%) (2.9, 63.2) Gastric or GE junction cancer 51 20 (39%) (26%, 54%) (1.9+, 63.0+) Small intestinal cancer 27 16 (59%) (39%, 78%) (3.7+, 57.3+) Brain cancer 27† 1 (4%)‡ (0%, 19%) 18.9 Ovarian cancer 25 8 (32%) (15%, 54%) (4.2, 56.6+) Biliary cancer 22 9 (41%) (21%, 64%) (6.2, 49.0+) Pancreatic cancer 22 4 (18%) (5%, 40%) (8.1, 24.3+) Sarcoma 14 3 (21%) (5%, 51%) (35.4+, 57.2+) Breast cancer 13 1 (8%) (0%,36%) 24.3+ Other§ 13 4 (31%) (9%, 61%) (6.2+, 32.3+) Cervical cancer 11 1 (9%) (0%, 41%) 63.9+ Neuroendocrine cancer 11 1 (9%) (0%, 41%) 13.3 Prostate cancer 8 1 (13%) (0%, 53%) 24.5+ Adrenocortical cancer 7 1 (14%) (0%, 58%) 4.2 Mesothelioma 7 0 (0%) (0%, 41%) Thyroid cancer 7 1 (14%) (0%, 58%) 8.2 Small cell lung cancer 6 2 (33%) (4%, 78%) (20.0, 47.5) Bladder cancer 6 3 (50%) (12%, 88%) (35.6+, 57.5+) Salivary cancer 5 2 (40%) (5%, 85%) (42.6+, 57.8+) Renal cell cancer 4 1 (25%) (0%, 81%) 22.0 * Results include patients in Cohort K of KEYNOTE-158 that were later determined to be pMMR or not MSI-H by central testing † Includes 6 pediatric patients with brain cancer ‡ In addition to the 1 adult responder, 1 pediatric patient had a radiographic complete response after initial growth of their tumor. § Includes tumor type (n): anal (3), HNSCC (1), nasopharyngeal (1), retroperitoneal (1), testicular (1), vaginal (1), vulvar (1), appendiceal adenocarcinoma, NOS (1), hepatocellular carcinoma (1), and carcinoma of unknown origin (1). Includes 1 pediatric patient with abdominal adenocarcinoma. + Denotes ongoing response Exploratory analysis by TMB In an exploratory analysis performed in 138 patients (Cohort K of KEYNOTE-158) who were tested retrospectively for tumor mutation burden (TMB) using an FDA-approved test, 45 (33%) had tumors with TMB score of <10 mut/Mb; ORR in these 45 patients was 6.7% (95% CI: 1.4, 18.3). Among the 45 patients with TMB score of <10 mut/Mb, 39 of the patients were not MSI-H/dMMR when tested using an FDA-approved test. 14.9 Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer The efficacy of KEYTRUDA was investigated in KEYNOTE-177 (NCT02563002), a multicenter, randomized, open-label, active-controlled trial that enrolled 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR CRC. MSI or MMR tumor status was determined locally using polymerase chain reaction (PCR) or immunohistochemistry (IHC), respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of the following chemotherapy regimens given intravenously every 2 weeks: • mFOLFOX6 (oxaliplatin, leucovorin, and FU) or mFOLFOX6 in combination with either bevacizumab or cetuximab: Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2400 mg/m2 over 46-48 hours. Bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly. • FOLFIRI (irinotecan, leucovorin, and FU) or FOLFIRI in combination with either bevacizumab or cetuximab: Irinotecan 180 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and FU 400 mg/m2 bolus on Day 1, then FU 2400 mg/m2 over 46-48 hours. Bevacizumab 5 mg/kg on Day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly. 116 Reference ID: 5493485 Treatment with KEYTRUDA or chemotherapy continued until RECIST v1.1-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks. Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression. The main efficacy outcome measures were PFS (as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) and OS. Additional efficacy outcome measures were ORR and DoR. A total of 307 patients were enrolled and randomized to KEYTRUDA (n=153) or chemotherapy (n=154). The baseline characteristics of these 307 patients were: median age of 63 years (range: 24 to 93), 47% age 65 or older; 50% male; 75% White and 16% Asian; 52% had an ECOG PS of 0 and 48% had an ECOG PS of 1; and 27% received prior adjuvant or neoadjuvant chemotherapy. Among 154 patients randomized to receive chemotherapy,143 received chemotherapy per the protocol. Of the 143 patients, 56% received mFOLFOX6, 44% received FOLFIRI, 70% received bevacizumab plus mFOLFOX6 or FOLFIRI, and 11% received cetuximab plus mFOLFOX6 or FOLFIRI. The trial demonstrated a statistically significant improvement in PFS for patients randomized to KEYTRUDA compared with chemotherapy. There was no statistically significant difference between KEYTRUDA and chemotherapy in the final OS analysis. Sixty percent of the patients who had been randomized to receive chemotherapy had crossed over to receive subsequent anti-PD-1/PD-L1 therapies including KEYTRUDA. The median follow-up time at the final analysis was 38.1 months (range: 0.2 to 58.7 months). Table 82 and Figure 19 summarize the key efficacy measures for KEYNOTE-177. Table 82: Efficacy Results in Patients with MSI-H or dMMR CRC in KEYNOTE-177 Endpoint KEYTRUDA 200 mg every 3 weeks n=153 Chemotherapy n=154 PFS Number (%) of patients with event 82 (54%) 113 (73%) Median in months (95% CI) 16.5 (5.4, 32.4) 8.2 (6.1, 10.2) Hazard ratio* (95% CI) 0.60 (0.45, 0.80) p-Value† 0.0004 OS‡ Number (%) of patients with event 62 (41%) 78 (51%) Median in months (95% CI) NR (49.2, NR) 36.7 (27.6, NR) Hazard ratio* (95% CI) 0.74 (0.53, 1.03) p-Value§ 0.0718 Objective Response Rate¶ ORR (95% CI) 44% (35.8, 52.0) 33% (25.8, 41.1) Complete response rate 11% 4% Partial response rate 33% 29% Duration of Response¶,# Median in months (range) NR (2.3+, 41.4+) 10.6 (2.8, 37.5+) % with duration ≥12 monthsÞ 75% 37% % with duration ≥24 monthsÞ 43% 18% * Based on Cox regression model † Two-sided p-Value based on log-rank test (compared to a significance level of 0.0234) ‡ Final OS analysis § Two-sided p-Value based on log-rank test (compared to a significance level of 0.0492) ¶ Based on confirmed response by BICR review # Based on n=67 patients with a response in the KEYTRUDA arm and n=51 patients with a response in the chemotherapy arm Þ Based on observed duration of response + Denotes ongoing response NR = not reached 117 Reference ID: 5493485 100 Treatment arm KEYT RUDA 90 C:hemotherap-y I 80 ' ~ 70 "' > ~ 60 :J en Q) -,,"i Q) 50 \ u:: c I..\ 0 .;; 40 \, "' Q) a, ,._ ... 0 30 ,.,_1 u. -'-'t-._ 20 --.+._L 10 'It"\. .. , 'l-t-1---1-1 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Time in Months Number at Risk KEYT RUDA: 153 96 77 72 64 60 55 37 20 7 5 0 0 Chemoth erapy: 154 100 68 43 33 22 18 11 4 3 0 0 0 Figure 19: Kaplan-Meier Curve for PFS in KEYNOTE-177 14.10 Gastric Cancer First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma The efficacy of KEYTRUDA in combination with trastuzumab plus fluoropyrimidine and platinum chemotherapy was investigated in KEYNOTE-811 (NCT03615326), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 698 patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who had not previously received systemic therapy for metastatic disease. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx™ kit. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by PD-L1 expression (CPS ≥1 or CPS <1), chemotherapy regimen (5-FU plus cisplatin [FP] or capecitabine plus oxaliplatin [CAPOX]), and geographic region (Europe/Israel/North America/Australia, Asia, or Rest of the World). Patients were randomized (1:1) to one of the following treatment arms: • KEYTRUDA 200 mg, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). KEYTRUDA was administered prior to trastuzumab and chemotherapy on Day 1 of each cycle. • Placebo, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). All study medications, except oral capecitabine, were administered as an intravenous infusion every 3-week cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. In an interim efficacy analysis, the major outcome measures assessed were ORR and DoR by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. 118 Reference ID: 5493485 At the time of the interim analysis, ORR and DoR were assessed in the first 264 patients randomized. Among the 264 patients, the population characteristics were: median age of 62 years (range: 19 to 84), 41% age 65 or older; 82% male; 63% White, 31% Asian, and 0.8% Black; 47% ECOG PS of 0 and 53% ECOG PS of 1. Ninety-seven percent of patients had metastatic disease (Stage IV) and 3% had locally advanced unresectable disease. Ninety-one percent (n=240) had tumors that were not MSI-H, 1% (n=2) had tumors that were MSI-H, and in 8% (n=22) the status was not known. Eighty-seven percent of patients received CAPOX. A statistically significant improvement in ORR was demonstrated in patients randomized to KEYTRUDA in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy. Efficacy results are summarized in Table 83. Table 83: Efficacy Results for KEYNOTE-811 Endpoint KEYTRUDA 200 mg every 3 weeks Trastuzumab Fluoropyrimidine and Platinum Chemotherapy n=133 Placebo Trastuzumab Fluoropyrimidine and Platinum Chemotherapy n=131 Objective Response Rate ORR* (95% CI) 74% (66, 82) 52% (43, 61) Complete response rate 11% 3.1% Partial response rate 63% 49% p-Value† <0.0001 Duration of Response n=99 n=68 Median in months (range) 10.6 (1.1+, 16.5+) 9.5 (1.4+, 15.4+) % with duration ≥6 months‡ 65% 53% * Response: Best objective response as confirmed complete response or partial response † p-Value based on stratified Miettinen and Nurminen method (compared to an alpha boundary of 0.002) ‡ Based on observed duration of response + Denotes ongoing response In a pre-specified subgroup analysis of ORR based on PD-L1 status, the ORR in patients with PD-L1­ positive disease (CPS ≥1) was 76% (95% CI: 67, 83) in the pembrolizumab arm (n=117) versus 51% (95% CI: 41, 60) in the control arm (n=112). In patients with tumors that were PD-L1 CPS<1, the ORR was 63% (95% CI: 35, 85) in the pembrolizumab arm (n=16) versus 58% (95% CI: 34, 80) in the control arm (n=19). In a subsequent interim analysis of pre-specified subgroups based on PD-L1 status in the full study population (n=698), the HR for PFS and OS in patients with PD-L1 CPS<1 (N=104) was 1.03 (95% CI: 0.65, 1.64) and 1.41 (95% CI: 0.90, 2.20), respectively. First-line Treatment of Locally Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction Adenocarcinoma The efficacy of KEYTRUDA in combination with fluoropyrimidine- and platinum-containing chemotherapy was investigated in KEYNOTE-859 (NCT03675737), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1579 patients with HER2-negative advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by PD-L1 expression (CPS ≥1 or CPS <1), chemotherapy regimen (FP or CAPOX), and geographic region (Europe/Israel/North America/Australia, Asia, or Rest of the World). Patients were randomized (1:1) to one of the following treatment arms; treatment was administered prior to chemotherapy on Day 1 of each cycle: • KEYTRUDA 200 mg, investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 and 5­ FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). 119 Reference ID: 5493485 • Placebo, investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). All study medications, except oral capecitabine, were administered as an intravenous infusion every 3-week cycle. Platinum agents could be administered for 6 or more cycles following local guidelines. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. The major efficacy outcome measure was OS. Additional secondary efficacy outcome measures included PFS, ORR, and DoR as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The population characteristics were: median age of 62 years (range: 21 to 86), 39% age 65 or older; 68% male and 32% female; 55% White, 34% Asian, 4.6% Multiple, 4.2% American Indian or Alaskan Native, 1.3% Black, and 0.2% Native Hawaiian or other Pacific Islander; 76% Not Hispanic or Latino and 21% Hispanic or Latino; 37% ECOG PS of 0 and 63% ECOG PS of 1. Ninety-seven percent of patients had metastatic disease (Stage IV) and 3% had locally advanced unresectable disease. Seventy-eight percent had tumors that expressed PD-L1 with a CPS ≥1 and 5% (n=74) had tumors that were MSI-H. Eighty-six percent of patients received CAPOX. A statistically significant improvement in OS, PFS, and ORR was demonstrated in patients randomized to KEYTRUDA in combination with chemotherapy compared with placebo in combination with chemotherapy at the time of a pre-specified interim analysis of OS. Efficacy results are summarized in Table 84 and Figures 20 and 21. 120 Reference ID: 5493485 Table 84: Efficacy Results* for KEYNOTE-859 Endpoint KEYTRUDA 200 mg every 3 weeks and FP or CAPOX n=790 Placebo and FP or CAPOX n=789 KEYTRUDA 200 mg every 3 weeks and FP or CAPOX n=618 Placebo and FP or CAPOX n=617 KEYTRUDA 200 mg every 3 weeks and FP or CAPOX n=279 Placebo and FP or CAPOX n=272 All Patients CPS≥1 CPS≥10 OS Number (%) of patients with event 603 (76) 666 (84) 464 (75) 526 (85) 188 (67) 226 (83) Median in months (95% CI) 12.9 (11.9, 14.0) 11.5 (10.6, 12.1) 13.0 (11.6, 14.2) 11.4 (10.5, 12.0) 15.7 (13.8, 19.3) 11.8 (10.3, 12.7) Hazard ratio† (95% CI) 0.78 (0.70, 0.87) 0.74 (0.65, 0.84) 0.65 (0.53, 0.79) p-Value (stratified log- rank)‡ <0.0001 <0.0001 <0.0001 PFS Number (%) of patients with event 572 (72) 608 (77) 443 (72%) 483 (78%) 190 (68) 210 (77) Median in months (95% CI) 6.9 (6.3, 7.2) 5.6 (5.5, 5.7) 6.9 (6.0, 7.2) 5.6 (5.4, 5.7) 8.1 (6.8, 8.5) 5.6 (5.4, 6.7) Hazard ratio† (95% CI) 0.76 (0.67, 0.85) 0.72 (0.63, 0.82) 0.62 (0.51, 0.76) p-Value (stratified log- rank)‡ <0.0001 <0.0001 <0.0001 Objective Response Rate ORR§ (95% CI) 51% (48, 55) 42% (38, 45) 52% (48, 56) 43% (39, 47) 61% (55, 66) 43% (37, 49) Complete response rate 9% 6% 10% 6% 13% 5% Partial response rate 42% 36% 42% 37% 48% 38% p-Value¶ <0.0001 0.0004 <0.0001 Duration of Response n=405 n=331 n=322 n=263 n=169 n=117 Median in months# (95% CI) Range in months 8.0 (7.0, 9.7) 1.2+, 41.5+ 5.7 (5.5, 6.9) 1.3+, 34.7+ 8.3 (7.0, 10.9) 1.2+, 41.5+ 5.6 (5.4, 6.9) 1.3+, 34.2+ 10.9 (8.0, 13.8) 1.2+, 41.5+ 5.8 (5.3, 7.0) 1.4+, 31.2+ * Based on a pre-specified interim analysis † Based on the stratified Cox proportional hazard model ‡ One-sided p-Value based on stratified log-rank test § Response: Best objective response as confirmed complete response or partial response ¶ One-sided p-Value based on stratified Miettinen & Nurminen method # Based on Kaplan-Meier estimates + Denotes ongoing response 121 Reference ID: 5493485 100....----------------------------, 90 80 70 60 50 40 30 20 10 0-+rr~~~~~~~~~~~~~~~~~~~~~~~~,....., 0 790 789 5 663 636 10 490 434 15 343 274 20 240 169 25 143 95 30 95 58 35 55 26 40 19 10 45 3 0 50 0 0 Figure 20: Kaplan-Meier Curve for Overall Survival by Treatment Arm in KEYNOTE-859 Treatment arm KEYTRUDA + Chemo Chemo Overall Survival (%) Time in Months Number at Risk KEYTRUDA + Chemo Chemo 122 Reference ID: 5493485 100----------------------------, 90 80 70 60 50 40 30 20 10 0 618 617 5 51 1 493 10 383 339 - ' ' 15 269 206 20 192 126 25 121 66 30 81 41 35 46 20 40 17 7 45 3 0 so 0 0 Figure 21: Kaplan-Meier Curve for Overall Survival in KEYNOTE-859 (CPS≥1) Treatment arm KEYTRUDA + Chemo Chemo Overall Survival (%) Time in Months Number at Risk KEYTRUDA + Chemo Chemo In an exploratory subgroup analysis in patients with PD-L1 CPS<1 (n=344) at the time of the pre-specified interim analysis of OS, the median OS was 12.7 months (95% CI: 11.4, 15.0) for the KEYTRUDA arm and 12.2 months (95% CI: 9.5, 14.0) for the placebo arm, with a HR of 0.92 (95% CI: 0.73, 1.17). 14.11 Esophageal Cancer First-line Treatment of Locally Advanced Unresectable or Metastatic Esophageal/Gastroesophageal Junction Cancer KEYNOTE-590 The efficacy of KEYTRUDA was investigated in KEYNOTE-590 (NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation. PD-L1 status was centrally determined in tumor specimens in all patients using the PD-L1 IHC 22C3 pharmDx kit. Patients with active autoimmune disease, a medical condition that required immunosuppression, or who received 123 Reference ID: 5493485 prior systemic therapy in the locally advanced or metastatic setting were ineligible. Randomization was stratified by tumor histology (squamous cell carcinoma vs. adenocarcinoma), geographic region (Asia vs. ex-Asia), and ECOG performance status (0 vs. 1). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion: • KEYTRUDA 200 mg on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months. • Placebo on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months. Treatment with KEYTRUDA or chemotherapy continued until unacceptable toxicity or disease progression. Patients could be treated with KEYTRUDA for up to 24 months in the absence of disease progression. The major efficacy outcome measures were OS and PFS as assessed by the investigator according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). The study pre-specified analyses of OS and PFS based on squamous cell histology, CPS ≥10, and in all patients. Additional efficacy outcome measures were ORR and DoR, according to modified RECIST v1.1, as assessed by the investigator. The study population characteristics were: median age of 63 years (range: 27 to 94), 43% age 65 or older; 83% male; 37% White, 53% Asian, and 1% Black; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. Ninety-one percent had M1 disease and 9% had M0 disease. Seventy-three percent had a tumor histology of squamous cell carcinoma, and 27% had adenocarcinoma. The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with chemotherapy, compared to chemotherapy. Table 85 and Figure 22 summarize the efficacy results for KEYNOTE-590 in all patients. 124 Reference ID: 5493485 Table 85: Efficacy Results in Patients with Locally Advanced Unresectable or Metastatic Esophageal Cancer in KEYNOTE-590 Endpoint KEYTRUDA 200 mg every 3 weeks Cisplatin FU n=373 Placebo Cisplatin FU n=376 OS Number (%) of events 262 (70) 309 (82) Median in months (95% CI) 12.4 (10.5, 14.0) 9.8 (8.8, 10.8) Hazard ratio* (95% CI) 0.73 (0.62, 0.86) p-Value† <0.0001 PFS Number of events (%) 297 (80) 333 (89) Median in months (95% CI) 6.3 (6.2, 6.9) 5.8 (5.0, 6.0) Hazard ratio* (95% CI) 0.65 (0.55, 0.76) p-Value† <0.0001 Objective Response Rate ORR, %‡ (95% CI) 45 (40, 50) 29 (25, 34) Number (%) of complete responses 24 (6) 9 (2.4) Number (%) of partial responses 144 (39) 101 (27) p-Value§ <0.0001 Duration of Response Median in months (range) 8.3 (1.2+, 31.0+) 6.0 (1.5+, 25.0+) * Based on the stratified Cox proportional hazard model † Based on a stratified log-rank test ‡ Confirmed complete response or partial response § Based on the stratified Miettinen and Nurminen method 125 Reference ID: 5493485 100 90 80 70 ~ # --.:::: 60 ro > -~ ::J 50 CJ) ro .... (I) 40 > 0 30 20 10 0 3 6 9 12 15 18 Ti me in Months Number at Risk KEYTRUDA +SOC:373 348 295 235 187 151 11 8 SOC: 376 338 27 4 200 147 108 8.2 21 68 51 24 36 28 27 17 15 T reatm,ent .a.nrn KEYTRUDA + S,QC soc 30 7 4! 33 2 1 36 0 0 Figure 22: Kaplan-Meier Curve for Overall Survival in KEYNOTE-590 In a pre-specified formal test of OS in patients with PD-L1 CPS ≥ 10 (n=383), the median was 13.5 months (95% CI: 11.1, 15.6) for the KEYTRUDA arm and 9.4 months (95% CI: 8.0, 10.7) for the placebo arm, with a HR of 0.62 (95% CI: 0.49, 0.78; p-Value < 0.0001). In an exploratory analysis, in patients with PD-L1 CPS < 10 (n=347), the median OS was 10.5 months (95% CI: 9.7, 13.5) for the KEYTRUDA arm and 10.6 months (95% CI: 8.8, 12.0) for the placebo arm, with a HR of 0.86 (95% CI: 0.68, 1.10). Previously Treated Recurrent Locally Advanced or Metastatic Esophageal Cancer KEYNOTE-181 The efficacy of KEYTRUDA was investigated in KEYNOTE-181 (NCT02564263), a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced disease. Patients with HER2/neu positive esophageal cancer were required to have received treatment with approved HER2/neu targeted therapy. All patients were required to have tumor specimens for PD-L1 testing at a central laboratory; PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. Patients with a history of non-infectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a medical condition that required immunosuppression were ineligible. Patients were randomized (1:1) to receive either KEYTRUDA 200 mg every 3 weeks or investigator’s choice of any of the following chemotherapy regimens, all given intravenously: paclitaxel 80-100 mg/m2 on Days 1, 8, and 15 of every 4-week cycle, docetaxel 75 mg/m2 every 3 weeks, or irinotecan 180 mg/m2 every 2 weeks. Randomization was stratified by tumor histology (esophageal squamous cell carcinoma [ESCC] vs. esophageal adenocarcinoma [EAC]/Siewert type I EAC of the gastroesophageal junction [GEJ]), and geographic region (Asia vs. ex-Asia). Treatment with KEYTRUDA or chemotherapy continued 126 Reference ID: 5493485 until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue beyond the first RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least 4 weeks later with repeat imaging. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measure was OS evaluated in the following co-primary populations: patients with ESCC, patients with tumors expressing PD-L1 CPS ≥10, and all randomized patients. Additional efficacy outcome measures were PFS, ORR, and DoR, according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. A total of 628 patients were enrolled and randomized to KEYTRUDA (n=314) or investigator’s treatment of choice (n=314). Of these 628 patients, 167 (27%) had ESCC that expressed PD-L1 with a CPS ≥10. Of these 167 patients, 85 patients were randomized to KEYTRUDA and 82 patients to investigator’s treatment of choice [paclitaxel (n=50), docetaxel (n=19), or irinotecan (n=13)]. The baseline characteristics of these 167 patients were: median age of 65 years (range: 33 to 80), 51% age 65 or older; 84% male; 32% White and 68% Asian; 38% had an ECOG PS of 0 and 62% had an ECOG PS of 1. Ninety percent had M1 disease and 10% had M0 disease. Prior to enrollment, 99% of patients had received platinum-based treatment and 84% had also received treatment with a fluoropyrimidine. Thirty- three percent of patients received prior treatment with a taxane. The observed OS hazard ratio was 0.77 (95% CI: 0.63, 0.96) in patients with ESCC, 0.70 (95% CI: 0.52, 0.94) in patients with tumors expressing PD-L1 CPS ≥10, and 0.89 (95% CI: 0.75, 1.05) in all randomized patients. On further examination in patients whose ESCC tumors expressed PD-L1 (CPS ≥10), an improvement in OS was observed among patients randomized to KEYTRUDA as compared with chemotherapy. Table 86 and Figure 23 summarize the key efficacy measures for KEYNOTE-181 for patients with ESCC CPS ≥10. Table 86: Efficacy Results in Patients with Recurrent or Metastatic ESCC (CPS ≥10) in KEYNOTE-181 Endpoint KEYTRUDA 200 mg every 3 weeks n=85 Chemotherapy n=82 OS Number (%) of patients with event 68 (80%) 72 (88%) Median in months (95% CI) 10.3 (7.0, 13.5) 6.7 (4.8, 8.6) Hazard ratio* (95% CI) 0.64 (0.46, 0.90) PFS Number (%) of patients with event 76 (89%) 76 (93%) Median in months (95% CI) 3.2 (2.1, 4.4) 2.3 (2.1, 3.4) Hazard ratio* (95% CI) 0.66 (0.48, 0.92) Objective Response Rate ORR (95% CI) 22 (14, 33) 7 (3, 15) Number (%) of complete responses 4 (5) 1 (1) Number (%) of partial responses 15 (18) 5 (6) Median duration of response in months (range) 9.3 (2.1+, 18.8+) 7.7 (4.3, 16.8+) * Based on the Cox regression model stratified by geographic region (Asia vs. ex-Asia) 127 Reference ID: 5493485 --1 Figure 23: Kaplan-Meier Curve for Overall Survival in KEYNOTE-181 (ESCC CPS ≥10) 100 90 80 70 60 50 40 30 20 10 0 Treatment arm KEYTRUDA Control 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 Time in Months Overall Survival (%) Number at Risk KEYTRUDA: 85 Control: 82 79 74 70 54 56 42 51 34 43 23 40 18 30 14 27 10 21 8 11 4 7 4 4 3 3 2 1 2 0 1 0 0 KEYNOTE-180 The efficacy of KEYTRUDA was investigated in KEYNOTE-180 (NCT02559687), a multicenter, non- randomized, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least 2 prior systemic treatments for advanced disease. With the exception of the number of prior lines of treatment, the eligibility criteria were similar to and the dosage regimen identical to KEYNOTE-181. The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR. Among the 121 patients enrolled, 29% (n=35) had ESCC that expressed PD-L1 CPS ≥10. The baseline characteristics of these 35 patients were: median age of 65 years (range: 47 to 81), 51% age 65 or older; 71% male; 26% White and 69% Asian; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. One hundred percent had M1 disease. The ORR in the 35 patients with ESCC expressing PD-L1 was 20% (95% CI: 8, 37). Among the 7 responding patients, the DoR ranged from 4.2 to 25.1+ months, with 5 patients (71%) having responses of 6 months or longer and 3 patients (57%) having responses of 12 months or longer. 14.12 Cervical Cancer FIGO 2014 Stage III-IVA Cervical Cancer with Chemoradiotherapy The efficacy of KEYTRUDA in combination with CRT (cisplatin and external beam radiation therapy [EBRT] followed by brachytherapy [BT]) was investigated in KEYNOTE-A18 (NCT04221945), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1060 patients with cervical 128 Reference ID: 5493485 cancer who had not previously received any definitive surgery, radiation, or systemic therapy for cervical cancer. There were 596 patients with FIGO 2014 Stage III-IVA (tumor involvement of the lower vagina with or without extension onto pelvic sidewall or hydronephrosis/non-functioning kidney or has spread to adjacent pelvic organs) with either node-positive or node-negative disease, and 462 patients with FIGO 2014 Stage IB2-IIB (tumor lesions >4 cm or clinically visible lesions that have spread beyond the uterus but have not extended onto the pelvic wall or to the lower third of vagina) with node-positive disease; two patients had FIGO 2014 Stage IVB disease. Randomization was stratified by planned type of EBRT (Intensity-modulated radiation therapy [IMRT] or volumetric modulated arc therapy [VMAT] vs. non-IMRT and non-VMAT), stage at screening of cervical cancer (FIGO 2014 Stage IB2-IIB vs. FIGO 2014 Stage III-IVA), and planned total radiotherapy dose (EBRT + brachytherapy dose of <70 Gy vs. ≥70 Gy as per equivalent dose [EQD2]). Patients were randomized (1:1) to one of two treatment arms: • KEYTRUDA 200 mg IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m2 IV weekly (5 cycles, an optional sixth infusion could be administered per local practice), and radiotherapy (EBRT followed by BT), followed by KEYTRUDA 400 mg IV every 6 weeks (15 cycles) • Placebo IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m2 IV weekly (5 cycles, an optional sixth infusion could be administered per local practice), and radiotherapy (EBRT followed by BT), followed by placebo IV every 6 weeks (15 cycles) Treatment continued until RECIST v1.1-defined progression of disease as determined by investigator or unacceptable toxicity. Assessment of tumor status was performed every 12 weeks from completion of CRT for the first two years, followed by every 24 weeks in year 3, and then annually. The major efficacy outcome measures were PFS as assessed by investigator according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, or histopathologic confirmation, and OS. Among the 596 patients with FIGO 2014 Stage III-IVA disease, the baseline characteristics were: median age of 52 years (range: 22 to 87), 17% age 65 or older; 36% White, 34% Asian, 1% Black; 38% Hispanic or Latino; 68% ECOG PS 0 and 32% ECOG PS 1; 93% with CPS ≥1; 70% had positive pelvic and/or positive para-aortic lymph node(s) and 30% had neither positive pelvic nor para-aortic lymph node(s); 83% had squamous cell carcinoma and 17% had non-squamous histology. Regarding radiation, 85% of patients received IMRT or VMAT EBRT, and the median EQD2 dose was 87 Gy (range: 7 to 114). The trial demonstrated a statistically significant improvement in PFS in the overall population. In an exploratory subgroup analysis for the 462 patients (44%) with FIGO 2014 Stage IB2-IIB disease, the PFS HR estimate was 0.91 (95% CI: 0.63, 1.31), indicating that the PFS improvement in the overall population was primarily attributed to the results seen in the subgroup of patients with FIGO 2014 Stage III-IVA disease. OS data were not mature at the time of PFS analysis, with 10% deaths in the overall population. The efficacy results in the exploratory subgroup analysis of 596 patients with FIGO 2014 Stage III-IVA disease are summarized in Table 87 and Figure 24. Table 87: Efficacy Results in KEYNOTE-A18 (Patients with FIGO 2014 Stage III-IVA Cervical Cancer) Endpoint KEYTRUDA 200 mg every 3 weeks and 400 mg every 6 weeks with CRT n=293 Placebo with CRT n=303 PFS by Investigator Number of patients with event (%) 61 (21%) 94 (31%) Median in months (95% CI) NR (NR, NR) NR (18.8, NR) 12-month PFS rate (95% CI) 81% (75, 85) 70% (64, 76) Hazard ratio* (95% CI) 0.59 (0.43, 0.82) * Based on the unstratified Cox proportional hazard model CRT = Chemoradiotherapy NR = not reached 129 Reference ID: 5493485 100 90 80 70 60 50 40 30 20 10 0 0 293 303 3 254 261 6 223 209 9 186 163 12 163 142 15 129 109 18 96 78 21 62 46 24 11 8 27 2 0 30 0 0 Figure 24: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-A18 (Patients with FIGO 2014 Stage III-IVA Cervical Cancer) Treatment arm KEYTRUDA + CRT CRT Progression-Free Survival (%) Time in Months Number at Risk KEYTRUDA + CRT CRT Persistent, Recurrent, or Metastatic Cervical Cancer The efficacy of KEYTRUDA in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826 (NCT03635567), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent. Patients were enrolled regardless of tumor PD-L1 expression status. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by metastatic status at initial diagnosis, investigator decision to use bevacizumab, and PD-L1 status (CPS <1 vs. CPS 1 to <10 vs. CPS ≥10). Patients were randomized (1:1) to one of the two treatment groups: • Treatment Group 1: KEYTRUDA 200 mg plus chemotherapy with or without bevacizumab • Treatment Group 2: Placebo plus chemotherapy with or without bevacizumab The investigator selected one of the following four treatment regimens prior to randomization: 1. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 130 Reference ID: 5493485 2. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 + bevacizumab 15 mg/kg 3. Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min 4. Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min + bevacizumab 15 mg/kg All study medications were administered as an intravenous infusion. All study treatments were administered on Day 1 of each 3-week treatment cycle. Cisplatin could be administered on Day 2 of each 3-week treatment cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed every 9 weeks for the first year, followed by every 12 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by investigator according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR and DoR, according to RECIST v1.1, as assessed by investigator. Of the 617 enrolled patients, 548 patients (89%) had tumors expressing PD-L1 with a CPS ≥1. Among these 548 enrolled patients with tumors expressing PD-L1, 273 patients were randomized to KEYTRUDA in combination with chemotherapy with or without bevacizumab, and 275 patients were randomized to placebo in combination with chemotherapy with or without bevacizumab. Sixty-three percent of the 548 patients received bevacizumab as part of study treatment. The baseline characteristics of the 548 patients were: median age of 51 years (range: 22 to 82), 16% age 65 or older; 59% White, 18% Asian, 6% American Indian or Alaska Native, and 1% Black; 37% Hispanic or Latino; 56% ECOG performance status 0 and 43% ECOG performance status 1. Seventy-five percent had squamous cell carcinoma, 21% adenocarcinoma, and 5% adenosquamous histology, and 32% of patients had metastatic disease at diagnosis. At study entry, 21% of patients had metastatic disease only and 79% had persistent or recurrent disease with or without distant metastases, of whom 39% had received prior chemoradiation only and 17% had received prior chemoradiation plus surgery. A statistically significant improvement in OS and PFS was demonstrated in patients randomized to receive KEYTRUDA compared with patients randomized to receive placebo. An updated OS analysis was conducted at the time of final analysis when 354 deaths in the CPS ≥1 population were observed. Table 88 and Figure 25 summarize the key efficacy measures for KEYNOTE-826 for patients with tumors expressing PD-L1 (CPS ≥1). 131 Reference ID: 5493485 Table 88: Efficacy Results in Patients with Persistent, Recurrent, or Metastatic Cervical Cancer (CPS ≥1) in KEYNOTE-826 Endpoint KEYTRUDA 200 mg every 3 weeks and chemotherapy* with or without bevacizumab n=273 Placebo and chemotherapy* with or without bevacizumab n=275 OS Number of patients with event (%) 118 (43.2) 154 (56.0) Median in months (95% CI) NR (19.8, NR) 16.3 (14.5, 19.4) Hazard ratio† (95% CI) 0.64 (0.50, 0.81) p-Value‡ 0.0001 Updated OS Number of patients with event (%) 153 (56.0%) 201 (73.1%) Median in months (95% CI) 28.6 (22.1, 38.0) 16.5 (14.5, 20.0) Hazard ratio† (95% CI) 0.60 (0.49, 0.74) PFS Number of patients with event (%) 157 (57.5) 198 (72.0) Median in months (95% CI) 10.4 (9.7, 12.3) 8.2 (6.3, 8.5) Hazard ratio† (95% CI) 0.62 (0.50, 0.77) p-Value§ < 0.0001 Objective Response Rate ORR¶ (95% CI) 68% (62, 74) 50% (44, 56) Complete response rate 23% 13% Partial response rate 45% 37% Duration of Response Median in months (range) 18.0 (1.3+, 24.2+) 10.4 (1.5+, 22.0+) * Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) † Based on the stratified Cox proportional hazard model ‡ p-Value (one-sided) is compared with the allocated alpha of 0.0055 for this interim analysis (with 72% of the planned number of events for final analysis) § p-Value (one-sided) is compared with the allocated alpha of 0.0014 for this interim analysis (with 82% of the planned number of events for final analysis) ¶ Response: Best objective response as confirmed complete response or partial response + Denotes ongoing response NR = not reached 132 Reference ID: 5493485 100 ~-----------------------~ 90 80 70 60 50 40 30 20 10 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 273 261 251 231 206 189 168 157 146 136 128 116 90 52 22 2 0 275 261 235 207 173 149 129 117 107 91 81 68 45 24 3 0 0 Figure 25: Kaplan-Meier Curve for Overall Survival in KEYNOTE-826 (CPS ≥1)* ,† Treatment arm KEYTRUDA + Chemotherapy Chemotherapy Overall Survival (%) Time in Months Number at Risk KEYTRUDA + Chemotherapy Chemotherapy *Treatment arms include KEYTRUDA plus chemotherapy, with or without bevacizumab, versus placebo plus chemotherapy, with or without bevacizumab. †Based on the protocol-specified final OS analysis Previously Treated Recurrent or Metastatic Cervical Cancer The efficacy of KEYTRUDA was investigated in 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort (Cohort E) in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label, multi-cohort trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Patients without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR, and DoR. Among the 98 patients in Cohort E, 77 (79%) had tumors that expressed PD-L1 with a CPS ≥ 1 and received at least one line of chemotherapy in the metastatic setting. PD-L1 status was determined using the IHC 22C3 pharmDx kit. The baseline characteristics of these 77 patients were: median age of 45 years (range: 27 to 75); 81% White, 14% Asian, and 3% Black; 32% ECOG PS of 0 and 68% ECOG PS of 1; 92% had squamous cell carcinoma, 6% adenocarcinoma, and 1% adenosquamous histology; 133 Reference ID: 5493485 95% had M1 disease and 5% had recurrent disease; and 35% had one and 65% had two or more prior lines of therapy in the recurrent or metastatic setting. No responses were observed in patients whose tumors did not have PD-L1 expression (CPS ˂1). Efficacy results are summarized in Table 89 for patients with PD-L1 expression (CPS ≥1). Table 89: Efficacy Results in Patients with Recurrent or Metastatic Cervical Cancer (CPS ≥1) in KEYNOTE-158 Endpoint KEYTRUDA 200 mg every 3 weeks n=77* Objective Response Rate ORR (95% CI) 14.3% (7.4, 24.1) Complete response rate 2.6% Partial response rate 11.7% Duration of Response Median in months (range) NR (4.1, 18.6+)† % with duration ≥6 months 91% * Median follow-up time of 11.7 months (range 0.6 to 22.7 months) † Based on patients (n=11) with a response by independent review + Denotes ongoing response NR = not reached 14.13 Hepatocellular Carcinoma Previously Treated HCC The efficacy of KEYTRUDA was investigated in KEYNOTE-394 (NCT03062358), a multicenter, randomized, placebo-controlled, double-blind trial conducted in Asia in patients with Barcelona Clinic Liver Cancer (BCLC) Stage B or C HCC, who were previously treated with sorafenib or oxaliplatin-based chemotherapy and who were not amenable to or were refractory to local-regional therapy. Patients were also required to have Child-Pugh A liver function. Patients with hepatitis B had treated controlled disease (HBV viral load <2000 IU/mL or <104 copies/mL). Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Patients with hepatic encephalopathy, main branch portal venous invasion, clinically apparent ascites, or esophageal or gastric variceal bleeding within the last 6 months were also ineligible. Randomization was stratified by prior treatment: sorafenib vs. oxaliplatin-based chemotherapy, macrovascular invasion, and etiology (active HBV vs. others (active HCV, non-infected)). Patients were randomized (2:1) to receive pembrolizumab 200 mg intravenously every 3 weeks or placebo. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Assessment of tumor status was performed every 6 weeks. The main efficacy outcome measure was OS. Additional efficacy outcome measures were PFS, ORR, and DoR, as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study enrolled 453 patients, and 360 (79%) had active hepatitis B. The population characteristics in patients with active hepatitis B were: median age of 52 years (range: 23 to 82), 16% age 65 or older; 86% male; 100% Asian; 42% ECOG PS of 0 and 58% ECOG PS of 1; 90% received prior sorafenib and 10% received prior oxaliplatin-based chemotherapy. Patient characteristics also included extrahepatic disease (77%), macrovascular invasion (10%), BCLC stage C (93%) and B (7%), and baseline AFP ≥200 ng/mL (57%). KEYNOTE-394 demonstrated improved OS in patients with HCC secondary to hepatitis B randomized to KEYTRUDA compared with placebo. Efficacy results are summarized in Table 90 and Figure 26. 134 Reference ID: 5493485 Table 90: Efficacy Results in Patients with Hepatocellular Carcinoma in KEYNOTE-394 Endpoint KEYTRUDA 200 mg every 3 weeks n=236 Placebo n=124 OS* Number (%) of patients with events 172 (73) 105 (85) Median in months (95% CI) 13.9 (12.5, 17.9) 13.0 (10.1, 15.6) Hazard ratio† (95% CI) 0.78 (0.61, 0.99) PFS‡ Number (%) of patients with events 189 (80) 108 (87) Median in months (95% CI) 2 (1.4, 2.7) 2.3 (1.4, 2.8) Hazard ratio† (95% CI) 0.78 (0.61, 1.00) Objective Response Rate‡ ORR§ (95% CI) 11% (7, 16) 1.6% (0.2, 5.7) Number (%) of complete responses 2 (0.9%) 1 (0.8%) Number (%) of partial responses 24 (10%) 1 (0.8%) Duration of Response* n=28 n=2 Median in months¶ (range) 23.9 (2.6+, 44.4+) 5.6 (3.0+, 5.6) * Results at the pre-specified final OS analysis † Based on the stratified Cox proportional hazard model ‡ Results at pre-specified interim OS analysis § Confirmed complete response or partial response ¶ Based on Kaplan-Meier estimate + Denotes ongoing response 135 Reference ID: 5493485 100~~-----------------------------~ 90 80 70 60 50 40 I ·,. 30 20 10 0 -;m,fflfflJ'""""IJfflffllfflJlffl"""l'ITlfflffl"(ffllfflfflJffl''"'""'""""JfflfflTITIJIITll""'l"""""rmnm""""''""l"""""l[lfflTlll""""'""""'"""'l"""""l""'"""""lfflfflf"""""l""'1fflJffl"""'lmmnn1 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 236 228 204174 157 145 134 118110 103 89 68 57 49 44 38 28 21 18 13 11 9 6 3 0 124 119 108 93 82 7 4 64 55 50 44 36 30 25 20 16 13 7 4 3 2 2 0 0 0 0 Figure 26: Kaplan-Meier Curve for Overall Survival in KEYNOTE-394 Treatment arm KEYTRUDA Placebo Overall Survival (%) Time in Months Number at Risk KEYTRUDA Placebo 14.14 Biliary Tract Cancer The efficacy of KEYTRUDA in combination with gemcitabine and cisplatin chemotherapy was investigated in KEYNOTE-966 (NCT04003636), a multicenter, randomized, double-blind, placebo- controlled trial that enrolled 1069 patients with locally advanced unresectable or metastatic BTC, who had not received prior systemic therapy in the advanced disease setting. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by region (Asia vs. non-Asia), locally advanced versus metastatic, and site of origin (gallbladder, intrahepatic or extrahepatic cholangiocarcinoma). Patients were randomized (1:1) to KEYTRUDA 200 mg on Day 1 plus gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on Day 1 and Day 8 every 3 weeks, or placebo on Day 1 plus gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on Day 1 and Day 8 every 3 weeks. Study medications were administered via intravenous infusion. Treatment continued until unacceptable toxicity or disease progression. For pembrolizumab, treatment continued for a maximum of 35 cycles, or approximately 24 months. For gemcitabine, treatment could be continued beyond 8 cycles while for cisplatin, treatment could be administered for a maximum of 8 cycles. 136 Reference ID: 5493485 Administration of KEYTRUDA with chemotherapy was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Assessment of tumor status was performed at baseline and then every 6 weeks through 54 weeks, followed by every 12 weeks thereafter. Study population characteristics were median age of 64 years (range: 23 to 85), 47% age 65 or older; 52% male; 49% White, 46% Asian, 1.3% Black or African American; 10% Hispanic or Latino; 46% ECOG PS of 0 and 54% ECOG PS of 1; 31% of patients had a history of hepatitis B infection, and 3% had a history of hepatitis C infection. The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS, ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Table 91 and Figure 27 summarize the efficacy results for KEYNOTE-966. Table 91: Efficacy Results in KEYNOTE-966 Endpoint KEYTRUDA 200 mg every 3 weeks with gemcitabine/cisplatin n=533 Placebo with gemcitabine/cisplatin n=536 OS* Number of patients with event (%) 414 (78%) 443 (83%) Median in months (95% CI) 12.7 (11.5, 13.6) 10.9 (9.9, 11.6) Hazard ratio† (95% CI) 0.83 (0.72, 0.95) p-Value‡ 0.0034 PFS§ Number (%) of patients with event 361 (68%) 391 (73%) Median in months (95% CI) 6.5 (5.7, 6.9) 5.6 (5.1, 6.6) Hazard ratio† (95% CI) 0.86 (0.75, 1.00) p-Value‡ NS Objective Response Rate§ ORR¶ (95% CI) 29% (25, 33) 29% (25, 33) Number (%) of complete responses 11 (2.1%) 7 (1.3%) Number (%) of partial responses 142 (27%) 146 (27%) p-Value # NS Duration of Response* n=156 n=152 Median in months Þ (95% CI) 8.3 (6.9, 10.2) 6.8 (5.7, 7.1) * Results at the pre-specified final OS analysis † Based on the stratified Cox proportional hazard model ‡ One-sided p-Value based on a stratified log-rank test § Results at pre-specified final analysis of PFS and ORR ¶ Confirmed complete response or partial response # One-sided p-Value based on the stratified Miettinen and Nurminen analysis Þ Based on Kaplan-Meier estimate NS = not significant 137 Reference ID: 5493485 100 90 80 70 60 so 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 533 505 469 430 374 326 275 238 204 175 142 108 88 56 35 21 16 8 5 0 0 536 504 454 394 349 287 236 213 181 148 115 81 59 43 28 20 14 7 1 0 0 Figure 27: Kaplan-Meier Curve for Overall Survival in KEYNOTE-966 Treatment arm KEYTRUDA + Chemotherapy Placebo + Chemotherapy Overall Survival (%) Time in Months Number at Risk KEYTRUDA + Chemotherapy Placebo + Chemotherapy 14.15 Merkel Cell Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-017 (NCT02267603) and KEYNOTE-913 (NCT03783078), two multicenter, non-randomized, open-label trials that enrolled 105 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received KEYTRUDA 2 mg/kg (KEYNOTE-017) or 200 mg (KEYNOTE-913) every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. The major efficacy outcome measures were ORR and DoR as assessed by BICR per RECIST v1.1. Among the 105 patients enrolled, the median age was 73 years (range: 38 to 91), 79% were age 65 or older; 62% were male; 80% were White, race in 19% was unknown or missing, and 1% were Asian; 53% had ECOG PS of 0, and 47% had ECOG PS of 1. Thirteen percent had stage IIIB disease and 84% had stage IV. Seventy-six percent of patients had prior surgery and 51% had prior radiation therapy. 138 Reference ID: 5493485 Efficacy results are summarized in Table 92. Table 92: Efficacy Results in KEYNOTE-017 and KEYNOTE-913 Endpoint KEYNOTE-017 KEYTRUDA 2 mg/kg every 3 weeks n=50 KEYNOTE-913 KEYTRUDA 200 mg or 2 mg/kg every 3 weeks n=55 Objective Response Rate ORR (95% CI) 56% (41, 70) 49% (35, 63) Complete responses, n (%) 12 (24%) 9 (16%) Partial responses, n (%) 16 (32%) 18 (33%) Duration of Response n=28 n=27 Median DoR in months (range) NR (5.9, 34.5+) NR (4.8, 25.4+) Patients with duration ≥6 months, n (%) 27 (96%) 25 (93%) Patients with duration ≥12 months, n (%) 15 (54%) 19 (70%) + Denotes ongoing response NR = not reached 14.16 Renal Cell Carcinoma First-line treatment with axitinib KEYNOTE-426 The efficacy of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus “Rest of the World”). Patients were randomized (1:1) to one of the following treatment arms: • KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with axitinib 5 mg orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for 2 consecutive cycles (6 weeks) could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity. • Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks. Treatment with KEYTRUDA and axitinib continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Administration of KEYTRUDA and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at Week 12, then every 6 weeks thereafter until Week 54, and then every 12 weeks thereafter. The study population characteristics were: median age of 62 years (range: 26 to 90), 38% age 65 or older; 73% male; 79% White and 16% Asian; 20% and 80% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate, and 13% poor. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR, as assessed by BICR. A statistically significant improvement in OS was demonstrated at the first pre-specified interim analysis in patients randomized to KEYTRUDA in combination with axitinib compared with sunitinib. The trial also demonstrated statistically significant improvements in PFS and ORR. An updated OS analysis was conducted when 418 deaths were observed based on the planned number of deaths for the pre-specified final analysis. Table 93 and Figure 28 summarize the efficacy results for KEYNOTE-426. 139 Reference ID: 5493485 Table 93: Efficacy Results in KEYNOTE-426 Endpoint KEYTRUDA 200 mg every 3 weeks and Axitinib n=432 Sunitinib n=429 OS Number of patients with event (%) 59 (14%) 97 (23%) Median in months (95% CI) NR (NR, NR) NR (NR, NR) Hazard ratio* (95% CI) 0.53 (0.38, 0.74) p-Value† <0.0001‡ Updated OS Number of patients with event (%) 193 (45%) 225 (52%) Median in months (95% CI) 45.7 (43.6, NR) 40.1 (34.3, 44.2) Hazard ratio* (95% CI) 0.73 (0.60, 0.88) PFS Number of patients with event (%) 183 (42%) 213 (50%) Median in months (95% CI) 15.1 (12.6, 17.7) 11.0 (8.7, 12.5) Hazard ratio* (95% CI) 0.69 (0.56, 0.84) p-Value† 0.0001§ Objective Response Rate ORR¶ (95% CI) 59% (54, 64) 36% (31, 40) Complete response rate 6% 2% Partial response rate 53% 34% p-Value# <0.0001 * Based on the stratified Cox proportional hazard model † Based on stratified log-rank test ‡ p-Value (one-sided) is compared with the allocated alpha of 0.0001 for this interim analysis (with 39% of the planned number of events for final analysis). § p-Value (one-sided) is compared with the allocated alpha of 0.0013 for this interim analysis (with 81% of the planned number of events for final analysis). ¶ Response: Best objective response as confirmed complete response or partial response # Based on Miettinen and Nurminen method stratified by IMDC risk group and geographic region NR = not reached 140 Reference ID: 5493485 ro > ·2: ::::, Vl ro cij 0 60 so 40 30 20 10 0 Number at Risk KEYTRUDA + Axitinib Sunitinib 0 Treatment arm --- KEYTRUDA + Axitinib - - - - - - • Sunitinib 6 12 18 432 407 384 345 429 379 336 306 - --1 •• , __ ""'•1"1'1~ ~1111 'filllfl~ 1H 11--1 24 30 36 42 48 54 Time in Months 318 286 259 141 16 0 279 252 224 110 12 0 Figure 28: Kaplan-Meier Curve for Updated Overall Survival in KEYNOTE-426 In an exploratory analysis, the updated analysis of OS in patients with IMDC favorable, intermediate, intermediate/poor, and poor risk demonstrated a HR of 1.17 (95% CI: 0.76, 1.80), 0.67 (95% CI: 0.52, 0.86), 0.64 (95% CI: 0.52, 0.80), and 0.51 (95% CI: 0.32, 0.81), respectively. First-line treatment with lenvatinib KEYNOTE-581 The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-581 (NCT02811861), a multicenter, open-label, randomized trial conducted in 1069 patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified by geographic region (North America versus Western Europe versus “Rest of the World”) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favorable versus intermediate versus poor risk). Patients were randomized (1:1:1) to one of the following treatment arms: • KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with lenvatinib 20 mg orally once daily. • Lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily. • Sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks. Treatment continued until unacceptable toxicity or disease progression. Administration of KEYTRUDA with lenvatinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. KEYTRUDA was continued for a 141 Reference ID: 5493485 maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every 8 weeks. The study population characteristics were: median age of 62 years (range: 29 to 88 years), 42% age 65 or older; 75% male; 74% White, 21% Asian, 1% Black, and 2% other races; 18% and 82% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by MSKCC risk categories was 27% favorable, 64% intermediate, and 9% poor. Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%). The major efficacy outcome measures were PFS, as assessed by independent radiologic review (IRC) according to RECIST v1.1, and OS. Additional efficacy outcome measures included confirmed ORR as assessed by IRC. KEYTRUDA in combination with lenvatinib demonstrated statistically significant improvements in PFS, OS, and ORR compared with sunitinib. An updated OS analysis was conducted when 304 deaths were observed based on the planned number of deaths for the pre-specified final analysis. Table 94 and Figures 29 and 30 summarize the efficacy results for KEYNOTE-581. Table 94: Efficacy Results in KEYNOTE-581 Endpoint KEYTRUDA 200 mg every 3 weeks and Lenvatinib n=355 Sunitinib n=357 Progression-Free Survival (PFS) Number of events, n (%) 160 (45%) 205 (57%) Progressive disease 145 (41%) 196 (55%) Death 15 (4%) 9 (3%) Median PFS in months (95% CI) 23.9 (20.8, 27.7) 9.2 (6.0, 11.0) Hazard ratio* (95% CI) 0.39 (0.32, 0.49) p-Value† <0.0001 Overall Survival (OS) Number of deaths, n (%) 80 (23%) 101 (28%) Median OS in months (95% CI) NR (33.6, NR) NR (NR, NR) Hazard ratio* (95% CI) 0.66 (0.49, 0.88) p-Value† 0.0049 Updated OS Number of deaths, n (%) 149 (42%) 159 (45%) Median OS in months (95% CI) 53.7 (48.7, NR) 54.3 (40.9, NR) Hazard ratio* (95% CI) 0.79 (0.63, 0.99) Objective Response Rate (Confirmed) ORR, n (%) 252 (71%) 129 (36%) (95% CI) (66, 76) (31, 41) Complete response rate 16% 4% Partial response rate 55% 32% p-Value‡ <0.0001 Tumor assessments were based on RECIST 1.1; only confirmed responses are included for ORR. Data cutoff date = 28 Aug 2020, Updated OS cutoff date = 31 July 2022 CI = confidence interval; NR= Not reached * Hazard ratio is based on a Cox Proportional Hazards Model. Stratified by geographic region and MSKCC prognostic groups. † Two-sided p-Value based on stratified log-rank test. ‡ Two-sided p-Value based upon CMH test. 142 Reference ID: 5493485 Number at Risk 100 90 80 e 10 ro > ·~ :::, 60 (f) <I) <I) 50 u: C: 0 ·.; 40 "' <I) a, 0 30 a:. 20 10 Treatment arm KEYTRUOA + Lenvatinib Sunitinib 0 -1nw...,,....,,'"""'""""""""...,,'""'",,.....,......,....,,"'""''"""'""""...,, .... .,......,,....,,'""'""'"'"..,.....,,'""'",,...,, 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Ti me in Months KEYTRUDA + Lenvatinib: 355 321 300 276 259 23.5 213 186 160 136 126 106 80 56 30 14 6 3 0 Sunitinib: 357 262 218 145 124 107 85 69 62 49 42 32 25 16 9 3 2 0 0 0 Figure 29: Kaplan-Meier Curve for PFS in KEYNOTE-581 143 Reference ID: 5493485 100 't 'I- 90 11' ii, 'I l, 80 70 ::R ~ 60 "iii > -~ 50 :J (/) ~ <I) > 0 40 30 20 10 0 0 6 12 18 Number at Risk KEYTRUDA + Lenvatinib 355 338 313 296 Sunitinib 357 308 264 242 24 30 36 42 Time in Months 269 245 216 158 226 208 188 145 48 Treatment arm KEYTRUDA + Lenvatinib Sunitinib H, 54 60 117 34 5 108 33 3 66 0 0 Figure 30: Kaplan-Meier Curve for Updated Overall Survival in KEYNOTE-581 KEYNOTE-B61 The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-B61 (NCT04704219), a multicenter, single-arm trial that enrolled 160 patients with advanced or metastatic non-clear cell RCC in the first-line setting. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received KEYTRUDA 400 mg every 6 weeks in combination with lenvatinib 20 mg orally once daily. KEYTRUDA was continued for a maximum of 24 months; however, lenvatinib could be continued beyond 24 months. Treatment continued until unacceptable toxicity or disease progression. Administration of KEYTRUDA with lenvatinib was permitted beyond RECIST-defined disease progression if the patient was considered by the investigator to be deriving clinical benefit. Among the 158 treated patients, the baseline characteristics were: median age of 60 years (range: 24 to 87 years); 71% male; 86% White, 8% Asian, and 3% Black; <1% Hispanic or Latino; 22% and 78% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; histologic subtypes were 59% papillary, 18% chromophobe, 4% translocation, <1% medullary, 13% unclassified, and 6% other; patient distribution by IMDC risk categories was 35% favorable, 54% intermediate, and 10% poor. Common sites of metastases in patients were lymph node (65%), lung (35%), bone (30%), and liver (21%). 144 Reference ID: 5493485 The major efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Additional efficacy outcome measures included DOR as assessed by BICR using RECIST 1.1. Efficacy results are summarized in Table 95. Table 95: Efficacy Results in KEYNOTE-B61 Endpoint KEYTRUDA 400 mg every 6 weeks and Lenvatinib n=158 Objective Response Rate (Confirmed) ORR (95% CI) 51% (43, 59) Complete response 8% Partial response 42% Duration of Response* Median in months (range) 19.5 (1.5+, 23.5+) CI = confidence interval * Based on Kaplan-Meier estimates + Denotes ongoing response Adjuvant Treatment of RCC (KEYNOTE-564) The efficacy of KEYTRUDA was investigated as adjuvant therapy for RCC in KEYNOTE-564 (NCT03142334), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in 994 patients with intermediate-high or high risk of recurrence of RCC, or M1 no evidence of disease (NED). The intermediate-high risk category included: pT2 with Grade 4 or sarcomatoid features; pT3, any Grade without nodal involvement (N0) or distant metastases (M0). The high risk category included: pT4, any Grade N0 and M0; any pT, any Grade with nodal involvement and M0. The M1 NED category included patients with metastatic disease who had undergone complete resection of primary and metastatic lesions. Patients must have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants) with negative surgical margins ≥4 weeks prior to the time of screening. Patients were excluded from the trial if they had received prior systemic therapy for advanced RCC. Patients with active autoimmune disease or a medical condition that required immunosuppression were also ineligible. Patients were randomized to KEYTRUDA 200 mg administered intravenously every 3 weeks or placebo for up to 1 year until disease recurrence or unacceptable toxicity. Randomization was stratified by metastasis status (M0, M1 NED); M0 group was further stratified by ECOG PS (0,1) and geographic region (US, non-US). The study population characteristics were: median age of 60 years (range: 25 to 84), 33% age 65 or older; 71% male; 75% White, 14% Asian, 9% Unknown, 1% Black or African American, 1% American Indian or Alaska Native, 1% Multiracial; 13% Hispanic or Latino, 78% Not Hispanic or Latino, 8% Unknown; and 85% ECOG PS of 0 and 15% ECOG PS of 1. Ninety-four percent of patients enrolled had N0 disease; 11% had sarcomatoid features; 86% were intermediate-high risk; 8% were high risk; and 6% were M1 NED. Ninety-two percent of patients had a radical nephrectomy, and 8% had a partial nephrectomy. The major efficacy outcome measure was investigator-assessed disease-free survival (DFS), defined as time to recurrence, metastasis, or death. An additional outcome measure was OS. Statistically significant improvements in DFS and OS were demonstrated at pre-specified interim analyses in patients randomized to the KEYTRUDA arm compared with placebo. Efficacy results are summarized in Table 96 and Figures 31 and 32. 145 Reference ID: 5493485 Number at Risk KEYTRUDA Placebo ~ !:!.., C1l > -~ :J (/) Q) ~ LL di Vl C1l Q) Vl i:S 100 90 80 70 60 50 40 30 20 10 0 0 496 498 5 457 436 I ' 10 414 389 15 371 341 20 25 Time in Months 233 209 151 145 30 61 56 35 21 19 Treatment arm KEYTRUDA Placebo 40 45 0 0 Table 96: Efficacy Results in KEYNOTE-564 Endpoint KEYTRUDA 200 mg every 3 weeks n=496 Placebo n=498 DFS Number (%) of patients with event 109 (22%) 151 (30%) Median in months (95% CI) NR NR Hazard ratio* (95% CI) 0.68 (0.53, 0.87) p-Value† 0.0010‡ 24-month DFS rate (95% CI) 77% (73, 81) 68% (64, 72) OS Number (%) of patients with event 55 (11%) 86 (17%) Median in months (95% CI) NR (NR, NR) NR (NR, NR) Hazard ratio* (95% CI) 0.62 (0.44, 0.87) p-Value† 0.0024§ 48-month OS rate (95% CI) 91% (88, 93) 86% (83, 89) * Based on the stratified Cox proportional hazard model † Based on stratified log-rank test ‡ p-Value (one-sided) is compared with a boundary of 0.0114. § p-Value (one-sided) is compared with a boundary of 0.0072. NR = not reached Figure 31: Kaplan-Meier Curve for Disease-Free Survival in KEYNOTE-564 146 Reference ID: 5493485 90 80 .....__,u~,~ 70 60 50 40 30 20 10 0 --tmTTTTT1'TflTT1TTTTT1rfTTTT1rTITTT1rnm"rTTTTfl'TTTTTl'TTT!TfflTTTTTTfTTTTITTTTTfTT1TTTTT1'TflTT1'TTTTT1rfTTTT1rTTTT'l1rnm"rTTTTfl'TTTTTl'TTT!TfflTTTTTTfTTTTTTT1TTfTT1TTTm'Tj 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 496 489 486 484 479 470 468 462 451 443 397 270 168 81 22 0 498 494 487 483 476 463 455 441 433 423 382 248 155 79 22 0 Figure 32: Kaplan-Meier Curve for Overall Survival in KEYNOTE-564 Overall Survival (%) Treatment arm KEYTRUDA Placebo Time in Months Number at Risk KEYTRUDA Placebo 14.17 Endometrial Carcinoma In Combination with Paclitaxel and Carboplatin for the Treatment of Primary Advanced or Recurrent Endometrial Carcinoma The efficacy of KEYTRUDA in combination with paclitaxel and carboplatin was investigated in KEYNOTE-868/NRG-GY018 (NCT03914612), a multicenter, randomized, double-blind, placebo-controlled trial in 810 patients with advanced or recurrent endometrial carcinoma. The study design included two separate cohorts based on MMR status; 222 (27%) patients were in dMMR cohort, 588 (73%) patients were in pMMR cohort. The trial enrolled measurable Stage III, measurable Stage IVA, Stage IVB or recurrent endometrial cancer (with or without measurable disease). Patients who had not received prior systemic therapy or had received prior chemotherapy in the adjuvant setting were eligible. Patients who had received prior adjuvant chemotherapy were only eligible if their chemotherapy-free interval was at least 12 months. Patients with endometrial sarcoma, including carcinosarcoma, or patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified according to MMR status, ECOG PS (0 or 1 vs. 2), and prior adjuvant chemotherapy. Patients were randomized (1:1) to one of the following treatment arms: 147 Reference ID: 5493485 • KEYTRUDA 200 mg every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for 6 cycles, followed by KEYTRUDA 400 mg every 6 weeks for up to 14 cycles. • Placebo every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for 6 cycles, followed by placebo every 6 weeks for up to 14 cycles. All study medications were administered as an intravenous infusion on Day 1 of each treatment cycle. Treatment continued until disease progression, unacceptable toxicity, or a maximum of 20 cycles (up to approximately 24 months). Patients with measurable disease who had RECIST-defined stable disease or partial response at the completion of cycle 6 were permitted to continue receiving paclitaxel and carboplatin with KEYTRUDA or placebo for up to 10 cycles as determined by the investigator. Assessment of tumor status was performed every 9 weeks for the first 9 months and then every 12 weeks thereafter. The major efficacy outcome measure was PFS as assessed by the investigator according to RECIST 1.1. An additional efficacy outcome measure was OS. The dMMR population characteristics were: median age of 66 years (range: 37 to 86), 55% age 65 or older; 79% White, 9% Black, and 3% Asian; 5% Hispanic or Latino; 64% ECOG PS of 0, 33% ECOG PS of 1, and 3% ECOG PS of 2; 61% had recurrent disease and 39% had primary or persistent disease; 5% received prior adjuvant chemotherapy and 43% received prior radiotherapy. The histologic subtypes were endometrioid carcinoma (81%), adenocarcinoma NOS (11%), serous carcinoma (2%), and other (6%). The pMMR population characteristics were: median age of 66 years (range: 29 to 94), 54% age 65 or older; 72% White, 16% Black, and 5% Asian; 6% Hispanic or Latino; 67% ECOG PS of 0, 30% ECOG PS of 1, and 3% ECOG PS of 2; 56% had recurrent disease and 44% had primary or persistent disease; 26% received prior adjuvant chemotherapy and 41% received prior radiotherapy. The histologic subtypes were endometrioid carcinoma (52%), serous carcinoma (26%), adenocarcinoma NOS (10%), clear cell carcinoma (7%), and other (5%). The trial demonstrated statistically significant improvements in PFS for patients randomized to KEYTRUDA in combination with paclitaxel and carboplatin compared to placebo in combination with paclitaxel and carboplatin in both the dMMR and pMMR populations. Table 97 and Figures 33 and 34 summarize the efficacy results for KEYNOTE-868 by MMR status. At the time of the PFS analysis, OS data were not mature with 12% deaths in the dMMR population and 17% deaths in the pMMR population. Table 97: Efficacy Results in KEYNOTE-868 Endpoint dMMR Population pMMR Population KEYTRUDA with paclitaxel and carboplatin n=110 Placebo with paclitaxel and carboplatin n=112 KEYTRUDA with paclitaxel and carboplatin n=294 Placebo with paclitaxel and carboplatin n=294 PFS* Number (%) of patients with event 26 (24%) 57 (51%) 91 (31%) 124 (42%) Median in months (95% CI) NR (30.7, NR) 6.5 (6.4, 8.7) 11.1 (8.7, 13.5) 8.5 (7.2, 8.8) Hazard ratio† (95% CI) 0.30 (0.19, 0.48) 0.60 (0.46, 0.78) p-Value‡ <0.0001 <0.0001 * Based on interim PFS analysis; the information fractions for interim analyses were 49% for dMMR and 55% for pMMR. † Based on the stratified Cox proportional hazard model ‡ Based on the stratified log-rank test NR = not reached 148 Reference ID: 5493485 100~------------------------~ 90 80 ' 70 I- I \ 60 I I 50 ~l I 40 30 20 10 I I L_ir~ I I ~-1-Hf---,I~, I I ----- , I 0 --f-r-T"T"T"T'T"T"T'T"T"T'T"T"T'T"T"T'T"T".-r"T"~.-r"T"~~..,......,..,......,-rr,..,......,-rr,-rr,-rr,..,......,"T"T""O"T"T""O"T"T'"O"T"T'"O"T"T'"O.....-i 0 110 112 6 78 58 12 33 18 18 17 8 24 8 4 30 6 3 36 2 0 42 0 0 Figure 33: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-868 (dMMR Population) Treatment arm KEYTRUDA+Chemotherapy* Chemotherapy* Progression-Free Survival (%) Time in Months Number at Risk KEYTRUDA+Chemotherapy* Chemotherapy* *Chemotherapy (paclitaxel and carboplatin) 149 Reference ID: 5493485 100--r-or----rr--------------------------, 90 80 70 60 50 40 , I ' 30 20 10 0 -;-.-.,........, ......... ,.......,..........,,...........,........, ......... ,.......,..........,,...........,........, ......... ,.......,..........,,...........,........,"'T"T'",.......,."T""T"'l,..........T"T""T"'T"T'",.......,."T""T"'lr-ri 0 294 294 6 140 126 12 36 22 18 14 8 24 30 3 3 36 0 0 Figure 34: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-868 (pMMR Population) Treatment arm KEYTRUDA+Chemotherapy* Chemotherapy* Progression-Free Survival (%) Time in Months Number at Risk KEYTRUDA+Chemotherapy* Chemotherapy* *Chemotherapy (paclitaxel and carboplatin) In Combination with Lenvatinib for the Treatment of Advanced Endometrial Carcinoma That Is pMMR or Not MSI-H The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-775 (NCT03517449), a multicenter, open-label, randomized, active-controlled trial that enrolled 827 patients with advanced endometrial carcinoma who had been previously treated with at least one prior platinum- based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Patients with endometrial sarcoma, including carcinosarcoma, or patients who had active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients with endometrial carcinoma that were pMMR (using the VENTANA MMR RxDx Panel test) or not MSI-H were stratified by ECOG performance status, geographic region, and history of pelvic radiation. Patients were randomized (1:1) to one of the following treatment arms: • KEYTRUDA 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily. • Investigator’s choice, consisting of either doxorubicin 60 mg/m2 every 3 weeks or paclitaxel 80 mg/m2 given weekly, 3 weeks on/1 week off. 150 Reference ID: 5493485 Treatment with KEYTRUDA and lenvatinib continued until RECIST v1.1-defined progression of disease as verified by BICR, unacceptable toxicity, or for KEYTRUDA, a maximum of 24 months. Treatment was permitted beyond RECIST v1.1-defined disease progression if the treating investigator considered the patient to be deriving clinical benefit, and the treatment was tolerated. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR and DoR, as assessed by BICR. Among the 697 pMMR patients, 346 patients were randomized to KEYTRUDA in combination with lenvatinib, and 351 patients were randomized to investigator’s choice of doxorubicin (n=254) or paclitaxel (n=97). The pMMR population characteristics were: median age of 65 years (range: 30 to 86), 52% age 65 or older; 62% White, 22% Asian, and 3% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1. The histologic subtypes were endometrioid carcinoma (55%), serous (30%), clear cell carcinoma (7%), mixed (4%), and other (3%). All 697 of these patients received prior systemic therapy for endometrial carcinoma: 67% had one, 30% had two, and 3% had three or more prior systemic therapies. Thirty-seven percent of patients received only prior neoadjuvant or adjuvant therapy. Efficacy results for the pMMR or not MSI-H patients are summarized in Table 98 and Figures 35 and 36. Table 98: Efficacy Results in KEYNOTE-775 Endometrial Carcinoma (pMMR or not MSI-H) Endpoint KEYTRUDA 200 mg every 3 weeks and Lenvatinib n=346 Doxorubicin or Paclitaxel n=351 OS Number (%) of patients with event 165 (48%) 203 (58%) Median in months (95% CI) 17.4 (14.2, 19.9) 12.0 (10.8, 13.3) Hazard ratio* (95% CI) 0.68 (0.56, 0.84) p-Value† 0.0001 PFS Number (%) of patients with event 247 (71%) 238 (68%) Median in months (95% CI) 6.6 (5.6, 7.4) 3.8 (3.6, 5.0) Hazard ratio* (95% CI) 0.60 (0.50, 0.72) p-Value† <0.0001 Objective Response Rate ORR‡ (95% CI) 30% (26, 36) 15% (12, 19) Complete response rate 5% 3% Partial response rate 25% 13% p-Value§ <0.0001 Duration of Response n=105 n=53 Median in months (range) 9.2 (1.6+, 23.7+) 5.7 (0.0+, 24.2+) * Based on the stratified Cox regression model † Based on stratified log-rank test ‡ Response: Best objective response as confirmed complete response or partial response § Based on Miettinen and Nurminen method stratified by ECOG performance status, geographic region, and history of pelvic radiation 151 Reference ID: 5493485 100 90 80 70 ~ 60 ro > ·~ :::, 50 CJ) ro li; > 0 40 30 20 10 0 0 Number at Risk KEYTRUDA + Lenvatinib: 346 Chemotherapy: 351 3 Treatment arm KEYTRUOA + Leovatinib Chemotherapy 6 9 12 Time in Months 322 319 285 262 232 201 160 120 15 109 70 18 62 33 21 28 11 24 5 3 27 0 0 Figure 35: Kaplan-Meier Curve for Overall Survival in KEYNOTE-775 (pMMR or Not MSI-H) 152 Reference ID: 5493485 100 90 80 ~ 70 m > -~ 60 ::::i (f) (I!) (I!) 50 '- LL c 0 00 40 00 (I!) '- OJ 0 30 '- Cl.. 20 10 0 Number at Risk KEYTRUDA + Lenvatinib: Chemotherapy: 0 346 351 3 264 177 165 83 9 12 Time i11 Months 11 2 37 60 15 15 39 8 18 30 3 Treatment a.nm KEYTRUDA + Lem,ati nib C:hernofherapy 21 12 1 24 5 1 27 0 0 Figure 36: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-775 (pMMR or Not MSI-H) As a Single Agent for the Treatment of Advanced MSI-H or dMMR Endometrial Carcinoma The efficacy of KEYTRUDA was investigated in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label, multi-cohort trial. The trial enrolled 90 patients with unresectable or metastatic MSI-H or dMMR endometrial carcinoma in Cohorts D and K who received at least one dose of KEYTRUDA. MSI or MMR tumor status was determined using polymerase chain reaction (PCR) or immunohistochemistry (IHC), respectively. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Patients treated with KEYTRUDA without disease progression could be treated for up to 24 months. Assessment of tumor status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Among the 90 patients evaluated, the baseline characteristics were: median age of 64 years (range: 42 to 86); 83% White, 8% Asian, and 3% Black; 12% Hispanic or Latino; 39% ECOG PS of 0 and 61% ECOG PS of 1; 96% had M1 disease and 4% had M0 disease at study entry; and 51% had one and 48% had two or more prior lines of therapy. Nine patients received only adjuvant therapy and one patient received only neoadjuvant and adjuvant therapy before participating in the study. Efficacy results are summarized in Table 99. 153 Reference ID: 5493485 Table 99: Efficacy Results in Patients with Advanced MSI-H or dMMR Endometrial Carcinoma in KEYNOTE-158 Endpoint KEYTRUDA n=90* Objective Response Rate ORR (95% CI) 46% (35, 56) Complete response rate 12% Partial response rate 33% Duration of Response n=41 Median in months (range) NR (2.9, 55.7+) % with duration ≥12 months 68% % with duration ≥24 months 44% * Median follow-up time of 16.0 months (range 0.5 to 62.1 months) + Denotes ongoing response NR = not reached 14.18 Tumor Mutational Burden-High Cancer The efficacy of KEYTRUDA was investigated in a prospectively-planned retrospective analysis of 10 cohorts (A through J) of patients with various previously treated unresectable or metastatic solid tumors with high tumor mutation burden (TMB-H) who were enrolled in a multicenter, non-randomized, open-label trial, KEYNOTE-158 (NCT02628067). The trial excluded patients who previously received an anti-PD-1 or other immune-modulating monoclonal antibody, or who had an autoimmune disease, or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Assessment of tumor status was performed every 9 weeks for the first 12 months and every 12 weeks thereafter. The statistical analysis plan pre-specified ≥10 and ≥13 mutations per megabase using the FoundationOne CDx assay as cutpoints to assess TMB. Testing of TMB was blinded with respect to clinical outcomes. The major efficacy outcome measures were ORR and DoR in patients who received at least one dose of KEYTRUDA as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. In KEYNOTE-158, 1050 patients were included in the efficacy analysis population. TMB was analyzed in the subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements. Of the 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB ≥10 mutations per megabase. Among the 102 patients with TMB-H advanced solid tumors, the study population characteristics were: median age of 61 years (range: 27 to 80), 34% age 65 or older; 34% male; 81% White; and 41% ECOG PS of 0 and 58% ECOG PS of 1. Fifty-six percent of patients had at least two prior lines of therapy. Efficacy results are summarized in Tables 100 and 101. 154 Reference ID: 5493485 Table 100: Efficacy Results for Patients with TMB-H Cancer in KEYNOTE-158 Endpoint KEYTRUDA 200 mg every 3 weeks TMB ≥10 mut/Mb n=102* TMB ≥13 mut/Mb n=70 Objective Response Rate ORR (95% CI) 29% (21, 39) 37% (26, 50) Complete response rate 4% 3% Partial response rate 25% 34% Duration of Response n=30 n=26 Median in months (range)† NR (2.2+, 34.8+) NR (2.2+, 34.8+) % with duration ≥12 months 57% 58% % with duration ≥24 months 50% 50% * Median follow-up time of 11.1 months † From product-limit (Kaplan-Meier) method for censored data + Denotes ongoing response NR = not reached Table 101: Response by Tumor Type (TMB ≥10 mut/Mb) N Objective Response Rate n (%) 95% CI Duration of Response range (months) Overall* 102 30 (29%) (21%, 39%) (2.2+, 34.8+) Small cell lung cancer 34 10 (29%) (15%, 47%) (4.1, 32.5+) Cervical cancer 16 5 (31%) (11%, 59%) (3.7+, 34.8+) Endometrial cancer 15 7 (47%) (21%, 73%) (8.4+, 33.9+) Anal cancer 14 1 (7%) (0.2%, 34%) 18.8+ Vulvar cancer 12 2 (17%) (2%, 48%) (8.8, 11.0) Neuroendocrine cancer 5 2 (40%) (5%, 85%) (2.2+, 32.6+) Salivary cancer 3 PR, SD, PD 31.3+ Thyroid cancer 2 CR, CR (8.2, 33.2+) Mesothelioma cancer 1 PD * No TMB-H patients were identified in the cholangiocarcinoma cohort CR = complete response PR = partial response SD = stable disease PD = progressive disease In an exploratory analysis in 32 patients enrolled in KEYNOTE-158 whose cancer had TMB ≥10 mut/Mb and <13 mut/Mb, the ORR was 13% (95% CI: 4%, 29%), including two complete responses and two partial responses. 14.19 Cutaneous Squamous Cell Carcinoma The efficacy of KEYTRUDA was investigated in patients with recurrent or metastatic cSCC or locally advanced cSCC enrolled in KEYNOTE-629 (NCT03284424), a multicenter, multi-cohort, non-randomized, open-label trial. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until documented disease progression, unacceptable toxicity, or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of KEYTRUDA during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Assessment of tumor status was performed every 6 weeks during the first year, and every 9 weeks during the second year. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Among the 105 patients with recurrent or metastatic cSCC treated, the study population characteristics were: median age of 72 years (range: 29 to 95), 71% age 65 or older; 76% male; 70% White, 25% race 155 Reference ID: 5493485 unknown; 34% ECOG PS of 0 and 66% ECOG PS of 1. Forty-five percent of patients had locally recurrent only cSCC, 24% had metastatic only cSCC, and 31% had both locally recurrent and metastatic cSCC. Eighty-seven percent received one or more prior lines of therapy; 73% received prior radiation therapy. Among the 54 patients with locally advanced cSCC treated, the study population characteristics were: median age of 76 years (range: 35 to 95), 80% age 65 or older; 72% male; 83% White, 13% race unknown; 41% ECOG PS of 0 and 59% ECOG PS of 1. Twenty-two percent received one or more prior lines of therapy; 63% received prior radiation therapy. Efficacy results are summarized in Table 102. Table 102: Efficacy Results in KEYNOTE-629 Endpoint KEYTRUDA Recurrent or Metastatic cSCC n=105 KEYTRUDA Locally Advanced cSCC n=54 Objective Response Rate ORR (95% CI) 35% (26, 45) 52% (38, 66) Complete response rate 12% 22% Partial response rate 23% 30% Duration of Response* n=37 n=28 Median in months (range) NR (2.7, 64.2+) 47.2 (1.0+, 49.9+) % with duration ≥6 months 76% 89% % with duration ≥12 months 68% 75% * Median follow-up time: recurrent or metastatic cSCC: 23.8 months; locally advanced cSCC: 48.0 months + Denotes ongoing response 14.20 Triple-Negative Breast Cancer Neoadjuvant and Adjuvant Treatment of High-Risk Early-Stage TNBC The efficacy of KEYTRUDA in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-522 (NCT03036488), a randomized (2:1), multicenter, double-blind, placebo-controlled trial conducted in 1174 patients with newly diagnosed previously untreated high-risk early-stage TNBC (tumor size >1 cm but ≤2 cm in diameter with nodal involvement or tumor size >2 cm in diameter regardless of nodal involvement). Patients were enrolled regardless of tumor PD-L1 expression. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by nodal status (positive vs. negative), tumor size (T1/T2 vs. T3/T4), and choice of carboplatin (dosed every 3 weeks vs. weekly). Patients were randomized (2:1) to one of the following two treatment arms; all study medications were administered intravenously: • Arm 1: • Four cycles of preoperative KEYTRUDA 200 mg every 3 weeks on Day 1 of cycles 1-4 of treatment regimen in combination with: o Carboplatin • AUC 5 mg/mL/min every 3 weeks on Day 1 of cycles 1-4 of treatment regimen -or­ • AUC 1.5 mg/mL/min every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen -and­ o Paclitaxel 80 mg/m2 every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen 156 Reference ID: 5493485 • Followed by four additional cycles of preoperative KEYTRUDA 200 mg every 3 weeks on Day 1 of cycles 5-8 of treatment regimen in combination with: o Doxorubicin 60 mg/m2 -or- epirubicin 90 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen -and­ o Cyclophosphamide 600 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen • Following surgery, nine cycles of KEYTRUDA 200 mg every 3 weeks were administered. • Arm 2: • Four cycles of preoperative placebo every 3 weeks on Day 1 of cycles 1-4 of treatment regimen in combination with: o Carboplatin • AUC 5 mg/mL/min every 3 weeks on Day 1 of cycles 1-4 of treatment regimen -or­ • AUC 1.5 mg/mL/min every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen -and­ o Paclitaxel 80 mg/m2 every week on Days 1, 8, and 15 of cycles 1-4 of treatment regimen • Followed by four cycles of preoperative placebo every 3 weeks on Day 1 of cycles 5-8 of treatment regimen in combination with: o Doxorubicin 60 mg/m2 -or- epirubicin 90 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen -and­ o Cyclophosphamide 600 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen • Following surgery, nine cycles of placebo every 3 weeks were administered. The main efficacy outcomes were pCR rate and EFS. pCR was defined as absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0) and was assessed by the blinded local pathologist at the time of definitive surgery. EFS was defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes definitive surgery, local or distant recurrence, second primary malignancy, or death due to any cause. An additional efficacy outcome was overall survival (OS). The study population characteristics were: median age of 49 years (range: 22 to 80), 11% age 65 or older; 99.9% female; 64% White, 20% Asian, 4.5% Black, and 1.8% American Indian or Alaska Native; 87% ECOG PS of 0 and 13% ECOG PS of 1; 56% were pre-menopausal status and 44% were post-menopausal status; 7% were primary Tumor 1 (T1), 68% T2, 19% T3, and 7% T4; 49% were nodal involvement 0 (N0), 40% N1, 11% N2, and 0.2% N3; 75% of patients were overall Stage II and 25% were Stage III. Table 103 and Figure 37 summarize the efficacy results for KEYNOTE-522. At the protocol pre-specified IA4 interim analysis of OS, OS data were not mature with 45% of the required events for the final analysis. 157 Reference ID: 5493485 Table 103: Efficacy Results in KEYNOTE-522 Endpoint KEYTRUDA 200 mg every 3 weeks with chemotherapy/KEYTRUDA n=784 Placebo with chemotherapy/Placebo n=390 pCR (ypT0/Tis ypN0)* Number of patients with pCR 494 217 pCR Rate (%), (95% CI) 63.0 (59.5, 66.4) 55.6 (50.6, 60.6) Treatment difference (%) estimate (95% CI)†,‡ 7.5 (1.6, 13.4) EFS Number of patients with event (%) 123 (16%) 93 (24%) Hazard ratio (95% CI)§ 0.63 (0.48, 0.82) p-Value¶,# 0.00031 * Based on the entire intention-to-treat population n=1174 patients † Based on a pre-specified pCR interim analysis in n=602 patients, the pCR rate difference was statistically significant (p=0.00055 compared to a significance level of 0.003). ‡ Based on Miettinen and Nurminen method stratified by nodal status, tumor size, and choice of carboplatin § Based on stratified Cox regression model ¶ Based on a pre-specified EFS interim analysis (compared to a significance level of 0.0052) # Based on log-rank test stratified by nodal status, tumor size, and choice of carboplatin 158 Reference ID: 5493485 100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 - ••• 12 15 18 21 24 27 30 33 36 39 42 45 48 51 784 781 769 751 728 718 702 692 681 671 652 551 433 303 165 28 0 0 390 386 382 368 358 342 328 319 310 304 297 250 195 140 83 17 0 0 Figure 37: Kaplan-Meier Curve for Event-Free Survival in KEYNOTE-522 Treatment arm [||| censored] KEYTRUDA + Chemo/KEYTRUDA Placebo + Chemo/Placebo Event-Free Survival (%) Time in Months Number at Risk KEYTRUDA + Chemo/KEYTRUDA: Placebo + Chemo/Placebo: Locally Recurrent Unresectable or Metastatic TNBC The efficacy of KEYTRUDA in combination with paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin was investigated in KEYNOTE-355 (NCT02819518), a multicenter, double-blind, randomized, placebo-controlled trial conducted in 847 patients with locally recurrent unresectable or metastatic TNBC, regardless of tumor PD-L1 expression, who had not been previously treated with chemotherapy in the metastatic setting. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by chemotherapy treatment (paclitaxel or paclitaxel protein-bound vs. gemcitabine and carboplatin), tumor PD-L1 expression (CPS ≥1 vs. CPS <1) according to the PD-L1 IHC 22C3 pharmDx kit, and prior treatment with the same class of chemotherapy in the neoadjuvant setting (yes vs. no). Patients were randomized (2:1) to one of the following treatment arms; all study medications were administered via intravenous infusion: • KEYTRUDA 200 mg on Day 1 every 3 weeks in combination with paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 every 28 days, paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days. 159 Reference ID: 5493485 • Placebo on Day 1 every 3 weeks in combination with paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 every 28 days, paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days. Assessment of tumor status was performed at Weeks 8, 16, and 24, then every 9 weeks for the first year, and every 12 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, tested in the subgroup of patients with CPS ≥10. Additional efficacy outcome measures were ORR and DoR as assessed by BICR. The study population characteristics for patients were: median age of 53 years (range: 22 to 85), 21% age 65 or older; 100% female; 68% White, 21% Asian, and 4% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1; and 68% were post-menopausal status. Seventy-five percent of patients had tumor PD-L1 expression CPS ≥1 and 38% had tumor PD-L1 expression CPS ≥10. Table 104 and Figures 38 and 39 summarize the efficacy results for KEYNOTE-355. Table 104: Efficacy Results in KEYNOTE-355 (CPS ≥10) Endpoint KEYTRUDA 200 mg every 3 weeks with chemotherapy n=220 Placebo every 3 weeks with chemotherapy n=103 OS* Number of patients with event (%) 155 (70%) 84 (82%) Median in months (95% CI) 23 (19.0, 26.3) 16.1 (12.6, 18.8) Hazard ratio† (95% CI) 0.73 (0.55, 0.95) p-Value‡ 0.0093 PFS§ Number of patients with event (%) 136 (62%) 79 (77%) Median in months (95% CI) 9.7 (7.6, 11.3) 5.6 (5.3, 7.5) Hazard ratio† (95% CI) 0.65 (0.49, 0.86) p-Value¶ 0.0012 Objective Response Rate (Confirmed)* ORR (95% CI) 53% (46, 59) 41% (31, 51) Complete response rate 17% 14% Partial response rate 35% 27% Duration of Response* n=116 n=42 Median in months (95% CI) 12.8 (9.9, 25.9) 7.3 (5.5, 15.4) * Based on the pre-specified final analysis † Based on stratified Cox regression model ‡ One-sided p-Value based on stratified log-rank test (compared to a significance level of 0.0113) § Based on a pre-specified interim analysis ¶ One-sided p-Value based on stratified log-rank test (compared to a significance level of 0.00411) 160 Reference ID: 5493485 60 50 40 30 I - - I 11 I ------ 20 '•H l ~ - rn I- - HI- - -H -U- - ~ 10 0 --tm-rmm,rmm"rmrm"""""'""'"'""'"""'""'"''"""''"""''"""'""""""""rmrm"""""'""'"'""""""""'"''""""""",,,.,,,"""'""""'"""'""""'""''"" 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 220 214 193 171 154 139 127 116 105 91 84 78 73 59 43 31 17 2 0 103 98 91 77 66 55 46 39 35 30 25 22 22 17 12 8 6 2 0 Figure 38: Kaplan-Meier Curve for Overall Survival in KEYNOTE-355 (CPS ≥10) Treatment arm KEYTRUDA + Chemo Placebo + Chemo Overall Survival (%) Time in Months Number at Risk KEYTRUDA + Chemo Placebo + Chemo 161 Reference ID: 5493485 100 90 80 ~ 70 rn > 2: 60 ::J (/J Cl) Cl) 50 Li: c _Q "' 40 "' ~ CJ) 0 30 ([_ 20 10 0 0 Number at Risk KEYT RU DA + Ch emo: 220 Placebo + Chemo 103 3 6 173 12.2 80 41 9 96 30 12 15 18 Time in Months 63 18 52 15 44 12 21 37 8 24 25 8 T reatm:ent ann KEYTRUDA t-Chemo Plac,,l>o • Ch.emo 27 12 7 30 5 3 33 0 36 0 0 Figure 39: Kaplan-Meier Curve for Progression-Free Survival in KEYNOTE-355 (CPS ≥10) 14.21 Adult Classical Hodgkin Lymphoma and Adult Primary Mediastinal Large B-Cell Lymphoma: Additional Dosing Regimen of 400 mg Every 6 Weeks The efficacy and safety of KEYTRUDA using a dosage of 400 mg every 6 weeks for the classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma indications for adults was primarily based on the dose/exposure efficacy and safety relationships and observed pharmacokinetic data in patients with melanoma [see Clinical Pharmacology (12.2)]. 16 HOW SUPPLIED/STORAGE AND HANDLING KEYTRUDA injection (clear to slightly opalescent, colorless to slightly yellow solution): Carton containing one 100 mg/4 mL (25 mg/mL), single-dose vial (NDC 0006-3026-02) Carton containing two 100 mg/4 mL (25 mg/mL), single-dose vials (NDC 0006-3026-04) Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Immune-Mediated Adverse Reactions • Inform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after discontinuation of treatment, and may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA. These reactions may include: • Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)]. 162 Reference ID: 5493485 • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.1)]. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.1)]. • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of adrenal insufficiency, hypophysitis, hypothyroidism, hyperthyroidism, or Type 1 diabetes mellitus [see Warnings and Precautions (5.1)]. • Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis [see Warnings and Precautions (5.1)]. • Severe skin reactions: Advise patients to contact their healthcare provider immediately for any signs or symptoms of severe skin reactions, SJS or TEN [see Warnings and Precautions (5.1)]. • Other immune-mediated adverse reactions: o Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new or worsening signs or symptoms [see Warnings and Precautions (5.1)]. o Advise patients of the risk of solid organ transplant rejection and other transplant (including corneal graft) rejection. Advise patients to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection and other transplant (including corneal graft) rejection [see Warnings and Precautions (5.1)]. Infusion-Related Reactions • Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion- related reactions [see Warnings and Precautions (5.2)]. Complications of Allogeneic HSCT • Advise patients of the risk of post-allogeneic hematopoietic stem cell transplantation complications [see Warnings and Precautions (5.3)]. Embryo-Fetal Toxicity • Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)]. • Advise females of reproductive potential to use effective contraception during treatment with KEYTRUDA and for 4 months after the last dose [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)]. Lactation • Advise women not to breastfeed during treatment with KEYTRUDA and for 4 months after the last dose [see Use in Specific Populations (8.2)]. Laboratory Tests • Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions (5.1)]. Manufactured by: Merck Sharp & Dohme LLC Rahway, NJ 07065, USA U.S. License No. 0002 For patent information: www.msd.com/research/patent The trademarks depicted herein are owned by their respective companies. 163 Reference ID: 5493485 Copyright © 2014-XXXX Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. uspi-mk3475-iv-XXXXrXXX 164 Reference ID: 5493485
custom-source
2025-02-12T15:47:42.219637
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use UNLOXCYT safely and effectively. See full prescribing information for UNLOXCYT. UNLOXCYT (cosibelimab-ipdl) injection, for intravenous use Initial U.S. Approval: 2024 -----------------------------INDICATIONS AND USAGE-------------------------­ UNLOXCYT is a programmed death ligand-1 (PD-L1) blocking antibody indicated for the treatment of adults with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who are not candidates for curative surgery or curative radiation. (1.1) ------------------------DOSAGE AND ADMINISTRATION---------------------­ The recommended dosage of UNLOXCYT is 1,200 mg as an intravenous infusion over 60 minutes every 3 weeks. (2.1) -----------------------DOSAGE FORMS AND STRENGTHS-------------------­ Injection: 300 mg/5 mL (60 mg/mL) solution in a single-dose vial. (3) ------------------------------CONTRAINDICATIONS------------------------------­ None. (4) -------------------------WARNINGS AND PRECAUTIONS---------------------­ • Immune-Mediated Adverse Reactions (5.1) o Immune-mediated adverse reactions can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune- mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, and solid organ transplant rejection. o Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. o Withhold or permanently discontinue UNLOXCYT based on the severity of reaction. (2.2) • Infusion-Related Reactions: Interrupt, slow the rate of infusion, or permanently discontinue based on severity of reaction. (2.2, 5.2) • Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD­ L1 blocking antibody. (5.3) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.4, 8.1, 8.3) ------------------------------ADVERSE REACTIONS--------------------------------­ The most common adverse reactions (≥10%) were fatigue, musculoskeletal pain, rash, diarrhea, hypothyroidism, constipation, nausea, headache, pruritus, edema, localized infection, and urinary tract infection. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Checkpoint Therapeutics at +1-212-574-2830 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------------USE IN SPECIFIC POPULATIONS----------------------­ Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised date: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Dose Modifications for Adverse Reactions 2.3 Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Severe and Fatal Immune-Mediated Adverse Reactions 5.2 Infusion-Related Reactions 5.3 Complications of Allogeneic HSCT 5.4 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Cutaneous Squamous Cell Carcinoma (CSCC) 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 5495934 1 FULL PRESCRIBING INFORMATION 1. INDICATIONS AND USAGE UNLOXCYT is indicated for the treatment of adults with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who are not candidates for curative surgery or curative radiation. 2. DOSAGE AND ADMINISTRATION 2.1. Recommended Dosage The recommended dosage of UNLOXCYT is 1,200 mg administered as an intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. 2.2. Dose Modifications for Adverse Reactions No dose reductions of UNLOXCYT are recommended. In general, withhold UNLOXCYT for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue UNLOXCYT for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to a prednisone equivalent of 10 mg or less per day within 12 weeks of initiating steroids. Dosage modifications for UNLOXCYT for adverse reactions that require management different from these general guidelines are summarized in Table 1. Table 1: Recommended Dose Modifications for Adverse Reactions Adverse Reaction Severitya UNLOXCYT Dosage Modifications Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] Pneumonitis Grade 2 Withholdb Grade 3 or 4 Permanently discontinue Colitis Grade 2 or 3 Withholdb Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN Withholdb AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Hepatitis with tumor involvement of the liverc Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to Withholdb 2 Reference ID: 5495934 Adverse Reaction Severitya UNLOXCYT Dosage Modifications more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Endocrinopathiesd Grade 3 or 4 Withhold until clinically stable or permanently discontinue, depending on severityb Nephritis with renal dysfunction Grade 2 or 3 increased blood creatinine Withholdb Grade 4 increased blood creatinine Permanently discontinue Exfoliative dermatologic conditions Suspected SJS, TEN, or DRESS Withholdb Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grade 2, 3 or 4 Permanently discontinue Neurological toxicities Grade 2 Withholdb Grade 3 or 4 Permanently discontinue Other Adverse Reactions Infusion-related reactions [see Warnings and Precautions (5.2)] Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue ALT = alanine aminotransferase; AST = aspartate aminotransferase; DRESS: drug rash with eosinophilia and systemic symptoms; SJS: Stevens-Johnson Syndrome; TEN: toxic epidermal necrolysis; ULN: upper limit of normal. a Based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 5. b Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce corticosteroid to a prednisone equivalent of 10 mg/day or less within 12 weeks of initiating steroids. c If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue UNLOXCYT based on recommendations for hepatitis with no tumor involvement of the liver. d Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved. 3 Reference ID: 5495934 2.3. Preparation and Administration Visually inspect the vial for particulate matter and discoloration. UNLOXCYT is clear to opalescent, colorless to yellow or slightly brown. Discard the vial if visible particles are observed. Do not shake the vial. Preparation for Intravenous Infusion: • Add 20 mL (1,200 mg) of UNLOXCYT to a 250 mL intravenous infusion bag containing 0.9% Sodium Chloride Injection. UNLOXCYT is compatible with an infusion bag made of polyolefin or polyvinyl chloride. • Mix diluted solution by gentle inversion. Do not shake. • Discard any unused portion left in the vial. Storage of Infusion Solution: The prepared infusion solution may be stored either: • At room temperature up to 25°C (77°F) for no more than 24 hours from the time of preparation until the end of infusion. • Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from time of preparation until end of infusion. If refrigerated, allow the diluted solution to come to room temperature prior to administration. • Discard after 24 hours. • Do not freeze. Administration: • Visually inspect the infusion bag for particulate matter and discoloration prior to administration. Discard if the solution is discolored or contains particulate matter. • Administer by intravenous infusion over 60 minutes through an intravenous line containing a sterile, in-line or add-on of 0.2-micron to 0.22-micron filter. • Do not administer UNLOXCYT as an intravenous push or bolus injection. • Do not co-administer other drugs through the same infusion line. 3. DOSAGE FORMS AND STRENGTHS Injection: 300 mg/5 mL (60 mg/mL), clear to opalescent, colorless to yellow or slightly brown solution in a single-dose vial. 4. CONTRAINDICATIONS None. 4 Reference ID: 5495934 5. WARNINGS AND PRECAUTIONS 5.1. Severe and Fatal Immune-Mediated Adverse Reactions UNLOXCYT is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed in WARNINGS AND PRECAUTIONS may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which can be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting a PD-1/PD­ L1–blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1–blocking antibodies, they can also manifest after discontinuation of PD-1/PD-L1–blocking antibodies. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1–blocking antibodies. Monitor closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function tests at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue UNLOXCYT depending on severity [see Dosage and Administration (2.2)]. In general, if UNLOXCYT requires interruption or discontinuation, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reaction is not controlled with corticosteroids. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies, dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis UNLOXCYT can cause immune-mediated pneumonitis. In patients treated with other PD-1/PD­ L1–blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 1% (3/223, Grade 2) of patients receiving UNLOXCYT. Pneumonitis led to withholding of UNLOXCYT in 0.4% (1/223) of patients. All 3 patients required systemic corticosteroids and pneumonitis did not resolve. One patient in whom UNLOXCYT was withheld for pneumonitis, had UNLOXCYT reinitiated after symptom improvement and had recurrence of pneumonitis. Immune-Mediated Colitis 5 Reference ID: 5495934 UNLOXCYT can cause immune-mediated colitis, which may present with diarrhea, abdominal pain, and lower gastrointestinal (GI) bleeding. Cytomegalovirus infection/reactivation has occurred in patients with corticosteroid-refractory immune-mediated colitis treated with PD- 1/PD-L1–blocking antibodies. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 0.4% (1/223, Grade 1) of patients receiving UNLOXCYT. Systemic corticosteroids were required in the patient experiencing colitis. The event of colitis did not resolve, and UNLOXCYT was not reinitiated. Immune-Mediated Hepatitis UNLOXCYT can cause immune-mediated hepatitis, defined as requiring the use of systemic corticosteroids and the absence of a clear alternate etiology. Immune-Mediated Endocrinopathies Adrenal Insufficiency UNLOXCYT can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment per institutional guidelines, including hormone replacement as clinically indicated. Withhold or permanently discontinue UNLOXCYT depending on severity [see Dosage and Administration (2.2)]. Adrenal insufficiency occurred in 0.9% (2/223) of patients receiving UNLOXCYT, including Grade 2 in 0.4% (1/223) of patients. UNLOXCYT was withheld for adrenal insufficiency in one of these patients and was reinitiated after symptom improvement. Systemic corticosteroids were required in both patients with adrenal insufficiency. Hypophysitis UNLOXCYT can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue UNLOXCYT depending on severity [see Dosage and Administration (2.3)]. Thyroid Disorders UNLOXCYT can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue UNLOXCYT depending on severity [see Dosage and Administration (2.2)]. Hypothyroidism: Hypothyroidism occurred in 10% (22/223) of patients receiving UNLOXCYT, including Grade 2 in 5% (10/223) of patients. Hypothyroidism resolved in 7 of the 22 patients. Hyperthyroidism: Hyperthyroidism occurred in 5% (12/223) of patients receiving UNLOXCYT, including Grade 2 in 0.4% (1/223) of patients. Hyperthyroidism resolved in 10 of the 12 patients. Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis UNLOXCYT can cause type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment 6 Reference ID: 5495934 with insulin as clinically indicated. Withhold or permanently discontinue UNLOXCYT depending on severity [see Dosage and Administration (2.2)]. Immune-Mediated Nephritis with Renal Dysfunction UNLOXCYT can cause immune-mediated nephritis, defined as the required use of systemic corticosteroids or other immunosuppressants and the absence of a clear alternate etiology. Immune-Mediated Dermatologic Adverse Reactions UNLOXCYT can cause immune-mediated rash or dermatitis. Bullous and exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), have occurred with PD-1/PD-L1–blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes. Withhold or permanently discontinue UNLOXCYT depending on severity [see Dosage and Administration (2.2)]. Immune-mediated dermatologic adverse reactions occurred in 7% (15/223) of patients receiving UNLOXCYT, including Grade 3 in 0.9% (2/223) of patients and Grade 2 in 4% (9/223) of patients. Dermatologic adverse reactions led to permanent discontinuation of UNLOXCYT in 0.4% (1/223) of patients and withholding of UNLOXCYT in 0.9% (2/223) of patients. Systemic corticosteroids were required in 33% (5/15) of patients with dermatologic adverse reactions. Dermatologic adverse reactions resolved in 7 of the 15 patients. Of the 2 patients in whom UNLOXCYT was withheld for dermatologic adverse reactions, 1 patient reinitiated UNLOXCYT after symptom improvement and had recurrence of the dermatologic adverse reaction, which resolved after UNLOXCYT was withheld a second time. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred in <1% of the 223 patients who received UNLOXCYT [see Adverse Reactions (6.1)] or were reported with the use of other PD-1/PD-L1–blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis. Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy. Ocular: Uveitis, iritis, other ocular inflammatory toxicities. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt­ Koyanagi-Harada–like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis, including increases in serum amylase and lipase levels, gastritis, duodenitis. Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica. Endocrine: Hypoparathyroidism. 7 Reference ID: 5495934 Other (Hematologic/Immune): Autoimmune hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection. 5.2. Infusion-Related Reactions UNLOXCYT can cause severe or life-threatening infusion-related reactions. Infusion-related infusion reactions were reported in 11% (24/223) of patients, including Grade 2 in 5.8% (13/223) of patients receiving UNLOXCYT. Monitor patients for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion or permanently discontinue UNLOXCYT based on severity of reaction [see Dosage and Administration (2.2)]. Consider premedication with an antipyretic and/or an antihistamine for patients who have had previous systemic reactions to infusions of therapeutic proteins. 5.3. Complications of Allogeneic HSCT Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1–blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1–blocking antibody prior to or after an allogeneic HSCT. 5.4. Embryo-Fetal Toxicity Based on its mechanism of action, UNLOXCYT can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus, resulting in fetal death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with UNLOXCYT and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. 6. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1)] • Infusion-related reactions [see Warnings and Precautions (5.2)] • Complications of Allogeneic HSCT [see Warnings and Precautions (5.3)] 6.1. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical 8 Reference ID: 5495934 trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to UNLOXCYT as a single agent in 223 patients in two open-label, single-arm, multicohort studies, including 141 patients with advanced CSCC and 82 patients with other solid tumors and hematologic malignancies. UNLOXCYT was administered intravenously at doses of 800 mg every 2 weeks (n=174), 1,200 mg every 3 weeks (n=35), or other doses (n=14). Among the 223 patients, 54% were exposed for ≥24 weeks and 17% were exposed for >72 weeks. The safety of UNLOXCYT was evaluated in Study CK-301-101 in 141 patients with metastatic or locally advanced disease CSCC [see Clinical Studies (14)]. Patients received UNLOXCYT 800 mg every 2 weeks (n=115) or 1,200 mg every 3 weeks (n=26) as an intravenous infusion until disease progression or unacceptable toxicity. The median duration of exposure was 36 weeks (2 weeks to 3.7 years). Serious adverse reactions occurred in 31% of advanced patients with CSCC who received UNLOXCYT. The most frequent serious adverse reactions (> 2% of patients) were sepsis (2.8%), pneumonia (2.8%) and pyrexia (2.1%). Permanent discontinuation of UNLOXCYT due to an adverse reaction occurred in 8% of patients. Adverse reactions resulting in permanent discontinuation of UNLOXCYT were COVID-19, COVID-19 pneumonia, sepsis, ulcerative keratitis, tumor thrombosis, axillary pain, paresthesia, cholestasis, hepatic cytolysis, wound hemorrhage, neck pain, pemphigoid, and eye pain (1 patient each). Dosage interruptions due to an adverse reaction occurred in 36% of patients who received UNLOXCYT. The adverse reaction that required dosage interruption in ≥ 2% of patients who received UNLOXCYT was COVID-19 (2%). The most common (> 10%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, hypothyroidism, constipation nausea, headache, pruritus, edema, localized infection, and urinary tract infection. Table 2 and Table 3 summarize adverse reactions and laboratory abnormalities, respectively in CK-301-101. 9 Reference ID: 5495934 Table 2: Adverse Reactions in ≥ 10% of Patients with Metastatic or Locally Advanced CSCC Receiving UNLOXCYT in Study CK-301-101 UNLOXCYT N = 141 % System Organ Class Preferred Term All Grades % Grade 3 or 4 % General disorders and administrative site conditions Fatigue* Edema* 33 11 3 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain* 25 3 Skin and subcutaneous tissue disorders Rash* Pruritus* 23 12 1 0 Endocrine disorder Hypothyroidism* 14 0 Gastrointestinal disorders Diarrhea Nausea Constipation 14 13 13 0 0 0 Nervous system disorders Headache* 12 0 Infections and infestations Localized infection Urinary tract infection* 10 10 0.7 0 Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03 (or later version) * Represents a composite of multiple related terms 10 Reference ID: 5495934 Table 3: Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in ≥ 1% of Patients with Metastatic or Locally Advanced CSCC Receiving UNLOXCYT in Study CK-301-101 Laboratory Abnormality UNLOXCYT (N = 141) All Grades %a Grade 3 or 4 %a Hematology Hemoglobin decreased 45 4 Lymphocytes decreased 41 6 Platelets decreased 14 1 Leukocytes decreased 10 1 Chemistry Sodium decreased 38 5 Alkaline phosphatase increased 26 1 Alanine transferase increased 25 4 Lipase increased 25 3 Aspartate transaminase increased 24 3 Potassium increased 23 3 Calcium increased 14 2 Toxicity graded per NCI CTCAE v5 a The denominator used to calculate the rate varied from 122-140 based on the number of patients with a baseline value and at least one post-treatment value. 8. USE IN SPECIFIC POPULATIONS 8.1. Pregnancy Risk Summary Based on its mechanism of action, UNLOXCYT can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of UNLOXCYT in pregnant women. Animal studies have demonstrated that inhibition of the PD­ 1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death (see Data). Human IgG1 immunoglobulins (IgG1) are known to cross the placental barrier; therefore, cosibelimab-ipdl has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data: Animal reproduction studies have not been conducted with cosibelimab-ipdl to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering UNLOXCYT during pregnancy include increased rates of abortion or stillbirth. As reported in 11 Reference ID: 5495934 the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD­ L1 knockout mice. Based on its mechanism of action, fetal exposure to UNLOXCYT may increase the risk of developing immune-mediated disorders or altering the normal immune response. 8.2. Lactation Risk Summary There is no information regarding the presence of cosibelimab-ipdl in human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment and for 4 months after the last dose of UNLOXCYT. 8.3. Females and Males of Reproductive Potential UNLOXCYT can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating UNLOXCYT [see Use in Specific Populations (8.1)]. Contraception Females: Advise females of reproductive potential to use effective contraception during treatment with UNLOXCYT and for 4 months after the last dose. 8.4. Pediatric Use The safety and effectiveness of UNLOXCYT have not been established in pediatric patients. 8.5. Geriatric Use Of the 141 patients treated with UNLOXCYT as a single agent, 21% (29) were younger than 65 years, 31% (44) were aged 65 through 75 years, and 48% (68) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. 11. DESCRIPTION Cosibelimab-ipdl is a human programmed death ligand-1 (PD-L1) blocking antibody. Cosibelimab-ipdl is a human IgG1 lambda monoclonal antibody. Cosibelimab-ipdl is produced in Chinese hamster ovary (CHO) cells and has a calculated molecular weight of approximately 147 kDa. UNLOXCYT (cosibelimab-ipdl) injection for intravenous use is a sterile, preservative-free, clear to opalescent, colorless to yellow or slightly brown solution. It is supplied in single-dose vials. Each vial contains 300 mg of UNLOXCYT in 5 mL of solution with a pH of 5.3. Each mL of solution contains 60 mg of cosibelimab-ipdl, acetic acid (0.24 mg), mannitol (37.35 mg), polysorbate 80 (1.1 mg), sodium acetate (1.31 mg), sodium chloride (4.09 mg), and Water for Injection, USP. 12 Reference ID: 5495934 12. CLINICAL PHARMACOLOGY 12.1. Mechanism of Action PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Cosibelimab-ipdl binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1. This interaction releases the inhibitory effects of PD-L1 on the anti-tumor immune response. Cosibelimab-ipdl has also been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. 12.2. Pharmacodynamics Cosibelimab-ipdl exposure-response relationships and the time course of pharmacodynamic responses have not been fully characterized. 12.3. Pharmacokinetics Cosibelimab-ipdl pharmacokinetic parameters are presented as geometric mean (coefficient of variation) unless otherwise stated. At the recommended dosage, the cosibelimab-ipdl steady-state maximum plasma concentration (Cmax) is 492 µg/mL (24.3%) and area under curve (AUC) is 112000 µg*h/mL (39.6%). Cosibelimab-ipdl Cmax and AUC increased proportionally over the dose range of 800 mg to 1,200 mg following single dosing. Steady-state concentrations of cosibelimab-ipdl are reached by 12 weeks. At 1,200 mg every 3 weeks, the mean cosibelimab-ipdl concentrations (coefficient of variation, CV%) at steady-state ranged between a minimum concentration of 120 µg/L (46.3%) and a maximum concentration of 453 µg/L (22.2%). Steady-state exposure was achieved after 84 days of treatment. In patients with CSCC, cosibelimab-ipdl steady-state exposure at 1,200 mg every 3 weeks (the recommended dosage) was comparable to the exposure at 800 mg every 2 weeks. Distribution Cosibelimab-ipdl steady state volume of distribution is approximately 5.67 L (19.7%). Elimination Cosibelimab-ipdl steady state elimination half-life is 17.8 days (43.8%), and the clearance is 0.256 L/day (41%). Specific Populations No clinically significant differences in the pharmacokinetics of cosibelimab-ipdl were observed based on age (24.8 to 95.0 years), sex, race (79.6% White, 10.7% Asian, 0.5% African American, and 1.5% other), ethnicity (76.9% Not Hispanic/Latino and 4.9% Hispanic/Latino), ADA and nAb status, albumin (22 to 51 g/L), tumor type, tumor diameter, and renal impairment (CLcr 15 mL/min and higher). The effect of severe hepatic impairment (bilirubin > 3 x ULN and any AST) on cosibelimab-ipdl pharmacokinetics is unknown. 13 Reference ID: 5495934 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of UNLOXCYT or of other cosibelimab products. Anti-drug antibody (ADA) and neutralizing antibody (nAb) responses were monitored throughout the treatment period where the benefit to risk ratio was assessed. ADAs were detected in 65/133 (49%) of patients treated with UNLOXCYT and nAbs were detected in 2/65 (3.0%) of the patients. UNLOXCYT-treated patients who developed anti-cosibelimab antibodies had reduced UNLOXCYT concentrations (20% lower compared to UNLOXCYT-treated subjects who did not develop anti-cosibelimab-ipdl antibodies). There was no clinically significant effect of anti-cosibelimab-ipdl antibodies on the efficacy or safety of cosibelimab-ipdl. 13. NONCLINICAL TOXICOLOGY 13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been performed to assess the potential of cosibelimab-ipdl for carcinogenicity or genotoxicity. Fertility studies have not been conducted with cosibelimab-ipdl in animals. In 1- and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs up to the highest dose tested of 100 mg/kg/dose; however, many animals in these studies were not sexually mature. 13.2. Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1–blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus. 14. CLINICAL STUDIES 14.1. Cutaneous Squamous Cell Carcinoma (CSCC) The efficacy of UNLOXCYT was evaluated in Study CK-301-101 (NCT03212404), a multicenter, multicohort, open-label study in patients with metastatic CSCC (mCSCC) or locally advanced CSCC (laCSCC) who were not candidates for curative surgery or curative radiation. Patients were excluded if they had the following: active or suspected autoimmune disease, allogeneic transplant within 6 months prior to treatment, prior treatment with anti–PD-1/PD-L1 blocking antibodies or other immune checkpoint inhibitor therapy, uncontrolled or significant cardiovascular disease, ECOG PS ≥ 2, or infection with HIV, hepatitis B or hepatitis C. Patients received UNLOXCYT 800 mg every 2 weeks until disease progression or unacceptable toxicity. Tumor response assessments were performed every 8 weeks for the first 8 months and 14 Reference ID: 5495934 every 12 weeks thereafter. The major efficacy outcomes were objective response rate (ORR) and duration of response (DOR) as assessed by an independent central review committee (ICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. For patients with laCSCC with externally visible target lesions not assessable by radiologic imaging, ORR was determined by ICR assessments of digital photography (WHO criteria). The efficacy population consisted of 109 patients. The median age was 75 years (range 37-95); 78% were ≥ 65 years; 72% were male; 85% were White; 6% were Asian; 1% were Black or African American; 7% were race unknown or missing; 34% had ECOG performance status of 0 and 66% had ECOG performance score of 1. Seven percent of patients received at least one prior anti-cancer systemic therapy, 66% of patients had prior surgery and 69% of patients had prior radiotherapy. Efficacy results are summarized in Table 4. Table 4: Efficacy Results for Study CK-301-101 Efficacy Endpoints mCSCC N = 78 laCSCC N = 31 Objective Response Rate (ORR) ORR, n (%) (95% CI) 37 (47) (36, 59) 15 (48) (30, 67) Complete response, n (%) 6 (8) 3 (10) Partial response, n (%) 31 (40) 12 (39) Duration of Response (DOR) Number of responders N=37 N=15 Median DOR in monthsa (Range) NR (1.4+, 34.1+) 17.7 (3.7+, 17.7) Responders with observed DOR ≥ 6 months, n (%)b 31 (84) 13 (87) Responders with observed DOR ≥ 12 months, n (%)b 20 (54) 3 (20) CI: confidence interval; NR: not reached; +: Denotes ongoing at last assessment. a Based on Kaplan-Meier estimate. b The numerator includes the number of patients whose observed DOR reached at least the specified times of 6 or 12 months. Patients who did not have the opportunity to reach the specified timepoint were included in the denominator only. 16. HOW SUPPLIED/STORAGE AND HANDLING UNLOXCYT (cosibelimab-ipdl) injection is a clear to opalescent, colorless to yellow or slightly brown solution supplied in a carton containing one 300 mg/5 mL (60 mg/mL), single-dose vial (NDC 83444-301-10). Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze or shake. 17. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Immune-Mediated Adverse Reactions 15 Reference ID: 5495934 Advise patients that UNLOXCYT can cause immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of UNLOXCYT including the following [see Warnings and Precautions (5.1)]: • Pneumonitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pneumonitis, including new or worsening symptoms of cough, chest pain, or shortness of breath. • Colitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of colitis, including diarrhea, blood or mucus in stools, or severe abdominal pain. • Hepatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatitis. • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, or type 1 diabetes mellitus. • Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis. • Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately if they develop a new rash. • Other Immune-Mediated Adverse Reactions: o Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new signs or symptoms [see Warnings and Precautions (5.1)]. o Advise patients of the risk of solid organ transplant rejection and other transplant (including corneal graft) rejection. Advise patients to contact their healthcare provider immediately for signs or symptoms of organ transplant (including corneal graft) rejection [see Warnings and Precautions (5.1)]. Infusion-Related Reactions Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)]. Complications of Allogeneic HSCT or Solid Organ Transplant Rejection Advise patients to contact their healthcare provider immediately if they develop signs or symptoms of post-allogeneic HSCT complications or of solid organ transplant rejection [see Warnings and Precautions (5.1, 5.3)]. Embryo-Fetal Toxicity • Advise females of reproductive potential that UNLOXCYT can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)]. • Advise females of reproductive potential to use effective contraception during treatment with UNLOXCYT and for 4 months after the last dose [see Use in Specific Populations (8.3)]. 16 Reference ID: 5495934 Lactation • Advise female patients not to breastfeed during treatment with UNLOXCYT and for 4 months after the last dose [see Use in Specific Populations (8.2)]. Trademarks are owned by or licensed to Checkpoint Therapeutics, Inc. Manufactured and distributed by: Checkpoint Therapeutics, Inc. 95 Sawyer Road, Suite 110 Waltham, MA 02453 U.S. License No. XXXXX 17 Reference ID: 5495934 MEDICATION GUIDE UNLOXCYT (un-LOX-sit) (cosibelimab-ipdl) injection What is the most important information I should know about UNLOXCYT? UNLOXCYT is a medicine that may treat a type of skin cancer by working with your immune system. UNLOXCYT can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended. Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including: Lung problems. • cough • chest pain • shortness of breath Intestinal problems. • diarrhea (loose stools) or more frequent bowel movements than usual • stools that are black, tarry, sticky, or have blood or mucus • severe stomach-area (abdomen) pain or tenderness Liver problems. • yellowing of your skin or the whites of your eyes • dark urine (tea colored) • severe nausea or vomiting • bleeding or bruising more easily than • pain on the right side of your stomach area (abdomen) normal Hormone gland problems. • headache that will not go away or unusual headaches • urinating more often than usual • eye sensitivity to light • hair loss • eye problems • feeling cold • rapid heartbeat • constipation • increased sweating • your voice gets deeper • extreme tiredness • dizziness or fainting • weight gain or weight loss • changes in mood or behavior, such as • feeling more hungry or thirsty than usual decreased sex drive, irritability, or forgetfulness Kidney problems: • decrease in your amount urine • swelling of your ankles • blood in your urine • loss of appetite Skin problems. • rash • painful sores or ulcers in mouth or nose, • itching throat, or genital area • fever or flu-like symptoms • swollen lymph nodes • skin blistering or peeling Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with UNLOXCYT. Call or see your healthcare provider right way for any new or worsening signs or symptoms which may include: • chest pain, irregular heartbeat, shortness of breath or swelling of ankles • confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs • double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight • persistent or severe muscle pain or weakness, muscle cramps • low red blood cells, bruising Reference ID: 5495934 Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include: • nausea • dizziness • chills or shaking • feel like passing out • itching or rash • fever • flushing • back or neck pain • shortness of breath or wheezing Rejection of a transplanted organ. Your healthcare provider should tell you what signs and symptoms you should report and monitor you, depending on the type of organ transplant that you have had. Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with UNLOXCYT. Your healthcare provider will monitor you for these complications. Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with UNLOXCYT. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with UNLOXCYT if you have severe side effects. What is UNLOXCYT? UNLOXCYT is a prescription medicine used to treat adults with a type of skin cancer called cutaneous squamous cell carcinoma (CSCC). UNLOXCYT may be used to treat CSCC that has spread or cannot be cured by surgery or radiation. It is not known if UNLOXCYT is safe and effective in children. Before you receive UNLOXCYT, tell your healthcare provider about all your medical conditions, including if you: • have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus • have received an organ transplant, including corneal transplant. • have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic) • have received radiation treatment to your chest area • have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome. • are pregnant or plan to become pregnant. UNLOXCYT can harm your unborn baby. Females who are able to become pregnant: o Your healthcare provider will give you a pregnancy test before you start treatment with UNLOXCYT. o You should use an effective method of birth control during your treatment and for 4 months after the last dose of UNLOXCYT. Talk to your healthcare provider about birth control methods that you can use during this time. o Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with UNLOXCYT. • are breastfeeding or plan to breastfeed. It is not known if UNLOXCYT passes into your breast milk. Do not breastfeed during treatment and for 4 months after the last dose of UNLOXCYT. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will I receive UNLOXCYT? • Your healthcare provider will give you UNLOXCYT into your vein through an intravenous (IV) line over 60 minutes. • UNLOXCYT is usually given every 3 weeks. • Your healthcare provider will decide how many treatments you will need. • Your healthcare provider will do blood tests to check you for side effects. • If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment. Reference ID: 5495934 What are the possible side effects of UNLOXCYT? UNLOXCYT can cause serious side effects. • See “What is the most important information I should know about UNLOXCYT?” The most common side effects of UNLOXCYT include tiredness or weakness, muscle or bone pain, rash, diarrhea, low thyroid hormone levels (hypothyroidism), constipation, nausea, headache, itchy skin, swelling, infection, and urinary tract infection. These are not all the possible side effects of UNLOXCYT. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General Information about the safe and effective use of UNLOXCYT. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about UNLOXCYT, talk with your healthcare provider. You can ask your healthcare provider for information about UNLOXCYT that is written for healthcare professionals. What are the ingredients of UNLOXCYT? Active Ingredient: cosibelimab-ipdl Inactive ingredients: acetic acid, mannitol, polysorbate 80, sodium acetate, sodium chloride, and Water for Injection. Manufactured and distributed by: Checkpoint Therapeutics, Inc., 95 Sawyer Road, Suite 110 Waltham, MA, 02453 U.S. License No XXXXX This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 12/2024 Reference ID: 5495934
custom-source
2025-02-12T15:47:42.503696
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761297s000lbl.pdf', 'application_number': 761297, 'submission_type': 'ORIG ', 'submission_number': 1}
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PURIFIED CORTROPHIN® GEL (Repository Corticotropin Injection USP) Rx only DESCRIPTION Purified Cortrophin Gel is a porcine derived purified corticotropin (ACTH) in a sterile solution of gelatin. It is made up of a complex mixture of ACTH, ACTH related peptides and other porcine pituitary derived peptides. The drug product is a sterile preparation containing 80 USP units per mL and it contains 0.5% phenol (as preservative), 15.0% gelatin (for prolonged activity), water for injection, and the pH is adjusted with hydrochloric acid and sodium hydroxide. Purified Cortrophin Gel contains the porcine derived ACTH (1-39) with the following amino acid sequence: Ser- Tyr- Ser- Met- Glu- His- Phe- Arg- Trp- Gly­ 1 2 3 4 5 6 7 8 9 10 Lys- Pro- Val- Gly- Lys- Lys- Arg- Arg- Pro- Val­ 11 12 13 14 15 16 17 18 19 20 Lys- Val- Tyr- Pro- Asn- Gly- Ala- Glu- Asp- Glu­ 21 22 23 24 25 26 27 28 29 30 Leu- Ala- Glu- Ala- Phe- Pro- Leu- Glu- Phe- OH 31 32 33 34 35 36 37 38 39 CLINICAL PHARMACOLOGY Purified Cortrophin Gel is the anterior pituitary hormone which stimulates the functioning adrenal cortex to produce and secrete adrenocortical hormones. Following administration of a single intramuscular injection of 80 Units of Cortrophin Gel to healthy volunteers (n=20) in an open label pharmacodynamic study, the median time (range) to reach peak cortisol concentration was 8 (3-12) hours. The baseline corrected geometric mean maximum (CV%) cortisol levels were 34.52 µg/dL (28.2%). INDICATIONS AND USAGE Purified Cortrophin Gel is indicated in the following disorders: 1. Rheumatic disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Psoriatic arthritis. Reference ID: 5495496 Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). Ankylosing spondylitis. Acute gouty arthritis. 2. Collagen diseases: During an exacerbation or as maintenance therapy in selected cases of: Systemic lupus erythematosus. Systemic dermatomyositis (polymyositis). 3. Dermatologic diseases: Severe erythema multiforme (Stevens-Johnson syndrome). Severe psoriasis. 4. Allergic states: Atopic dermatitis. Serum sickness. 5. Ophthalmic diseases: Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: Allergic conjunctivitis. Keratitis. Iritis and iridocyclitis. Diffuse posterior uveitis and choroiditis. Optic neuritis. Chorioretinitis. Anterior segment inflammation. 6. Respiratory diseases: Symptomatic sarcoidosis. 7. Edematous states: To induce a diuresis or a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus. 8. Nervous system: Acute exacerbations of multiple sclerosis. CONTRAINDICATIONS Purified Cortrophin Gel is contraindicated for intravenous administration. Purified Cortrophin Gel is contraindicated in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, hypertension, or sensitivity to proteins derived from porcine sources. Purified Cortrophin Gel is contraindicated in patients with primary adrenocortical insufficiency or adrenocortical hyperfunction. WARNINGS Reference ID: 5495496 Chronic administration of corticotropin may lead to adverse effects which are not reversible. This product should not be administered for treatment until adrenal responsiveness has been verified with the route of administration which will be utilized during treatment, intramuscularly or subcutaneously. A rise in urinary and plasma corticosteroid values provides direct evidence of a stimulatory effect. Although the action of corticotropin is similar to that of exogenous adrenocortical steroids the quantity of adrenocorticoid may be variable. In patients who receive prolonged corticotropin therapy the additional use of rapidly acting corticosteroids before, during and after an unusual stressful situation is indicated. Masking Symptoms of Other Diseases Corticotropin may only suppress symptoms and signs of chronic disease without altering the natural course of the disease. Immunogenicity Potential Purified Cortrophin Gel is immunogenic. Limited available data suggest that a patient may develop antibodies to Purified Cortrophin Gel after chronic administration and loss of endogenous ACTH and Purified Cortrophin Gel activity. Prolonged administration of Purified Cortrophin Gel may increase the risk of hypersensitivity reactions. Sensitivity to porcine protein should be considered before starting therapy and during the course of treatment should symptoms arise. Ophthalmic Effects Prolonged use of corticotropin may produce posterior subcapsular cataracts and glaucoma with possible damage to the optic nerves. Infections Corticotropin may mask some signs of infection, and new infections including those of the eye due to fungi or viruses may appear during its use. There may be decreased resistance and inability to localize infection when corticotropin is used. Elevated Blood Pressure, Salt and Water Retention, and Hypokalemia Corticotropin can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. Dietary salt restriction and potassium supplementation may be necessary. Corticotropin increases calcium excretion. Vaccination While on corticotropin therapy, patients should not be vaccinated against smallpox. Other immunization procedures should be undertaken with caution in patients who are receiving corticotropin, especially when high doses are administered because of the possible hazards of neurological complications and lack of antibody response. Reference ID: 5495496 PRECAUTIONS General Patients with latent tuberculosis or tuberculin reactivity who receive corticotropin should be closely observed as reactivation of the disease may occur. During prolonged corticotropin therapy, these patients should receive chemoprophylaxis. Skin testing should be performed prior to treatment of all patients with suspected sensitivity to porcine protein. Immediately following intramuscular or subcutaneous administration of corticotropin all patients should be observed carefully for sensitivity reactions. Relative adrenocortical insufficiency induced by prolonged corticotropin therapy may be minimized by gradual reduction of corticotropin dosage. This type of insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress during that period, hormone therapy should be reinstituted. There is an enhanced effect of corticotropin in patients with hypothyroidism and in those with cirrhosis. The lowest possible dosage of corticotropin should be used to control the condition under treatment, and when reduction in dosage is possible the reduction should be gradual. Corticotropin should be administered for treatment only when the disease is intractable to more conventional therapy. Corticotropin should be adjunctive and not the sole therapy in the treatment of a disease. Since maximal corticotropin stimulation of the adrenals may be limited during the first few days of treatment, other drugs should be administered when an immediate therapeutic effect is desirable. When infection is present appropriate anti-infective therapy should be administered during corticotropin and following discontinuation of corticotropin therapy. Treatment of acute gouty arthritis should be limited to a few days. Since rebound attacks may occur when corticotropin is discontinued, conventional concomitant therapy should be administered during corticotropin treatment, and for several days after it is stopped. Psychic derangements may appear when corticotropin is used, ranging from euphoria, insomnia, mood swings, personality changes, and depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticotropin. Corticotropin should be used with caution in patients with diabetes, abscess, pyogenic infections, diverticulitis, renal insufficiency, and myasthenia gravis. Growth and development of infants and children on prolonged corticotropin therapy should be carefully observed. Reference ID: 5495496 Although controlled clinical trials have shown ACTH to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that it affects the ultimate outcome or natural history of the disease. Since complications of treatment with ACTH are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment. Drug Interactions Aspirin should be used cautiously in conjunction with corticotropin in hypoprothrombinemia. Pregnancy Since fetal abnormalities have been observed in experimental animals, use of this drug in pregnancy, nursing mothers, or women of childbearing potential requires that the potential benefits of the drug be weighed against the potential hazards to the mother and embryo or fetus. Infants born of mothers who have received substantial doses of corticotropin during pregnancy should be carefully observed for signs of hypoadrenalism. ADVERSE REACTIONS Fluid and Electrolyte Disturbances Sodium retention. Hypokalemic alkalosis. Fluid retention. Calcium loss. Potassium loss. Musculoskeletal Muscle weakness. Loss of muscle mass. Steroid myopathy. Osteoporosis. Vertebral compression fractures. Aseptic necrosis of femoral and humeral heads. Pathologic fracture of long bones. Gastrointestinal Peptic ulcer with possible perforation and hemorrhage. Abdominal distention. Ulcerative esophagitis. Pancreatitis. Dermatologic Injection site reactions. Impaired wound healing. Increased sweating. Reference ID: 5495496 Thin fragile skin. Suppression of skin test reactions. Petechiae and ecchymoses. Acne. Hyperpigmentation. Facial erythema. Cardiovascular Hypertension. Congestive heart failure. Necrotizing angiitis. Neurological Convulsions. Increased intracranial pressure with papilledema (pseudo-tumor cerebri), usually after treatment. Headache. Vertigo. Endocrine Menstrual irregularities. Development of Cushingoid state. Suppression of growth in children. Secondary adrenocortical and pituitary insufficiency, particularly in times of stress, as in trauma, surgery or illness. Decreased carbohydrate tolerance. Manifestations of latent diabetes mellitus. Increased requirements for insulin or oral hypoglycemic agents in diabetics. Hirsutism. Ophthalmic Posterior subcapsular cataracts. Increased intraocular pressure. Glaucoma with possible damage to optic nerve. Exophthalmos. Metabolic Negative nitrogen balance due to protein catabolism. Allergic reactions Allergic reactions manifesting as dizziness, nausea and vomiting, shock, skin reactions, especially in patients with allergic responses to proteins. Miscellaneous Weight gain. Abscess. Development of antibodies and loss of stimulatory effect. Reference ID: 5495496 To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800­ 308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DOSAGE AND ADMINISTRATION Standard tests for verification of adrenal responsiveness to corticotropin may utilize as much as 80 units as a single injection or one or more injections of a lesser dosage. Verification tests should be performed prior to treatment with corticotropins. The test should utilize the route(s) of administration proposed for treatment. Following verification dosage should be individualized according to the disease under treatment and the general medical condition of each patient. Frequency and dose of the drug should be determined by considering severity of the disease, plasma and urine corticosteroid levels and the initial response of the patient. Only gradual change in dosage schedules should be attempted, after full drug effects have become apparent. This product may be administered subcutaneously or intramuscularly. In the treatment of acute exacerbations of multiple sclerosis daily subcutaneous or intramuscular doses of 80-120 units for 2-3 weeks. The chronic administration of more than 40 units daily may be associated with uncontrollable adverse effects. When reduction in dosage is indicated this should be accomplished gradually by either reducing the amount of each injection, or administering injections at longer intervals, or by a combination of both of the above. During reduction of dosage, careful consideration should be given to the disease being treated, the general medical condition of the patient and the duration over which corticotropin was administered. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. HOW SUPPLIED/STORAGE AND HANDLING Purified Cortrophin Gel is supplied sterile in 1 mL and 5 mL multiple-dose vials. Package Size Total Volume NDC 1 mL multiple-dose vial 80 USP units/mL 62559-860-11 5 mL multiple-dose vial 400 USP units/5 mL 62559-860-15 Storage Store Purified Cortrophin Gel vials refrigerated at 2° to 8°C (36° to 46°F). After first use discard Purified Cortrophin Gel vials per the table below. Write the revised expiration date in the space provided on the carton labeling. Reference ID: 5495496 Package Size Discard By cl.Iii l'illlnr c Ullirul,/, lfi(·, 1 mL multiple-dose vial 6 months after first use or by the expiration date stamped on the vial, whichever occurs first. 5 mL multiple-dose vial 28 days after first use or by the expiration date stamped on the vial, whichever occurs first. Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623 10233 Rev 12/24 Reference ID: 5495496 INSTRUCTIONS FOR USE Purified Cortrophin® Gel (Repository Corticotropin Injection USP) for intramuscular or subcutaneous use This Instructions for Use contains information on how to inject Purified Cortrophin Gel. Your healthcare provider should show you how to prepare and inject Purified Cortrophin Gel the right way before you inject it for the first time. Do not try to inject yourself until you have been shown the right way to give your injections by your healthcare provider. Important information about how to inject Purified Cortrophin Gel • Purified Cortrophin Gel is given as an injection into the muscle or under the skin as directed by your healthcare provider. Do not inject it into a vein or take by mouth. • Inject Purified Cortrophin Gel exactly as your healthcare provider tells you. Your healthcare provider will tell you where to give the injection, how much to give, how often and when to give it. • Do not use Purified Cortrophin Gel until your healthcare provider has taught you how to give the injection. Before starting, collect all of the supplies that you will need to use for preparing and injecting Purified Cortrophin Gel. You will need the following supplies: • Vial of Purified Cortrophin Gel • Syringe • Needle for withdrawal (20G or as prescribed by your healthcare provider) • Needle for injection (23G or as prescribed by your healthcare provider) • 2 alcohol pads • Cotton balls or gauze pad • Bandage (if needed) • Sharps container for throwing away used syringes and needles (see “Disposing of used needles and syringe”) Preparing Purified Cortrophin Gel • Wash your hands well and dry with a clean towel. • Remove the vial from the refrigerator. Check the expiration date on the vial. Do not use if the expiration date has passed. • Purified Cortrophin Gel will be a solid gel when refrigerated and it needs to be warmed to a liquid gel before injecting. Warm the solid gel in the vial by rolling between your hands for a few minutes. Do not microwave or heat on the stove. Reference ID: 5495496 • Remove (flip off) the plastic cap from the top of the Purified Cortrophin Gel vial and throw it away in the trash. Do not put the plastic cap back on the vial. • Wipe the top of the vial rubber stopper with a new sterile alcohol pad. • Use a new sterile 20G needle (or needle prescribed for withdrawal) and syringe to draw up the amount of Purified Cortrophin Gel your healthcare provider has told you to use. Injecting Purified Cortrophin Gel • Prepare the skin where you are going to give the injection by wiping it with a new sterile alcohol pad. Allow to air dry. • Replace the 20G needle (or needle prescribed for withdrawal) used for drawing the Purified Cortrophin Gel from the vial with the 23G needle (or needle prescribed for injection). Do not use the 20G needle for injecting. • Give the injection the way your healthcare provider has instructed you. • There may be a little bleeding at the injection site. You can press a cotton ball or gauze pad over the injection site (do not rub). • If needed, you may cover the injection site with a bandage. • Return the vial to the refrigerator as soon as possible. Disposing of your used needles and syringe • Put your used needles and syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) your used needles and syringe in your household trash. • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. Reference ID: 5495496 There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Storing Purified Cortrophin Gel • Store vials of Purified Cortrophin Gel in the refrigerator between 36°F to 46°F (2°C to 8°C). • 1 mL vials: Throw away (discard) any 1 mL vials 6 months after first use or by the expiration date printed on the label, whichever occurs first. • 5 mL vials: Throw away (discard) any 5 mL vials 28 days after first use or by the expiration date printed on the label, whichever occurs first. • Write the revised discard by date in the space provided on the carton labeling. Keep Purified Cortrophin Gel and all medicines out of the reach of children. Distributed by: ANI Pharmaceuticals, Inc., Baudette, MN 56623 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: October 2023 Reference ID: 5495496
custom-source
2025-02-12T15:47:42.509871
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/008975s015lbl.pdf', 'application_number': 8975, 'submission_type': 'SUPPL ', 'submission_number': 15}
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use XERAVA safely and effectively. See full prescribing information for XERAVA. XERAVA® (eravacycline) for injection, for intravenous use Initial U.S. Approval: 2018 ------------------------------RECENT MAJOR CHANGES---------------------------­ Dosage and Administration (2.4) 12/2024 -------------------------------INDICATIONS AND USAGE---------------------------­ XERAVA is a tetracycline class antibacterial indicated for the treatment of complicated intra-abdominal infections in patients 18 years of age and older. (1.1) Limitations of Use XERAVA is not indicated for the treatment of complicated urinary tract infections (cUTI). (1.1) To reduce the development of drug-resistant bacteria and maintain the effectiveness of XERAVA and other antibacterial drugs, XERAVA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. (1.2) ----------------------------DOSAGE AND ADMINISTRATION---------------------­ • Administer XERAVA for injection 1 mg/kg by intravenous infusion over approximately 60 minutes every 12 hours for a total duration of 4 to 14 days. (2.1) • Severe Hepatic Impairment (Child Pugh C): 1 mg/kg XERAVA every 12 hours on Day 1, then 1 mg/kg every 24 hours starting on Day 2 for a total duration of 4 to 14 days. (2.2) • Concomitant Use of a Strong Cytochrome P450 (CYP) Isoenzyme 3A Inducer: 1.5 mg/kg XERAVA every 12 hours for a total duration of 4 to 14 days. (2.3) • See full prescribing information for the preparation of XERAVA. (2.4) -------------------------DOSAGE FORMS AND STRENGTHS---------------------­ • For injection: 50 mg and 100 mg of eravacycline (equivalent to 63.5 mg and 127 mg eravacycline dihydrochloride, respectively) as a lyophilized powder in a single-dose vial for reconstitution and further dilution. (3) ------------------------------------CONTRAINDICATIONS------------------------------­ Known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or any of the excipients in XERAVA. (4, 5, 6) -----------------------------WARNINGS AND PRECAUTIONS-----------------------­ • Hypersensitivity Reactions: Life-threatening hypersensitivity (anaphylactic) reactions have been reported with tetracycline antibacterial drugs, including XERAVA. Avoid use in patients with known hypersensitivity to tetracyclines. (5.1) • Tooth Discoloration and Enamel Hypoplasia: The use of XERAVA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown) and enamel hypoplasia. (5.2, 8.1, 8.4) • Inhibition of Bone Growth: The use of XERAVA during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. (5.3, 8.1, 8.4) • Clostridioides difficile-Associated Diarrhea: Evaluate if diarrhea occurs. (5.4) -----------------------------------ADVERSE REACTIONS-------------------------------­ Most common adverse reactions (incidence ≥ 3%) are infusion site reactions, nausea, and vomiting. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Tetraphase Pharmaceuticals, Inc., at 1-800-651-3861 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------------------DRUG INTERACTIONS-------------------------------­ • Strong CYP 3A Inducers: Co-administration decreases the exposure of eravacycline; increase XERAVA dose with concomitant use. (2.3, 7.1, 12.3) • Anticoagulant Drugs: Downward adjustment of anticoagulant dosage may be required. (7.2) -----------------------------USE IN SPECIFIC POPULATIONS-----------------------­ Lactation: Breastfeeding is not recommended during treatment with XERAVA. (8.2) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Complicated Intra-abdominal Infections 1.2 Usage 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Adult Dosage 2.2 Dosage Modifications in Patients with Hepatic Impairment 2.3 Dosage Modifications in Patients with Concomitant Use of a Strong Cytochrome P450 Isoenzymes (CYP)3A Inducer 2.4 Preparation and Administration 2.5 Drug Compatibilities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 5.2 Tooth Discoloration and Enamel Hypoplasia 5.3 Inhibition of Bone Growth 5.4 Clostridioides difficile-Associated Diarrhea 5.5 Tetracycline Class Adverse Reactions 5.6 Potential for Microbial Overgrowth 5.7 Development of Drug-Resistant Bacteria 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on XERAVA 7.2 Effect of XERAVA on Other Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14. CLINICAL STUDIES 14.1 Complicated Intra-abdominal Infections in Adults 14.2 Complicated Urinary Tract Infections (cUTI) in Adults 16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17. PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed Reference ID: 5495908 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Complicated Intra-abdominal Infections XERAVA is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasonis in patients 18 years or older [see Microbiology (12.4) and Clinical Studies (14.1)]. Limitations of Use XERAVA is not indicated for the treatment of complicated urinary tract infections (cUTI) [see Clinical Studies (14.2)]. 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of XERAVA and other antibacterial drugs, XERAVA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Adult Dosage The recommended dose regimen of XERAVA is 1 mg/kg every 12 hours. Administer intravenous infusions of XERAVA over approximately 60 minutes every 12 hours. The recommended duration of treatment with XERAVA for cIAI is 4 to 14 days. The duration of therapy should be guided by the severity and location of infection and the patient’s clinical response. 2.2 Dosage Modifications in Patients with Hepatic Impairment In patients with severe hepatic impairment (Child Pugh C), administer XERAVA 1 mg/kg every 12 hours on Day 1 followed by XERAVA 1 mg/kg every 24 hours starting on Day 2 for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 2.3 Dosage Modifications in Patients with Concomitant Use of a Strong Cytochrome P450 (CYP) Isoenzyme 3A Inducer With concomitant use of a strong CYP3A inducer, administer XERAVA 1.5 mg/kg every Reference ID: 5495908 2 12 hours for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with concomitant use of a weak or moderate CYP3A inducer [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 2.4 Preparation and Administration XERAVA is for intravenous infusion only. Each vial is for a single dose only. Preparation XERAVA is supplied as a sterile yellow to orange dry powder in a single-dose vial that must be reconstituted and further diluted prior to intravenous infusion as outlined below. XERAVA does not contain preservatives. Aseptic technique must be used for reconstitution and dilution as follows: 1. Calculate the dose of XERAVA based on the patient weight (1 mg/kg actual body weight). Prepare the required dose for intravenous infusion by reconstituting the appropriate number of vials needed. Reconstitute each vial of XERAVA with 5 mL of Sterile Water for Injection, USP or with 5 mL of 0.9% Sodium Chloride Injection, USP, which will deliver the following: • XERAVA 50 mg vial will deliver 50 mg (10 mg/mL) of eravacycline (free base equivalents). • XERAVA 100 mg vial will deliver 100 mg (20 mg/mL) of eravacycline (free base equivalents). 2. Swirl the vial gently until the powder has dissolved entirely. Avoid shaking or rapid movement as it may cause foaming. The reconstituted XERAVA solution should be a clear, pale yellow to orange solution. Do not use the solution if you notice any particles or the solution is cloudy. Reconstituted solution is not for direct injection. The stability of the solution after reconstitution in the vial has been demonstrated for 1 hour at room temperature (not to exceed 25°C/77°F). If the reconstituted solution in the vial is not diluted in the infusion bag within 1 hour, the reconstituted vial content must be discarded. 3. The reconstituted XERAVA solution is further diluted for intravenous infusion to a target concentration of 0.3 mg/mL, in a 0.9% Sodium Chloride Injection, USP infusion bag before intravenous infusion. To dilute the reconstituted solution, withdraw the full or partial reconstituted vial content from each vial and add it into the infusion bag to generate an infusion solution with a target concentration of 0.3 mg/mL (within a range of 0.2 to 0.6 mg/mL). Do not shake the bag. 4. The diluted solutions must be infused within 12 hours if stored at room temperature (not to exceed 25°C/77°F) or within 8 days if stored refrigerated at 2°C to 8°C (36°F to 46°F). Reconstituted XERAVA solutions and diluted XERAVA infusion solutions should not be frozen. 5. Visually inspect the diluted XERAVA solution for particulate matter and discoloration prior to administration (the XERAVA infusion solution for administration is clear and ranges from light yellow to orange). Discard unused portions of the reconstituted and diluted solution. Reference ID: 5495908 3 Administration of the Intravenous Infusion The diluted XERAVA solution is administered as an intravenous infusion over approximately 60 minutes. XERAVA may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of XERAVA with 0.9% Sodium Chloride Injection, USP. 2.5 Drug Compatibilities XERAVA is compatible with 0.9% Sodium Chloride Injection, USP. The compatibility of XERAVA with other drugs and infusion solutions has not been established. XERAVA should not be mixed with other drugs or added to solutions containing other drugs. 3 DOSAGE FORMS AND STRENGTHS XERAVA for injection is a yellow to orange, sterile, preservative-free, lyophilized powder in single-dose vials for reconstitution and further dilution. XERAVA is available in two strengths: • 50 mg of eravacycline (equivalent to 63.5 mg eravacycline dihydrochloride) • 100 mg of eravacycline (equivalent to 127 mg eravacycline dihydrochloride) 4 CONTRAINDICATIONS XERAVA is contraindicated for use in patients with known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or to any of the excipients [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Life-threatening hypersensitivity (anaphylactic) reactions have been reported with XERAVA [see Adverse Reactions (6.1)]. XERAVA is structurally similar to other tetracycline-class antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline- class antibacterial drugs. Discontinue XERAVA if an allergic reaction occurs. 5.2 Tooth Discoloration and Enamel Hypoplasia The use of XERAVA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-grey-brown). This adverse reaction is more common during long-term use of the tetracycline class drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported with tetracycline class drugs. Advise the patient of the potential risk to the fetus if XERAVA is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)]. Reference ID: 5495908 4 5.3 Inhibition of Bone Growth The use of XERAVA during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Advise the patient of the potential risk to the fetus if XERAVA is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4)]. 5.4 Clostridioides difficile-Associated Diarrhea Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.5 Tetracycline Class Adverse Reactions XERAVA is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti- anabolic action which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests, have been reported for other tetracycline-class antibacterial drugs, and may occur with XERAVA. Discontinue XERAVA if any of these adverse reactions is suspected. 5.6 Potential for Microbial Overgrowth XERAVA use may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue XERAVA and institute appropriate therapy. 5.7 Development of Drug-Resistant Bacteria Prescribing XERAVA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug- resistant bacteria [see Indications and Usage (1.2)]. Reference ID: 5495908 5 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in the Warnings and Precautions section: • Hypersensitivity Reactions [Warning and Precautions (5.1)] • Tooth Discoloration [Warning and Precautions (5.2)] • Inhibition of Bone Growth [Warning and Precautions (5.3)] • Clostridioides difficile-Associated Diarrhea [Warning and Precautions (5.4)] • Tetracycline Class Adverse Reactions [Warning and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. XERAVA was evaluated in 3 active-controlled clinical trials (Trial 1, Trial 2, and Trial 3) in adults with cIAI. These trials included two Phase 3 trials (Trial 1 and Trial 2) and one Phase 2 trial (Trial 3, NCT01265784). The Phase 3 trials included 520 patients treated with XERAVA and 517 patients treated with comparator antibacterial drugs (ertapenem or meropenem). The median age of patients treated with XERAVA was 56 years, ranging between 18 and 93 years old; 30% were age 65 years and older. Patients treated with XERAVA were predominantly male (57%) and Caucasian (98%). The XERAVA-treated population included 31% obese patients (BMI ≥ 30 kg/m2) and 8% with baseline moderate to severe renal impairment (calculated creatinine clearance 15 to less than 60 mL/min). Among the trials, 66 (13%) of patients had baseline moderate hepatic impairment (Child Pugh B); patients with severe hepatic impairment (Child Pugh C) were excluded from the trials. Adverse Reactions Leading to Discontinuation Treatment discontinuation due to an adverse reaction occurred in 2% (11/520) of patients receiving XERAVA and 2% (11/517) of patients receiving the comparator. The most commonly reported adverse reactions leading to discontinuation of XERAVA were related to gastrointestinal disorders. Most Common Adverse Reactions Adverse reactions occurring at 3% or greater in patients receiving XERAVA were infusion site reactions, nausea, and vomiting. Table 1 lists adverse reactions occurring in ≥ 1% of patients receiving XERAVA and with incidences greater than the comparator in the Phase 3 cIAI clinical trials. A similar adverse reaction profile was observed in the Phase 2 cIAI clinical trial (Trial 3). Reference ID: 5495908 6 Table 1: Selected Adverse Reactions Reported in ≥ 1% of Patients Receiving XERAVA in the Phase 3 cIAI Trials (Trial 1 and Trial 2) Adverse Reactions XERAVAa N=520 n (%) Comparatorsb N=517 n (%) Infusion site reactionsc 40 (7.7) 10 (1.9) Nausea 34 (6.5) 3 (0.6) Vomiting 19 (3.7) 13 (2.5) Diarrhea 12 (2.3) 8 (1.5) Hypotension 7 (1.3) 2 (0.4) Wound dehiscence 7 (1.3) 1 (0.2) Abbreviations: IV=intravenous a XERAVA dose equals 1 mg/kg every 12 hours IV. b Comparators include ertapenem 1 g every 24 hours IV and meropenem 1 g every 8 hours IV. c Infusion site reactions include: catheter/vessel puncture site pain, infusion site extravasation, infusion site hypoaesthesia, infusion/injection site phlebitis, infusion site thrombosis, injection site/vessel puncture site erythema, phlebitis, phlebitis superficial, thrombophlebitis, and vessel puncture site swelling. Other Adverse Reactions of XERAVA The following selected adverse reactions were reported in XERAVA-treated patients at a rate of less than 1% in the Phase 3 trials: Cardiac disorders: palpitations Gastrointestinal System: acute pancreatitis, pancreatic necrosis General Disorders and Administrative Site Conditions: chest pain Immune system disorders: hypersensitivity Laboratory Investigations: increased amylase, increased lipase, increased alanine aminotransferase, prolonged activated partial thromboplastin time, decreased renal clearance of creatinine, increased gamma-glutamyltransferase, decreased white blood cell count, neutropenia Metabolism and nutrition disorders: hypocalcemia Nervous System: dizziness, dysgeusia Psychiatric disorders: anxiety, insomnia, depression Respiratory, Thoracic, and Mediastinal System: pleural effusion, dyspnea Skin and subcutaneous tissue disorders: rash, hyperhidrosis Reference ID: 5495908 7 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on XERAVA Strong CYP3A Inducers Concomitant use of strong CYP3A inducers decreases the exposure of eravacycline, which may reduce the efficacy of XERAVA [see Clinical Pharmacology (12.3)]. Increase XERAVA dose in patients with concomitant use of a strong CYP3A inducer [see Dosage and Administration (2.3)]. 7.2 Effect of XERAVA on other Drugs Anticoagulant Drugs Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary XERAVA, like other tetracycline-class antibacterial drugs, may cause discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy [see Warnings and Precautions (5.1, 5.2), Use in Specific Populations (8.4)]. The limited available data with XERAVA use in pregnant women are insufficient to inform drug-associated risk of major birth defects and miscarriages. Animal studies indicate that eravacycline crosses the placenta and is found in fetal plasma; doses greater than approximately 3- and 2.8- times the clinical exposure, based on AUC in rats and rabbits, respectively, administered during the period of organogenesis, were associated with decreased ossification, decreased fetal body weight, and/or increased post-implantation loss (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Embryo-fetal development studies in rats and rabbits reported no treatment-related effects at approximately 3 and 2.8 times the clinical exposure (based on AUC). Dosing was during the period of organogenesis, i.e., gestation days 7-17 in rats and gestation days 7-19 in rabbits. Higher doses, approximately 8.6 and 6.3 times the clinical exposure (based on AUC) in rats and rabbits, respectively, were associated with fetal effects including increased post-implantation loss, reduced fetal body weights, and delays in skeletal ossification in both species, and abortion in the rabbit. A peri-natal and post-natal rat toxicity study demonstrated that eravacycline crosses the placenta and is found in fetal plasma following intravenous administration to the dams. This study did not Reference ID: 5495908 8 demonstrate anatomical malformations, but there were early decreases in pup weight that were later comparable to controls and a non-significant trend toward increased stillbirths or dead pups during lactation. F1 males from dams treated with 10 mg/kg/day eravacycline that continued to fertility testing had decreased testis and epididymis weights at approximately post-natal day 111 that may have been at least partially related to lower body weights in this group. Tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. 8.2 Lactation Risk Summary It is not known whether XERAVA is excreted in human breast milk. Eravacycline (and its metabolites) is excreted in the milk of lactating rats (see Data). Tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including eravacycline, by the breastfed infant is not known. There are no data on the effects of XERAVA on the breastfed infant, or the effects on milk production. Because there are other antibacterial drug options available to treat cIAI in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with XERAVA and for 4 days (based on half-life) after the last dose. Data Animal Data Eravacycline (and its metabolites) was excreted in the milk of lactating rats on post-natal day 15 following intravenous administration of 3, 5, and 10 mg/kg/day eravacycline. 8.3 Females and Males of Reproductive Potential Infertility Based on animal studies, XERAVA can lead to impaired spermiation and sperm maturation, resulting in abnormal sperm morphology and poor motility. The effect is reversible in rats. The long-term effects of XERAVA on male fertility have not been studied [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of XERAVA in pediatric patients have not been established. Due to the adverse effects of the tetracycline-class of drugs, including XERAVA on tooth development and bone growth, use of XERAVA in pediatric patients less than 8 years of age is not recommended [see Warnings and Precautions (5.1, 5.2)]. 8.5 Geriatric Use Of the total number of patients with cIAI who received XERAVA in Phase 3 clinical trials (n = 520), 158 subjects were ≥ 65 years of age, while 59 subjects were ≥ 75 years of age. No overall differences in safety or efficacy were observed between these subjects and younger subjects. Reference ID: 5495908 9 F H3C, ,,.CH3 N • OJN · 2HCI NH2 H OH 0 0 No clinically relevant differences in the pharmacokinetics of eravacycline were observed with respect to age in a population pharmacokinetic analysis of eravacycline [see Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment No dosage adjustment is warranted for XERAVA in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Adjust XERAVA dosage in patients with severe hepatic impairment (Child Pugh C) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dosage adjustment is necessary for XERAVA in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No reports of overdose were reported in clinical trials. In the case of suspected overdose, XERAVA should be discontinued and the patient monitored for adverse reactions. Hemodialysis is not expected to remove significant quantities of XERAVA [see Clinical Pharmacology (12.3)]. 11 DESCRIPTION XERAVA contains eravacycline, a synthetic tetracycline-class antibacterial agent for intravenous administration. Chemically, eravacycline is a C7-, C9-substituted sancycline derivative. The chemical name of eravacycline dihydrochloride is [(4S,4aS,5aR,12aS)-4-(dimethylamino)-7­ fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[2-(pyrrolidin-1-yl) acetamido]­ 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide] dihydrochloride. The molecular formula for eravacycline dihydrochloride is C27H31FN4O8•2HCl, and its molecular weight is 631.5. The following represents the chemical structure of eravacycline dihydrochloride: XERAVA is a sterile, preservative-free, yellow to orange, lyophilized powder in a glass single- dose vial for intravenous infusion after reconstitution and dilution. XERAVA is supplied in two (2) strengths as follows: Reference ID: 5495908 10 • Each 50 mg single-dose vial contains 50 mg of eravacycline (equivalent to 63.5 mg of eravacycline dihydrochloride) and the excipient, mannitol (150 mg). Sodium hydroxide and hydrochloric acid are used as needed for pH adjustment to 5.5 to 7.0. • Each 100 mg single-dose vial contains 100 mg of eravacycline (equivalent to 127 mg of eravacycline dihydrochloride) and the excipient, mannitol (150 mg). Sodium hydroxide and hydrochloric acid are used as needed for pH adjustment to 5.5 to 7.0. The amount of sodium in XERAVA lyophilized powder is negligible. Following reconstitution and dilution to a target concentration of 0.3 mg/mL in 0.9% Sodium Chloride Injection, USP, each XERAVA dose would contain 3.54 mg/mL of sodium [see Dosage and Administration (2.4)]. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eravacycline is an antibacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics The AUC divided by the MIC of eravacycline has been shown to be the best predictor of activity. Based on the flat exposure-response relationship observed in clinical studies, eravacycline exposure achieved with the recommended dosage regimen appears to be on the plateau of the exposure-response curve. Cardiac Electrophysiology The effect of XERAVA on the QTc interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, single-dose, crossover thorough QTc study in 60 healthy adult subjects. At the 1.5 mg/kg single dose (1.5 times the maximum approved recommended dose), XERAVA did not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics Following single-dose intravenous administration, eravacycline AUC and Cmax increase approximately dose-proportionally over doses from 1 mg/kg to 3 mg/kg (3 times the approved dose). The mean exposure of eravacycline after single and multiple intravenous infusions (approximately 60 minutes) of 1 mg/kg administered to healthy adults every 12 hours is presented in Table 2. There is approximately 45% accumulation following intravenous dosing of 1 mg/kg every 12 hours. Table 2: Mean (%CV) Plasma Exposure of Eravacycline After Single and Multiple Intravenous Dose in Healthy Adults Exposure [Arithmetic Mean (%CV)] Reference ID: 5495908 11 Cmax (ng/mL) AUC0-12 (ng∙h/mL) Day 1 2125 (15) 4305 (14)a Day 10 1825 (16) 6309 (15)b Abbreviations: Cmax = maximum observed plasma concentration, CV = coefficient of variation; AUC0-12 = area under the plasma concentration- time curve from time 0 to 12 hours. aAUC of day 1 equals AUC0-12 after the first dose of eravacycline. bAUC of day 10 equals steady state AUC0-12. Distribution Protein binding of eravacycline to human plasma proteins increases with increasing plasma concentrations, with 79% to 90% (bound) at plasma concentrations ranging from 100 to 10,000 ng/mL. The volume of distribution at steady-state is approximately 321 L. Elimination The mean elimination half-life is 20 hours. Metabolism Eravacycline is metabolized primarily by CYP3A4- and FMO-mediated oxidation. Excretion Following a single intravenous dose of radiolabeled eravacycline 60 mg, approximately 34% of the dose is excreted in urine and 47% in feces as unchanged eravacycline (20% in urine and 17% in feces) and metabolites. Specific Populations No clinically significant differences in the pharmacokinetics of eravacycline were observed based on age (18-86 years), sex, and race. Patients with Renal Impairment The geometric least square mean Cmax for eravacycline was increased by 8.8% for subjects with end stage renal disease (ESRD) versus healthy subjects with 90% CI -19.4, 45.2. The geometric least square mean AUC0-inf for eravacycline was decreased by 4.0% for subjects with ESRD versus healthy subjects with 90% CI -14.0, 12.3 [see Use in Specific Populations (8.7)]. Patients with Hepatic Impairment Eravacycline Cmax was 13.9%, 16.3%, and 19.7% higher in subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), and severe (Child-Pugh Class C) hepatic impairment versus healthy subjects, respectively. Eravacycline AUC0-inf was 22.9%, 37.9%, and 110.3% higher in subjects with mild, moderate, and severe hepatic impairment versus healthy subjects, respectively [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)]. Drug Interaction Studies Clinical Studies Concomitant use of rifampin (strong CYP3A4/3A5 inducer) decreased eravacycline AUC by 35% and increased eravacycline clearance by 54% [see Dosage and Administration (2.3) and Drug Interactions (7.1)]. Concomitant use of itraconazole (strong CYP3A inhibitor) increased eravacycline Cmax by 5% and AUC0-t by 32%, and decreased eravacycline clearance by 32%. Reference ID: 5495908 12 In Vitro Studies Eravacycline is a substrate for the transporters P-gp, organic anion transporter peptide OATP1B1 and OATP1B3. Eravacycline is not a substrate for breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic ion transporter (OAT)1, OAT3, OCT1, OCT2, multidrug and toxin extrusion (protein) (MATE)1, or MATE2-K transporters. Eravacycline is not an inhibitor of BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K transporters. Eravacycline is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Eravacycline is not an inducer of CYP1A2, 2B6, or 3A4. 12.4 Microbiology Mechanism of Action Eravacycline is a fluorocycline antibacterial within the tetracycline class of antibacterial drugs. Eravacycline disrupts bacterial protein synthesis by binding to the 30S ribosomal subunit thus preventing the incorporation of amino acid residues into elongating peptide chains. In general, eravacycline is bacteriostatic against gram-positive bacteria (e.g., Staphylococcus aureus and Enterococcus faecalis); however, in vitro bactericidal activity has been demonstrated against certain strains of Escherichia coli and Klebsiella pneumoniae. Resistance Eravacycline resistance in some bacteria is associated with upregulated, non-specific intrinsic multidrug-resistant (MDR) efflux, and target-site modifications such as to the 16s rRNA or certain 30S ribosomal proteins (e.g., S10). The C7 and C9 substitutions in eravacycline are not present in any naturally occurring or semisynthetic tetracyclines and the substitution pattern imparts microbiological activities including in vitro activity against gram-positive and gram-negative strains expressing certain tetracycline-specific resistance mechanism(s) [i.e., efflux mediated by tet(A), tet(B), and tet(K); ribosomal protection as encoded by tet(M) and tet(Q)]. Activity of eravacycline was demonstrated in vitro against Enterobacteriaceae in the presence of certain beta-lactamases, including extended spectrum β-lactamases, and AmpC. However, some beta-lactamase-producing isolates may confer resistance to eravacycline via other resistance mechanisms. The overall frequency of spontaneous mutants in the gram-positive organisms tested was in the range of 10-9 to 10-10 at 4 times the eravacycline Minimum Inhibitory Concentration (MIC). Reference ID: 5495908 13 Multistep selection of gram-negative strains resulted in a 16- to 32-times increase in eravacycline MIC for one isolate of Escherichia coli and Klebsiella pneumoniae, respectively. The frequency of spontaneous mutations in K. pneumoniae was 10-7 to 10-8 at 4 times the eravacycline MIC. Interaction with Other Antimicrobials In vitro studies have not demonstrated antagonism between XERAVA and other commonly used antibacterial drugs for the indicated pathogens. Antimicrobial Activity XERAVA has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]: Aerobic bacteria Gram-positive bacteria Enterococcus faecalis Enterococcus faecium Staphylococcus aureus Streptococcus anginosus group Gram-negative bacteria Citrobacter freundii Enterobacter cloacae Escherichia coli Klebsiella oxytoca Klebsiella pneumoniae Anaerobic bacteria Gram-positive bacteria Clostridium perfringens Gram-negative bacteria Bacteroides caccae Bacteroides fragilis Bacteroides ovatus Bacteroides thetaiotaomicron Bacteroides uniformis Bacteroides vulgatus Parabacteroides distasonis The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for eravacycline against isolates of similar genus or organism group. However, the efficacy of eravacycline in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Reference ID: 5495908 14 Aerobic bacteria Gram-positive bacteria Streptococcus salivarius group Gram-negative bacteria Citrobacter koseri Enterobacter aerogenes Susceptibility Test Methods For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see https://www.fda.gov/STIC. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with eravacycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterial drugs, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). Eravacycline was not genotoxic in a standard battery of assays, including an in vitro mammalian cell mutation assay, an in vitro clastogenicity assay, and an in vivo rat bone marrow micronucleus assay. There are no human data on the effect of eravacycline on fertility. Eravacycline did not affect mating or fertility in male rats following intravenous administration at a dose approximating a clinical dose of 0.65 mg/kg/day (approximately 1.5 times the clinical exposure, based on AUC determined in a separate study), however, eravacycline administration at higher doses was associated with adverse reactions on male fertility and spermatogenesis that were at least partially reversible after a 70-day recovery period (1 spermatogenic cycle). Decreased sperm counts, abnormal sperm morphology, and reduced sperm motility were observed with testicular effects (impaired spermiation and sperm maturation). There were no adverse reactions on mating or fertility in female rats administered intravenous eravacycline at a dose approximating a clinical dose of 3.2 mg/kg/day (approximately 18 times the clinical exposure based on AUC determined in a separate study in unmated females). Decreased sperm counts and eravacycline-related lesions noted in the testes and epididymides were seen in general toxicology studies in rats and were reversible. These findings were anticipated effects for a tetracycline-class compound. 13.2 Animal Toxicology and/or Pharmacology In repeated dose toxicity studies in rats, dogs and monkeys, lymphoid depletion/atrophy of lymph nodes, spleen and thymus, decreased erythrocytes, reticulocytes, leukocytes, and platelets (dog and monkey), in association with bone marrow hypocellularity, and adverse gastrointestinal effects (dog and monkey) were observed with eravacycline. These findings were reversible or partially reversible during recovery periods of 3 to 7 weeks. Reference ID: 5495908 15 Bone discoloration, which was not fully reversible over recovery periods of up to 7 weeks, was observed in rats and monkeys after 13 weeks of dosing and in the juvenile rat study after dosing over post-natal days 21-70. Intravenous administration of eravacycline has been associated with a histamine response in rat and dog studies. 14 CLINICAL STUDIES 14.1 Complicated Intra-abdominal Infections in Adults A total of 1,041 adults hospitalized with cIAI were enrolled in two Phase 3, randomized, double- blind, active-controlled, multinational, multicenter trials (Trial 1, NCT01844856, and Trial 2, NCT02784704). These studies compared XERAVA (1 mg/kg intravenous every 12 hours) with either ertapenem (1 g every 24 hours) or meropenem (1 g every 8 hours) as the active comparator for 4 to 14 days of therapy. Complicated intra-abdominal infections included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis. The microbiologic intent-to-treat (micro-ITT) population, which included all patients who had at least one baseline intra-abdominal pathogen, consisted of 846 patients in the two trials. Populations in Trial 1 and Trial 2 were similar. The median age was 56 years and 56% were male. The majority of patients (95%) were from Europe; 5% were from the United States. The most common primary cIAI diagnosis was intra-abdominal abscess(es), occurring in 60% of patients. Bacteremia at baseline was present in 8% of patients. Clinical cure was defined as complete resolution or significant improvement of signs or symptoms of the index infection at the Test of Cure (TOC) visit which occurred 25 to 31 days after randomization. Selected clinical responses were reviewed by a Surgical Adjudication Committee. Table 3 presents the clinical cure rates in the micro-ITT population. Clinical cure rates at the TOC visit for selected pathogens are presented in Table 4. Table 3: Clinical Cure Rates at TOC in the Phase 3 cIAI Trials, Micro-ITT Population Trial 1 Trial 2 XERAVAa N=220 n (%) Ertapenemb N=226 n (%) XERAVAa N=195 n (%) Meropenemc N=205 n (%) Clinical cure 191 (86.8) 198 (87.6) 177 (90.8) 187 (91.2) Difference (95% CI)d -0.80 (-7.1, 5.5) -0.5 (-6.3, 5.3) Abbreviations: CI = confidence interval; IV = intravenous; micro-ITT = all randomized subjects who had baseline bacterial pathogens that caused cIAI and against at least one of which the investigational drug has in vitro antibacterial activity; N = number of subjects in the micro-ITT population; n = number within a specific category with a clinical cure based on the Surgical Adjudication Committee assessment (if available); TOC = Test of Cure. aXERAVA dose equals 1 mg/kg every 12 hours IV. bErtapenem dose equals1 g every 24 hours IV cMeropenem dose equals 1 g every 8 hours IV. dTreatment Difference = Difference in clinical cure rates (eravacycline minus ertapenem or meropenem). Confidence intervals are calculated using the unadjusted Miettinen-Nurminen method Reference ID: 5495908 16 Table 4: Clinical Cure Rates at TOC by Selected Baseline Pathogens in Pooled Phase 3 cIAI Trials, Micro-ITT Population Pathogen XERAVAa N=415 n/N1 (%) Comparatorsb N=431 n/N1 (%) Enterobacteriaceae 271/314 (86.3) 289/325 (88.9) Citrobacter freundii 19/22 (86.4) 8/10 (80.0) Enterobacter cloacae complex 17/21 (81.0) 23/24 (95.8) Escherichia coli 220/253 (87.0) 237/266 (89.1) Klebsiella oxytoca 14/15 (93.3) 16/19 (84.2) Klebsiella pneumoniae 37/39 (94.9) 42/50 (84.0) Enterococcus faecalis 45/54 (83.3) 47/54 (87.0) Enterococcus faecium 38/45 (84.4) 48/53 (90.6) Staphylococcus aureus 24/24 (100.0) 12/14 (85.7) Streptococcus anginosus groupc 79/92 (85.9) 50/59 (84.7) Anaerobesd 186/215 (86.5) 194/214 (90.7) Abbreviations: IV = intravenous; N = Number of subjects in the micro-ITT Population; N1 = Number of subjects with a specific pathogen; n = Number of subjects with a clinical cure at the TOC visit. Percentages are calculated as 100 × (n/N1); TOC = Test of Cure aXERAVA dose equals 1 mg/kg every 12 hours IV. bComparators include Ertapenem 1 g every 24 hours IV and Meropenem 1 g every 8 hours IV. cIncludes Streptococcus anginosus, Streptococcus constellatus, and Streptococcus intermedius dIncludes Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Parabacteroides distasonis. 14.2 Complicated Urinary Tract Infections (cUTI) in Adults Two randomized, double-blind, active-controlled, clinical trials (Trial 4, NCT01978938, and Trial 5, NCT03032510) evaluated the efficacy and safety of once-daily intravenous eravacycline for the treatment of patients with complicated urinary tract infections (cUTI). Trial 4 included an optional switch from IV to oral therapy with eravacycline. The trials did not demonstrate the efficacy of XERAVA for the combined endpoints of clinical cure and microbiological success in the microbiological intent-to-treat (micro-ITT) population at the test-of-cure visit [see Indications and Usage (1)]. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied XERAVA (eravacycline) for injection is a yellow to orange, sterile, preservative-free powder for reconstitution in single-dose 10-mL clear glass vials with a rubber stopper and an aluminum overseal. XERAVA is supplied in the following configurations: • XERAVA 50 mg vial contains 50 mg of eravacycline (equivalent to 63.5 mg of eravacycline dihydrochloride). Each vial is packaged in a single-dose vial carton (NDC 71773-050-05) and supplied in a 12-vial carton containing 12 single-dose vial cartons— NDC 71773-050-12. Reference ID: 5495908 17 • XERAVA 100 mg vial contains 100 mg of eravacycline (equivalent to 127 mg of eravacycline dihydrochloride). Each vial is packaged in a single-dose vial carton (NDC 71773-100-05) and supplied in shrink wrap packaging, containing 12 single-dose vial cartons— NDC 71773-100-12. 16.2 Storage and Handling Prior to reconstitution, XERAVA should be stored at 2°C to 8°C (36°F to 46°F) [see Dosage and Administration (2.4)]. Keep vial in carton until use. 17 PATIENT COUNSELING INFORMATION Serious Allergic Reactions Advise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask patient about any previous hypersensitivity reactions to antibacterial drugs including tetracycline or other allergens [see Warnings and Precautions (5.1)]. Tooth Discoloration and Inhibition of Bone Growth Advise patients that XERAVA, like other tetracycline-class drugs, may cause permanent tooth discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy. Advise patients that they should tell their healthcare provider right away if they become pregnant [see Warnings and Precautions (5.2, 5.3) and Use in Specific Populations (8.1, 8.4)]. Lactation Advise women not to breastfeed during treatment with XERAVA and for 4 days after the last dose [see Use in Specific Populations (8.2)]. Diarrhea Diarrhea is a common problem caused by antibacterial drugs, including XERAVA, which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drug, patients can develop watery and bloody stools (with or without stomach cramps and fever) which may be a sign of a more serious intestinal infection, even as late as 2 or more months after having taken the last dose of the antibacterial drug. If this occurs, instruct patients to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.4)]. Tetracycline Class Adverse Reactions Inform patients that XERAVA is similar to tetracycline-class antibacterial drugs and may have similar adverse reactions [see Warnings and Precautions (5.5)]. Overgrowth of Non-susceptible Microorganisms Inform patients that antibacterial drugs including XERAVA may promote the overgrowth of non-susceptible microorganisms, including fungi [see Warnings and Precautions (5.6)]. Reference ID: 5495908 18 Antibacterial Resistance Patients should be counseled that antibacterial drugs including XERAVA should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When XERAVA is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by XERAVA or other antibacterial drugs in the future. Distributed by: Tetraphase Pharmaceuticals, Inc. Waltham, MA 02451 XERAVA is a registered trademark of Tetraphase Pharmaceuticals, Inc. ©2024 Tetraphase Pharmaceuticals, Inc. All rights reserved. Reference ID: 5495908 19
custom-source
2025-02-12T15:47:42.730662
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ORKAMBI safely and effectively. See full prescribing information for ORKAMBI. -------------------------------CONTRAINDICATIONS-----------------------------­  None. (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ ORKAMBI® (lumacaftor and ivacaftor) tablets, for oral use ORKAMBI® (lumacaftor and ivacaftor) oral granules Initial U.S. Approval: 2015 ----------------------------INDICATIONS AND USAGE--------------------------­ ORKAMBI is a combination of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, and lumacaftor, indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. (1) Limitations of Use: The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation. (1) ----------------------DOSAGE AND ADMINISTRATION----------------------­ Age Group Weight Dose 7 kg to <9 kg 1 packet of lumacaftor 75 mg/ivacaftor 94 mg granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg granules 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) 1 through 2 years 9 kg to <14 kg ≥14 kg 2 through 5 years <14 kg ≥14 kg 6 through 11 years - 12 years and older - Administration Mixed with one teaspoon (5 mL) of soft food or liquid and administered orally every 12 hours with fat- containing food Taken orally every 12 hours with fat- containing food  Reduce dosage in patients with moderate or severe hepatic impairment. (2.2, 8.6, 12.3)  When initiating ORKAMBI in patients taking strong CYP3A inhibitors, reduce ORKAMBI dosage for the first week of treatment. (2.3, 7.1, 12.3) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­  Tablets: lumacaftor 100 mg and ivacaftor 125 mg; lumacaftor 200 mg and ivacaftor 125 mg. (3)  Oral granules: Unit-dose packets of lumacaftor 75 mg and ivacaftor 94 mg; lumacaftor 100 mg and ivacaftor 125 mg; lumacaftor 150 mg and ivacaftor 188 mg. (3)  Use in patients with advanced liver disease: ORKAMBI should be used with caution in these patients and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dosage should be reduced. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre­ existing cirrhosis with portal hypertension. (2.2, 5.1, 6.1)  Liver-related events: Elevated transaminases (ALT/AST) have been observed in some cases associated with elevated bilirubin. Measure serum transaminases and bilirubin before initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Interrupt dosing in patients with ALT or AST >5 x upper limit of normal (ULN), or ALT or AST >3 x ULN with bilirubin >2 x ULN. Following resolution, consider the benefits and risks of resuming dosing. (5.2, 6.1)  Hypersensitivity reactions: Angioedema and anaphylaxis have been reported with ORKAMBI in the postmarketing setting. Initiate appropriate therapy in the event of a hypersensitivity reaction. (5.3)  Respiratory events: Chest discomfort, dyspnea, and respiration abnormal were observed more commonly during initiation of ORKAMBI. Clinical experience in patients with percent predicted FEV1 (ppFEV1) <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy. (5.4, 6.1)  Blood pressure: Increased blood pressure has been observed in some patients. Periodically monitor blood pressure in all patients. (5.5, 6.1)  Drug interactions: Use with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index may decrease systemic exposure of the medicinal products and co-administration is not recommended. Hormonal contraceptives should not be relied upon as an effective method of contraception and their use is associated with increased menstruation-related adverse reactions. Use with strong CYP3A inducers may diminish exposure of ivacaftor, which may diminish its effectiveness; therefore, co-administration is not recommended. (5.6, 6.1, 7, 12.3)  Cataracts: Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Baseline and follow-up examinations are recommended in pediatric patients initiating ORKAMBI. (5.7) ------------------------------ADVERSE REACTIONS------------------------------­ The most common adverse reactions to ORKAMBI (occurring in ≥5% of patients with CF homozygous for the F508del mutation in the CFTR gene) were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, influenza. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA­ 1088 or www.fda.gov/medwatch. -----------------------------DRUG INTERACTIONS------------------------------­ See Full Prescribing Information for a complete list. (2.3, 7, 12.3) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Adults and Pediatric Patients Aged 1 Year and Older 2.2 Dosage Adjustment for Patients with Hepatic Impairment 2.3 Dosage Adjustment for Patients Taking CYP3A Inhibitors 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Use in Patients with Advanced Liver Disease 5.2 Liver-related Events 5.3 Hypersensitivity Reactions, Including Anaphylaxis 5.4 Respiratory Events 5.5 Effect on Blood Pressure 5.6 Drug Interactions 5.7 Cataracts 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Inhibitors of CYP3A 7.2 Inducers of CYP3A 7.3 CYP3A Substrates 7.4 CYP2B6 and CYP2C Substrates 7.5 Digoxin and Other P-gp Substrates 7.6 Anti-allergics and Systemic Corticosteroids 7.7 Antibiotics 7.8 Antifungals 7.9 Anti-inflammatories 7.10 Antidepressants 7.11 Hormonal Contraceptives 1 Reference ID: 5495367 8 7.12 Oral Hypoglycemics 7.13 Proton Pump Inhibitors, H2 Blockers, Antacids 7.14 Warfarin 7.15 Concomitant Drugs That Do Not Need Dosage Adjustment USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 8.8 Patients with Severe Lung Dysfunction 8.9 Patients After Organ Transplantation 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 2 Reference ID: 5495367 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE ORKAMBI is indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. Limitations of Use The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Adults and Pediatric Patients Aged 1 Year and Older The recommended dosage of ORKAMBI in adults and pediatric patients aged one year and older is based on patient’s age and weight as described in Table 1. Evening Dose Table 1: Recommended Oral Dosage of ORKAMBI in Patients Aged 1 Year and Older Age Group Weight ORKAMBI Daily Dose (every 12 hours) Morning Dose 1 through 2 years 7 kg to <9 kg 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules 9 kg to <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules ≥14 kg 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 2 through 5 years <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules ≥14 kg 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 6 through 11 years - 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) 12 years and older - 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) Administration Instructions for ORKAMBI Oral Granules The entire content of each packet of oral granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and the mixture completely consumed. Some examples of soft foods or liquids include puréed fruits or vegetables, flavored yogurt or pudding, applesauce, water, milk, breast milk, infant formula or juice. Food should be at room temperature or below. Each packet is for single use only. Once mixed, the product has been shown to be stable for one hour, and therefore should be ingested during this period. Administration with Fat-Containing Food for ORKAMBI Tablets and Oral Granules A fat-containing meal or snack should be consumed just before or just after dosing for all formulations. Examples of appropriate fat-containing foods include eggs, avocados, nuts, butter, peanut butter, cheese pizza, breast milk, infant formula, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc. Missed Dose If a patient misses a dose and remembers the missed dose within 6 hours, the patient should take the dose with fat-containing food. If more than 6 hours elapsed after the recommended dosing time, the patient should skip that dose and resume the normal schedule for the following dose. A double dose should not be taken to make up for the forgotten dose [see Clinical Pharmacology (12.3) and Patient Counseling Information (17)]. 2.2 Dosage Adjustment for Patients with Hepatic Impairment For dosage adjustment for patients with hepatic impairment, refer to Table 2. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening or less frequently, or 1 packet of oral granules once daily or less frequently in patients with severe hepatic impairment after weighing the risks and benefits of treatment [see Dosage and Administration (2.1), Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. Evening Dose 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg Table 2: Recommended Dosage for Patients with Hepatic Impairment Age Group Weight Morning Dose Mild (Child-Pugh Class A) 1 through 2 years 7 kg to <9 kg 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules 9 kg to <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules ≥14 kg 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 2 through 5 years <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules ≥14 kg 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 6 through 11 years - 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) 12 years and older - 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) oral granules 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) Moderate (Child­ 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral 1 through 2 years 7 kg to <9 kg Pugh Class B) granules granules every other day 3 Reference ID: 5495367 9 kg to <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 2 through 5 years <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules every other day 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral 1 packet of lumacaftor 150 mg/ivacaftor 188 mg ≥14 kg granules oral granules every other day 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules every other day 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral 1 packet of lumacaftor 150 mg/ivacaftor 188 mg ≥14 kg granules oral granules every other day 1 tablet of lumacaftor 100 mg/ivacaftor 125 mg 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg 12 years and older - 1 tablet of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral 7 kg to <9 kg granules* 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral 1 through 2 years 9 kg to <14 kg granules* 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral ≥14 kg N/A granules* Severe (Child- Pugh Class C) 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral <14 kg granules* 2 through 5 years 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral ≥14 kg granules* 6 through 11 years - 1 tablet of lumacaftor 100 mg/ivacaftor 125 mg * 1 tablet of lumacaftor 100 mg/ivacaftor 125 mg * 12 years and older - 1 tablet of lumacaftor 200 mg/ivacaftor 125 mg * 1 tablet of lumacaftor 200 mg/ivacaftor 125 mg * 2.3 Dosage Adjustment for Patients Taking CYP3A Inhibitors No dosage adjustment is necessary when CYP3A inhibitors are initiated in patients already taking ORKAMBI. However, when initiating ORKAMBI in patients currently taking strong CYP3A inhibitors, reduce the ORKAMBI dosage for the first week of treatment based on age as follows [see Dosage and Administration (2.1) and Drug Interactions (7.1)]:  1 through 5 years of age: 1 packet of granules every other day  6 years of age and older: 1 tablet daily Following this one-week period, resume the recommended daily dosage. If ORKAMBI is interrupted for more than one-week and then re-initiated while taking strong CYP3A inhibitors, reduce the ORKAMBI dosage for the first week of treatment re-initiation based on age as follows:  1 through 5 years of age: 1 packet of granules every other day  6 years of age and older: 1 tablet daily Following this one-week period, resume the recommended daily dosage. 3 DOSAGE FORMS AND STRENGTHS  Tablets: 100 mg lumacaftor and 125 mg ivacaftor; supplied as pink, oval-shaped, film-coated, fixed-dose combination tablets containing 100 mg of lumacaftor and 125 mg of ivacaftor. Each tablet is printed with the characters “1V125” in black ink on one side and plain on the other.  Tablets: 200 mg lumacaftor and 125 mg ivacaftor; supplied as pink, oval-shaped, film-coated, fixed-dose combination tablets containing 200 mg of lumacaftor and 125 mg of ivacaftor. Each tablet is printed with the characters “2V125” in black ink on one side and plain on the other.  Oral granules: Unit-dose packets containing lumacaftor 75 mg/ivacaftor 94 mg or lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg per packet; supplied as small, white to off-white granules in unit-dose packets. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Use in Patients with Advanced Liver Disease Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI. Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dosage should be reduced [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.2 Liver-related Events Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin. It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST >5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations >3 x ULN when associated with bilirubin elevations >2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing [see Adverse Reactions (6.1)]. 6 through 11 years - 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) * or less frequently. 4 Reference ID: 5495367 5.3 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting [see Adverse Reactions (6.2)]. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue ORKAMBI and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ORKAMBI. 5.4 Respiratory Events Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI compared to those who received placebo. These events have led to drug discontinuation and can be serious, particularly in patients with advanced lung disease (percent predicted FEV1 <40). Clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy [see Adverse Reactions (6.1)]. 5.5 Effect on Blood Pressure Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI [see Adverse Reactions (6.1)]. 5.6 Drug Interactions Substrates of CYP3A Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended. ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular (27% in women using hormonal contraceptives compared with 3% in women not using hormonal contraceptives). Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI [see Adverse Reactions (6.1), Drug Interactions (7.3, 7.11), and Clinical Pharmacology (12.3)]. Strong CYP3A Inducers Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers (e.g., rifampin, St. John’s wort [Hypericum perforatum]) is not recommended [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. 5.7 Cataracts Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded [see Use in Specific Populations (8.4)]. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating ORKAMBI treatment. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label:  Use in Patients with Advanced Liver Disease [see Warnings and Precautions (5.1)]  Liver-related Events [see Warnings and Precautions (5.2)]  Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.3)]  Respiratory Events [see Warnings and Precautions (5.4)]  Effect on Blood Pressure [see Warnings and Precautions (5.5)]  Cataracts [see Warnings and Precautions (5.7)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The overall safety profile of ORKAMBI is based on the pooled data from 1108 patients with CF aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene and who received at least one dose of study drug in two double-blind, placebo-controlled, Phase 3 clinical trials, each with 24 weeks of treatment (Trials 1 and 2). In addition, the following clinical trials have been conducted:  A 24-week, open-label trial (Trial 3) in 58 patients with CF aged 6 through 11 years homozygous for the F508del-CFTR mutation.  A 24-week, placebo-controlled trial (Trial 4) in 204 patients aged 6 through 11 years homozygous for the F508del-CFTR mutation.  A 24-week, open-label trial (Trial 5) in 46 patients aged 12 years and older homozygous for the F508del-CFTR mutation and with advanced lung disease (ppFEV1 <40).  A 24-week, open-label trial (Trial 6) in 60 patients aged 2 through 5 years homozygous for the F508del-CFTR mutation.  A 24-week, open-label trial (Trial 7) in 46 patients aged 1 through 2 years homozygous for the F508del-CFTR mutation. Of the 1108 patients, in the pooled analyses of Trial 1 and Trial 2, 49% were female and 99% were Caucasian; 369 patients received ORKAMBI every 12 hours and 370 patients received placebo. The proportion of patients who prematurely discontinued study drug due to adverse events was 5% for patients treated with ORKAMBI and 2% for patients who received placebo. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients. Table 3 shows adverse reactions occurring in ≥5% of patients with CF aged 12 years and older treated with ORKAMBI who are homozygous for the F508del mutation in the CFTR gene that also occurred at a higher rate than in patients who received placebo in the two double-blind, placebo-controlled trials. 5 Reference ID: 5495367 Table 3: Incidence of Adverse Drug Reactions in ≥5% of ORKAMBI-Treated Patients Aged 12 Years and Older Who are Homozygous for the F508del Mutation in the CFTR Gene in 2 Placebo-Controlled Phase 3 Clinical Trials of 24 Weeks Duration Adverse Reaction ORKAMBI Placebo (Preferred Term) N=369 N=370 (%) (%) Dyspnea 48 (13) 29 (8) Nasopharyngitis 48 (13) 40 (11) Nausea 46 (13) 28 (8) Diarrhea 45 (12) 31 (8) Upper respiratory tract infection 37 (10) 20 (5) Fatigue 34 (9) 29 (8) Respiration abnormal 32 (9) 22 (6) Blood creatine phosphokinase increased 27 (7) 20 (5) Rash 25 (7) 7 (2) Flatulence 24 (7) 11 (3) Rhinorrhea 21 (6) 15 (4) Influenza 19 (5) 8 (2) The safety profile from two pediatric trials in CF patients aged 6 through 11 years who are homozygous for the F508del-CFTR mutation, a 24-week, open-label, multicenter safety trial in 58 patients (Trial 3) and a 24-week, placebo-controlled, clinical trial (Trial 4) in 204 patients (103 received lumacaftor 200 mg/ivacaftor 250 mg every 12 hours and 101 received placebo), was similar to that observed in Trials 1 and 2. Adverse reactions that are not listed in Table 3, and that occurred in ≥5% of lumacaftor/ivacaftor-treated patients with an incidence of ≥3% higher than placebo included: productive cough (17.5% vs 5.9%), nasal congestion (16.5% vs 7.9%), headache (12.6% vs 8.9%), abdominal pain upper (12.6% vs 6.9%), and sputum increased (10.7% vs 2.0%). In a 24-week, open-label, multicenter, study in 60 patients aged 2 through 5 years with CF who were homozygous for the F508del-CFTR mutation (Trial 6) the safety profile was similar to that observed in studies in patients aged 6 years and older [see Clinical Pharmacology (12.2)]. In a 24-week, open-label, multicenter, study in 46 patients aged 1 through 2 years with CF who were homozygous for the F508del-CFTR mutation (Trial 7) the safety profile was similar to that observed in studies in patients aged 2 years and older [see Clinical Pharmacology (12.2)]. Additional information on selected adverse reactions from trials is detailed below: Description of Selected Adverse Drug Reactions Liver-related Adverse Reactions In Trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN elevations were similar between patients treated with ORKAMBI and those who received placebo. Three patients who received ORKAMBI had liver-related serious adverse reactions, including two reported as transaminase elevations and one as hepatic encephalopathy, compared to none in the placebo group. Of these three, one had elevated transaminases (>3 x ULN) associated with bilirubin elevation >2 x ULN. Following discontinuation or interruption of ORKAMBI, transaminases decreased to <3 x ULN. Among six patients with pre-existing cirrhosis and/or portal hypertension who received ORKAMBI, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The event occurred within five days of the start of dosing and resolved following discontinuation of ORKAMBI [see Warnings and Precautions (5.1, 5.2)]. During the 24-week, open-label, clinical trial in 58 patients aged 6 through 11 years (Trial 3), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 5%, 9%, and 19%. No patients had total bilirubin levels >2 x ULN. Lumacaftor/ivacaftor dosing was maintained or successfully resumed after interruption in all patients with transaminase elevations, except one patient who discontinued treatment permanently. During the 24-week, placebo-controlled, clinical trial in 204 patients aged 6 through 11 years (Trial 4), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 1%, 5%, and 13% in the lumacaftor/ivacaftor patients, and 2%, 3%, and 8% in the placebo-treated patients. No patients had total bilirubin levels >2 x ULN. Two patients in the lumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment permanently due to transaminase elevations. During the 24-week, open-label, clinical trial in 60 patients aged 2 through 5 years (Trial 6), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 8.3% (5/60), 11.7% (7/60), and 15.0% (9/60). No patients had total bilirubin levels >2 x ULN. Three patients discontinued lumacaftor/ivacaftor treatment permanently due to transaminase elevations. During the 24-week, open-label, clinical trial in 46 patients aged 1 through 2 years (Trial 7), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 2.2% (1/46), 4.3% (2/46), and 10.9% (5/46), respectively. No patients had total bilirubin levels >2 x ULN. One patient discontinued lumacaftor/ivacaftor treatment permanently due to transaminase elevations. Respiratory Adverse Reactions In Trials 1 and 2, the incidence of respiratory symptom-related adverse reactions (e.g., chest discomfort, dyspnea, and respiration abnormal) was more common in patients treated with ORKAMBI (22%) compared to patients who received placebo (14%). The incidence of these adverse reactions was more common in patients treated with ORKAMBI with lower pre-treatment FEV1. In patients treated with ORKAMBI, the majority of the events began during the first week of treatment [see Warnings and Precautions (5.4)]. During the 24-week, open-label, clinical trial in 46 patients aged 12 years and older (Trial 5) with advanced lung disease (ppFEV1<40) [mean ppFEV129.1 at baseline (range: 18.3 to 42.0)], the incidence of respiratory symptom-related adverse reactions was 65% [see Warnings and Precautions (5.4)]. During the 24-week, open-label, clinical trial (Trial 3) in 58 patients aged 6 through 11 years (mean baseline ppFEV1 was 91.4), the incidence of respiratory symptom-related adverse reactions was 3% (2/58). 6 Reference ID: 5495367 During the 24-week, placebo-controlled, clinical trial (Trial 4) in patients aged 6 through 11 years [mean ppFEV1 89.8 at baseline (range: 48.6 to 119.6)], the incidence of respiratory symptom-related adverse reactions was 11% in lumacaftor/ivacaftor patients and 9% in placebo patients. A decline in ppFEV1 at initiation of therapy was observed during serial post-dose spirometry assessments. The absolute change from pre-dose at 4-6 hours post-dose was -7.7 on Day 1 and -1.3 on Day 15 in lumacaftor/ivacaftor patients. The post-dose decline was resolved by Week 16. Menstrual Abnormalities In Trials 1 and 2, the incidence of combined menstrual abnormality adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular) was more common in female patients treated with ORKAMBI (10%) compared to placebo (2%). These events occurred more frequently in the subset of female patients treated with ORKAMBI who were using hormonal contraceptives (27%) compared to those not using hormonal contraceptives (3%) [see Warnings and Precautions (5.6) and Drug Interactions (7.11)]. Increased Blood Pressure In Trials 1 and 2, adverse reactions related to increases in blood pressure (e.g., hypertension, blood pressure increased) were reported in 1.1% (4/369) of patients treated with ORKAMBI and in no patients who received placebo. The proportion of patients who experienced a systolic blood pressure value >140 mmHg or a diastolic blood pressure >90 mmHg on at least two occasions was 3.6% and 2.2% in patients treated with ORKAMBI, respectively, compared with 1.6% and 0.5% in patients who received placebo [see Warnings and Precautions (5.5)]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ORKAMBI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary: liver function decompensation including liver failure leading to death in patients with pre-existing cirrhosis with portal hypertension [see Warnings and Precautions (5.1)]. Immune system disorders: anaphylaxis, angioedema 7 DRUG INTERACTIONS Potential for Other Drugs to Affect Lumacaftor/Ivacaftor 7.1 Inhibitors of CYP3A Co-administration of lumacaftor/ivacaftor with itraconazole, a strong CYP3A inhibitor, did not impact the exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of lumacaftor on CYP3A, at steady-state, the net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours (the approved dose of ivacaftor monotherapy). Therefore, no dosage adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking ORKAMBI. However, when initiating ORKAMBI in patients taking strong CYP3A inhibitors, reduce the ORKAMBI dosage as recommended for the first week of treatment to allow for the steady-state induction effect of lumacaftor. Following this period, continue with the recommended daily dose [see Dosage and Administration (2.3)]. Examples of strong CYP3A inhibitors include:  ketoconazole, itraconazole, posaconazole, and voriconazole.  telithromycin, clarithromycin. No dosage adjustment is recommended when used with moderate or weak CYP3A inhibitors. 7.2 Inducers of CYP3A Co-administration of lumacaftor/ivacaftor with rifampin, a strong CYP3A inducer, had minimal effect on the exposure of lumacaftor, but decreased ivacaftor exposure (AUC) by 57%. This may reduce the effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum), is not recommended [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. No dosage adjustment is recommended when used with moderate or weak CYP3A inducers. Potential for Lumacaftor/Ivacaftor to Affect Other Drugs 7.3 CYP3A Substrates Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by approximately 80%. Administration of ORKAMBI may decrease systemic exposure of medicinal products which are substrates of CYP3A, thereby decreasing the therapeutic effect of the medicinal product. Co-administration of ORKAMBI is not recommended with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)] such as:  Benzodiazepines: midazolam, triazolam (consider an alternative to these benzodiazepines).  Immunosuppressants: cyclosporine, everolimus, sirolimus, and tacrolimus (avoid the use of ORKAMBI). 7.4 CYP2B6 and CYP2C Substrates In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of ORKAMBI with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates. 7.5 Digoxin and Other P-gp Substrates Based on in vitro results which showed P-gp inhibition and pregnane-X-receptor (PXR) activation, lumacaftor has the potential to both inhibit and induce P-gp. Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of ORKAMBI with P-gp substrates may alter the exposure of these substrates. Monitor the serum concentration of digoxin and titrate the digoxin dose to obtain the desired clinical effect. 7.6 Anti-allergics and Systemic Corticosteroids ORKAMBI may decrease the exposure of montelukast, which may reduce its efficacy. No dosage adjustment for montelukast is recommended. Employ appropriate clinical monitoring, as is reasonable, when co-administered with ORKAMBI. Concomitant use of ORKAMBI may reduce the exposure and effectiveness of prednisone and methylprednisolone. A higher dose of these systemic corticosteroids may be required to obtain the desired clinical effect. 7 Reference ID: 5495367 7.7 Antibiotics Concomitant use of ORKAMBI may decrease the exposure of clarithromycin, erythromycin, and telithromycin, which may reduce the effectiveness of these antibiotics. Consider an alternative to these antibiotics, such as ciprofloxacin, azithromycin, and levofloxacin. 7.8 Antifungals Concomitant use of ORKAMBI may reduce the exposure and effectiveness of itraconazole, ketoconazole, posaconazole, and voriconazole. Concomitant use of ORKAMBI with these antifungals is not recommended. Monitor patients closely for breakthrough fungal infections if such drugs are necessary. Consider an alternative such as fluconazole. 7.9 Anti-inflammatories Concomitant use of ORKAMBI may reduce the exposure and effectiveness of ibuprofen. A higher dose of ibuprofen may be required to obtain the desired clinical effect. 7.10 Antidepressants Concomitant use of ORKAMBI may reduce the exposure and effectiveness of citalopram, escitalopram, and sertraline. A higher dose of these antidepressants may be required to obtain the desired clinical effect. 7.11 Hormonal Contraceptives ORKAMBI may decrease hormonal contraceptive exposure, reducing the effectiveness. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI. Concomitant use of ORKAMBI with hormonal contraceptives increased the menstrual abnormality events [see Adverse Reactions (6.1)]. Avoid concomitant use unless the benefit outweighs the risks. 7.12 Oral Hypoglycemics Concomitant use of ORKAMBI may reduce the exposure and effectiveness of repaglinide and may alter the exposure of sulfonylurea. A dosage adjustment may be required to obtain the desired clinical effect. No dosage adjustment is recommended for metformin. 7.13 Proton Pump Inhibitors, H2 Blockers, Antacids ORKAMBI may reduce the exposure and effectiveness of proton pump inhibitors such as omeprazole, esomeprazole, and lansoprazole, and may alter the exposure of ranitidine. A dose adjustment may be required to obtain the desired clinical effect. No dose adjustment is recommended for calcium carbonate antacid. 7.14 Warfarin ORKAMBI may alter the exposure of warfarin. Monitor the international normalized ratio (INR) when warfarin co-administration with ORKAMBI is required. 7.15 Concomitant Drugs That Do Not Need Dosage Adjustment No dosage adjustment of ORKAMBI or concomitant drug is recommended when ORKAMBI is given with the following: azithromycin, aztreonam, budesonide, ceftazidime, cetirizine, ciprofloxacin, colistimethate, colistin, dornase alfa, fluticasone, ipratropium, levofloxacin, pancreatin, pancrelipase, salbutamol, salmeterol, sulfamethoxazole, trimethoprim, tiotropium, and tobramycin. Based on the metabolism and route of elimination, ORKAMBI is not expected to impact the exposure of these drugs. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are limited and incomplete human data from clinical trials and postmarketing reports on use of ORKAMBI or its individual components, lumacaftor or ivacaftor, in pregnant women to inform a drug-associated risk. In animal reproduction studies, oral administration of lumacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse effects on fetal development at doses that produced maternal exposures up to approximately 8 (rats) and 5 (rabbits) times the exposure at the maximum recommended human dose (MRHD). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse effects on fetal development at doses that produced maternal exposures up to approximately 7 (rats) and 45 (rabbits) times the exposure at the MRHD. No adverse developmental effects were observed after oral administration of either lumacaftor or ivacaftor to pregnant rats from organogenesis through lactation at doses that produced maternal exposures approximately 8 and 5 times the exposures at the MRHD, respectively (see Data). There are no animal reproduction studies with concomitant administration of lumacaftor and ivacaftor. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Lumacaftor In an embryo-fetal development (EFD) study, pregnant rats were administered lumacaftor at oral doses of 500, 1000, or 2000 mg/kg/day during the period of organogenesis from gestation days 7-17. Lumacaftor did not affect fetal development or survival at exposures up to 8 times the MRHD (on an AUC basis at maternal oral doses up to 2000 mg/kg/day). In an EFD study, pregnant rabbits were administered lumacaftor at oral doses of 50, 100, or 200 mg/kg/day during the period of organogenesis from gestation days 7-19. Lumacaftor did not affect fetal development or survival at exposures up to 5 times the MRHD (on an AUC basis at maternal oral doses up to 200 mg/kg/day). Maternal toxicity as evidenced by decreased body weight, decreased food consumption, and clinical signs was observed at 100 and 200 mg/kg/day without any adverse fetal effects. In a pre- and post-natal development study in pregnant female rats administered lumacaftor at 250, 500, or 1000 mg/kg/day from gestation day 6 through lactation day 20, lumacaftor had no effects on delivery or growth and development of offspring at exposures up to 8 times the MRHD (on an AUC basis at maternal oral doses up to 1000 mg/kg/day). Placental transfer of lumacaftor was observed in pregnant rats and rabbits. Ivacaftor In an EFD study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day during the period of organogenesis from gestation days 7-17. Ivacaftor did not affect fetal survival at exposures up to 7 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 200 mg/kg/day). Maternal toxicity (i.e., decreased mean body weight and body weight gain) was observed at 100 and 200 mg/kg/day (5 and 7 times the exposure at the MRHD, respectively) and was associated with a decrease in fetal body weights at a maternal dose of 200 mg/kg/day (7 times the MRHD). In an EFD study, pregnant rabbits were administered ivacaftor at oral doses of 25, 50, or 100 mg/kg/day during the period of organogenesis from gestation days 7-19. Ivacaftor did not affect fetal development or survival at exposures up to 45 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). Maternal toxicity (i.e., death, decreased food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was observed at doses greater than or equal to 50 mg/kg/day (approximately 15 times the MRHD). In a pre- and post-natal development study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day from gestation day 7 through lactation day 20. Ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a 8 Reference ID: 5495367 maternally toxic dose that produced exposures 7 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). Placental transfer of ivacaftor was observed in pregnant rats and rabbits. 8.2 Lactation Risk Summary There is no information regarding the presence of lumacaftor or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Both lumacaftor and ivacaftor are excreted into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ORKAMBI and any potential adverse effects on the breastfed child from ORKAMBI or from the underlying maternal condition. Data Lumacaftor Lacteal excretion of lumacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-lumacaftor administered 9 to 11 days postpartum to lactating mothers (dams). Exposure (AUC0-24h) values for lumacaftor in milk were approximately 40% of plasma levels. Ivacaftor Lacteal excretion of ivacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-ivacaftor administered 9 to 10 days postpartum to lactating mothers (dams). Exposure (AUC0-24h) values for ivacaftor in milk were approximately 1.5 times higher than plasma levels. 8.3 Females and Males of Reproductive Potential ORKAMBI may decrease hormonal contraceptive exposure, reducing the effectiveness. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI [see Warnings and Precautions (5.6) and Drug Interactions (7.11)]. 8.4 Pediatric Use The safety and effectiveness of ORKAMBI in pediatric patients aged one year and older have been established. Use of ORKAMBI in these age groups is supported by evidence from adequate and well-controlled studies of ORKAMBI in patients aged 12 years and older [see Clinical Studies (14) and Adverse Reactions (6.1)] with additional data as follows:  Extrapolation of efficacy in patients aged 12 years and older homozygous for the F508del mutation in the CFTR gene to pediatric patients aged 1 through 11 years with support from population pharmacokinetic analyses showing similar drug exposure levels in patients aged 12 years and older and in patients aged 1 through 11 years [see Clinical Pharmacology (12.3)].  Safety data were obtained from a 24-week, open-label, clinical trial in 58 patients aged 6 through 11 years, mean age 9 years (Trial 3) and a 24-week, placebo- controlled, clinical trial in 204 patients aged 6 through 11 years (Trial 4). Trial 3 evaluated subjects with a screening ppFEV1 ≥40 [mean ppFEV1 91.4 at baseline (range: 55 to 122.7)]. Trial 4 evaluated subjects with a screening ppFEV1 ≥70 [mean ppFEV1 89.8 at baseline (range: 48.6 to 119.6)]. The safety profile of ORKAMBI in pediatric patients 6 through 11 years of age was similar to that in patients aged 12 years and older [see Adverse Reactions (6.1)]. In Trial 3, spirometry (ppFEV1) was assessed as a planned safety endpoint. The within-group LS mean absolute change from baseline in ppFEV1 at Week 24 was 2.5 percentage points. At the Week 26 safety follow-up visit (following a planned discontinuation) ppFEV1 was also assessed. The within-group LS mean absolute change in ppFEV1 from Week 24 at Week 26 was -3.2 percentage points.  Additional safety data were obtained from Trial 6, a 24-week, open-label, clinical trial in 60 patients aged 2 through 5 years at screening (mean age at baseline 3.7 years). The safety profile in Trial 6 was similar to that in patients aged 6 years and older [see Adverse Reactions (6.1)].  Additional safety data were obtained from Trial 7, a 24-week, open-label, clinical trial in 46 patients aged 1 to 2 years at screening (mean age at baseline 18.1 months). The safety profile in Trial 7 was similar to that in patients aged 2 years and older [see Adverse Reactions (6.1)].  Safety was evaluated in a 96-week open-label clinical trial (Trial 8) in 52 patients (39 rolled over from Trial 7 and 13 ORKAMBI naïve) aged 1 to 2 years. Adverse reactions from trial 8 were generally similar to those reported in Trial 7. The safety and effectiveness of ORKAMBI in patients with CF younger than 1 year of age have not been established. Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded [see Warnings and Precautions (5.7)]. Juvenile Animal Toxicity Data In a juvenile toxicology study in which ivacaftor was administered to rats from post-natal days 7 to 35, cataracts were observed at all dose levels, ranging from 0.3 to 2 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at oral doses of 10-50 mg/kg/day). This finding has not been observed in older animals. 8.5 Geriatric Use CF is largely a disease of children and young adults. Clinical trials of ORKAMBI did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment No dosage adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A dose reduction to 2 tablets in the morning and 1 tablet in the evening is recommended for patients aged 6 years and older with moderate hepatic impairment (Child-Pugh Class B). A dose reduction to 1 packet of oral granules in the morning daily and 1 packet of oral granules in the evening every other day is recommended for patients aged 1 to 5 years old with moderate hepatic impairment (Child-Pugh Class B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening or less frequently, or 1 packet of oral granules once daily or less frequently in patients with severe hepatic impairment after weighing the risks and benefits of treatment [see Warnings and Precautions (5.1), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. 8.7 Renal Impairment ORKAMBI has not been studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease. No dosage adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended while using ORKAMBI in patients with severe renal impairment (creatinine clearance ≤30 mL/min) or end-stage renal disease. 8.8 Patients with Severe Lung Dysfunction The Phase 3 trials (Trials 1 and 2 [see Clinical Studies (14)]) included 29 patients receiving ORKAMBI with ppFEV1 <40 at baseline. The treatment effect in this subgroup was comparable to that observed in patients with ppFEV1 ≥40. 9 Reference ID: 5495367 8.9 Patients After Organ Transplantation ORKAMBI has not been studied in patients with CF who have undergone organ transplantation. Use in transplanted patients is not recommended due to potential drug-drug interactions [see Drug Interactions (7.3)]. 10 OVERDOSAGE There have been no reports of overdose with ORKAMBI. The highest repeated dose was lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h administered to 49 healthy subjects for 7 days in a trial evaluating the effect of ORKAMBI on electrocardiograms (ECGs). Adverse events reported at an increased incidence of ≥5% compared to the lumacaftor 600 mg/ivacaftor 250 mg dosing period and placebo included: headache (29%), transaminase increased (18%), and generalized rash (10%). No specific antidote is available for overdose with ORKAMBI. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. 11 DESCRIPTION The active ingredients in ORKAMBI tablets are lumacaftor, which has the following chemical name: 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5­ yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, and ivacaftor, a CFTR potentiator, which has the following chemical name: N-(2,4-di-tert­ butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. The molecular formula for lumacaftor is C24H18F2N2O5 and for ivacaftor is C24H28N2O3. The molecular weights for lumacaftor and ivacaftor are 452.41 and 392.49, respectively. The structural formulas are: lumacaftor ivacaftor Lumacaftor is a white to off-white powder that is practically insoluble in water (0.02 mg/mL). Ivacaftor is a white to off-white powder that is practically insoluble in water (<0.05 µg/mL). ORKAMBI is available as a pink, oval-shaped, film-coated tablet for oral administration containing 200 mg of lumacaftor and 125 mg of ivacaftor. Each ORKAMBI tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor, and the following inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac. ORKAMBI is also available as a pink, oval-shaped, film-coated tablet for oral administration containing 100 mg of lumacaftor and 125 mg of ivacaftor. Each ORKAMBI tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor, and the following inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac. ORKAMBI is also available as white to off-white granules for oral administration and enclosed in a unit-dose packet containing lumacaftor 75 mg/ivacaftor 94 mg, lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg per packet. Each unit-dose packet of ORKAMBI oral granules contains lumacaftor 75 mg/ivacaftor 94 mg, lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg per packet and the following inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; povidone; and sodium lauryl sulfate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation results in protein misfolding, causing a defect in cellular processing and trafficking that targets the protein for degradation and therefore reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface is less stable and has low channel-open probability (defective gating activity) compared to wild-type CFTR protein. Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport. In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit. 12.2 Pharmacodynamics Sweat Chloride Evaluation Changes in sweat chloride in response to relevant doses of lumacaftor alone or in combination with ivacaftor were evaluated in a double-blind, placebo-controlled, Phase 2 clinical trial in patients with CF aged 18 years and older either homozygous or heterozygous for the F508del mutation. In that trial, 10 patients (homozygous for F508del) completed dosing with lumacaftor alone 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h for an additional 28 days and 25 10 Reference ID: 5495367 patients (homozygous or heterozygous for F508del) completed dosing with placebo. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as mean change in sweat chloride from baseline to Day 28 compared to placebo was -8.2 mmol/L (95% CI: -14, -2). The treatment difference between the combination of lumacaftor 400 mg/ivacaftor 250 mg q12h and placebo evaluated as mean change in sweat chloride from baseline to Day 56 compared to placebo was -11 mmol/L (95% CI: -18, -4). Changes in sweat chloride in response to lumacaftor/ivacaftor were also evaluated in a 24-week, open-label, clinical trial (Trial 3) in 58 patients with CF, aged 6 through 11 years (homozygous for F508del) who received lumacaftor 200 mg/ivacaftor 250 mg q12h for 24 weeks. Patients treated with lumacaftor/ivacaftor had a reduction in sweat chloride at Day 15 that was sustained through Week 24. The within-group LS mean absolute change from baseline in sweat chloride was -20.4 mmol/L at Day 15 and -24.8 mmol/L at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The within-group LS mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was 21.3 mmol/L. Changes in sweat chloride in response to lumacaftor/ivacaftor were also evaluated in a 24-week, open-label, clinical trial (Trial 6) in 60 patients with CF, aged 2 through 5 years (homozygous for F508del) who received either lumacaftor 100 mg/ivacaftor 125 mg every 12 hours or lumacaftor 150 mg/ivacaftor 188 mg every 12 hours for 24 weeks. Treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at Week 4 that was sustained through Week 24. The mean absolute change from baseline in sweat chloride was –31.7 mmol/L (95% CI: -35.7, -27.6) at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was an increase of 33.0 mmol/L (95% CI: 28.9, 37.1; P<0.0001). Changes in sweat chloride in response to lumacaftor/ivacaftor were evaluated in a 24-week, open-label, clinical trial (Trial 7) in 46 patients with CF, aged 1 through 2 years (homozygous for F508del) who received lumacaftor 75 mg/ivacaftor 94 mg (patient weighing 7 kg to <9 kg at screening), lumacaftor 100 mg/ivacaftor 125 mg (patient weighing 9 kg to <14 kg at screening), lumacaftor 150 mg/ivacaftor 188 mg (patient weighing ≥14 kg at screening), every 12 hours for 24 weeks. Treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at Week 4 which was sustained through Week 24. The mean absolute change from baseline in sweat chloride at Week 24 was -29.1 mmol/L (95% CI: -34.8, -23.4). In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off- drug response. The mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was 27.3 mmol/L (95% CI: 22.3, 32.3). There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (ppFEV1). Cardiac Electrophysiology The effect of multiple doses of lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h on QTc interval was evaluated in a randomized, placebo- and active-controlled (400 mg moxifloxacin), parallel, thorough QT study in 168 healthy subjects. No meaningful changes in QTc interval were observed with either lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h dose groups. A maximum decrease in mean heart rate of up to 8 beats per minute (bpm) from baseline was observed with lumacaftor/ivacaftor treatment. In Trials 1 and 2, a similar decrease in heart rate was observed in patients during initiation of ORKAMBI (lumacaftor 400 mg/ivacaftor 250 mg q12h). 12.3 Pharmacokinetics The exposure (AUC) of lumacaftor is approximately 2-fold higher in healthy adult volunteers compared to exposure in patients with CF. The exposure of ivacaftor is similar between healthy adult volunteers and patients with CF. After twice daily dosing, steady-state plasma concentrations of lumacaftor and ivacaftor in healthy subjects were generally reached after approximately 7 days of treatment, with an accumulation ratio of approximately 1.9 for lumacaftor. The steady-state exposure of ivacaftor is lower than that of Day 1 due to the CYP3A induction effect of lumacaftor. Table 4: Mean (SD) Pharmacokinetic Parameters of Lumacaftor and Ivacaftor at Steady-State in Subjects with CF Drug t½* Cmax AUC0-12h (h) (μg/mL) (μg∙h/mL) Lumacaftor 400 mg q12h/ Lumacaftor 25.0 (7.96) 25.2 (9.94) 198 (64.8) Ivacaftor 250 mg q12h Ivacaftor 0.602 (0.304) 9.34 (3.81) 3.66 (2.25) * Based on lumacaftor 200 mg q12h/ivacaftor 250 mg q12h studied in healthy subjects. Absorption When a single dose of lumacaftor/ivacaftor was administered with fat-containing foods, lumacaftor exposure was approximately 2 times higher and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state. Following multiple oral dose administration of lumacaftor in combination with ivacaftor, the exposure of lumacaftor generally increased proportional to dose over the range of 200 mg every 24 hours to 400 mg every 12 hours. The median (range) tmax of lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state. Following multiple oral dose administration of ivacaftor in combination with lumacaftor, the exposure of ivacaftor generally increased with dose from 150 mg every 12 hours to 250 mg every 12 hours. The median (range) tmax of ivacaftor is approximately 4.0 hours (2.0; 6.0) in the fed state. Distribution Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of 200 mg every 24 hours for 28 days to patients with CF in a fed state, the mean (±SD) for apparent volumes of distribution was 86.0 (69.8) L. Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Elimination The half-life of lumacaftor is approximately 26 hours in patients with CF. The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/hr (29.4%) for patients with CF. The half-life of ivacaftor when given with lumacaftor is approximately 9 hours in healthy subjects. The typical CL/F (CV), of ivacaftor when given in combination with lumacaftor was estimated to be 25.1 L/hr (40.5%) for patients with CF. Metabolism Lumacaftor is not extensively metabolized in humans with the majority of lumacaftor excreted unchanged in the feces. In vitro and in vivo data indicate that lumacaftor is mainly metabolized via oxidation and glucuronidation. Ivacaftor is extensively metabolized in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. Excretion Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged in the feces. There was minimal elimination of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent). 11 Reference ID: 5495367 Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine). Specific Populations Pediatric Patients The following conclusions about exposures between adults and the pediatric population are based on population pharmacokinetics (PK) analyses: Table 5: Mean (SD) Lumacaftor and Ivacaftor Exposure by Age Group Age Group Weight Dose Mean Lumacaftor (SD)* AUCss (µg∙h/mL) Mean Ivacaftor (SD)** AUCss (µg∙h/mL) 7 kg to <9 kg lumacaftor 75 mg/ivacaftor 94 mg every 12 hours. 234 7.98 Patients aged 1 to <2 years 9 kg to <14 kg lumacaftor 100 mg/ivacaftor 125 mg every 12 hours. 191 (40.6) ≥14 kg lumacaftor 150 mg/ivacaftor 188 mg every 12 hours. 116 Patients aged 2 through 5 years <14 kg lumacaftor 100 mg/ivacaftor 125 mg every 12 hours. 180 (45.5) 5.35 (1.61) 5.82 5.92 (4.61) ≥14 kg lumacaftor 150 mg/ivacaftor 188 mg every 12 hours. 217 (48.6) 5.90 (1.93) Patients aged 6 through 11 years - lumacaftor 200 mg/ivacaftor 250 mg every 12 hours. 203 (57.4) 5.26 (3.08) Patients aged 12 to <18 years - lumacaftor 400 mg/ivacaftor 250 mg every 12 hours. 241 (61.4) 3.90 (1.56) *The mean lumacaftor (SD) AUCss is comparable to the mean AUCss in patients aged 12 years and older administered ORKAMBI tablets. **The mean ivacaftor (SD) AUCss is comparable to the mean AUCss in patients aged 12 years and older administered ORKAMBI tablets. Male and Female Patients The pharmacokinetics of ORKAMBI was evaluated using a population PK analyses of data from clinical studies of lumacaftor given in combination with ivacaftor. Results indicate no clinically relevant difference in pharmacokinetic parameters for lumacaftor and ivacaftor between males and females. Patients with Renal Impairment Pharmacokinetic studies have not been performed with ORKAMBI in patients with renal impairment [see Use in Specific Populations (8.7)]. Patients with Hepatic Impairment Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had approximately 50% higher exposures (AUC0-12h) and approximately 30% higher Cmax for both lumacaftor and ivacaftor compared with healthy subjects matched for demographics. Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5 to 6) or severe hepatic impairment (Child-Pugh Class C, score 10 to 15) receiving ORKAMBI [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Adverse Reactions (6), and Use in Specific Populations (8.6)]. Drug Interaction Studies Drug interaction studies were performed with lumacaftor/ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (7)]. Potential for Lumacaftor/Ivacaftor to Affect Other Drugs Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by 80%. Ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. The net effect of lumacaftor/ivacaftor therapy is strong CYP3A induction [see Drug Interactions (7.3)]. Based on in vitro results which showed P-gp inhibition and PXR activation, lumacaftor has the potential to both inhibit and induce P-gp. A clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of ORKAMBI with P-gp substrates may alter the exposure of these substrates [see Drug Interactions (7.5)]. In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. In vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of ORKAMBI with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates [see Drug Interactions (7.4)]. Potential for Other Drugs to Affect Lumacaftor/Ivacaftor Lumacaftor exposure is not affected by concomitant CYP3A inducers or inhibitors. Exposure of ivacaftor when given in combination with lumacaftor is reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors [see Dosage and Administration (2.3), Warnings and Precautions (5.6), and Drug Interactions (7)]. The effects of co-administered drugs on the exposure of lumacaftor and ivacaftor are shown in Table 6 [see Dosage and Administration (2.3), Warnings and Precautions (5.6), and Drug Interactions (7)]. 12 Reference ID: 5495367 Table 6: Impact of Other Drugs on Lumacaftor 200 mg q12h/Ivacaftor 250 mg q12h Co-administered Drug Dose of Co-administered Drug Effect on PK* Mean Ratio (90% CI) of Lumacaftor and Ivacaftor No Effect=1.0 AUC Cmax CYP3A inhibitor: itraconazole 200 mg once daily ↔ Lumacaftor 0.97 (0.91, 1.02) 0.99 (0.92, 1.05) ↑ Ivacaftor 4.30† (3.78, 4.88) 3.64† (3.19, 4.17) CYP3A inducer: rifampin 600 mg once daily ↔ Lumacaftor 0.87 (0.81, 0.93) 0.96 (0.87, 1.05) ↓ Ivacaftor 0.43 (0.38, 0.49) 0.50 (0.43, 0.58) Other: ciprofloxacin 750 mg q12h ↔ Lumacaftor 0.86 (0.79, 0.95) 0.88 (0.80, 0.97) ↔ Ivacaftor 1.29 (1.12, 1.48) 1.29 (1.11, 1.49) * ↑ = increase, ↓ = decrease, ↔ = no change. † The net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours, the approved dose of ivacaftor monotherapy. CI = Confidence Interval; PK = Pharmacokinetics. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with ORKAMBI; however, studies are available for individual components, lumacaftor and ivacaftor, as described below. Lumacaftor A two-year study in Sprague-Dawley rats and a 26-week study in transgenic Tg.rasH2 mice were conducted to assess carcinogenic potential of lumacaftor. No evidence of tumorigenicity was observed in rats at lumacaftor oral doses up to 1000 mg/kg/day (approximately 5 and 13 times the MRHD on a lumacaftor AUC basis in males and females, respectively). No evidence of tumorigenicity was observed in Tg.rasH2 mice at lumacaftor oral doses up to 1500 and 2000 mg/kg/day in female and male mice, respectively. Lumacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test. Lumacaftor had no effects on fertility and reproductive performance indices in male and female rats at an oral dose of 1000 mg/kg/day (approximately 3 and 8 times, respectively, the MRHD on a lumacaftor AUC basis). Ivacaftor Two-year studies were conducted in mice and rats to assess carcinogenic potential of ivacaftor. No evidence of tumorigenicity was observed in mice and rats at ivacaftor oral doses up to 200 mg/kg/day and 50 mg/kg/day, respectively (approximately equivalent to 3 and 10 times the MRHD based on summed AUCs of ivacaftor and its metabolites). Ivacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test. Ivacaftor impaired fertility and reproductive performance indices in male and female rats at an oral dose of 200 mg/kg/day (approximately 15 and 7 times the MRHD based on summed AUCs of ivacaftor and its metabolites). Increases in prolonged diestrus were observed in females at 200 mg/kg/day. Ivacaftor also increased the number of females with all nonviable embryos and decreased corpora lutea, implantations, and viable embryos in rats at 200 mg/kg/day (approximately 7 times the MRHD based on summed AUCs of ivacaftor and its metabolites) when dams were dosed prior to and during early pregnancy. These impairments of fertility and reproductive performance in male and female rats at 200 mg/kg/day were attributed to severe toxicity. No effects on male or female fertility and reproductive performance indices were observed at an oral dose of ≤100 mg/kg/day (approximately 8 and 5 times the MRHD based on summed AUCs of ivacaftor and its metabolites). 14 CLINICAL STUDIES Dose Ranging Dose ranging for the clinical program consisted primarily of one double-blind, placebo-controlled, multiple-cohort trial which included 97 Caucasian patients with CF (homozygous for the F508del mutation) aged 18 years and older with a screening ppFEV1 ≥40. In the trial, 76 patients (homozygous for the F508del mutation) were randomized to receive lumacaftor alone at once daily doses of 200 mg, 400 mg, or 600 mg or 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h and 27 patients (homozygous or heterozygous for the F508del mutation) received placebo. During the initial 28-day lumacaftor monotherapy period, treatment with lumacaftor demonstrated a dose-dependent decrease in ppFEV1 compared to placebo. Changes from Day 1 at Day 28 in ppFEV1 compared to placebo were 0.24, -1.4, -2.7, and -4.6 for the 200 mg once daily, 400 mg once daily, 600 mg once daily, and 400 mg q12h lumacaftor doses, respectively. Following the addition of ivacaftor 250 mg q12h, the changes from Day 1 at Day 56 in ppFEV1 compared to placebo were 3.8, 2.7, 5.6, and 4.2, respectively. Sweat chloride was also assessed in this trial. Following the initial 28 days of lumacaftor monotherapy, the changes from Day 1 at Day 28 in sweat chloride compared to placebo were -4.9, -8.3, -6.1, and -8.2 mmol/L for the 200 mg once daily, 400 mg once daily, 600 mg once daily, and 400 mg q12h lumacaftor doses, respectively. Following the addition of ivacaftor 250 mg q12h, the changes from Day 1 at Day 56 in sweat chloride compared to placebo were -5.0, -9.8, -9.5, and -11 mmol/L, respectively. These data supported the evaluation of lumacaftor 400 mg/ivacaftor 250 mg q12h (ORKAMBI) and lumacaftor 600 mg once daily/ivacaftor 250 mg q12h in the confirmatory trials. 13 Reference ID: 5495367 BL Day Week 15 4 Week • - Placebo Trial 1 Visit Week 16 ,... LUM 400 mg q12h/lVA 2S0 mg q12h Week 24 BL Day Week 15 4 Woek • -- Placebo Trial 2 Visit Week 16 ,... LUM 400 mg q12h/lVA 250 mg q12h Week 24 Confirmatory The efficacy of ORKAMBI in patients with CF who are homozygous for the F508del mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled, 24-week clinical trials (Trials 1 and 2) in 1108 clinically stable patients with CF of whom 369 patients received ORKAMBI twice daily. Trial 1 evaluated 549 patients with CF who were aged 12 years and older (mean age 25.1 years) with ppFEV1 at screening between 40-90 [mean ppFEV1 60.7 at baseline (range: 31.1 to 94.0)]. Trial 2 evaluated 559 patients aged 12 years and older (mean age 25.0 years) with ppFEV1 at screening between 40-90 [mean ppFEV1 60.5 at baseline (range: 31.3 to 99.8)]. Patients with a history of colonization with organisms such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus, or who had 3 or more abnormal liver function tests (ALT, AST, AP, GGT ≥3 x the ULN or total bilirubin ≥2 x the ULN) were excluded. Patients in both trials were randomized 1:1:1 to receive either ORKAMBI (lumacaftor 400 mg q12h/ivacaftor 250 mg q12h; or lumacaftor 600 mg once daily/ivacaftor 250 mg q12h) or placebo. Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF therapies (e.g., bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). The primary efficacy endpoint in both trials was change in lung function as determined by absolute change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24. In both trials, treatment with ORKAMBI resulted in a statistically significant improvement in ppFEV1. The treatment difference between ORKAMBI and placebo for the mean absolute change in ppFEV1 from baseline at Week 24 (assessed as the average of the treatment effects at Week 16 and at Week 24) was 2.6 percentage points [95% CI (1.2, 4.0)] in Trial 1 (P=0.0003) and 3.0 percentage points [95% CI (1.6, 4.4)] in Trial 2 (P<0.0001). These changes persisted throughout the 24-week treatment period (see Figure 1). Improvements in ppFEV1 were observed regardless of age, disease severity, sex, and geographic region. Figure 1. Absolute Change From Baseline at Each Visit in Percent Predicted FEV1 in Trial 1 and Trial 2. LS = Least Squares; q12h = every 12 hours Key secondary efficacy variables included relative change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24; absolute change from baseline in BMI at Week 24; absolute change from baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain score at Week 24, a measure of respiratory symptoms relevant to patients with CF such as cough, sputum production, and difficulty breathing; proportion of patients achieving ≥5% relative change from baseline in ppFEV1 using the average of Week 16 and Week 24; and number of pulmonary exacerbations through Week 24. For the purposes of these trials, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. Trial 2 ORKAMBI Placebo LUM 400 mg q12h/IVA (n=187) 250 mg q12h (n=187) 5.3 – (2.7, 7.8) P<0.0001‡ 0.4 – (0.2, 0.5) P=0.0001‡ Table 7: Summary of Other Efficacy Endpoints in Trials 1 and 2* Trial 1 Placebo (n=184) ORKAMBI LUM 400 mg q12h/IVA 250 mg q12h (n=182) Relative change in ppFEV1 at Week 24† (%) Treatment difference (95% CI) – 4.3 (1.9, 6.8) P=0.0006‡ Absolute change in BMI at Week 24 (kg/m2) Treatment difference (95% CI) – 0.1 (-0.1, 0.3) Absolute change in Treatment 1.5 CFQ-R Respiratory Domain Score (Points) at Week 24 difference (95% CI) – (-1.7, 4.7) – 2.9 (-0.3, 6.0) Proportion of patients with ≥5% relative change in ppFEV1 at Week 24† % 22% 37% 23% 41% Odds ratio (95% CI) – 2.1 (1.3, 3.3) – 2.4 (1.5, 3.7) Number of pulmonary exacerbations through Week 24 # of events (rate per 48 weeks) 112 (1.1) 73 (0.7) 139 (1.2) 79 (0.7) Rate ratio (95% CI) – 0.7 (0.5, 0.9) – 0.6 (0.4, 0.8) * In each trial, a hierarchical testing procedure was performed within each active treatment arm for primary and secondary endpoints vs. placebo; at each step, P≤0.0250 and all previous tests also meeting this level of significance was required for statistical significance. † Assessed as the average of the treatment effects at Week 16 and Week 24. ‡ Indicates statistical significance confirmed in the hierarchical testing procedure. Other efficacy measures considered not statistically significant. 14 Reference ID: 5495367 16 HOW SUPPLIED/STORAGE AND HANDLING ORKAMBI (lumacaftor 200 mg/ivacaftor 125 mg) is supplied as pink, oval-shaped tablets; each tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor, printed with “2V125” in black ink on one side and plain on the other, and is packaged as follows: 112–count tablet box containing a 4-week supply (4 weekly cartons of 7 daily blister strips with 4 tablets per strip). NDC 51167-809-01 ORKAMBI (lumacaftor 100 mg/ivacaftor 125 mg) is supplied as pink, oval-shaped tablets; each tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor, printed with “1V125” in black ink on one side and plain on the other, and is packaged as follows: 112–count tablet box containing a 4-week supply (4 weekly cartons of 7 daily blister strips with 4 tablets per strip). NDC 51167-700-02 ORKAMBI (lumacaftor/ivacaftor) oral granules are supplied as small white to off-white granules and enclosed in unit-dose packets as follows: 56-count carton (contains 56 unit-dose packets of lumacaftor 75 mg/ivacaftor 94 mg per packet) NDC 51167-122-01 56-count carton (contains 56 unit-dose packets of lumacaftor 100 mg/ivacaftor 125 mg per packet) NDC 51167-900-01 56-count carton (contains 56 unit-dose packets of lumacaftor 150 mg/ivacaftor 188 mg per packet) NDC 51167-500-02 Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Advanced Liver Disease Inform patients that worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease occurred in some patients treated with ORKAMBI. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI [see Warnings and Precautions (5.1)]. Abnormalities in Liver Function and Testing Inform patients that abnormalities in liver function have occurred in patients treated with ORKAMBI. Blood tests to measure transaminases (ALT and AST) and bilirubin will be performed prior to initiating ORKAMBI, every 3 months during the first year of therapy, and annually thereafter. Advise patients to contact their healthcare provider if they develop symptoms consistent with hepatotoxicity [see Warnings and Precautions (5.2)]. Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions including angioedema and anaphylaxis are possible with use of ORKAMBI. Inform patients of the early signs of hypersensitivity reactions including rash, hives, itching, facial swelling, tightness of the chest and wheezing. Advise patients to discontinue use of ORKAMBI immediately and contact their physician or go to the emergency department if these symptoms occur. Respiratory Events Inform patients that chest discomfort, dyspnea, and respiration abnormal were more common during initiation of ORKAMBI therapy, especially in patients with advanced lung disease and to contact their healthcare provider if they develop any of these symptoms [see Warnings and Precautions (5.4)]. Effect on Blood Pressure Inform patients that increased blood pressure has been observed in some patients treated with ORKAMBI and that periodic monitoring of their blood pressure during treatment is recommended and to contact their healthcare provider if they develop elevated blood pressure or notice elevations in pre-existing high blood pressure [see Warnings and Precautions (5.5)]. Drug Interactions with CYP3A Inhibitors and Inducers  Advise patients to inform their healthcare providers of all concomitant medications, herbal and dietary supplements. Advise patients to avoid grapefruit products during the first week after treatment initiation with ORKAMBI [see Dosage and Administration (2.3), Warnings and Precautions (5.6), and Drug Interactions (7)].  Instruct post-menarchal patients including females of reproductive potential on alternative methods of birth control because hormonal contraceptives should not be relied upon as an effective method of contraception. ORKAMBI may decrease the effectiveness of hormonal contraceptives and there is an increased incidence of menstruation-related adverse reactions when co-administered with ORKAMBI [see Warnings and Precautions (5.6), Adverse Reactions (6.1), and Drug Interactions (7.11)]. Cataracts Inform patients that abnormalities of the eye lens (cataract) have been noted in some children and adolescents receiving ORKAMBI. Advise pediatric patients and their caregivers that they will receive ophthalmological examinations before initiating and during ORKAMBI treatment. Advise pediatric patients and/or their caregivers to contact their healthcare provider if they experience visual changes [see Warnings and Precautions (5.7)]. Administration Inform patients that ORKAMBI should be taken with fat-containing food. A typical CF diet will satisfy this requirement. Examples of fat-containing foods include eggs, avocados, nuts, butter, peanut butter, cheese pizza, breast milk, infant formula, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc. [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Inform patients and caregivers that ORKAMBI oral granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and completely consumed to ensure delivery of the entire dose. Food or liquid should be at or below room temperature. Once mixed, the product has been shown to be stable for one hour, and therefore should be consumed during this period. Some examples of appropriate soft foods or liquids may include puréed fruits or vegetables, flavored yogurt or pudding, applesauce, water, milk, breast milk, infant formula or juice. Inform patients that if a dose is missed and they remember the missed dose within 6 hours, the patients should take the dose with fat-containing food. If more than 6 hours elapsed after the usual dosing time, the patients should skip that dose and resume the normal schedule for the following dose. Patients should be informed not to take a double dose to make up for the forgotten dose [see Dosage and Administration (2.1)]. 15 Reference ID: 5495367 .. VERTEX Manufactured for Vertex Pharmaceuticals Incorporated 50 Northern Avenue Boston, MA 02210 ORKAMBI, the ORKAMBI logo, VERTEX, and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2024 Vertex Pharmaceuticals Incorporated ALL RIGHTS RESERVED 16 Reference ID: 5495367 PATIENT INFORMATION ORKAMBI (or-KAM-bee) (lumacaftor and ivacaftor) tablets for oral use (lumacaftor and ivacaftor) oral granules What is ORKAMBI? • ORKAMBI is a prescription medicine used for the treatment of cystic fibrosis (CF) in people aged 1 year and older who have two copies of the F508del mutation (F508del/F508del) in their CFTR gene. • ORKAMBI should not be used in people other than those who have two copies of the F508del mutation in their CFTR gene. It is not known if ORKAMBI is safe and effective in children under 1 year of age. Before taking ORKAMBI, tell your doctor about all of your medical conditions, including if you: • have or have had liver problems. • are allergic to ORKAMBI or any ingredients in ORKAMBI. See the end of this patient information leaflet for a complete list of ingredients in ORKAMBI. • have kidney problems. • have lung problems. • have had an organ transplant. • are using birth control (hormonal contraceptives, including oral, injectable, transdermal, or implantable forms). Hormonal contraceptives should not be used as a method of birth control when taking ORKAMBI. Talk to your doctor about the best birth control method you should use while taking ORKAMBI. • are pregnant or plan to become pregnant. It is not known if ORKAMBI will harm your unborn baby. You and your doctor should decide if you will take ORKAMBI while you are pregnant. • are breastfeeding or planning to breastfeed. It is not known if ORKAMBI passes into your breast milk. You and your doctor should decide if you will take ORKAMBI while you are breastfeeding. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ORKAMBI may affect the way other medicines work, and other medicines may affect how ORKAMBI works. The dose of ORKAMBI may need to be adjusted when taken with certain medicines. Ask your doctor or pharmacist for a list of these medicines if you are not sure. Especially tell your doctor if you take: • antibiotics: rifampin (RIFAMATE®, RIFATER®) or rifabutin (MYCOBUTIN®). • seizure medicines: phenobarbital, carbamazepine (TEGRETOL®, CARBATROL®, EQUETRO®), or phenytoin (DILANTIN®, PHENYTEK®). • sedatives and anti-anxiety medicines: triazolam (HALCION®) or midazolam (DORMICUM®, HYPNOVEL®, and VERSED®). • immunosuppressant medicines: cyclosporine, everolimus (ZORTRESS®), sirolimus (RAPAMUNE®), or tacrolimus (ASTAGRAF XL®, ENVARSUS® XR, PROGRAF®, and PROTOPIC®). • St. John’s wort (Hypericum perforatum). • antifungal medicines including ketoconazole, itraconazole (such as SPORANOX®), posaconazole (such as NOXAFIL®), or voriconazole (such as VFEND®). • antibiotics including telithromycin, clarithromycin (such as BIAXIN®), or erythromycin (such as ERY-TAB®). Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I take ORKAMBI? • Take ORKAMBI exactly as your doctor tells you to take it. • Always take ORKAMBI tablets or granules with foods that contain fat. Examples of fat-containing foods include eggs, avocados, nuts, butter, peanut butter, cheese pizza, breast milk, infant formula, whole-milk dairy products (such as whole milk, cheese, and yogurt). • Take your doses of ORKAMBI 12 hours apart. • ORKAMBI tablets (aged 6 years and older): o Each ORKAMBI box contains 4 weekly cartons. o Each carton contains 7 daily blister strips. o Each blister strip contains 4 tablets so you can take 2 tablets for the morning and 2 tablets for the evening. o You may cut along the dotted line to separate your morning dose from your evening dose. 1 Reference ID: 5495367 o To take your morning dose, unpeel the paper backing from a blister strip (do not push tablet through backing) to remove 2 ORKAMBI tablets and take them with fat-containing food. o 12 hours after your previous dose, open another blister strip (do not push tablet through backing) to remove 2 ORKAMBI tablets and take them with fat-containing food. • ORKAMBI oral granules (aged 1 to under 6 years old): o Hold the packet with the cut line on top. o Shake the packet gently to settle the ORKAMBI granules. o Tear or cut packet open along cut line. o Carefully pour all of the ORKAMBI granules in the packet into one teaspoon (5 mL) of soft food or liquid in a small container (like an empty bowl). o The food or liquid should be at or below room temperature. Examples of soft foods or liquids include puréed fruits or vegetables, flavored yogurt or pudding, applesauce, water, milk, breast milk, infant formula or juice.Mix the ORKAMBI granules with food or liquid. o After mixing, give ORKAMBI within 1 hour. Make sure all medicine is taken. o Give a child fat-containing food just before or just after the ORKAMBI granules dose (see examples above). • If you miss a dose within 6 hours of when you usually take it, take your dose with fat-containing food as soon as possible. • If you miss a dose and it is more than 6 hours after the time you usually take it, skip that dose only and take the next dose when you usually take it. Do not take 2 doses at the same time to make up for your missed dose. • Tell your doctor if you stop ORKAMBI for more than 1-week. Your doctor may need to change your dose of ORKAMBI or other medicines you take. What should I avoid while taking ORKAMBI? Do not eat or drink grapefruit products during your first week of treatment with ORKAMBI. Eating or drinking grapefruit products can increase the amount of ORKAMBI in your blood. What are the possible side effects of ORKAMBI? ORKAMBI can cause serious side effects, including: • Worsening of liver function in people with severe liver disease. The worsening of liver function can be serious or cause death. Talk to your doctor if you have been told you have liver disease as your doctor may need to adjust the dose of ORKAMBI. • High liver enzymes in the blood, which can be a sign of liver injury in people receiving ORKAMBI. Your doctor will do blood tests to check your liver: o before you start ORKAMBI o every 3 months during your first year of taking ORKAMBI o every year while you are taking ORKAMBI Call your doctor right away if you have any of the following symptoms of liver problems: o pain or discomfort in the upper right stomach o yellowing of your skin or the white part of your (abdominal) area eyes o loss of appetite o nausea or vomiting o dark, amber-colored urine o confusion • Serious Allergic Reactions can happen to people who are treated with ORKAMBI. Call your doctor or go to the emergency room right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction may include: o rash or hives o swelling of the face, lips, and/or tongue, difficulty swallowing o tightness of the chest or throat or difficulty breathing o light-headedness or dizziness • Breathing problems such as trouble breathing, shortness of breath or chest tightness in people when starting ORKAMBI, especially in people who have poor lung function. If you have poor lung function, your doctor may monitor you more closely when you start ORKAMBI. Call your doctor right away if you have trouble breathing, shortness of breath or chest tightness. • An increase in blood pressure in some people receiving ORKAMBI. Your doctor should monitor your blood pressure during treatment with ORKAMBI. Call your doctor right away if you have an increase in blood pressure. 2 Reference ID: 5495367 ... VERTEX - • Abnormality of the eye lens (cataract) in some children and adolescents receiving ORKAMBI. If you are a child or adolescent, your doctor should perform eye examinations before and during treatment with ORKAMBI to look for cataracts. The most common side effects of ORKAMBI include: • breathing problems such as shortness of breath and • rash chest tightness • gas • nausea • common cold, including sore throat, stuffy or runny • diarrhea nose • fatigue • flu or flu-like symptoms • increase in a certain blood enzyme called creatine • irregular, missed, or abnormal periods (menses) and phosphokinase increase in the amount of menstrual bleeding Additional side effects in children Side effects seen in children are similar to those seen in adults and adolescents. Additional common side effects seen in children include: • cough with sputum • stomach pain • stuffy nose • increase in sputum • headache Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of ORKAMBI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ORKAMBI? • Store ORKAMBI at room temperature between 68°F to 77°F (20°C to 25°C). Keep ORKAMBI and all medicines out of the reach of children. General information about the safe and effective use of ORKAMBI. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ORKAMBI for a condition for which it was not prescribed. Do not give ORKAMBI to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about ORKAMBI that is written for health professionals. What are the ingredients in ORKAMBI? ORKAMBI tablets: Active ingredients: lumacaftor and ivacaftor Inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains: carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains: ammonium hydroxide, iron oxide black, propylene glycol, and shellac. ORKAMBI oral granules Active ingredients: lumacaftor and ivacaftor Inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; povidone; and sodium lauryl sulfate. Manufactured for: Vertex Pharmaceuticals Incorporated; 50 Northern Avenue, Boston, MA 02210 For more information, go to www.orkambi.com or call 1-877-752-5933. ORKAMBI, the ORKAMBI logo, VERTEX, and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2023 Vertex Pharmaceuticals Incorporated This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 08/2023 3 Reference ID: 5495367
custom-source
2025-02-12T15:47:43.549399
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FARESTON® safely and effectively. See full prescribing information for FARESTON®. FARESTON® (toremifene citrate) 60 mg Tablets oral administration Initial U.S. Approval: 1997 WARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration-related manner [see Clinical Pharmacology (12.2)]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions (5.1)]. ----------------------------INDICATIONS ANDUSAGE--------------------------­ FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. (1) ----------------------DOSAGE AND ADMINISTRATION----------------------­ • 60 mg once daily, orally (2) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ • 60 mg tablet is round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side. (3) -------------------------------CONTRAINDICATIONS-----------------------------­ • Hypersensitivity to the drug(4.1) • QT Prolongation, Hypokalemia, Hypomagnesemia (4.2) FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: QT PROLONGATION 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Hypersensitivity to the Drug 4.2 QT Prolongation, Hypokalemia, Hypomagnesemia 5 WARNINGS AND PRECAUTIONS 5.1 Prolongation of the QT Interval 5.2 Hepatotoxicity 5.3 Hypercalcemia and Tumor Flare 5.4 Risk of Uterine Malignancy 5.5 General 5.6 Laboratory Tests 5.7 Use in Pregnancy 5.8 Women of Childbearing Potential 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-marketing Experience -----------------------WARNINGS AND PRECAUTIONS-----------------------­ • Prolongation of the QT Interval(5.1) • Heptatotoxicty (5.2) • Hypercalcemia and Tumor Flare (5.3) • Risk of Uterine Malignancy (5.4) • General (5.5) • Laboratory Tests (5.6) • Pregnancy: Fetal harm may occur when administered to a pregnant woman. Women should be advised not to become pregnant when taking FARESTON. (5.7, 8.1) • Women of Childbearing Potential: Use effective nonhormonal contraception during FARESTON therapy.(5.8) ------------------------------ADVERSE REACTIONS------------------------------­ Most common adverse reactions are hot flashes, sweating, nausea and vaginal discharge. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Kyowa Kirin, Inc. at 1­ 800-305-FARESTON (1-800-305-3273) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------­ • Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. (7.1) • Agents that prolong QT should be avoided. (7.2) • Coadministration with a strong CYP3A4 inducer may result in a relevant decrease in FARESTON exposure and should be avoided. (7.3) • Coadministration with a strong CYP3A4 inhibitor can result in a relevant increase in FARESTON exposure and should be avoided. (7.4) • CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be used with caution and require careful monitoring. (7.6) -----------------------USE IN SPECIFIC POPULATIONS-----------------------­ • Nursing Mothers: Discontinue drug or nursing taking into account the importance of the drug to the mother.(8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised 12/2024 Reference ID: 5494543 1 7 DRUG INTERACTIONS 7.1 Drugs that Decrease Renal Calcium Excretion 7.2 Agents that Prolong QT 7.3 Effect of Strong CYP3A4 Inducers on Toremifene 7.4 Effect of Strong CYP3A4 Inhibitors on Toremifene 7.5 Effect of Toremifene on CYP3A4Substrates 7.6 Effect of Toremifene on CYP2C9 Substrates 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Nursing Mothers 8.3 Pediatric Use 8.4 Geriatric Use 8.5 Renal Impairment 8.6 Hepatic Impairment 8.7 Race 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility 14 CLINICAL STUDIES 16 SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5494543 2 FULL PRESCRIBING INFORMATION WARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration-related manner [see Clinical Pharmacology (12.2)]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. 2 DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. 3 DOSAGE FORMS AND STRENGTHS Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side. 4 CONTRAINDICATIONS 4.1 Hypersensitivity to the Drug FARESTON is contraindicated in patients with known hypersensitivity to the drug. 4.2 QT Prolongation, Hypokalemia, Hypomagnesemia Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia. 5 WARNINGS AND PRECAUTIONS 5.1 Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner [see Clinical Pharmacology (12.2)]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)]. 5.2 Hepatotoxicity Hepatotoxicity, both increases in the serum concentration for grade 3 and 4 transaminitis and hyperbilirubinemia, including jaundice, hepatitis, and non-alcoholic fatty liver disease, have also been reported in clinical trials and postmarketing with FARESTON. Liver function tests should be performed periodically. [see Adverse Reactions (6.1), Post-marketing Experience (6.2)] 5.3 Hypercalcemia and Tumor Flare As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued. 5.4 Risk of Uterine Malignancy Endometrial cancer, endometrial hypertrophy, hyperplasia, and uterine polyps have been reported in some patients treated with FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology (13.1)]. Long-term use of FARESTON has not been established in patients with pre-existing Reference ID: 5494543 3 endometrial hyperplasia. All patients should have baseline and annual gynecological examinations. In particular, patients at high risk of endometrial cancer should be closely monitored. 5.5 General Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions (5.2)]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia. 5.6 Laboratory Tests Periodic complete blood counts, calcium levels, and liver function tests should be obtained. 5.7 Use in Pregnancy Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5.8 Women of Childbearing Potential FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. 6.1 Clinical Trials Experience Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment. The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related. North American Study FAR60 TAM20 n = 221 n = 215 Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4% Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below. Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies (14)]. Reference ID: 5494543 4 Adverse Reactions North American Eastern E ropean No rdic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) Cardiac Cardiac Failure 2 (1) 1 (<1) - 1 (<1) 2 (1) 3 (1.5) Myocardial Infarction 2 (1) 3 (1.5) 1 (<1) 2 (1) - 1 (<1) Arrhythmia - - - - 3 (1.5) 1 (<1) Angina Pectoris - - 1 (<1) - 1 (<1) 2 (1) Ocular* Cataracts 22 (10) 16 (7.5) - - - 5 (3) Dry Eyes 20 (9) 16 (7.5) - - - - Abnormal Visual Fields 8 (4) 10 (5) - - - 1 (<1) Corneal Keratopathy 4 (2) 2 (1) - - - - Glaucoma 3 (1.5) 2 (1) 1 (<1) - - 1 (<1) Abnormal - - - - 3 (1.5) - Vision/Diplopia Thromboembolic Pulmonary Embolism 4 (2) 2 (1) 1 (<1) - - 1 (<1) Thrombophlebitis - 2 (1) 1 (<1) 1 (<1) 4 (2) 3 (1.5) Thrombosis - 1 (<1) 1 (<1) - 3 (1.5) 4 (2) CVA/TIA 1 (<1) - - 1 (<1) 4 (2) 4 (2) Elevated Liver Tests** AST 11 (5) 4 (2) 30 (19) 22 (15) 32 (15) 35 (17) Alkaline Phosphatase 41 (19) 24 (11) 16 (10) 13 (9) 18 (8) 31 (15) Bilirubin 3 (1.5) 4 (2) 2 (1) 1 (<1) 2 (1) 3 (1.5) Hypercalcemia 6 (3) 6 (3) 1 (<1) - - - * Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual ophthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: AST >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: AST, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal). Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. 6.2 Post-marketing Experience The following adverse reactions were identified during post approval use of FARESTON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge. Hepatototoxicity [see Warnings and Precautions (5.2)] Risk of Uterine Malignancy [see Warnings and Precautions (5.4)] Hypertriglyceridemia Reference ID: 5494543 5 7 DRUG INTERACTIONS 7.1 Drugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. Reference ID: 5494543 6 7.2 Agents that Prolong QT The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see Boxed Warning and Warnings and Precautions (5.1)]. 7.3 Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s Wort, lower the steady-state concentration of toremifene in serum. 7.4 Effect of Strong CYP3A4 Inhibitors on Toremifene In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively. N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning and Warnings and Precautions (5.1)]. 7.5 Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam Cmax and AUC were reduced by less than 20%. Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely. 7.6 Effect of Toremifene on CYP2C9 Substrates In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.6).] Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Reference ID: 5494543 7 In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies. Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo- fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly. Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits. In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis). Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol inutero. 8.2 Nursing Mothers It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARESTON, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use There is no indication for use of FARESTON in pediatric patients. 8.4 Geriatric Use The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted. 8.5 Renal Impairment The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. 8.6 Hepatic Impairment The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N­ demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. 8.7 Race The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in FARESTON effectiveness or safety were noted. 10 OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement. Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry Reference ID: 5494543 8 QO_ ri .. OCH.CH,<~ f",coai {H, r 0 . HO-,-COOH CH~I CH:iCOOH parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose- limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic. 11 DESCRIPTION FARESTON (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene. FARESTON is an estrogen agonist/antagonist. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro-1,2­ diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: and the molecular formula is C26H28ClNO • C6H8O7. The molecular weight of toremifene citrate is 598.10. The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCl at 37˚C is 0.38 mg/mL. FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. 12.2 Pharmacodynamics Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH). Effects on Cardiac Electrophysiology The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions (7.2)]. Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions (5.1)]. Table 1: QTc Prolongation in Healthy Male Volunteers Treatment Arm Mean (90% CI) ∆∆QTc, ms ∆QTc > 60 ms (n, %) QTc > 500 ms (n, %) Toremifene 20 mg (N = 47) 7 (0.9, 13.6) 0 0 Toremifene 80 mg (N = 47) 26 (21.1, 31.2) 2 (4.3%) 0 Toremifene 300 mg (N = 48) 65 (60.1, 69.2) 43 (89.6%) 5 (10.4%) Reference ID: 5494543 9 12.3 Pharmacokinetics Absorption – Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks. Distribution – Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin. Metabolism – Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto- induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies. Elimination – The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation. Renal insufficiency – The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function. Hepatic insufficiency – The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Geriatric patients – The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted. Food – The rate and extent of absorption of FARESTON are not influenced by food; thus FARESTON may be taken with or without food. Race – The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in FARESTON effectiveness or safety were noted. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment Reference ID: 5494543 10 at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks. 14 CLINICAL STUDIES Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of FARESTON for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen- receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table). Clinical Studies Study North Am erican Eastern Eur pean Nordic Treatment Group FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 No. Patients 221 215 157 149 214 201 Responses CR1 + PR2 14 + 33 11 + 30 7 + 25 3 + 28 19 + 48 19 + 56 RR3 (CR + PR)% 21.3 19.1 20.4 20.8 31.3 37.3 Difference in RR 2.2 -0.4 -6.0 95% CI4 for Difference in RR -5.8 to 10.2 -9.5 to 8.6 -15.1 to 3.1 Time to Progression (TTP) Median TTP (mo.) 5.6 5.8 4.9 5.0 7.3 10.2 Hazard Ratio (TAM/FAR) 95% CI4 for Hazard Ratio (%) 1.01 0.81 to 1.26 1.02 0.79 to 1.31 0.80 0.64 to 1.00 Survival (S) Median S (mo.) 33.6 34.0 25.4 23.4 33.0 38.7 Hazard Ratio (TAM/FAR) 95% CI4 for Hazard Ratio (%) 0.94 0.74 to 1.24 0.96 0.72 to 1.28 0.94 0.73 to 1.22 1CR = complete response; 2PR = partial response; 3RR = response rate; 4CI = confidence interval The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of 22.6% and 28.7%, median times to progression of 5.6 and 6.1 months, and median survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months). Reference ID: 5494543 11 16 SUPPLIED/STORAGE AND HANDLING FARESTON Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white. FARESTON Tablets are identified with TO 60 embossed on one side. FARESTON Tablets are available as: NDC 42747-327-30 bottles of 30 NDC 42747-327-72 samples of 7 Store at 25°C (77°F). Excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature.] Protect from heat and light. 17 PATIENT COUNSELING INFORMATION Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding or other gynecological symptoms (changes in vaginal discharge, pelvic pain or pressure) occur. Patients should have a gynecological examination prior to initiation of therapy and at regular intervals while on therapy. Liver disorders including transaminits grade 3 and 4, hyperbilirubinemia with jaundice have been reported in patients using FARESTON. Patients should have liver function tests performed periodically while on therapy. FARESTON may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. Premenopausal women using FARESTON should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur [see Warnings and Precautions (5.7)]. Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur. Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner [see Boxed Warning, Warnings and Precautions (5.1), and Clinical Pharmacology (12.2)]. Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during FARESTON treatment. Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s Wort) and toremifene, can reduce concentrations of co-administered drugs [see Drug Interactions (7.3)]. Distributed by: Kyowa Kirin, Inc. Princeton, NJ 08540 Product covered by Orion Product Patents and related patent numbers © 2023 Kyowa Kirin, Inc. All rights reserved. Reference ID: 5494543 12
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2025-02-12T15:47:43.738461
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ORKAMBI safely and effectively. See full prescribing information for ORKAMBI. -------------------------------CONTRAINDICATIONS-----------------------------­  None. (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ ORKAMBI® (lumacaftor and ivacaftor) tablets, for oral use ORKAMBI® (lumacaftor and ivacaftor) oral granules Initial U.S. Approval: 2015 ----------------------------INDICATIONS AND USAGE--------------------------­ ORKAMBI is a combination of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, and lumacaftor, indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. (1) Limitations of Use: The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation. (1) ----------------------DOSAGE AND ADMINISTRATION----------------------­ Age Group Weight Dose 7 kg to <9 kg 1 packet of lumacaftor 75 mg/ivacaftor 94 mg granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg granules 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) 1 through 2 years 9 kg to <14 kg ≥14 kg 2 through 5 years <14 kg ≥14 kg 6 through 11 years - 12 years and older - Administration Mixed with one teaspoon (5 mL) of soft food or liquid and administered orally every 12 hours with fat- containing food Taken orally every 12 hours with fat- containing food  Reduce dosage in patients with moderate or severe hepatic impairment. (2.2, 8.6, 12.3)  When initiating ORKAMBI in patients taking strong CYP3A inhibitors, reduce ORKAMBI dosage for the first week of treatment. (2.3, 7.1, 12.3) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­  Tablets: lumacaftor 100 mg and ivacaftor 125 mg; lumacaftor 200 mg and ivacaftor 125 mg. (3)  Oral granules: Unit-dose packets of lumacaftor 75 mg and ivacaftor 94 mg; lumacaftor 100 mg and ivacaftor 125 mg; lumacaftor 150 mg and ivacaftor 188 mg. (3)  Use in patients with advanced liver disease: ORKAMBI should be used with caution in these patients and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dosage should be reduced. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre­ existing cirrhosis with portal hypertension. (2.2, 5.1, 6.1)  Liver-related events: Elevated transaminases (ALT/AST) have been observed in some cases associated with elevated bilirubin. Measure serum transaminases and bilirubin before initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Interrupt dosing in patients with ALT or AST >5 x upper limit of normal (ULN), or ALT or AST >3 x ULN with bilirubin >2 x ULN. Following resolution, consider the benefits and risks of resuming dosing. (5.2, 6.1)  Hypersensitivity reactions: Angioedema and anaphylaxis have been reported with ORKAMBI in the postmarketing setting. Initiate appropriate therapy in the event of a hypersensitivity reaction. (5.3)  Respiratory events: Chest discomfort, dyspnea, and respiration abnormal were observed more commonly during initiation of ORKAMBI. Clinical experience in patients with percent predicted FEV1 (ppFEV1) <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy. (5.4, 6.1)  Blood pressure: Increased blood pressure has been observed in some patients. Periodically monitor blood pressure in all patients. (5.5, 6.1)  Drug interactions: Use with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index may decrease systemic exposure of the medicinal products and co-administration is not recommended. Hormonal contraceptives should not be relied upon as an effective method of contraception and their use is associated with increased menstruation-related adverse reactions. Use with strong CYP3A inducers may diminish exposure of ivacaftor, which may diminish its effectiveness; therefore, co-administration is not recommended. (5.6, 6.1, 7, 12.3)  Cataracts: Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Baseline and follow-up examinations are recommended in pediatric patients initiating ORKAMBI. (5.7) ------------------------------ADVERSE REACTIONS------------------------------­ The most common adverse reactions to ORKAMBI (occurring in ≥5% of patients with CF homozygous for the F508del mutation in the CFTR gene) were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, influenza. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA­ 1088 or www.fda.gov/medwatch. -----------------------------DRUG INTERACTIONS------------------------------­ See Full Prescribing Information for a complete list. (2.3, 7, 12.3) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Adults and Pediatric Patients Aged 1 Year and Older 2.2 Dosage Adjustment for Patients with Hepatic Impairment 2.3 Dosage Adjustment for Patients Taking CYP3A Inhibitors 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Use in Patients with Advanced Liver Disease 5.2 Liver-related Events 5.3 Hypersensitivity Reactions, Including Anaphylaxis 5.4 Respiratory Events 5.5 Effect on Blood Pressure 5.6 Drug Interactions 5.7 Cataracts 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Inhibitors of CYP3A 7.2 Inducers of CYP3A 7.3 CYP3A Substrates 7.4 CYP2B6 and CYP2C Substrates 7.5 Digoxin and Other P-gp Substrates 7.6 Anti-allergics and Systemic Corticosteroids 7.7 Antibiotics 7.8 Antifungals 7.9 Anti-inflammatories 7.10 Antidepressants 7.11 Hormonal Contraceptives 1 Reference ID: 5495367 8 7.12 Oral Hypoglycemics 7.13 Proton Pump Inhibitors, H2 Blockers, Antacids 7.14 Warfarin 7.15 Concomitant Drugs That Do Not Need Dosage Adjustment USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 8.8 Patients with Severe Lung Dysfunction 8.9 Patients After Organ Transplantation 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 2 Reference ID: 5495367 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE ORKAMBI is indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. Limitations of Use The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Adults and Pediatric Patients Aged 1 Year and Older The recommended dosage of ORKAMBI in adults and pediatric patients aged one year and older is based on patient’s age and weight as described in Table 1. Evening Dose Table 1: Recommended Oral Dosage of ORKAMBI in Patients Aged 1 Year and Older Age Group Weight ORKAMBI Daily Dose (every 12 hours) Morning Dose 1 through 2 years 7 kg to <9 kg 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules 9 kg to <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules ≥14 kg 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 2 through 5 years <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules ≥14 kg 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 6 through 11 years - 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) 12 years and older - 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) Administration Instructions for ORKAMBI Oral Granules The entire content of each packet of oral granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and the mixture completely consumed. Some examples of soft foods or liquids include puréed fruits or vegetables, flavored yogurt or pudding, applesauce, water, milk, breast milk, infant formula or juice. Food should be at room temperature or below. Each packet is for single use only. Once mixed, the product has been shown to be stable for one hour, and therefore should be ingested during this period. Administration with Fat-Containing Food for ORKAMBI Tablets and Oral Granules A fat-containing meal or snack should be consumed just before or just after dosing for all formulations. Examples of appropriate fat-containing foods include eggs, avocados, nuts, butter, peanut butter, cheese pizza, breast milk, infant formula, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc. Missed Dose If a patient misses a dose and remembers the missed dose within 6 hours, the patient should take the dose with fat-containing food. If more than 6 hours elapsed after the recommended dosing time, the patient should skip that dose and resume the normal schedule for the following dose. A double dose should not be taken to make up for the forgotten dose [see Clinical Pharmacology (12.3) and Patient Counseling Information (17)]. 2.2 Dosage Adjustment for Patients with Hepatic Impairment For dosage adjustment for patients with hepatic impairment, refer to Table 2. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening or less frequently, or 1 packet of oral granules once daily or less frequently in patients with severe hepatic impairment after weighing the risks and benefits of treatment [see Dosage and Administration (2.1), Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. Evening Dose 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 1 packet of lumacaftor 150 mg/ivacaftor 188 mg Table 2: Recommended Dosage for Patients with Hepatic Impairment Age Group Weight Morning Dose Mild (Child-Pugh Class A) 1 through 2 years 7 kg to <9 kg 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral granules 9 kg to <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules ≥14 kg 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 2 through 5 years <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules ≥14 kg 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral granules 6 through 11 years - 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) 12 years and older - 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) oral granules 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) Moderate (Child­ 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral 1 through 2 years 7 kg to <9 kg Pugh Class B) granules granules every other day 3 Reference ID: 5495367 9 kg to <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 2 through 5 years <14 kg 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules every other day 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral 1 packet of lumacaftor 150 mg/ivacaftor 188 mg ≥14 kg granules oral granules every other day 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral granules every other day 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral 1 packet of lumacaftor 150 mg/ivacaftor 188 mg ≥14 kg granules oral granules every other day 1 tablet of lumacaftor 100 mg/ivacaftor 125 mg 2 tablets of lumacaftor 200 mg/ivacaftor 125 mg 12 years and older - 1 tablet of lumacaftor 200 mg/ivacaftor 125 mg (lumacaftor 400 mg/ivacaftor 250 mg per dose) 1 packet of lumacaftor 75 mg/ivacaftor 94 mg oral 7 kg to <9 kg granules* 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral 1 through 2 years 9 kg to <14 kg granules* 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral ≥14 kg N/A granules* Severe (Child- Pugh Class C) 1 packet of lumacaftor 100 mg/ivacaftor 125 mg oral <14 kg granules* 2 through 5 years 1 packet of lumacaftor 150 mg/ivacaftor 188 mg oral ≥14 kg granules* 6 through 11 years - 1 tablet of lumacaftor 100 mg/ivacaftor 125 mg * 1 tablet of lumacaftor 100 mg/ivacaftor 125 mg * 12 years and older - 1 tablet of lumacaftor 200 mg/ivacaftor 125 mg * 1 tablet of lumacaftor 200 mg/ivacaftor 125 mg * 2.3 Dosage Adjustment for Patients Taking CYP3A Inhibitors No dosage adjustment is necessary when CYP3A inhibitors are initiated in patients already taking ORKAMBI. However, when initiating ORKAMBI in patients currently taking strong CYP3A inhibitors, reduce the ORKAMBI dosage for the first week of treatment based on age as follows [see Dosage and Administration (2.1) and Drug Interactions (7.1)]:  1 through 5 years of age: 1 packet of granules every other day  6 years of age and older: 1 tablet daily Following this one-week period, resume the recommended daily dosage. If ORKAMBI is interrupted for more than one-week and then re-initiated while taking strong CYP3A inhibitors, reduce the ORKAMBI dosage for the first week of treatment re-initiation based on age as follows:  1 through 5 years of age: 1 packet of granules every other day  6 years of age and older: 1 tablet daily Following this one-week period, resume the recommended daily dosage. 3 DOSAGE FORMS AND STRENGTHS  Tablets: 100 mg lumacaftor and 125 mg ivacaftor; supplied as pink, oval-shaped, film-coated, fixed-dose combination tablets containing 100 mg of lumacaftor and 125 mg of ivacaftor. Each tablet is printed with the characters “1V125” in black ink on one side and plain on the other.  Tablets: 200 mg lumacaftor and 125 mg ivacaftor; supplied as pink, oval-shaped, film-coated, fixed-dose combination tablets containing 200 mg of lumacaftor and 125 mg of ivacaftor. Each tablet is printed with the characters “2V125” in black ink on one side and plain on the other.  Oral granules: Unit-dose packets containing lumacaftor 75 mg/ivacaftor 94 mg or lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg per packet; supplied as small, white to off-white granules in unit-dose packets. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Use in Patients with Advanced Liver Disease Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI. Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dosage should be reduced [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.2 Liver-related Events Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin. It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST >5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations >3 x ULN when associated with bilirubin elevations >2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing [see Adverse Reactions (6.1)]. 6 through 11 years - 2 tablets of lumacaftor 100 mg/ivacaftor 125 mg (lumacaftor 200 mg/ivacaftor 250 mg per dose) * or less frequently. 4 Reference ID: 5495367 5.3 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting [see Adverse Reactions (6.2)]. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue ORKAMBI and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ORKAMBI. 5.4 Respiratory Events Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI compared to those who received placebo. These events have led to drug discontinuation and can be serious, particularly in patients with advanced lung disease (percent predicted FEV1 <40). Clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy [see Adverse Reactions (6.1)]. 5.5 Effect on Blood Pressure Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI [see Adverse Reactions (6.1)]. 5.6 Drug Interactions Substrates of CYP3A Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended. ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular (27% in women using hormonal contraceptives compared with 3% in women not using hormonal contraceptives). Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI [see Adverse Reactions (6.1), Drug Interactions (7.3, 7.11), and Clinical Pharmacology (12.3)]. Strong CYP3A Inducers Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers (e.g., rifampin, St. John’s wort [Hypericum perforatum]) is not recommended [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. 5.7 Cataracts Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded [see Use in Specific Populations (8.4)]. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating ORKAMBI treatment. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label:  Use in Patients with Advanced Liver Disease [see Warnings and Precautions (5.1)]  Liver-related Events [see Warnings and Precautions (5.2)]  Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.3)]  Respiratory Events [see Warnings and Precautions (5.4)]  Effect on Blood Pressure [see Warnings and Precautions (5.5)]  Cataracts [see Warnings and Precautions (5.7)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The overall safety profile of ORKAMBI is based on the pooled data from 1108 patients with CF aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene and who received at least one dose of study drug in two double-blind, placebo-controlled, Phase 3 clinical trials, each with 24 weeks of treatment (Trials 1 and 2). In addition, the following clinical trials have been conducted:  A 24-week, open-label trial (Trial 3) in 58 patients with CF aged 6 through 11 years homozygous for the F508del-CFTR mutation.  A 24-week, placebo-controlled trial (Trial 4) in 204 patients aged 6 through 11 years homozygous for the F508del-CFTR mutation.  A 24-week, open-label trial (Trial 5) in 46 patients aged 12 years and older homozygous for the F508del-CFTR mutation and with advanced lung disease (ppFEV1 <40).  A 24-week, open-label trial (Trial 6) in 60 patients aged 2 through 5 years homozygous for the F508del-CFTR mutation.  A 24-week, open-label trial (Trial 7) in 46 patients aged 1 through 2 years homozygous for the F508del-CFTR mutation. Of the 1108 patients, in the pooled analyses of Trial 1 and Trial 2, 49% were female and 99% were Caucasian; 369 patients received ORKAMBI every 12 hours and 370 patients received placebo. The proportion of patients who prematurely discontinued study drug due to adverse events was 5% for patients treated with ORKAMBI and 2% for patients who received placebo. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients. Table 3 shows adverse reactions occurring in ≥5% of patients with CF aged 12 years and older treated with ORKAMBI who are homozygous for the F508del mutation in the CFTR gene that also occurred at a higher rate than in patients who received placebo in the two double-blind, placebo-controlled trials. 5 Reference ID: 5495367 Table 3: Incidence of Adverse Drug Reactions in ≥5% of ORKAMBI-Treated Patients Aged 12 Years and Older Who are Homozygous for the F508del Mutation in the CFTR Gene in 2 Placebo-Controlled Phase 3 Clinical Trials of 24 Weeks Duration Adverse Reaction ORKAMBI Placebo (Preferred Term) N=369 N=370 (%) (%) Dyspnea 48 (13) 29 (8) Nasopharyngitis 48 (13) 40 (11) Nausea 46 (13) 28 (8) Diarrhea 45 (12) 31 (8) Upper respiratory tract infection 37 (10) 20 (5) Fatigue 34 (9) 29 (8) Respiration abnormal 32 (9) 22 (6) Blood creatine phosphokinase increased 27 (7) 20 (5) Rash 25 (7) 7 (2) Flatulence 24 (7) 11 (3) Rhinorrhea 21 (6) 15 (4) Influenza 19 (5) 8 (2) The safety profile from two pediatric trials in CF patients aged 6 through 11 years who are homozygous for the F508del-CFTR mutation, a 24-week, open-label, multicenter safety trial in 58 patients (Trial 3) and a 24-week, placebo-controlled, clinical trial (Trial 4) in 204 patients (103 received lumacaftor 200 mg/ivacaftor 250 mg every 12 hours and 101 received placebo), was similar to that observed in Trials 1 and 2. Adverse reactions that are not listed in Table 3, and that occurred in ≥5% of lumacaftor/ivacaftor-treated patients with an incidence of ≥3% higher than placebo included: productive cough (17.5% vs 5.9%), nasal congestion (16.5% vs 7.9%), headache (12.6% vs 8.9%), abdominal pain upper (12.6% vs 6.9%), and sputum increased (10.7% vs 2.0%). In a 24-week, open-label, multicenter, study in 60 patients aged 2 through 5 years with CF who were homozygous for the F508del-CFTR mutation (Trial 6) the safety profile was similar to that observed in studies in patients aged 6 years and older [see Clinical Pharmacology (12.2)]. In a 24-week, open-label, multicenter, study in 46 patients aged 1 through 2 years with CF who were homozygous for the F508del-CFTR mutation (Trial 7) the safety profile was similar to that observed in studies in patients aged 2 years and older [see Clinical Pharmacology (12.2)]. Additional information on selected adverse reactions from trials is detailed below: Description of Selected Adverse Drug Reactions Liver-related Adverse Reactions In Trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN elevations were similar between patients treated with ORKAMBI and those who received placebo. Three patients who received ORKAMBI had liver-related serious adverse reactions, including two reported as transaminase elevations and one as hepatic encephalopathy, compared to none in the placebo group. Of these three, one had elevated transaminases (>3 x ULN) associated with bilirubin elevation >2 x ULN. Following discontinuation or interruption of ORKAMBI, transaminases decreased to <3 x ULN. Among six patients with pre-existing cirrhosis and/or portal hypertension who received ORKAMBI, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The event occurred within five days of the start of dosing and resolved following discontinuation of ORKAMBI [see Warnings and Precautions (5.1, 5.2)]. During the 24-week, open-label, clinical trial in 58 patients aged 6 through 11 years (Trial 3), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 5%, 9%, and 19%. No patients had total bilirubin levels >2 x ULN. Lumacaftor/ivacaftor dosing was maintained or successfully resumed after interruption in all patients with transaminase elevations, except one patient who discontinued treatment permanently. During the 24-week, placebo-controlled, clinical trial in 204 patients aged 6 through 11 years (Trial 4), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 1%, 5%, and 13% in the lumacaftor/ivacaftor patients, and 2%, 3%, and 8% in the placebo-treated patients. No patients had total bilirubin levels >2 x ULN. Two patients in the lumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment permanently due to transaminase elevations. During the 24-week, open-label, clinical trial in 60 patients aged 2 through 5 years (Trial 6), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 8.3% (5/60), 11.7% (7/60), and 15.0% (9/60). No patients had total bilirubin levels >2 x ULN. Three patients discontinued lumacaftor/ivacaftor treatment permanently due to transaminase elevations. During the 24-week, open-label, clinical trial in 46 patients aged 1 through 2 years (Trial 7), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 2.2% (1/46), 4.3% (2/46), and 10.9% (5/46), respectively. No patients had total bilirubin levels >2 x ULN. One patient discontinued lumacaftor/ivacaftor treatment permanently due to transaminase elevations. Respiratory Adverse Reactions In Trials 1 and 2, the incidence of respiratory symptom-related adverse reactions (e.g., chest discomfort, dyspnea, and respiration abnormal) was more common in patients treated with ORKAMBI (22%) compared to patients who received placebo (14%). The incidence of these adverse reactions was more common in patients treated with ORKAMBI with lower pre-treatment FEV1. In patients treated with ORKAMBI, the majority of the events began during the first week of treatment [see Warnings and Precautions (5.4)]. During the 24-week, open-label, clinical trial in 46 patients aged 12 years and older (Trial 5) with advanced lung disease (ppFEV1<40) [mean ppFEV129.1 at baseline (range: 18.3 to 42.0)], the incidence of respiratory symptom-related adverse reactions was 65% [see Warnings and Precautions (5.4)]. During the 24-week, open-label, clinical trial (Trial 3) in 58 patients aged 6 through 11 years (mean baseline ppFEV1 was 91.4), the incidence of respiratory symptom-related adverse reactions was 3% (2/58). 6 Reference ID: 5495367 During the 24-week, placebo-controlled, clinical trial (Trial 4) in patients aged 6 through 11 years [mean ppFEV1 89.8 at baseline (range: 48.6 to 119.6)], the incidence of respiratory symptom-related adverse reactions was 11% in lumacaftor/ivacaftor patients and 9% in placebo patients. A decline in ppFEV1 at initiation of therapy was observed during serial post-dose spirometry assessments. The absolute change from pre-dose at 4-6 hours post-dose was -7.7 on Day 1 and -1.3 on Day 15 in lumacaftor/ivacaftor patients. The post-dose decline was resolved by Week 16. Menstrual Abnormalities In Trials 1 and 2, the incidence of combined menstrual abnormality adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular) was more common in female patients treated with ORKAMBI (10%) compared to placebo (2%). These events occurred more frequently in the subset of female patients treated with ORKAMBI who were using hormonal contraceptives (27%) compared to those not using hormonal contraceptives (3%) [see Warnings and Precautions (5.6) and Drug Interactions (7.11)]. Increased Blood Pressure In Trials 1 and 2, adverse reactions related to increases in blood pressure (e.g., hypertension, blood pressure increased) were reported in 1.1% (4/369) of patients treated with ORKAMBI and in no patients who received placebo. The proportion of patients who experienced a systolic blood pressure value >140 mmHg or a diastolic blood pressure >90 mmHg on at least two occasions was 3.6% and 2.2% in patients treated with ORKAMBI, respectively, compared with 1.6% and 0.5% in patients who received placebo [see Warnings and Precautions (5.5)]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ORKAMBI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary: liver function decompensation including liver failure leading to death in patients with pre-existing cirrhosis with portal hypertension [see Warnings and Precautions (5.1)]. Immune system disorders: anaphylaxis, angioedema 7 DRUG INTERACTIONS Potential for Other Drugs to Affect Lumacaftor/Ivacaftor 7.1 Inhibitors of CYP3A Co-administration of lumacaftor/ivacaftor with itraconazole, a strong CYP3A inhibitor, did not impact the exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of lumacaftor on CYP3A, at steady-state, the net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours (the approved dose of ivacaftor monotherapy). Therefore, no dosage adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking ORKAMBI. However, when initiating ORKAMBI in patients taking strong CYP3A inhibitors, reduce the ORKAMBI dosage as recommended for the first week of treatment to allow for the steady-state induction effect of lumacaftor. Following this period, continue with the recommended daily dose [see Dosage and Administration (2.3)]. Examples of strong CYP3A inhibitors include:  ketoconazole, itraconazole, posaconazole, and voriconazole.  telithromycin, clarithromycin. No dosage adjustment is recommended when used with moderate or weak CYP3A inhibitors. 7.2 Inducers of CYP3A Co-administration of lumacaftor/ivacaftor with rifampin, a strong CYP3A inducer, had minimal effect on the exposure of lumacaftor, but decreased ivacaftor exposure (AUC) by 57%. This may reduce the effectiveness of ORKAMBI. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum), is not recommended [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. No dosage adjustment is recommended when used with moderate or weak CYP3A inducers. Potential for Lumacaftor/Ivacaftor to Affect Other Drugs 7.3 CYP3A Substrates Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by approximately 80%. Administration of ORKAMBI may decrease systemic exposure of medicinal products which are substrates of CYP3A, thereby decreasing the therapeutic effect of the medicinal product. Co-administration of ORKAMBI is not recommended with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)] such as:  Benzodiazepines: midazolam, triazolam (consider an alternative to these benzodiazepines).  Immunosuppressants: cyclosporine, everolimus, sirolimus, and tacrolimus (avoid the use of ORKAMBI). 7.4 CYP2B6 and CYP2C Substrates In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of ORKAMBI with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates. 7.5 Digoxin and Other P-gp Substrates Based on in vitro results which showed P-gp inhibition and pregnane-X-receptor (PXR) activation, lumacaftor has the potential to both inhibit and induce P-gp. Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of ORKAMBI with P-gp substrates may alter the exposure of these substrates. Monitor the serum concentration of digoxin and titrate the digoxin dose to obtain the desired clinical effect. 7.6 Anti-allergics and Systemic Corticosteroids ORKAMBI may decrease the exposure of montelukast, which may reduce its efficacy. No dosage adjustment for montelukast is recommended. Employ appropriate clinical monitoring, as is reasonable, when co-administered with ORKAMBI. Concomitant use of ORKAMBI may reduce the exposure and effectiveness of prednisone and methylprednisolone. A higher dose of these systemic corticosteroids may be required to obtain the desired clinical effect. 7 Reference ID: 5495367 7.7 Antibiotics Concomitant use of ORKAMBI may decrease the exposure of clarithromycin, erythromycin, and telithromycin, which may reduce the effectiveness of these antibiotics. Consider an alternative to these antibiotics, such as ciprofloxacin, azithromycin, and levofloxacin. 7.8 Antifungals Concomitant use of ORKAMBI may reduce the exposure and effectiveness of itraconazole, ketoconazole, posaconazole, and voriconazole. Concomitant use of ORKAMBI with these antifungals is not recommended. Monitor patients closely for breakthrough fungal infections if such drugs are necessary. Consider an alternative such as fluconazole. 7.9 Anti-inflammatories Concomitant use of ORKAMBI may reduce the exposure and effectiveness of ibuprofen. A higher dose of ibuprofen may be required to obtain the desired clinical effect. 7.10 Antidepressants Concomitant use of ORKAMBI may reduce the exposure and effectiveness of citalopram, escitalopram, and sertraline. A higher dose of these antidepressants may be required to obtain the desired clinical effect. 7.11 Hormonal Contraceptives ORKAMBI may decrease hormonal contraceptive exposure, reducing the effectiveness. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI. Concomitant use of ORKAMBI with hormonal contraceptives increased the menstrual abnormality events [see Adverse Reactions (6.1)]. Avoid concomitant use unless the benefit outweighs the risks. 7.12 Oral Hypoglycemics Concomitant use of ORKAMBI may reduce the exposure and effectiveness of repaglinide and may alter the exposure of sulfonylurea. A dosage adjustment may be required to obtain the desired clinical effect. No dosage adjustment is recommended for metformin. 7.13 Proton Pump Inhibitors, H2 Blockers, Antacids ORKAMBI may reduce the exposure and effectiveness of proton pump inhibitors such as omeprazole, esomeprazole, and lansoprazole, and may alter the exposure of ranitidine. A dose adjustment may be required to obtain the desired clinical effect. No dose adjustment is recommended for calcium carbonate antacid. 7.14 Warfarin ORKAMBI may alter the exposure of warfarin. Monitor the international normalized ratio (INR) when warfarin co-administration with ORKAMBI is required. 7.15 Concomitant Drugs That Do Not Need Dosage Adjustment No dosage adjustment of ORKAMBI or concomitant drug is recommended when ORKAMBI is given with the following: azithromycin, aztreonam, budesonide, ceftazidime, cetirizine, ciprofloxacin, colistimethate, colistin, dornase alfa, fluticasone, ipratropium, levofloxacin, pancreatin, pancrelipase, salbutamol, salmeterol, sulfamethoxazole, trimethoprim, tiotropium, and tobramycin. Based on the metabolism and route of elimination, ORKAMBI is not expected to impact the exposure of these drugs. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are limited and incomplete human data from clinical trials and postmarketing reports on use of ORKAMBI or its individual components, lumacaftor or ivacaftor, in pregnant women to inform a drug-associated risk. In animal reproduction studies, oral administration of lumacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse effects on fetal development at doses that produced maternal exposures up to approximately 8 (rats) and 5 (rabbits) times the exposure at the maximum recommended human dose (MRHD). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse effects on fetal development at doses that produced maternal exposures up to approximately 7 (rats) and 45 (rabbits) times the exposure at the MRHD. No adverse developmental effects were observed after oral administration of either lumacaftor or ivacaftor to pregnant rats from organogenesis through lactation at doses that produced maternal exposures approximately 8 and 5 times the exposures at the MRHD, respectively (see Data). There are no animal reproduction studies with concomitant administration of lumacaftor and ivacaftor. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Lumacaftor In an embryo-fetal development (EFD) study, pregnant rats were administered lumacaftor at oral doses of 500, 1000, or 2000 mg/kg/day during the period of organogenesis from gestation days 7-17. Lumacaftor did not affect fetal development or survival at exposures up to 8 times the MRHD (on an AUC basis at maternal oral doses up to 2000 mg/kg/day). In an EFD study, pregnant rabbits were administered lumacaftor at oral doses of 50, 100, or 200 mg/kg/day during the period of organogenesis from gestation days 7-19. Lumacaftor did not affect fetal development or survival at exposures up to 5 times the MRHD (on an AUC basis at maternal oral doses up to 200 mg/kg/day). Maternal toxicity as evidenced by decreased body weight, decreased food consumption, and clinical signs was observed at 100 and 200 mg/kg/day without any adverse fetal effects. In a pre- and post-natal development study in pregnant female rats administered lumacaftor at 250, 500, or 1000 mg/kg/day from gestation day 6 through lactation day 20, lumacaftor had no effects on delivery or growth and development of offspring at exposures up to 8 times the MRHD (on an AUC basis at maternal oral doses up to 1000 mg/kg/day). Placental transfer of lumacaftor was observed in pregnant rats and rabbits. Ivacaftor In an EFD study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day during the period of organogenesis from gestation days 7-17. Ivacaftor did not affect fetal survival at exposures up to 7 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 200 mg/kg/day). Maternal toxicity (i.e., decreased mean body weight and body weight gain) was observed at 100 and 200 mg/kg/day (5 and 7 times the exposure at the MRHD, respectively) and was associated with a decrease in fetal body weights at a maternal dose of 200 mg/kg/day (7 times the MRHD). In an EFD study, pregnant rabbits were administered ivacaftor at oral doses of 25, 50, or 100 mg/kg/day during the period of organogenesis from gestation days 7-19. Ivacaftor did not affect fetal development or survival at exposures up to 45 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). Maternal toxicity (i.e., death, decreased food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was observed at doses greater than or equal to 50 mg/kg/day (approximately 15 times the MRHD). In a pre- and post-natal development study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day from gestation day 7 through lactation day 20. Ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a 8 Reference ID: 5495367 maternally toxic dose that produced exposures 7 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). Placental transfer of ivacaftor was observed in pregnant rats and rabbits. 8.2 Lactation Risk Summary There is no information regarding the presence of lumacaftor or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Both lumacaftor and ivacaftor are excreted into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ORKAMBI and any potential adverse effects on the breastfed child from ORKAMBI or from the underlying maternal condition. Data Lumacaftor Lacteal excretion of lumacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-lumacaftor administered 9 to 11 days postpartum to lactating mothers (dams). Exposure (AUC0-24h) values for lumacaftor in milk were approximately 40% of plasma levels. Ivacaftor Lacteal excretion of ivacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-ivacaftor administered 9 to 10 days postpartum to lactating mothers (dams). Exposure (AUC0-24h) values for ivacaftor in milk were approximately 1.5 times higher than plasma levels. 8.3 Females and Males of Reproductive Potential ORKAMBI may decrease hormonal contraceptive exposure, reducing the effectiveness. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI [see Warnings and Precautions (5.6) and Drug Interactions (7.11)]. 8.4 Pediatric Use The safety and effectiveness of ORKAMBI in pediatric patients aged one year and older have been established. Use of ORKAMBI in these age groups is supported by evidence from adequate and well-controlled studies of ORKAMBI in patients aged 12 years and older [see Clinical Studies (14) and Adverse Reactions (6.1)] with additional data as follows:  Extrapolation of efficacy in patients aged 12 years and older homozygous for the F508del mutation in the CFTR gene to pediatric patients aged 1 through 11 years with support from population pharmacokinetic analyses showing similar drug exposure levels in patients aged 12 years and older and in patients aged 1 through 11 years [see Clinical Pharmacology (12.3)].  Safety data were obtained from a 24-week, open-label, clinical trial in 58 patients aged 6 through 11 years, mean age 9 years (Trial 3) and a 24-week, placebo- controlled, clinical trial in 204 patients aged 6 through 11 years (Trial 4). Trial 3 evaluated subjects with a screening ppFEV1 ≥40 [mean ppFEV1 91.4 at baseline (range: 55 to 122.7)]. Trial 4 evaluated subjects with a screening ppFEV1 ≥70 [mean ppFEV1 89.8 at baseline (range: 48.6 to 119.6)]. The safety profile of ORKAMBI in pediatric patients 6 through 11 years of age was similar to that in patients aged 12 years and older [see Adverse Reactions (6.1)]. In Trial 3, spirometry (ppFEV1) was assessed as a planned safety endpoint. The within-group LS mean absolute change from baseline in ppFEV1 at Week 24 was 2.5 percentage points. At the Week 26 safety follow-up visit (following a planned discontinuation) ppFEV1 was also assessed. The within-group LS mean absolute change in ppFEV1 from Week 24 at Week 26 was -3.2 percentage points.  Additional safety data were obtained from Trial 6, a 24-week, open-label, clinical trial in 60 patients aged 2 through 5 years at screening (mean age at baseline 3.7 years). The safety profile in Trial 6 was similar to that in patients aged 6 years and older [see Adverse Reactions (6.1)].  Additional safety data were obtained from Trial 7, a 24-week, open-label, clinical trial in 46 patients aged 1 to 2 years at screening (mean age at baseline 18.1 months). The safety profile in Trial 7 was similar to that in patients aged 2 years and older [see Adverse Reactions (6.1)].  Safety was evaluated in a 96-week open-label clinical trial (Trial 8) in 52 patients (39 rolled over from Trial 7 and 13 ORKAMBI naïve) aged 1 to 2 years. Adverse reactions from trial 8 were generally similar to those reported in Trial 7. The safety and effectiveness of ORKAMBI in patients with CF younger than 1 year of age have not been established. Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded [see Warnings and Precautions (5.7)]. Juvenile Animal Toxicity Data In a juvenile toxicology study in which ivacaftor was administered to rats from post-natal days 7 to 35, cataracts were observed at all dose levels, ranging from 0.3 to 2 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at oral doses of 10-50 mg/kg/day). This finding has not been observed in older animals. 8.5 Geriatric Use CF is largely a disease of children and young adults. Clinical trials of ORKAMBI did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment No dosage adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A dose reduction to 2 tablets in the morning and 1 tablet in the evening is recommended for patients aged 6 years and older with moderate hepatic impairment (Child-Pugh Class B). A dose reduction to 1 packet of oral granules in the morning daily and 1 packet of oral granules in the evening every other day is recommended for patients aged 1 to 5 years old with moderate hepatic impairment (Child-Pugh Class B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening or less frequently, or 1 packet of oral granules once daily or less frequently in patients with severe hepatic impairment after weighing the risks and benefits of treatment [see Warnings and Precautions (5.1), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Patient Counseling Information (17)]. 8.7 Renal Impairment ORKAMBI has not been studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease. No dosage adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended while using ORKAMBI in patients with severe renal impairment (creatinine clearance ≤30 mL/min) or end-stage renal disease. 8.8 Patients with Severe Lung Dysfunction The Phase 3 trials (Trials 1 and 2 [see Clinical Studies (14)]) included 29 patients receiving ORKAMBI with ppFEV1 <40 at baseline. The treatment effect in this subgroup was comparable to that observed in patients with ppFEV1 ≥40. 9 Reference ID: 5495367 8.9 Patients After Organ Transplantation ORKAMBI has not been studied in patients with CF who have undergone organ transplantation. Use in transplanted patients is not recommended due to potential drug-drug interactions [see Drug Interactions (7.3)]. 10 OVERDOSAGE There have been no reports of overdose with ORKAMBI. The highest repeated dose was lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h administered to 49 healthy subjects for 7 days in a trial evaluating the effect of ORKAMBI on electrocardiograms (ECGs). Adverse events reported at an increased incidence of ≥5% compared to the lumacaftor 600 mg/ivacaftor 250 mg dosing period and placebo included: headache (29%), transaminase increased (18%), and generalized rash (10%). No specific antidote is available for overdose with ORKAMBI. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. 11 DESCRIPTION The active ingredients in ORKAMBI tablets are lumacaftor, which has the following chemical name: 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5­ yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, and ivacaftor, a CFTR potentiator, which has the following chemical name: N-(2,4-di-tert­ butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. The molecular formula for lumacaftor is C24H18F2N2O5 and for ivacaftor is C24H28N2O3. The molecular weights for lumacaftor and ivacaftor are 452.41 and 392.49, respectively. The structural formulas are: lumacaftor ivacaftor Lumacaftor is a white to off-white powder that is practically insoluble in water (0.02 mg/mL). Ivacaftor is a white to off-white powder that is practically insoluble in water (<0.05 µg/mL). ORKAMBI is available as a pink, oval-shaped, film-coated tablet for oral administration containing 200 mg of lumacaftor and 125 mg of ivacaftor. Each ORKAMBI tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor, and the following inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac. ORKAMBI is also available as a pink, oval-shaped, film-coated tablet for oral administration containing 100 mg of lumacaftor and 125 mg of ivacaftor. Each ORKAMBI tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor, and the following inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac. ORKAMBI is also available as white to off-white granules for oral administration and enclosed in a unit-dose packet containing lumacaftor 75 mg/ivacaftor 94 mg, lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg per packet. Each unit-dose packet of ORKAMBI oral granules contains lumacaftor 75 mg/ivacaftor 94 mg, lumacaftor 100 mg/ivacaftor 125 mg or lumacaftor 150 mg/ivacaftor 188 mg per packet and the following inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; povidone; and sodium lauryl sulfate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation results in protein misfolding, causing a defect in cellular processing and trafficking that targets the protein for degradation and therefore reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface is less stable and has low channel-open probability (defective gating activity) compared to wild-type CFTR protein. Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport. In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit. 12.2 Pharmacodynamics Sweat Chloride Evaluation Changes in sweat chloride in response to relevant doses of lumacaftor alone or in combination with ivacaftor were evaluated in a double-blind, placebo-controlled, Phase 2 clinical trial in patients with CF aged 18 years and older either homozygous or heterozygous for the F508del mutation. In that trial, 10 patients (homozygous for F508del) completed dosing with lumacaftor alone 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h for an additional 28 days and 25 10 Reference ID: 5495367 patients (homozygous or heterozygous for F508del) completed dosing with placebo. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as mean change in sweat chloride from baseline to Day 28 compared to placebo was -8.2 mmol/L (95% CI: -14, -2). The treatment difference between the combination of lumacaftor 400 mg/ivacaftor 250 mg q12h and placebo evaluated as mean change in sweat chloride from baseline to Day 56 compared to placebo was -11 mmol/L (95% CI: -18, -4). Changes in sweat chloride in response to lumacaftor/ivacaftor were also evaluated in a 24-week, open-label, clinical trial (Trial 3) in 58 patients with CF, aged 6 through 11 years (homozygous for F508del) who received lumacaftor 200 mg/ivacaftor 250 mg q12h for 24 weeks. Patients treated with lumacaftor/ivacaftor had a reduction in sweat chloride at Day 15 that was sustained through Week 24. The within-group LS mean absolute change from baseline in sweat chloride was -20.4 mmol/L at Day 15 and -24.8 mmol/L at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The within-group LS mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was 21.3 mmol/L. Changes in sweat chloride in response to lumacaftor/ivacaftor were also evaluated in a 24-week, open-label, clinical trial (Trial 6) in 60 patients with CF, aged 2 through 5 years (homozygous for F508del) who received either lumacaftor 100 mg/ivacaftor 125 mg every 12 hours or lumacaftor 150 mg/ivacaftor 188 mg every 12 hours for 24 weeks. Treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at Week 4 that was sustained through Week 24. The mean absolute change from baseline in sweat chloride was –31.7 mmol/L (95% CI: -35.7, -27.6) at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was an increase of 33.0 mmol/L (95% CI: 28.9, 37.1; P<0.0001). Changes in sweat chloride in response to lumacaftor/ivacaftor were evaluated in a 24-week, open-label, clinical trial (Trial 7) in 46 patients with CF, aged 1 through 2 years (homozygous for F508del) who received lumacaftor 75 mg/ivacaftor 94 mg (patient weighing 7 kg to <9 kg at screening), lumacaftor 100 mg/ivacaftor 125 mg (patient weighing 9 kg to <14 kg at screening), lumacaftor 150 mg/ivacaftor 188 mg (patient weighing ≥14 kg at screening), every 12 hours for 24 weeks. Treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at Week 4 which was sustained through Week 24. The mean absolute change from baseline in sweat chloride at Week 24 was -29.1 mmol/L (95% CI: -34.8, -23.4). In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off- drug response. The mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was 27.3 mmol/L (95% CI: 22.3, 32.3). There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (ppFEV1). Cardiac Electrophysiology The effect of multiple doses of lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h on QTc interval was evaluated in a randomized, placebo- and active-controlled (400 mg moxifloxacin), parallel, thorough QT study in 168 healthy subjects. No meaningful changes in QTc interval were observed with either lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h dose groups. A maximum decrease in mean heart rate of up to 8 beats per minute (bpm) from baseline was observed with lumacaftor/ivacaftor treatment. In Trials 1 and 2, a similar decrease in heart rate was observed in patients during initiation of ORKAMBI (lumacaftor 400 mg/ivacaftor 250 mg q12h). 12.3 Pharmacokinetics The exposure (AUC) of lumacaftor is approximately 2-fold higher in healthy adult volunteers compared to exposure in patients with CF. The exposure of ivacaftor is similar between healthy adult volunteers and patients with CF. After twice daily dosing, steady-state plasma concentrations of lumacaftor and ivacaftor in healthy subjects were generally reached after approximately 7 days of treatment, with an accumulation ratio of approximately 1.9 for lumacaftor. The steady-state exposure of ivacaftor is lower than that of Day 1 due to the CYP3A induction effect of lumacaftor. Table 4: Mean (SD) Pharmacokinetic Parameters of Lumacaftor and Ivacaftor at Steady-State in Subjects with CF Drug t½* Cmax AUC0-12h (h) (μg/mL) (μg∙h/mL) Lumacaftor 400 mg q12h/ Lumacaftor 25.0 (7.96) 25.2 (9.94) 198 (64.8) Ivacaftor 250 mg q12h Ivacaftor 0.602 (0.304) 9.34 (3.81) 3.66 (2.25) * Based on lumacaftor 200 mg q12h/ivacaftor 250 mg q12h studied in healthy subjects. Absorption When a single dose of lumacaftor/ivacaftor was administered with fat-containing foods, lumacaftor exposure was approximately 2 times higher and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state. Following multiple oral dose administration of lumacaftor in combination with ivacaftor, the exposure of lumacaftor generally increased proportional to dose over the range of 200 mg every 24 hours to 400 mg every 12 hours. The median (range) tmax of lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state. Following multiple oral dose administration of ivacaftor in combination with lumacaftor, the exposure of ivacaftor generally increased with dose from 150 mg every 12 hours to 250 mg every 12 hours. The median (range) tmax of ivacaftor is approximately 4.0 hours (2.0; 6.0) in the fed state. Distribution Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of 200 mg every 24 hours for 28 days to patients with CF in a fed state, the mean (±SD) for apparent volumes of distribution was 86.0 (69.8) L. Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Elimination The half-life of lumacaftor is approximately 26 hours in patients with CF. The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/hr (29.4%) for patients with CF. The half-life of ivacaftor when given with lumacaftor is approximately 9 hours in healthy subjects. The typical CL/F (CV), of ivacaftor when given in combination with lumacaftor was estimated to be 25.1 L/hr (40.5%) for patients with CF. Metabolism Lumacaftor is not extensively metabolized in humans with the majority of lumacaftor excreted unchanged in the feces. In vitro and in vivo data indicate that lumacaftor is mainly metabolized via oxidation and glucuronidation. Ivacaftor is extensively metabolized in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. Excretion Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged in the feces. There was minimal elimination of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent). 11 Reference ID: 5495367 Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine). Specific Populations Pediatric Patients The following conclusions about exposures between adults and the pediatric population are based on population pharmacokinetics (PK) analyses: Table 5: Mean (SD) Lumacaftor and Ivacaftor Exposure by Age Group Age Group Weight Dose Mean Lumacaftor (SD)* AUCss (µg∙h/mL) Mean Ivacaftor (SD)** AUCss (µg∙h/mL) 7 kg to <9 kg lumacaftor 75 mg/ivacaftor 94 mg every 12 hours. 234 7.98 Patients aged 1 to <2 years 9 kg to <14 kg lumacaftor 100 mg/ivacaftor 125 mg every 12 hours. 191 (40.6) ≥14 kg lumacaftor 150 mg/ivacaftor 188 mg every 12 hours. 116 Patients aged 2 through 5 years <14 kg lumacaftor 100 mg/ivacaftor 125 mg every 12 hours. 180 (45.5) 5.35 (1.61) 5.82 5.92 (4.61) ≥14 kg lumacaftor 150 mg/ivacaftor 188 mg every 12 hours. 217 (48.6) 5.90 (1.93) Patients aged 6 through 11 years - lumacaftor 200 mg/ivacaftor 250 mg every 12 hours. 203 (57.4) 5.26 (3.08) Patients aged 12 to <18 years - lumacaftor 400 mg/ivacaftor 250 mg every 12 hours. 241 (61.4) 3.90 (1.56) *The mean lumacaftor (SD) AUCss is comparable to the mean AUCss in patients aged 12 years and older administered ORKAMBI tablets. **The mean ivacaftor (SD) AUCss is comparable to the mean AUCss in patients aged 12 years and older administered ORKAMBI tablets. Male and Female Patients The pharmacokinetics of ORKAMBI was evaluated using a population PK analyses of data from clinical studies of lumacaftor given in combination with ivacaftor. Results indicate no clinically relevant difference in pharmacokinetic parameters for lumacaftor and ivacaftor between males and females. Patients with Renal Impairment Pharmacokinetic studies have not been performed with ORKAMBI in patients with renal impairment [see Use in Specific Populations (8.7)]. Patients with Hepatic Impairment Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had approximately 50% higher exposures (AUC0-12h) and approximately 30% higher Cmax for both lumacaftor and ivacaftor compared with healthy subjects matched for demographics. Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5 to 6) or severe hepatic impairment (Child-Pugh Class C, score 10 to 15) receiving ORKAMBI [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Adverse Reactions (6), and Use in Specific Populations (8.6)]. Drug Interaction Studies Drug interaction studies were performed with lumacaftor/ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (7)]. Potential for Lumacaftor/Ivacaftor to Affect Other Drugs Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by 80%. Ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. The net effect of lumacaftor/ivacaftor therapy is strong CYP3A induction [see Drug Interactions (7.3)]. Based on in vitro results which showed P-gp inhibition and PXR activation, lumacaftor has the potential to both inhibit and induce P-gp. A clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of ORKAMBI with P-gp substrates may alter the exposure of these substrates [see Drug Interactions (7.5)]. In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. In vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of ORKAMBI with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates [see Drug Interactions (7.4)]. Potential for Other Drugs to Affect Lumacaftor/Ivacaftor Lumacaftor exposure is not affected by concomitant CYP3A inducers or inhibitors. Exposure of ivacaftor when given in combination with lumacaftor is reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors [see Dosage and Administration (2.3), Warnings and Precautions (5.6), and Drug Interactions (7)]. The effects of co-administered drugs on the exposure of lumacaftor and ivacaftor are shown in Table 6 [see Dosage and Administration (2.3), Warnings and Precautions (5.6), and Drug Interactions (7)]. 12 Reference ID: 5495367 Table 6: Impact of Other Drugs on Lumacaftor 200 mg q12h/Ivacaftor 250 mg q12h Co-administered Drug Dose of Co-administered Drug Effect on PK* Mean Ratio (90% CI) of Lumacaftor and Ivacaftor No Effect=1.0 AUC Cmax CYP3A inhibitor: itraconazole 200 mg once daily ↔ Lumacaftor 0.97 (0.91, 1.02) 0.99 (0.92, 1.05) ↑ Ivacaftor 4.30† (3.78, 4.88) 3.64† (3.19, 4.17) CYP3A inducer: rifampin 600 mg once daily ↔ Lumacaftor 0.87 (0.81, 0.93) 0.96 (0.87, 1.05) ↓ Ivacaftor 0.43 (0.38, 0.49) 0.50 (0.43, 0.58) Other: ciprofloxacin 750 mg q12h ↔ Lumacaftor 0.86 (0.79, 0.95) 0.88 (0.80, 0.97) ↔ Ivacaftor 1.29 (1.12, 1.48) 1.29 (1.11, 1.49) * ↑ = increase, ↓ = decrease, ↔ = no change. † The net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours, the approved dose of ivacaftor monotherapy. CI = Confidence Interval; PK = Pharmacokinetics. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with ORKAMBI; however, studies are available for individual components, lumacaftor and ivacaftor, as described below. Lumacaftor A two-year study in Sprague-Dawley rats and a 26-week study in transgenic Tg.rasH2 mice were conducted to assess carcinogenic potential of lumacaftor. No evidence of tumorigenicity was observed in rats at lumacaftor oral doses up to 1000 mg/kg/day (approximately 5 and 13 times the MRHD on a lumacaftor AUC basis in males and females, respectively). No evidence of tumorigenicity was observed in Tg.rasH2 mice at lumacaftor oral doses up to 1500 and 2000 mg/kg/day in female and male mice, respectively. Lumacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test. Lumacaftor had no effects on fertility and reproductive performance indices in male and female rats at an oral dose of 1000 mg/kg/day (approximately 3 and 8 times, respectively, the MRHD on a lumacaftor AUC basis). Ivacaftor Two-year studies were conducted in mice and rats to assess carcinogenic potential of ivacaftor. No evidence of tumorigenicity was observed in mice and rats at ivacaftor oral doses up to 200 mg/kg/day and 50 mg/kg/day, respectively (approximately equivalent to 3 and 10 times the MRHD based on summed AUCs of ivacaftor and its metabolites). Ivacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test. Ivacaftor impaired fertility and reproductive performance indices in male and female rats at an oral dose of 200 mg/kg/day (approximately 15 and 7 times the MRHD based on summed AUCs of ivacaftor and its metabolites). Increases in prolonged diestrus were observed in females at 200 mg/kg/day. Ivacaftor also increased the number of females with all nonviable embryos and decreased corpora lutea, implantations, and viable embryos in rats at 200 mg/kg/day (approximately 7 times the MRHD based on summed AUCs of ivacaftor and its metabolites) when dams were dosed prior to and during early pregnancy. These impairments of fertility and reproductive performance in male and female rats at 200 mg/kg/day were attributed to severe toxicity. No effects on male or female fertility and reproductive performance indices were observed at an oral dose of ≤100 mg/kg/day (approximately 8 and 5 times the MRHD based on summed AUCs of ivacaftor and its metabolites). 14 CLINICAL STUDIES Dose Ranging Dose ranging for the clinical program consisted primarily of one double-blind, placebo-controlled, multiple-cohort trial which included 97 Caucasian patients with CF (homozygous for the F508del mutation) aged 18 years and older with a screening ppFEV1 ≥40. In the trial, 76 patients (homozygous for the F508del mutation) were randomized to receive lumacaftor alone at once daily doses of 200 mg, 400 mg, or 600 mg or 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h and 27 patients (homozygous or heterozygous for the F508del mutation) received placebo. During the initial 28-day lumacaftor monotherapy period, treatment with lumacaftor demonstrated a dose-dependent decrease in ppFEV1 compared to placebo. Changes from Day 1 at Day 28 in ppFEV1 compared to placebo were 0.24, -1.4, -2.7, and -4.6 for the 200 mg once daily, 400 mg once daily, 600 mg once daily, and 400 mg q12h lumacaftor doses, respectively. Following the addition of ivacaftor 250 mg q12h, the changes from Day 1 at Day 56 in ppFEV1 compared to placebo were 3.8, 2.7, 5.6, and 4.2, respectively. Sweat chloride was also assessed in this trial. Following the initial 28 days of lumacaftor monotherapy, the changes from Day 1 at Day 28 in sweat chloride compared to placebo were -4.9, -8.3, -6.1, and -8.2 mmol/L for the 200 mg once daily, 400 mg once daily, 600 mg once daily, and 400 mg q12h lumacaftor doses, respectively. Following the addition of ivacaftor 250 mg q12h, the changes from Day 1 at Day 56 in sweat chloride compared to placebo were -5.0, -9.8, -9.5, and -11 mmol/L, respectively. These data supported the evaluation of lumacaftor 400 mg/ivacaftor 250 mg q12h (ORKAMBI) and lumacaftor 600 mg once daily/ivacaftor 250 mg q12h in the confirmatory trials. 13 Reference ID: 5495367 BL Day Week 15 4 Week • - Placebo Trial 1 Visit Week 16 ,... LUM 400 mg q12h/lVA 2S0 mg q12h Week 24 BL Day Week 15 4 Woek • -- Placebo Trial 2 Visit Week 16 ,... LUM 400 mg q12h/lVA 250 mg q12h Week 24 Confirmatory The efficacy of ORKAMBI in patients with CF who are homozygous for the F508del mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled, 24-week clinical trials (Trials 1 and 2) in 1108 clinically stable patients with CF of whom 369 patients received ORKAMBI twice daily. Trial 1 evaluated 549 patients with CF who were aged 12 years and older (mean age 25.1 years) with ppFEV1 at screening between 40-90 [mean ppFEV1 60.7 at baseline (range: 31.1 to 94.0)]. Trial 2 evaluated 559 patients aged 12 years and older (mean age 25.0 years) with ppFEV1 at screening between 40-90 [mean ppFEV1 60.5 at baseline (range: 31.3 to 99.8)]. Patients with a history of colonization with organisms such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus, or who had 3 or more abnormal liver function tests (ALT, AST, AP, GGT ≥3 x the ULN or total bilirubin ≥2 x the ULN) were excluded. Patients in both trials were randomized 1:1:1 to receive either ORKAMBI (lumacaftor 400 mg q12h/ivacaftor 250 mg q12h; or lumacaftor 600 mg once daily/ivacaftor 250 mg q12h) or placebo. Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF therapies (e.g., bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). The primary efficacy endpoint in both trials was change in lung function as determined by absolute change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24. In both trials, treatment with ORKAMBI resulted in a statistically significant improvement in ppFEV1. The treatment difference between ORKAMBI and placebo for the mean absolute change in ppFEV1 from baseline at Week 24 (assessed as the average of the treatment effects at Week 16 and at Week 24) was 2.6 percentage points [95% CI (1.2, 4.0)] in Trial 1 (P=0.0003) and 3.0 percentage points [95% CI (1.6, 4.4)] in Trial 2 (P<0.0001). These changes persisted throughout the 24-week treatment period (see Figure 1). Improvements in ppFEV1 were observed regardless of age, disease severity, sex, and geographic region. Figure 1. Absolute Change From Baseline at Each Visit in Percent Predicted FEV1 in Trial 1 and Trial 2. LS = Least Squares; q12h = every 12 hours Key secondary efficacy variables included relative change from baseline in ppFEV1 at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24; absolute change from baseline in BMI at Week 24; absolute change from baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain score at Week 24, a measure of respiratory symptoms relevant to patients with CF such as cough, sputum production, and difficulty breathing; proportion of patients achieving ≥5% relative change from baseline in ppFEV1 using the average of Week 16 and Week 24; and number of pulmonary exacerbations through Week 24. For the purposes of these trials, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. Trial 2 ORKAMBI Placebo LUM 400 mg q12h/IVA (n=187) 250 mg q12h (n=187) 5.3 – (2.7, 7.8) P<0.0001‡ 0.4 – (0.2, 0.5) P=0.0001‡ Table 7: Summary of Other Efficacy Endpoints in Trials 1 and 2* Trial 1 Placebo (n=184) ORKAMBI LUM 400 mg q12h/IVA 250 mg q12h (n=182) Relative change in ppFEV1 at Week 24† (%) Treatment difference (95% CI) – 4.3 (1.9, 6.8) P=0.0006‡ Absolute change in BMI at Week 24 (kg/m2) Treatment difference (95% CI) – 0.1 (-0.1, 0.3) Absolute change in Treatment 1.5 CFQ-R Respiratory Domain Score (Points) at Week 24 difference (95% CI) – (-1.7, 4.7) – 2.9 (-0.3, 6.0) Proportion of patients with ≥5% relative change in ppFEV1 at Week 24† % 22% 37% 23% 41% Odds ratio (95% CI) – 2.1 (1.3, 3.3) – 2.4 (1.5, 3.7) Number of pulmonary exacerbations through Week 24 # of events (rate per 48 weeks) 112 (1.1) 73 (0.7) 139 (1.2) 79 (0.7) Rate ratio (95% CI) – 0.7 (0.5, 0.9) – 0.6 (0.4, 0.8) * In each trial, a hierarchical testing procedure was performed within each active treatment arm for primary and secondary endpoints vs. placebo; at each step, P≤0.0250 and all previous tests also meeting this level of significance was required for statistical significance. † Assessed as the average of the treatment effects at Week 16 and Week 24. ‡ Indicates statistical significance confirmed in the hierarchical testing procedure. Other efficacy measures considered not statistically significant. 14 Reference ID: 5495367 16 HOW SUPPLIED/STORAGE AND HANDLING ORKAMBI (lumacaftor 200 mg/ivacaftor 125 mg) is supplied as pink, oval-shaped tablets; each tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor, printed with “2V125” in black ink on one side and plain on the other, and is packaged as follows: 112–count tablet box containing a 4-week supply (4 weekly cartons of 7 daily blister strips with 4 tablets per strip). NDC 51167-809-01 ORKAMBI (lumacaftor 100 mg/ivacaftor 125 mg) is supplied as pink, oval-shaped tablets; each tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor, printed with “1V125” in black ink on one side and plain on the other, and is packaged as follows: 112–count tablet box containing a 4-week supply (4 weekly cartons of 7 daily blister strips with 4 tablets per strip). NDC 51167-700-02 ORKAMBI (lumacaftor/ivacaftor) oral granules are supplied as small white to off-white granules and enclosed in unit-dose packets as follows: 56-count carton (contains 56 unit-dose packets of lumacaftor 75 mg/ivacaftor 94 mg per packet) NDC 51167-122-01 56-count carton (contains 56 unit-dose packets of lumacaftor 100 mg/ivacaftor 125 mg per packet) NDC 51167-900-01 56-count carton (contains 56 unit-dose packets of lumacaftor 150 mg/ivacaftor 188 mg per packet) NDC 51167-500-02 Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Advanced Liver Disease Inform patients that worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease occurred in some patients treated with ORKAMBI. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI [see Warnings and Precautions (5.1)]. Abnormalities in Liver Function and Testing Inform patients that abnormalities in liver function have occurred in patients treated with ORKAMBI. Blood tests to measure transaminases (ALT and AST) and bilirubin will be performed prior to initiating ORKAMBI, every 3 months during the first year of therapy, and annually thereafter. Advise patients to contact their healthcare provider if they develop symptoms consistent with hepatotoxicity [see Warnings and Precautions (5.2)]. Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions including angioedema and anaphylaxis are possible with use of ORKAMBI. Inform patients of the early signs of hypersensitivity reactions including rash, hives, itching, facial swelling, tightness of the chest and wheezing. Advise patients to discontinue use of ORKAMBI immediately and contact their physician or go to the emergency department if these symptoms occur. Respiratory Events Inform patients that chest discomfort, dyspnea, and respiration abnormal were more common during initiation of ORKAMBI therapy, especially in patients with advanced lung disease and to contact their healthcare provider if they develop any of these symptoms [see Warnings and Precautions (5.4)]. Effect on Blood Pressure Inform patients that increased blood pressure has been observed in some patients treated with ORKAMBI and that periodic monitoring of their blood pressure during treatment is recommended and to contact their healthcare provider if they develop elevated blood pressure or notice elevations in pre-existing high blood pressure [see Warnings and Precautions (5.5)]. Drug Interactions with CYP3A Inhibitors and Inducers  Advise patients to inform their healthcare providers of all concomitant medications, herbal and dietary supplements. Advise patients to avoid grapefruit products during the first week after treatment initiation with ORKAMBI [see Dosage and Administration (2.3), Warnings and Precautions (5.6), and Drug Interactions (7)].  Instruct post-menarchal patients including females of reproductive potential on alternative methods of birth control because hormonal contraceptives should not be relied upon as an effective method of contraception. ORKAMBI may decrease the effectiveness of hormonal contraceptives and there is an increased incidence of menstruation-related adverse reactions when co-administered with ORKAMBI [see Warnings and Precautions (5.6), Adverse Reactions (6.1), and Drug Interactions (7.11)]. Cataracts Inform patients that abnormalities of the eye lens (cataract) have been noted in some children and adolescents receiving ORKAMBI. Advise pediatric patients and their caregivers that they will receive ophthalmological examinations before initiating and during ORKAMBI treatment. Advise pediatric patients and/or their caregivers to contact their healthcare provider if they experience visual changes [see Warnings and Precautions (5.7)]. Administration Inform patients that ORKAMBI should be taken with fat-containing food. A typical CF diet will satisfy this requirement. Examples of fat-containing foods include eggs, avocados, nuts, butter, peanut butter, cheese pizza, breast milk, infant formula, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc. [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Inform patients and caregivers that ORKAMBI oral granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and completely consumed to ensure delivery of the entire dose. Food or liquid should be at or below room temperature. Once mixed, the product has been shown to be stable for one hour, and therefore should be consumed during this period. Some examples of appropriate soft foods or liquids may include puréed fruits or vegetables, flavored yogurt or pudding, applesauce, water, milk, breast milk, infant formula or juice. Inform patients that if a dose is missed and they remember the missed dose within 6 hours, the patients should take the dose with fat-containing food. If more than 6 hours elapsed after the usual dosing time, the patients should skip that dose and resume the normal schedule for the following dose. Patients should be informed not to take a double dose to make up for the forgotten dose [see Dosage and Administration (2.1)]. 15 Reference ID: 5495367 .. VERTEX Manufactured for Vertex Pharmaceuticals Incorporated 50 Northern Avenue Boston, MA 02210 ORKAMBI, the ORKAMBI logo, VERTEX, and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2024 Vertex Pharmaceuticals Incorporated ALL RIGHTS RESERVED 16 Reference ID: 5495367 PATIENT INFORMATION ORKAMBI (or-KAM-bee) (lumacaftor and ivacaftor) tablets for oral use (lumacaftor and ivacaftor) oral granules What is ORKAMBI? • ORKAMBI is a prescription medicine used for the treatment of cystic fibrosis (CF) in people aged 1 year and older who have two copies of the F508del mutation (F508del/F508del) in their CFTR gene. • ORKAMBI should not be used in people other than those who have two copies of the F508del mutation in their CFTR gene. It is not known if ORKAMBI is safe and effective in children under 1 year of age. Before taking ORKAMBI, tell your doctor about all of your medical conditions, including if you: • have or have had liver problems. • are allergic to ORKAMBI or any ingredients in ORKAMBI. See the end of this patient information leaflet for a complete list of ingredients in ORKAMBI. • have kidney problems. • have lung problems. • have had an organ transplant. • are using birth control (hormonal contraceptives, including oral, injectable, transdermal, or implantable forms). Hormonal contraceptives should not be used as a method of birth control when taking ORKAMBI. Talk to your doctor about the best birth control method you should use while taking ORKAMBI. • are pregnant or plan to become pregnant. It is not known if ORKAMBI will harm your unborn baby. You and your doctor should decide if you will take ORKAMBI while you are pregnant. • are breastfeeding or planning to breastfeed. It is not known if ORKAMBI passes into your breast milk. You and your doctor should decide if you will take ORKAMBI while you are breastfeeding. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ORKAMBI may affect the way other medicines work, and other medicines may affect how ORKAMBI works. The dose of ORKAMBI may need to be adjusted when taken with certain medicines. Ask your doctor or pharmacist for a list of these medicines if you are not sure. Especially tell your doctor if you take: • antibiotics: rifampin (RIFAMATE®, RIFATER®) or rifabutin (MYCOBUTIN®). • seizure medicines: phenobarbital, carbamazepine (TEGRETOL®, CARBATROL®, EQUETRO®), or phenytoin (DILANTIN®, PHENYTEK®). • sedatives and anti-anxiety medicines: triazolam (HALCION®) or midazolam (DORMICUM®, HYPNOVEL®, and VERSED®). • immunosuppressant medicines: cyclosporine, everolimus (ZORTRESS®), sirolimus (RAPAMUNE®), or tacrolimus (ASTAGRAF XL®, ENVARSUS® XR, PROGRAF®, and PROTOPIC®). • St. John’s wort (Hypericum perforatum). • antifungal medicines including ketoconazole, itraconazole (such as SPORANOX®), posaconazole (such as NOXAFIL®), or voriconazole (such as VFEND®). • antibiotics including telithromycin, clarithromycin (such as BIAXIN®), or erythromycin (such as ERY-TAB®). Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I take ORKAMBI? • Take ORKAMBI exactly as your doctor tells you to take it. • Always take ORKAMBI tablets or granules with foods that contain fat. Examples of fat-containing foods include eggs, avocados, nuts, butter, peanut butter, cheese pizza, breast milk, infant formula, whole-milk dairy products (such as whole milk, cheese, and yogurt). • Take your doses of ORKAMBI 12 hours apart. • ORKAMBI tablets (aged 6 years and older): o Each ORKAMBI box contains 4 weekly cartons. o Each carton contains 7 daily blister strips. o Each blister strip contains 4 tablets so you can take 2 tablets for the morning and 2 tablets for the evening. o You may cut along the dotted line to separate your morning dose from your evening dose. 1 Reference ID: 5495367 o To take your morning dose, unpeel the paper backing from a blister strip (do not push tablet through backing) to remove 2 ORKAMBI tablets and take them with fat-containing food. o 12 hours after your previous dose, open another blister strip (do not push tablet through backing) to remove 2 ORKAMBI tablets and take them with fat-containing food. • ORKAMBI oral granules (aged 1 to under 6 years old): o Hold the packet with the cut line on top. o Shake the packet gently to settle the ORKAMBI granules. o Tear or cut packet open along cut line. o Carefully pour all of the ORKAMBI granules in the packet into one teaspoon (5 mL) of soft food or liquid in a small container (like an empty bowl). o The food or liquid should be at or below room temperature. Examples of soft foods or liquids include puréed fruits or vegetables, flavored yogurt or pudding, applesauce, water, milk, breast milk, infant formula or juice.Mix the ORKAMBI granules with food or liquid. o After mixing, give ORKAMBI within 1 hour. Make sure all medicine is taken. o Give a child fat-containing food just before or just after the ORKAMBI granules dose (see examples above). • If you miss a dose within 6 hours of when you usually take it, take your dose with fat-containing food as soon as possible. • If you miss a dose and it is more than 6 hours after the time you usually take it, skip that dose only and take the next dose when you usually take it. Do not take 2 doses at the same time to make up for your missed dose. • Tell your doctor if you stop ORKAMBI for more than 1-week. Your doctor may need to change your dose of ORKAMBI or other medicines you take. What should I avoid while taking ORKAMBI? Do not eat or drink grapefruit products during your first week of treatment with ORKAMBI. Eating or drinking grapefruit products can increase the amount of ORKAMBI in your blood. What are the possible side effects of ORKAMBI? ORKAMBI can cause serious side effects, including: • Worsening of liver function in people with severe liver disease. The worsening of liver function can be serious or cause death. Talk to your doctor if you have been told you have liver disease as your doctor may need to adjust the dose of ORKAMBI. • High liver enzymes in the blood, which can be a sign of liver injury in people receiving ORKAMBI. Your doctor will do blood tests to check your liver: o before you start ORKAMBI o every 3 months during your first year of taking ORKAMBI o every year while you are taking ORKAMBI Call your doctor right away if you have any of the following symptoms of liver problems: o pain or discomfort in the upper right stomach o yellowing of your skin or the white part of your (abdominal) area eyes o loss of appetite o nausea or vomiting o dark, amber-colored urine o confusion • Serious Allergic Reactions can happen to people who are treated with ORKAMBI. Call your doctor or go to the emergency room right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction may include: o rash or hives o swelling of the face, lips, and/or tongue, difficulty swallowing o tightness of the chest or throat or difficulty breathing o light-headedness or dizziness • Breathing problems such as trouble breathing, shortness of breath or chest tightness in people when starting ORKAMBI, especially in people who have poor lung function. If you have poor lung function, your doctor may monitor you more closely when you start ORKAMBI. Call your doctor right away if you have trouble breathing, shortness of breath or chest tightness. • An increase in blood pressure in some people receiving ORKAMBI. Your doctor should monitor your blood pressure during treatment with ORKAMBI. Call your doctor right away if you have an increase in blood pressure. 2 Reference ID: 5495367 ... VERTEX - • Abnormality of the eye lens (cataract) in some children and adolescents receiving ORKAMBI. If you are a child or adolescent, your doctor should perform eye examinations before and during treatment with ORKAMBI to look for cataracts. The most common side effects of ORKAMBI include: • breathing problems such as shortness of breath and • rash chest tightness • gas • nausea • common cold, including sore throat, stuffy or runny • diarrhea nose • fatigue • flu or flu-like symptoms • increase in a certain blood enzyme called creatine • irregular, missed, or abnormal periods (menses) and phosphokinase increase in the amount of menstrual bleeding Additional side effects in children Side effects seen in children are similar to those seen in adults and adolescents. Additional common side effects seen in children include: • cough with sputum • stomach pain • stuffy nose • increase in sputum • headache Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of ORKAMBI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ORKAMBI? • Store ORKAMBI at room temperature between 68°F to 77°F (20°C to 25°C). Keep ORKAMBI and all medicines out of the reach of children. General information about the safe and effective use of ORKAMBI. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ORKAMBI for a condition for which it was not prescribed. Do not give ORKAMBI to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about ORKAMBI that is written for health professionals. What are the ingredients in ORKAMBI? ORKAMBI tablets: Active ingredients: lumacaftor and ivacaftor Inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains: carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains: ammonium hydroxide, iron oxide black, propylene glycol, and shellac. ORKAMBI oral granules Active ingredients: lumacaftor and ivacaftor Inactive ingredients: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; povidone; and sodium lauryl sulfate. Manufactured for: Vertex Pharmaceuticals Incorporated; 50 Northern Avenue, Boston, MA 02210 For more information, go to www.orkambi.com or call 1-877-752-5933. ORKAMBI, the ORKAMBI logo, VERTEX, and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2023 Vertex Pharmaceuticals Incorporated This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 08/2023 3 Reference ID: 5495367
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2025-02-12T15:47:44.814310
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ONTRALFY™ safely and effectively. See full prescribing information for ONTRALFY. ONTRALFY™ (tizanidine oral solution) Initial U.S. Approval: 1996 ----------------------------INDICATIONS AND USAGE--------------------------- Ontralfy is a central alpha-2-adrenergic agonist indicated for the treatment of spasticity in adults. (1) ----------------------DOSAGE AND ADMINISTRATION----------------------­ • Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved. (2.1) • Recommended starting dose: 2 mg by mouth every 6 to 8 hours, as needed, up to a maximum of 3 doses in 24 hours. (2.2) • Dosage can be increased by 2 mg to 4 mg per dose every 1 to4 days; maximum total daily dosage is 36 mg. (2.2) • The pharmacokinetics of Ontralfy differ when taken with or without food. These differences could result in a change in tolerability and control of symptoms. Consistent administration with respect to food is recommended. (2.2, 12.3) • Patients with renal impairment (creatinine clearance <25 mL/min) or hepatic impairment: use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased. (2.3, 2.4) • To discontinue Ontralfy, decrease dose by 2 mg (5 mL) to 4 mg (10 mL) per day to minimize the risk of withdrawal adverse reactions. (2.5) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ • Oral Solution: 2 mg/5 mL tizanidine (3) -------------------------------CONTRAINDICATIONS-----------------------------­ • Concomitant use with strong CYP1A2 inhibitors (4, 7.1) • Patients with a history of hypersensitivity to tizanidine or the ingredients in Ontralfy (4, 5.5) -----------------------WARNINGS AND PRECAUTIONS-----------------------­ • Hypotension: monitor for signs and symptoms of hypotension, in particular in patients receiving concurrent antihypertensives;Ontralfy should not be used with other α2-adrenergic agonists. (5.1, 7.7) • Risk of liver injury: monitor ALTs; discontinue Ontralfy if liver injury occurs. (5.2) • Sedation: Ontralfy may interfere with everyday activities; sedative effects of Ontralfy, alcohol, and other central nervous system (CNS) depressants are additive. (5.3, 7.4) • Hallucinations: consider discontinuation of Ontralfy. (5.4) ------------------------------ADVERSE REACTIONS------------------------------­ The most common adverse reactions (greater than 10% of patients taking tizanidine and greater than in patients taking placebo) were dry mouth, somnolence, asthenia, and dizziness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Fidelity BioPharma Co. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------­ Moderate or weak CYP1A2 inhibitors: avoid concomitant use; may cause hypotension, bradycardia, or excessive drowsiness; if concomitant use is necessary and adverse reactions occur, reduce Ontralfy dosage or discontinue. (7.2,12.3) ------------------------USE IN SPECIFIC POPULATIONS----------------------­ • Pregnancy: Based on animal data, may cause fetal harm. (8.1) • Geriatric use: Ontralfy should be used with caution in elderly patients because clearance is decreased four-fold. (8.5) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Evaluation and Testing Before and After Initiating Ontralfy 2.2 Recommended Dosage Information 2.3 Recommended Dosage in Patients with Renal Impairment 2.4 Recommended Dosage in Patients with Hepatic Impairment 2.5 Discontinuation of Ontralfy 3 DOSAGE FORMS AND STRENGHTS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension 5.2 Liver Injury 5.3 Sedation 5.4 Hallucinosis/Psychotic-Like Symptoms 5.5 Hypersensitivity Reactions 5.6 Withdrawal Adverse Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Strong CYP1A2 Inhibitors 7.2 Moderate or Weak CYP1A2 Inhibitors 7.3 Oral Contraceptives 7.4 Alcohol and Other CNS Depressants 7.5 α2-Adrenergic Agonists 7.6 Antihypertensive Medications 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5493660 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Ontralfy is indicated for the treatment of spasticity in adults. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Evaluation and Testing Before and After Initiating Ontralfy Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved [see Warnings and Precautions (5.2)]. 2.2 Recommended Dosage The recommended starting dose is 2 mg (5 mL) by mouth every 6 to 8 hours, as needed, to a maximum of three doses in 24 hours. Dosage can be gradually increased every 1 to 4 days by 2 mg (5 mL) to 4 mg (10 mL) at each dose based on clinical response and tolerability. The maximum total daily dosage is 36 mg (90 mL). Single doses greater than 16 mg (40 mL) have not been studied. The pharmacokinetics of Ontralfy differ when taken with or without food [see Clinical Pharmacology (12.3)]. Ontralfy may be taken with or without food; however, consistent administration with respect to food is recommended to reduce variability in tizanidine plasma exposure. If administration with respect to food is changed, monitor patients for therapeutic effect or adverse reactions [see Clinical Pharmacology (12.3)]. Because of the short duration of therapeutic effect, treatment with Ontralfy should be reserved for those daily activities and times when relief of spasticity is most important. 2.3 Recommended Dosage in Patients with Renal Impairment In patients with creatinine clearance < 25 mL/min, use lower individual doses during titration. If higher doses are required, the individual doses rather than dosing frequency should be increased [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 2.4 Recommended Dosage in Patients with Hepatic Impairment In patients with hepatic impairment, use lower individual doses during titration. If higher doses are required, individual doses rather than dosing frequency should be increased [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. 2.5 Discontinuation of Ontralfy When discontinuing Ontralfy, particularly in patients who have been receiving high doses for long periods or who may be on concomitant treatment with narcotics, decrease the dosage by 2 mg (5 mL) to 4 mg (10 mL) per day to minimize the risk of withdrawal adverse reactions [see Drug Abuse and Dependence (9.3)]. 3 DOSAGE FORMS AND STRENGTHS Oral Solution: 2 mg/5 mL of tizanidine as a clear, colorless to pale yellow solution with a strawberry flavor. Reference ID: 5493660 4 CONTRAINDICATIONS Ontralfy is contraindicated in patients: • taking strong CYP1A2 inhibitors [see Drug Interactions (7.1)]. • with a history of hypersensitivity to tizanidine or the ingredients in Ontralfy. Symptoms have included anaphylaxis and angioedema [see Warnings and Precautions (5.5)] 5 WARNINGS AND PRECAUTIONS 5.1 Hypotension Ontralfy is an α2-adrenergic agonist that can produce hypotension [see Adverse Reactions (6.1) and Drug Interactions (7.5)]. Syncope has been reported in patients treated with tizanidine in the postmarketing setting. The risk of hypotension may be minimized by dose titration; monitoring for signs and symptoms of hypotension prior to dosage increase may minimize the risks associated with hypotension. In addition, patients moving from a supine to fixed upright position may be at increased risk for hypotension and orthostatic effects. Monitor for hypotension when Ontralfy is used in patients receiving concurrent antihypertensive therapy. It is not recommended that Ontralfy be used with other α2-adrenergic agonists. Clinically significant hypotension (decreases in both systolic and diastolic pressure) has been reported with concomitant administration of tizanidine and strong CYP1A2 inhibitors [see Clinical Pharmacology (12.3)]. Therefore, concomitant use of Ontralfy with strong CYP1A2 inhibitors is contraindicated [see Contraindications (4) and Drug Interactions (7.1)]. 5.2 Liver Injury Ontralfy may cause hepatocellular liver injury. Liver function test abnormality and hepatotoxicity have been observed with tizanidine, the active moiety of Ontralfy [see Adverse Reactions (6.1, 6.2)]. Monitoring of aminotransferase levels is recommended at baseline and 1 month after maximum dose is achieved, or if hepatic injury is suspected [see Dosage and Administration (2.1) and Use in Specific Populations (8.7)]. 5.3 Sedation Ontralfy can cause sedation, which may interfere with everyday activity. In the multiple dose studies of tizanidine, the prevalence of patients with sedation peaked following the first week of titration and then remained stable for the duration of the maintenance phase of the study [see Adverse Reactions (6.1)]. The CNS depressant effects of Ontralfy with alcohol and other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants) may be additive [see Drug Interactions (7.4)]. Monitor patients who take Ontralfy with another CNS depressant for symptoms of excess sedation. 5.4 Hallucinosis/Psychotic-Like Symptoms Tizanidine use has been associated with hallucinations. Formed, visual hallucinations or delusions were reported in 5 of 170 patients (3%) in two North American controlled clinical studies of tizanidine. Most of the patients were aware that the events were unreal. One patient developed psychosis in association with the hallucinations. One patient among these 5 continued to have problems for at least 2 weeks following discontinuation of tizanidine. Hallucinations Reference ID: 5493660 have also been reported with tizanidine use in the postmarketing setting. Consider discontinuing Ontralfy in patients who develop hallucinations. 5.5 Hypersensitivity Reactions Ontralfy can cause anaphylaxis. Signs and symptoms of hypersensitivity, including respiratory compromise, urticaria, and angioedema of the throat and tongue, have been reported. Ontralfy is contraindicated in patients with a history of hypersensitivity reactions to tizanidine [see Contraindications (4)]. 5.6 Withdrawal Adverse Reactions Ontralfy can cause withdrawal adverse reactions, which include rebound hypertension, tachycardia, and hypertonia. To minimize the risk of these reactions, particularly in patients who have been receiving high doses of Ontralfy (20 to 28 mg daily) for long periods of time (9 weeks or more) or who may be on concomitant treatment with narcotics, the Ontralfy dosage should be decreased slowly [see Dosage and Administration (2.5)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in other sections of the prescribing information: • Hypotension [see Warnings and Precautions (5.1)] • Liver Injury [see Warnings and Precautions (5.2)] • Sedation [see Warnings and Precautions (5.3)] • Hallucinosis/Psychotic-Like Symptoms [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Withdrawal Adverse Reactions [see Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of Ontralfy has been established from adequate and well-controlled studies of tizanidine tablets in adult patients with spasticity [see Clinical Studies (14)]. Below is a presentation of the adverse reactions of tizanidine tablets in these adequate and well-controlled studies. The safety of tizanidine has been evaluated in three double-blind, randomized, placebo- controlled clinical studies [see Clinical Studies (14)]. Two studies were conducted in patients with multiple sclerosis and one in patients with spinal cord injury. Each study had a 13-week active treatment period which included a 3-week titration phase to the maximum tolerated dose up to 36 mg/day in three divided doses, a 9-week plateau phase where the dose of tizanidine was held constant and a 1-week dose tapering period. In all, 264 patients received tizanidine and Reference ID: 5493660 261 patients received placebo. Across the three studies approximately 51% of patients were women, and the median dose during the plateau phase ranged from 20 to 28 mg/day. The most common adverse reactions (>10% of patients treated with tizanidine) reported in multiple dose, placebo-controlled clinical studies involving 264 patients with spasticity were dry mouth, somnolence/sedation, asthenia (weakness, fatigue and/or tiredness), and dizziness. Three- quarters of the patients rated the reactions as mild to moderate and one-quarter of the patients rated the reactions as being severe. These adverse reactions appeared to be dose related. Table 1 lists adverse reactions that were reported in greater than 2% of patients in three multiple dose, placebo-controlled studies who received tizanidine where the frequency in the tizanidine group was greater than the placebo group. Table 1: Multiple Dose, Placebo-Controlled Studies Adverse Reactions Reported in >2% of Patients Treated with Tizanidine Tablets and Incidence Greater than Placebo Adverse Reaction Placebo N = 261 % Tizanidine Tablet N = 264 % Dry mouth 10 49 Somnolence 10 48 Asthenia* 16 41 Dizziness 4 16 UTI 7 10 Infection 5 6 Liver test abnormality 2 6 Constipation 1 4 Vomiting 0 3 Speech disorder 0 3 Amblyopia (blurred vision) <1 3 Urinary frequency 2 3 Flu syndrome 2 3 Dyskinesia 0 3 Nervousness <1 3 Pharyngitis 1 3 Rhinitis 2 3 * includes weakness, fatigue, and/or tiredness In the single dose, placebo-controlled study involving 142 patients with spasticity due to multiple sclerosis (Study 1) [see Clinical Studies (14)], the patients were specifically asked if they had experienced any of the four most common adverse reactions: dry mouth, somnolence (drowsiness), asthenia (weakness, fatigue and/or tiredness), and dizziness. In addition, hypotension and bradycardia were observed. The occurrence of these reactions is summarized in Table 2. Other events were, in general, reported at a rate of 2% or less. Table 2: Single Dose, Placebo-Controlled Study—Common Adverse Reactions Reported Adverse Reaction Placebo N = 48 % Tizanidine Tablet, 8 mg, N = 45 % Tizanidine Tablet, 16 mg, N = 49 % Reference ID: 5493660 Somnolence 31 78 92 Dry mouth 35 76 88 Asthenia* 40 67 78 Dizziness 4 22 45 Hypotension 0 16 33 Bradycardia 0 2 10 *includes weakness, fatigue, and/or tiredness 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of tizanidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: Ventricular tachycardia, decreased blood pressure Hepatobiliary Disorders: Hepatotoxicity [see Warnings and Precautions (5.2)], hepatitis Musculoskeletal and Connective Tissue Disorders: arthralgia Nervous System Disorders: Convulsion, paresthesia, tremor, muscle spasms Psychiatric Disorders: Hallucinations [see Warnings and Precautions (5.4)], depression Skin and Subcutaneous Tissue Disorders: Stevens Johnson Syndrome, anaphylactic reaction [see Warnings and Precautions (5.6)], exfoliative dermatitis, rash 7 DRUG INTERACTIONS 7.1 Strong CYP1A2 Inhibitors Concomitant use of Ontralfy with strong cytochrome P450 1A2 (CYP1A2) inhibitors (e.g., fluvoxamine, ciprofloxacin) is contraindicated. Changes in pharmacokinetics of tizanidine when administered with a strong CYP1A2 inhibitor resulted in significantly decreased blood pressure, increased drowsiness, and increased psychomotor impairment [see Contraindications (4) and Clinical Pharmacology (12.3)]. 7.2 Moderate or Weak CYP1A2 Inhibitors Concomitant use of Ontralfy with moderate or weak CYP1A2 inhibitors (e.g., zileuton, antiarrhythmics [amiodarone, mexiletine, propafenone, and verapamil], cimetidine, famotidine, oral contraceptives, acyclovir, and ticlopidine) should be avoided. If concomitant use is clinically necessary, and adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce Ontralfy dosage or discontinue Ontralfy therapy [see Clinical Pharmacology (12.3)]. 7.3 Oral Contraceptives Concomitant use of Ontralfy with oral contraceptives is not recommended. However, if concomitant use is clinically necessary and adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue Ontralfy therapy [see Clinical Pharmacology (12.3)]. Reference ID: 5493660 7.4 Alcohol and Other CNS Depressants Alcohol increases the exposure of tizanidine after administration of Ontralfy. This was associated with an increase in adverse reactions of tizanidine. Concomitant use of Ontralfy with CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may cause additive CNS depressant effects, including sedation. Monitor patients who take Ontralfy with another CNS depressant for symptoms of excess sedation [see Clinical Pharmacology (12.3)]. 7.5 α2-Adrenergic Agonists Concomitant use of Ontralfy with other α2-adrenergic agonists is not recommended because hypotensive effects may be cumulative [see Warnings and Precautions (5.1)]. 7.6 Antihypertensive Medications Concomitant use of Ontralfy with antihypertensive medications may cause additive hypotensive effects [see Warnings and Precautions (5.1)]. Monitor patients who take Ontralfy with antihypertensive medications for hypotension. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with use of tizanidine in pregnant women. In animal studies, administration of tizanidine during pregnancy resulted in developmental toxicity (embryofetal and postnatal offspring mortality and growth deficits) at doses less than those used clinically, which were not associated with maternal toxicity (see Animal Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of tizanidine (0.3 to 100 mg/kg/day) to pregnant rats during the period of organogenesis resulted in embryofetal and postnatal offspring mortality and reductions in body weight at doses of 30 mg/kg/day and above. Maternal toxicity was observed at the highest dose tested. The no-effect dose for embryofetal developmental toxicity in rats (3 mg/kg/day) is similar to the maximum recommended human dose (MRHD) of 36 mg/day on a body surface area (mg/m2) basis. Oral administration of tizanidine (1 to 100 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in embryofetal and postnatal offspring mortality at all doses. Maternal toxicity was observed at the highest dose tested. Oral administration of tizanidine (10 and 30 mg/kg/day) during the perinatal period of pregnancy (2-6 days prior to delivery) resulted in increased postnatal offspring mortality at both doses. A no-effect dose for embryofetal developmental toxicity in rabbit was not identified. The lowest dose tested (1 mg/kg/day) is less Reference ID: 5493660 than the MRHD on a mg/m2 basis. In a pre- and postnatal development study in rats, oral administration of tizanidine (3 to 30 mg/kg/day) resulted in increased postnatal offspring mortality. A no-effect dose for pre- and postnatal developmental toxicity was not identified. The lowest dose tested (3 mg/kg/day) is similar to the MRHD on a mg/m2 basis, respectively. 8.2 Lactation Risk Summary There are no data on the presence of tizanidine in human milk, the effects on the breastfed infant, or the effects on human milk production. Animal studies have reported the presence of tizanidine in the milk of lactating animals. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Ontralfy and any potential adverse effects on the breastfed infant from Ontralfy or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential There are no adequate and well-controlled studies in humans on the effect of Ontralfy on female or male reproductive potential. Oral administration of tizanidine to male and female rats resulted in adverse effects on fertility [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Juvenile Animal Toxicity Data Oral administration of tizanidine (0, 1, 3, and 10 mg/kg/day) to juvenile rats from postnatal day (PND) 7 through PND 70 resulted in delayed sexual maturation in males at all doses, reduced body weight gain, delayed sexual maturation in females, and bilateral corneal crystals at the mid and high doses. Corneal crystals were still observed at the mid and high doses after a three-week recovery period. Neurobehavioral deficits were observed on a learning and memory task at the high dose. A no-effect dose for adverse effects on postnatal development was not identified. 8.5 Geriatric Use Tizanidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Clinical studies of tizanidine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Pharmacokinetic data showed that elderly subjects cleared tizanidine slower than the younger subjects [see Clinical Pharmacology (12.3)]. In elderly patients with renal insufficiency (creatinine clearance < 25 mL/min), tizanidine clearance is reduced compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. During titration, the individual doses should be reduced. If higher doses are required, individual doses rather than dosing frequency should be increased. Monitor elderly patients because they may have an increased risk for Reference ID: 5493660 adverse reactions associated with Ontralfy. 8.6 Renal Impairment In patients with renal insufficiency (creatinine clearance < 25 mL/min), clearance of tizanidine was reduced [see Clinical Pharmacology (12.3)]. In these patients, dosage reduction is recommended [see Dosage and Administration (2.3)]. Because the risk of adverse reactions to Ontralfy may be greater in patients with impaired renal function, monitor these patients closely for the onset or increase in severity of common adverse reactions [see Adverse Reactions (6.1)]. 8.7 Hepatic Impairment Ontralfy should be used with caution in patients with hepatic impairment. The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine [see Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)]. In patients with hepatic impairment, dosage reduction is recommended [see Dosage and Administration (2.4)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Ontralfy contains tizanidine, which is not a controlled substance. 9.2 Abuse Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Abuse potential was not evaluated in human studies. Rats were able to distinguish tizanidine from saline in a standard discrimination paradigm, after training, but failed to generalize the effects of morphine, cocaine, diazepam, or phenobarbital to tizanidine. 9.3 Dependence Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Tizanidine is closely related to clonidine, which is often abused in combination with narcotics and is known to cause symptoms of rebound upon abrupt withdrawal. Cases of rebound symptoms on sudden withdrawal of tizanidine have been reported. The case reports suggest that these patients were also misusing narcotics. Withdrawal symptoms included hypertension, tachycardia, hypertonia, tremor, and anxiety. Withdrawal symptoms are more likely to occur in cases where high doses are used, especially for prolonged periods, or with concomitant use of narcotics. If therapy needs to be discontinued, the dose should be decreased slowly to minimize the risk of withdrawal symptoms [see Dosage and Administration (2.5)]. Monkeys were shown to self-administer tizanidine in a dose-dependent manner, and abrupt cessation of tizanidine produced transient signs of withdrawal at doses > 35 times the maximum recommended human dose on a mg/m2 basis. These transient withdrawal signs (increased locomotion, body twitching, and aversive behavior toward the observer) were not reversed by naloxone administration. Reference ID: 5493660 N ~\ a =-.I Cl HCI 10 OVERDOSAGE A review of the safety surveillance database revealed cases of intentional and accidental tizanidine overdose. Some of the cases resulted in fatality and many of the intentional overdoses were with multiple drugs including CNS depressants. The clinical manifestations of tizanidine overdose were consistent with its known pharmacology. In the majority of cases a decrease in sensorium was observed including lethargy, somnolence, confusion and coma. Depressed cardiac function is also observed including most often bradycardia and hypotension. Respiratory depression is another common feature of tizanidine overdose. Should overdose occur, ensure the adequacy of an airway and monitor cardiovascular and respiratory function. Dialysis is not likely to be an efficient method of removing tizanidine from the body [see Description (11)]. In general, symptoms resolve within one to three days following discontinuation of tizanidine and administration of appropriate therapy. Because of the similar mechanism of action, symptoms and management of tizanidine overdose are similar to that following clonidine overdose. For the most recent information concerning the management of overdose, contact a poison control center. 11 DESCRIPTION Ontralfy contains tizanidine hydrochloride as the active ingredient, which is a central alpha2­ adrenergic agonist. Its chemical name is 5-chloro-4-(2-imidazolin-2-ylamino)-2,1,3­ benzothiadiazole monohydrochloride. It has a molecular formula of C9H8ClN5S.HCl and a molecular weight of 290.2. Its structural formula is: Tizanidine hydrochloride is a white to off-white, fine crystalline powder, which is odorless or with a faint characteristic odor. Tizanidine hydrochloride is slightly soluble in water and methanol; solubility in water decreases as the pH increases. Ontralfy is supplied as an oral solution. Each 5 mL contains 2 mg tizanidine (equivalent to 2.29 mg tizanidine hydrochloride), and the inactive ingredients anhydrous citric acid, edetate disodium dihydrate, flavor, methylparaben sodium, propylparaben sodium, purified water, sodium citrate anhydrous, and sucralose. Each 5 mL of Ontralfy contains 2 mg of sodium. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tizanidine is a central alpha-2-adrenergic receptor agonist and presumably reduces spasticity by increasing presynaptic inhibition of motor neurons. The effects of tizanidine are greatest on polysynaptic pathways. The overall effect of these actions is thought to reduce facilitation of spinal motor neurons. Reference ID: 5493660 12.2 Pharmacodynamics The CNS depressant effects of tizanidine and alcohol are additive [see Warnings and Precautions (5.3) and Drug Interactions (7.4)]. 12.3 Pharmacokinetics Tizanidine has linear pharmacokinetics over the doses studied in clinical development [1 mg (half the recommended dosage) to 20 mg]. Ontralfy oral solution has comparable bioavailability to tizanidine oral tablets under fasted and fed conditions and to tizanidine oral capsules under the fed condition. Absorption Following oral administration, tizanidine is essentially completely absorbed. The absolute oral bioavailability of tizanidine is approximately 40% (CV = 24%), due to extensive first-pass hepatic metabolism. Effect of Food In a single dose pharmacokinetic study in healthy adult subjects, the administration of Ontralfy following a standardized high-fat, high-calorie breakfast had minimal effect on the Cmax of tizanidine; however, AUC was increased by approximately 33% when compared to dosing under fasting condition. The median Tmax and mean elimination half-life (t1/2) are similar under both fasting and fed conditions. Distribution Tizanidine is extensively distributed throughout the body with a mean steady state volume of distribution of 2.4 L/kg (CV = 21%) following intravenous administration in healthy adult volunteers. Tizanidine is approximately 30% bound to plasma proteins. Elimination Metabolism Tizanidine has a half-life of approximately 2.5 hours (CV=33%). Approximately 95% of an administered dose is metabolized. The primary cytochrome P450 isoenzyme involved in tizanidine metabolism is CYP1A2. Tizanidine metabolites are not known to be active; their half- lives range from 20 to 40 hours. Excretion Following single and multiple oral dosing of 14C-tizanidine, an average of 60% and 20% of total radioactivity was recovered in the urine and feces, respectively. Reference ID: 5493660 Specific Populations Geriatric Patients No specific pharmacokinetic study was conducted to investigate age effects. Cross study comparison of pharmacokinetic data following single dose administration of 6 mg tizanidine showed that elderly subjects cleared the drug four times slower than younger subjects [see Use in Specific Populations (8.5)]. Patients with Hepatic Impairment The influence of hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. Because tizanidine is extensively metabolized in the liver, hepatic impairment would be expected to have significant effects on pharmacokinetics of tizanidine [see Use in Specific Populations (8.7)]. Patients with Renal Impairment Tizanidine clearance is reduced by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. [see Use in Specific Populations (8.6)]. Gender Effects No specific pharmacokinetic study was conducted to investigate gender effects. Retrospective analysis of pharmacokinetic data following single and multiple dose administration of 4 mg tizanidine, however, showed that gender had no effect on the pharmacokinetics of tizanidine. Drug Interactions CYP1A2 Inhibitors The effects of coadministration of fluvoxamine or ciprofloxacin, both strong CYP1A2 inhibitors, on the pharmacokinetics of a single 4 mg dose of tizanidine was studied in 10 healthy subjects. The Cmax, AUC, and half-life of tizanidine increased by 12-fold, 33-fold, and 3-fold, respectively, with coadministration of fluvoxamine. The Cmax and AUC of tizanidine increased by 7-fold and 10-fold, respectively, with coadministration of ciprofloxacin [see Contraindications (4)]. There have been no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine [see Drug Interactions (7.2)]. In vitro studies of cytochrome P450 isoenzymes using human liver microsomes indicate that neither tizanidine nor the major metabolites are likely to affect the metabolism of other drugs metabolized by cytochrome P450 isoenzymes. Oral Contraceptives No specific pharmacokinetic study was conducted to investigate interaction between oral contraceptives and Ontralfy. Retrospective analysis of population pharmacokinetic data following single and multiple dose administration of 4 mg tizanidine, however, showed that women concurrently taking oral contraceptives had 50% lower clearance of tizanidine compared Reference ID: 5493660 to women not on oral contraceptives [see Drug Interactions (7.3)]. Acetaminophen Tizanidine delayed the Tmax of acetaminophen by 16 minutes. Acetaminophen did not affect the pharmacokinetics of tizanidine. Alcohol Alcohol increased the AUC and Cmax of tizanidine by approximately 20% and 15%, respectively [see Drug Interactions (7.4)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Tizanidine was administered to mice for 78 weeks at oral doses up to 16 mg/kg/day, which is 2 times the maximum recommended human dose (MRHD) of 36 mg/day on a body surface area (mg/m2) basis. Tizanidine was administered to rats for 104 weeks at oral doses up to 9 mg/kg/day, which is 2.5 times the MRHD on a mg/m2 basis. There was no increase in tumors in either species. Mutagenesis Tizanidine was negative in in vitro (bacterial reverse mutation [Ames], mammalian gene mutation, and chromosomal aberration test in mammalian cells) and in vivo (bone marrow micronucleus, and cytogenetics) assay. Impairment of Fertility Oral administration of tizanidine to rats prior to and during mating and continuing during early pregnancy in females resulted in reduced fertility in male and female rats at doses of 30 and 10 mg/kg/day, respectively. No effect on fertility was observed at doses of 10 (male) and 3 (female) mg/kg/day, which are approximately 3 times and similar to the MRHD, respectively, on a mg/m2 basis. 14 CLINICAL STUDIES The efficacy of Ontralfy is supported by evidence from a relative bioavailability study in healthy adult subjects comparing Ontralfy to tizanidine tablets under fasted and fed conditions [see Clinical Pharmacology (12.3)]. The clinical studies described below were conducted using tizanidine tablets. The efficacy of tizanidine for the treatment of spasticity was demonstrated in two adequate and well-controlled studies in patients with multiple sclerosis or spinal cord injury (Studies 1 and 2). Single-Dose Study in Patients with Multiple Sclerosis with Spasticity In Study 1, 140 patients with spasticity caused by multiple sclerosis were randomized to receive single oral doses of 8 mg or 16 mg tizanidine, or placebo. Patients and assessors were blinded to Reference ID: 5493660 .!: E ~ -1 ··-··-··-··-··-··--··-··-··-_··--··--__r----, o, T 1 placebo ~ oL-.~-=-=-~1=-=-=--- ~ -------------------~ § i 1 ---------~--~---~---------T--------,----------7 3 4 5 6 Hours Post-Dose treatment assignment and efforts were made to reduce the likelihood that assessors would become aware indirectly of treatment assignment (e.g., they did not provide direct care to patients and were prohibited from asking questions about side effects). Response was assessed by physical examination; muscle tone was rated on a 5-point scale (Ashworth score) as follows: • 0 = normal muscle tone • 1 = slight spastic catch • 2 = more marked muscle resistance • 3 = considerable increase in tone, making passive movement difficult • 4 = a muscle immobilized by spasticity Spasm counts were also collected. Assessments were made at 1, 2, 3 and 6 hours after treatment. A statistically significant reduction of the Ashworth score for tizanidine compared to placebo was detected at 1, 2 and 3 hours after treatment. Figure 1 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. The greatest reduction in muscle tone was 1 to 2 hours after treatment. By 6 hours after treatment, muscle tone in the 8 mg and 16 mg tizanidine groups was indistinguishable from muscle tone in patients who received placebo. Within a given patient, improvement in muscle tone was correlated with plasma concentration. Plasma concentrations were variable from patient to patient at a given dose. Although 16 mg produced a larger effect, adverse reactions including hypotension were more common and more severe than in the 8 mg group. There were no differences in the number of spasms occurring in each group. Figure 1: Single Dose Study—Mean Change in Muscle Tone from Baseline as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline) Reference ID: 5493660 ·6~---------------------------~ ~ :: :::::::::::::···r:::::: _______ ■1---~(m=oa=:=i~=~=~i=:=~~=·s=m-=")- ~ .3 ·············i ······------~~----------------------------------1 - ·2 I e -1 ···························--------····························------1 ----------------------------------+---------------------------------+-------I a. • placebo • § o-1--------+--------__.j--'======='---I-------I • 1 ---------------l--------------------------------------------------1 End of Titration (Study Week 3) End of Maintenance (StudyWHk7) Endpoint (Last Observation carried Forward) Seven-Week Study in Patients with Spinal Cord Injury with Spasticity In a 7-week study (Study 2), 118 patients with spasticity secondary to spinal cord injury were randomized to either placebo or tizanidine. Steps similar to those taken in the first study were employed to ensure the integrity of blinding. Patients were titrated over 3 weeks up to a maximum tolerated dose or 36 mg daily given in three unequal doses (e.g., 10 mg given in the morning and afternoon and 16 mg given at night). Patients were then maintained on their maximally tolerated dose for 4 additional weeks (i.e., maintenance phase). Throughout the maintenance phase, muscle tone was assessed on the Ashworth scale within a period of 2.5 hours following either the morning or afternoon dose. The number of daytime spasms was recorded daily by patients. At endpoint (the protocol-specified time of outcome assessment), there was a statistically significant reduction in muscle tone and frequency of spasms in the tizanidine treated group compared to placebo. The reduction in muscle tone was not associated with a reduction in muscle strength (a desirable outcome) but also did not lead to any consistent advantage of tizanidine treated patients on measures of activities of daily living. Figure 2 below shows a comparison of the mean change in muscle tone from baseline as measured by the Ashworth scale. Figure 2: Seven Week Study—Mean Change in Muscle Tone 0.5–2.5 Hours After Dosing as Measured by the Ashworth Scale ± 95% Confidence Interval (A Negative Ashworth Score Signifies an Improvement in Muscle Tone from Baseline) Reference ID: 5493660 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Ontralfy contains 2 mg/5 mL tizanidine. It is a clear, colorless to pale yellow solution with strawberry flavor and is supplied in bottles of 473 mL with child-resistant closure (NDC 82919­ 626-16). 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in containers with child-resistant closure. 17 PATIENT COUNSELING INFORMATION Serious Drug Interactions Advise patients they should not take Ontralfy if they are taking fluvoxamine or ciprofloxacin because of the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation. Instruct patients to inform their healthcare providers when they start or stop taking any medication because of the risks associated with interaction between Ontralfy and other medicines [see Contraindications (4) and Drug Interactions (7)]. Ontralfy Dosing and Administration Tell patients to take Ontralfy exactly as prescribed (consistently either with or without food) [see Dosage and Administration (2.2)]. Inform patients that they should not take more Ontralfy than prescribed because of the risk of adverse events at single doses greater than 8 mg or total daily doses greater than 36 mg. Tell patients that they should not suddenly discontinue Ontralfy, because rebound hypertension and tachycardia may occur [see Warnings and Precautions (5.6)]. Hypotension Warn patients that they may experience hypotension and to be careful when changing from a lying or sitting to a standing position [see Warnings and Precautions (5.1)]. Sedation Tell patients that Ontralfy may cause them to become sedated or somnolent and they should be careful when performing activities that require alertness, such as driving a vehicle or operating machinery [see Warnings and Precautions (5.3)]. Tell patients that the sedation may be additive when Ontralfy is taken in conjunction with drugs (baclofen, benzodiazepines) or substances (e.g., alcohol) that act as CNS depressants. Remind patients that if they depend on their spasticity to sustain posture and balance in locomotion, or whenever spasticity is utilized to obtain increased function, that Ontralfy decreases spasticity and caution should be used. Hypersensitivity Reactions Inform patients of the signs and symptoms of severe allergic reactions and instruct them to discontinue Reference ID: 5493660 Ontralfy and seek immediate medical care should these signs and symptoms occur [see Warnings and Precautions (5.5)]. Manufactured for: Fidelity BioPharma Co., New Haven, CT 06510 2024 Fidelity BioPharma Co. All rights reserved. Reference ID: 5493660
custom-source
2025-02-12T15:47:45.056393
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TYENNE safely and effectively. See full prescribing information for TYENNE. TYENNE® (tocilizumab-aazg) injection, for intravenous or subcutaneous use Initial U.S. Approval: 2024 TYENNE® (tocilizumab-aazg) is biosimilar* to ACTEMRA® (tocilizumab). WARNING: RISK OF SERIOUS INFECTIONS See full prescribing information for complete boxed warning. • Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections have occurred in patients receiving tocilizumab products. (5.1) • If a serious infection develops, interrupt TYENNE until the infection is controlled. (5.1) • Perform test for latent TB; if positive, start treatment for TB prior to starting TYENNE. (5.1) • Monitor all patients for active TB during treatment, even if initial latent TB test is negative. (5.1) --------------------------RECENT MAJOR CHANGES------------------­ Warnings and Precautions (5.6) 12/2024 --------------------------INDICATIONS AND USAGE-------------------­ TYENNE® (tocilizumab-aazg) is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of: Rheumatoid Arthritis (RA) (1.1) • Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). Giant Cell Arteritis (GCA) (1.2) • Adult patients with giant cell arteritis. Polyarticular Juvenile Idiopathic Arthritis (PJIA) (1.3) • Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis. Systemic Juvenile Idiopathic Arthritis (SJIA) (1.4) • Patients 2 years of age and older with active systemic juvenile idiopathic arthritis. ------------------DOSAGE AND ADMINISTRATION----------------­ For RA, pJIA and sJIA, TYENNE may be used alone or in combination with methotrexate; and in RA, other non-biologic DMARDs may be used. (2) General Administration and Dosing Information (2.1) • RA, GCA, PJIA and SJIA – It is recommended that TYENNE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or ALT or AST above 1.5 times the upper limit of normal (ULN)(5.3, 5.4). • In RA patients, TYENNE doses exceeding 800 mg per infusion are not recommended. (2.2, 2.7, 12.3) • In GCA patients, TYENNE doses exceeding 600 mg per infusion are not recommended. (2.3, 12.3) Rheumatoid Arthritis (2.2) Recommended Adult Intravenous Dosage: When used in combination with non-biologic DMARDs or as monotherapy the recommended starting dose is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response. Recommended Adult Subcutaneous Dosage: Patients less than 100 kg 162 mg administered subcutaneously weight every other week, followed by an increase to every week based on clinical response Patients at or above 100 kg 162 mg administered subcutaneously weight every week Giant Cell Arteritis (2.3) Recommended Adult Intravenous Dosage: The recommended dose is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids. TYENNE can be used alone following discontinuation of glucocorticoids. Recommended Adult Subcutaneous Dosage: The recommended dose is 162 mg given once every week as a subcutaneous injection, in combination with a tapering course of glucocorticoids. A dose of 162 mg given once every other week as a subcutaneous injection, in combination with a tapering course of glucocorticoids, may be prescribed based on clinical considerations. TYENNE can be used alone following discontinuation of glucocorticoids. Polyarticular Juvenile Idiopathic Arthritis (2.4) Recommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous PJIA Dosage Patients less than 30 kg weight 162 mg once every three weeks Patients at or above 30 kg weight 162 mg once every two weeks Systemic Juvenile Idiopathic Arthritis (2.5) Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous SJIA Dosage Patients less than 30 kg weight 162 mg every two weeks Patients at or above 30 kg weight 162 mg every week Administration of Intravenous formulation (2.6) • For patients with RA, GCA, PJIA, and SJIA patients at or above 30 kg, dilute to 100 mL in 0.9% or 0.45% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique. • For PJIA, and SJIA patients less than 30 kg, dilute to 50 mL in 0.9% or 0.45% Sodium Chloride Injection, USP for intravenous infusion using aseptic technique. • Administer as a single intravenous drip infusion over 1 hour; do not administer as bolus or push. Administration of Subcutaneous formulation (2.7) • Follow the Instructions for Use for prefilled syringe and prefilled autoinjector Dose Modifications (2.8) Recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia. ------------------DOSAGE FORMS AND STRENGTHS-----------------­ Intravenous Infusion Injection: 80 mg/4 mL (20 mg/mL), 200 mg/10 mL (20 mg/mL), 400 mg/20 mL (20 mg/mL) in single-dose vials for further dilution prior to intravenous infusion (3) Subcutaneous Injection Injection: 162 mg/0.9 mL in a single-dose prefilled syringe or single-dose prefilled autoinjector (3) ---------------------------CONTRAINDICATIONS-----------------------­ Known hypersensitivity to tocilizumab products. (4) --------------------WARNINGS AND PRECAUTIONS----------------­ • Serious Infections – do not administer TYENNE during an active infection, including localized infections. If a serious infection develops, interrupt TYENNE until the infection is controlled. (5.1) • Gastrointestinal (GI) perforation—use with caution in patients who may be at increased risk. (5.2) • Hepatotoxicity- monitor patients for signs and symptoms of hepatic injury. Modify or discontinue TYENNE if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. (2.8, 5.3) Reference ID: 5495671 1 • Laboratory monitoring—recommended due to potential consequences of treatment-related changes in neutrophils, platelets, lipids, and liver function tests. (2.8, 5.4) • Hypersensitivity reactions, including anaphylaxis and death, and serious cutaneous reactions including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)- discontinue TYENNE, treat promptly, and monitor until reaction resolves (5.6) • Live vaccines—Avoid use with TYENNE (5.9, 7.3) -------------------------ADVERSE REACTIONS-------------------------­ Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, injection site reactions. (6) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF SERIOUS INFECTIONS 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis (RA) 1.2 Giant Cell Arteritis (GCA) 1.3 Polyarticular Juvenile Idiopathic Arthritis (PJIA) 1.4 Systemic Juvenile Idiopathic Arthritis (SJIA) 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations for Administration 2.2 Recommended Dosage for Rheumatoid Arthritis 2.3 Recommended Dosage for Giant Cell Arteritis 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis 2.5 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis 2.6 Preparation and Administration Instructions for Intravenous Infusion 2.7 Preparation and Administration Instructions for Subcutaneous Injection 2.8 Dosage Modifications due to Serious Infections or Laboratory Abnormalities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections 5.2 Gastrointestinal Perforations 5.3 Hepatotoxicity 5.4 Changes in Laboratory Parameters 5.5 Immunosuppression 5.6 Hypersensitivity Reactions, Including Anaphylaxis 5.7 Demyelinating Disorders 5.8 Active Hepatic Disease and Hepatic Impairment 5.9 Vaccinations 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) 6.2 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Subcutaneous Tocilizumab (Tocilizumab-SC) 6.3 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Subcutaneous Tocilizumab (Tocilizumab-SC) 6.4 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) 6.5 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Intravenous Tocilizumab (Tocilizumab-IV) 6.6 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Subcutaneous Tocilizumab (Tocilizumab-SC) -----------------USE IN SPECIFIC POPULATIONS-----------------­ • Pregnancy: Based on animal data, may cause fetal harm. (8.1) • Lactation: Discontinue drug or nursing taking into consideration importance of drug to mother. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of TYENNE has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s), strength(s), dosage form(s), and route(s) of administration) described in its Full Prescribing Information. Revised: 12/2024 6.7 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) 6.8 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Subcutaneous Tocilizumab (Tocilizumab-SC) 6.9 Post marketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Drugs for Treatment of Adult Indications 7.2 Interactions with CYP450 Substrates 7.3 Live Vaccines 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 9 DRUG ABUSE AND DEPENDENCE 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICALPHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICALTOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis – Intravenous Administration 14.2 Rheumatoid Arthritis – Subcutaneous Administration 14.3 Giant Cell Arteritis – Subcutaneous Administration 14.4 Giant Cell Arteritis – Intravenous Administration 14.5 Polyarticular Juvenile Idiopathic Arthritis – Intravenous Administration 14.6 Polyarticular Juvenile Idiopathic Arthritis – Subcutaneous Administration 14.7 Systemic Juvenile Idiopathic Arthritis – Intravenous Administration 14.8 Systemic Juvenile Idiopathic Arthritis – Subcutaneous Administration 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5495671 2 FULL PRESCRIBING INFORMATION WARNING: RISK OF SERIOUS INFECTIONS Patients treated with tocilizumab products including TYENNE are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt TYENNE until the infection is controlled. Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before TYENNE use and during therapy. Treatment for latent infection should be initiated prior to TYENNE use. • Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. • Bacterial, viral and other infections due to opportunistic pathogens. The risks and benefits of treatment with TYENNE should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with TYENNE including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)]. Reference ID: 5495671 3 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis (RA) TYENNE® (tocilizumab-aazg) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). 1.2 Giant Cell Arteritis (GCA) TYENNE® (tocilizumab-aazg) is indicated for the treatment of giant cell arteritis (GCA) in adult patients. 1.3 Polyarticular Juvenile Idiopathic Arthritis (PJIA) TYENNE® (tocilizumab-aazg) is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. 1.4 Systemic Juvenile Idiopathic Arthritis (SJIA) TYENNE® (tocilizumab-aazg) is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older. 2 DOSAGE AND ADMINISTRATION 2.1 General Considerations for Administration Not Recommended for Concomitant Use with Biological DMARDs Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection. Avoid using TYENNE with biological DMARDs. Baseline Laboratory Evaluation Prior to Treatment Obtain and assess baseline complete blood count (CBC) and liver function tests prior to treatment. RA, GCA, PJIA and SJIA – It is recommended that TYENNE not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or ALT or AST above 1.5 times the upper limit of normal (ULN) [see Warnings and Precautions (5.3, 5.4)]. 2.2 Recommended Dosage for Rheumatoid Arthritis TYENNE may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection. Recommended Intravenous Dosage Regimen: The recommended dosage of TYENNE for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response. • Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.1)]. • Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology (12.3)]. Recommended Subcutaneous Dosage Regimen: Patients less than 100 kg weight 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response Patients at or above 100 kg weight 162 mg administered subcutaneously every week Reference ID: 5495671 4 I I I I When transitioning from TYENNE intravenous therapy to subcutaneous administration administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.2)]. 2.3 Recommended Dosage for Giant Cell Arteritis Recommended Intravenous Dosage Regimen: The recommended dosage of TYENNE for adult patients given as a 60-minute single intravenous drip infusion is 6 mg per kg every 4 weeks in combination with a tapering course of glucocorticoids. TYENNE can be used alone following discontinuation of glucocorticoids. • Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)]. • Doses exceeding 600 mg per infusion are not recommended in GCA patients [see Clinical Pharmacology (12.3)]. Recommended Subcutaneous Dosage Regimen: The recommended dose of TYENNE for adult patients with GCA is 162 mg given once every week as a subcutaneous injection in combination with a tapering course of glucocorticoids. A dose of 162 mg given once every other week as a subcutaneous injection in combination with a tapering course of glucocorticoids may be prescribed based on clinical considerations. TYENNE can be used alone following discontinuation of glucocorticoids. When transitioning from TYENNE intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)]. 2.4 Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis TYENNE may be used as an intravenous infusion or as a subcutaneous injection alone or in combination with methotrexate. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. Recommended Intravenous Dosage Regimen: The recommended dosage of TYENNE for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is: Recommended Intravenous PJIA Dosage Every 4 Weeks Patients less than 30 kg weight 10 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous Dosage Regimen: Recommended Subcutaneous PJIA Dosage Patients less than 30 kg weight 162 mg once every 3 weeks Patients at or above 30 kg weight 162 mg once every 2 weeks When transitioning from TYENNE intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose. Reference ID: 5495671 5 I I Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)]. 2.5 Recommended Dosage for Systemic Juvenile Idiopathic Arthritis TYENNE may be used as an intravenous infusion or as a subcutaneous injection alone or in combination with methotrexate. Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate. Recommended Intravenous Dosage Regimen: The recommended dose of TYENNE for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is: Recommended Intravenous SJIA Dosage Every 2 Weeks Patients less than 30 kg weight 12 mg per kg Patients at or above 30 kg weight 8 mg per kg Recommended Subcutaneous Dosage Regimen: Recommended Subcutaneous SJIA Dosage Patients less than 30 kg weight 162 mg once every two weeks Patients at or above 30 kg weight 162 mg once every week When transitioning from TYENNE intravenous therapy to subcutaneous administration, administer the first subcutaneous dose when the next scheduled intravenous dose is due. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.8)]. 2.6 Preparation and Administration Instructions for Intravenous Infusion TYENNE for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows: • Use a sterile needle and syringe to prepare TYENNE. • Patients less than 30 kg: use a 50 mL infusion bag or bottle of 0.9% or 0.45% Sodium Chloride Injection, USP, and then follow steps 1 and 2 below. • Patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps 1 and 2 below. – Step 1. Withdraw a volume of 0.9% or 0.45% Sodium Chloride Injection, USP, equal to the volume of the TYENNE injection required for the patient’s dose from the infusion bag or bottle [see Dosage and Administration (2.2, 2.4, 2.5)]. For Intravenous Use: Volume of TYENNE Injection per kg of Body Weight Dosage Indication Volume of TYENNE injection per kg of body weight 4 mg/kg Adult RA 0.2 mL/kg 6mg/kg Adult GCA 0.3 mL/kg 8 mg/kg Adult RA SJIA and PJIA (greater than or equal to 30 kg of body weight) 0.4 mL/kg 10 mg/kg PJIA (less than 30 kg of body weight) 0.5 mL/kg 12 mg/kg SJIA (less than 30 kg of body weight) 0.6 mL/kg Reference ID: 5495671 6 – Step 2. Withdraw the amount of TYENNE for intravenous infusion from the vial(s) and add slowly into the 0.9% or 0.45% Sodium Chloride Injection, USP infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming. • The prepared solution for infusion should be used immediately. If not used immediately, the diluted tocilizumab solutions may be refrigerated at 36°F to 46°F (2°C to 8°C) up to 24 hours, or stored at room temperature at or below 77°F (25°C) for up to 4 hours and should be protected from light. Administration of diluted TYENNE solution must be completed within this period of time. • TYENNE solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used. • Allow the fully diluted TYENNE solution to reach room temperature prior to infusion. • The infusion should be administered over 60 minutes and must be administered with an infusion set. Do not administer as an intravenous push or bolus. • TYENNE should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of TYENNE with other drugs. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used. • Fully diluted TYENNE solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and bottles, and glass infusion bottles. 2.7 Preparation and Administration Instructions for Subcutaneous Injection • TYENNE for subcutaneous injection is not intended for intravenous drip infusion. • Assess suitability of patient for subcutaneous home use and instruct patients to inform a healthcare professional before administering the next dose if they experience any symptoms of allergic reaction. Patients should seek immediate medical attention if they develop symptoms of serious allergic reactions. TYENNE subcutaneous injection is intended for use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject TYENNE or the patient’s caregiver may administer TYENNE if a healthcare practitioner determines that it is appropriate. PJIA and SJIA patients may self-inject with the TYENNE prefilled syringe or autoinjector, or the patient’s caregiver may administer TYENNE if both the healthcare practitioner and the parent/legal guardian determine it is appropriate [see Use in Specific Populations (8.4)]. Patients, or patient caregivers, should be instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication administration. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use TYENNE prefilled syringes (PFS) or prefilled autoinjectors exhibiting particulate matter, cloudiness, or discoloration. TYENNE for subcutaneous administration should be clear and colorless to pale yellow. Do not use if any part of the PFS or autoinjector appears to be damaged. • Patients using TYENNE for subcutaneous administration should be instructed to inject the full amount in the syringe (0.9 mL) or full amount in the autoinjector (0.9 mL), which provides 162 mg of TYENNE, according to the directions provided in the IFU. • Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. Reference ID: 5495671 7 2.8 Dosage Modifications due to Serious Infections or Laboratory Abnormalities Serious Infections Hold TYENNE treatment if a patient develops a serious infection until the infection is controlled. Laboratory Abnormalities Rheumatoid Arthritis and Giant Cell Arteritis Liver Enzyme Abnormalities [see Warnings and Precautions (5.3, 5.4)] Lab Value Recommendation for RA Recommendation for GCA Greater than 1 to 3x ULN Dose modify concomitant DMARDs if appropriate For persistent increases in this range: • For patients receiving intravenous TYENNE, reduce dose to 4 mg per kg or hold TYENNE until ALT or AST have normalized • For patients receiving subcutaneous TYENNE, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume TYENNE at every other week and increase frequency to every week as clinically appropriate Dose modify immunomodulatory agents if appropriate For persistent increases in this range: • For patients receiving Intravenous TYENNE, hold TYENNE until ALT or AST have normalized • For patients receiving subcutaneous TYENNE, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume TYENNE at every other week and increase frequency to every week as clinically appropriate Greater than 3 to 5x ULN (confirmed by repeat testing) Hold TYENNE dosing until less than 3x ULN and follow recommendations above for greater than 1 to 3x ULN For persistent increases greater than 3x ULN, discontinue TYENNE Hold TYENNE dosing until less than 3x ULN and follow recommendations above for greater than 1 to 3x ULN For persistent increases greater than 3x ULN, discontinue TYENNE Greater than 5x ULN Discontinue TYENNE Discontinue TYENNE Reference ID: 5495671 8 Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5.4)] Lab Value (cells per mm3) Recommendation for RA Recommendation for GCA ANC greater than 1000 Maintain dose Maintain dose ANC 500 to 1000 Hold TYENNE dosing When ANC greater than 1000 cells per 3 mm : • For patients receiving intravenous TYENNE, resume TYENNE at 4 mg per kg and increase to 8 mg per kg as clinically appropriate • For patients receiving subcutaneous TYENNE, resume TYENNE at every other week and increase frequency to every week as clinically appropriate Hold TYENNE dosing When ANC greater than 1000 cells per 3 mm : • For patients receiving intravenous TYENNE, resume TYENNE at 6 mg per kg • For patients receiving subcutaneous TYENNE, resume TYENNE at every other week and increase frequency to every week as clinically appropriate ANC less than 500 Discontinue TYENNE Discontinue TYENNE Low Platelet Count [see Warnings and Precautions (5.4)] Lab Value (cells per mm3) Recommendation for RA Recommendation for GCA 50,000 to 100,000 Hold TYENNE dosing When platelet count is greater than 100,000 3 cells per mm : • For patients receiving intravenous TYENNE, resume TYENNE at 4 mg per kg and increase to 8 mg per kg as clinically appropriate • For patients receiving subcutaneous TYENNE, resume TYENNE at every other week and increase frequency to every week as clinically appropriate Hold TYENNE dosing When platelet count is greater than 100,000 cells per mm3: • For patients receiving intravenous TYENNE, resume TYENNE at 6 mg per kg • For patients receiving subcutaneous TYENNE, resume TYENNE at every other week and increase frequency to every week as clinically appropriate Less than 50,000 Discontinue TYENNE Discontinue TYENNE Polyarticular and Systemic Juvenile Idiopathic Arthritis Dose reduction of tocilizumab products has not been studied in the PJIA and SJIA populations. Dose interruptions of TYENNE are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined above for patients with RA and GCA. If appropriate, dose modify or stop concomitant methotrexate and/or other medications and hold TYENNE dosing until the clinical situation has been evaluated. In PJIA and SJIA the decision to discontinue TYENNE for a laboratory abnormality should be based upon the medical assessment of the individual patient. Reference ID: 5495671 9 3 DOSAGE FORMS AND STRENGTHS Intravenous Infusion Injection: 80 mg/4 mL (20 mg/mL), 200 mg/10 mL (20 mg/mL), 400 mg/20 mL (20 mg/mL) as a clear and colorless to pale yellow solution in single-dose vials for further dilution prior to intravenous infusion. Subcutaneous Injection Injection: 162 mg/0.9 mL clear and colorless to pale yellow solution in a single-dose prefilled syringe or single-dose prefilled autoinjector. 4 CONTRAINDICATIONS TYENNE is contraindicated in patients with known hypersensitivity to tocilizumab products [see Warnings and Precautions (5.6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including tocilizumab products. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with tocilizumab products. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections. Do not administer TYENNE in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating TYENNE in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of serious or an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with TYENNE, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.1), Adverse Reactions (6.1), and Patient Counseling Information (17)]. Hold TYENNE if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with TYENNE should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient. Tuberculosis Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating TYENNE. Consider anti-tuberculosis therapy prior to initiation of TYENNE in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested 10 Reference ID: 5495671 negative for latent tuberculosis infection prior to initiating therapy. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating TYENNE. Viral Reactivation Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with tocilizumab. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded. 5.2 Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with tocilizumab. Use TYENNE with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with fever, new onset abdominal symptoms, and a change in bowel habits for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)]. 5.3 Hepatotoxicity Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous tocilizumab products. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from months to years after treatment initiation with tocilizumab products. While most cases presented with marked elevations of transaminases (> 5 times ULN), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases. During randomized controlled studies, treatment with tocilizumab was associated with a higher incidence of transaminase elevations [see Adverse Reactions (6.1, 6.2, 6.5, 6.7)]. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with tocilizumab. For RA and GCA patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating TYENNE, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter. It is not recommended to initiate TYENNE treatment in RA or GCA patients with elevated transaminases ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than 5x ULN, discontinue TYENNE. For recommended modifications based upon increase in transaminases [see Dosage and Administration (2.8)]. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (e.g., ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range), TYENNE treatment should be interrupted and investigation done to establish the probable cause. TYENNE should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests. A similar pattern of liver enzyme elevation is noted with tocilizumab products treatment in the PJIA and SJIA populations. Monitor liver test panel at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. 5.4 Changes in Laboratory Parameters Patients with Rheumatoid Arthritis and Giant Cell Arteritis Reference ID: 5495671 11 Neutropenia Treatment with tocilizumab products was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience. – It is not recommended to initiate TYENNE treatment in RA and GCA patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm3. In patients who develop an absolute neutrophil count less than 500 per mm3 treatment is not recommended. – Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter [see Clinical Pharmacology (12.2)]. For recommended modifications based on ANC results [ see Dosage and Administration (2.8)]. Thrombocytopenia Treatment with tocilizumab products was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials [see Adverse Reactions (6.1, 6.2)]. – It is not recommended to initiate TYENNE treatment in RA and GCA patients with a platelet count below 100,000 per mm3. In patients who develop a platelet count less than 50,000 per mm3 treatment is not recommended. – Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts [see Dosage and Administration (2.8)]. Elevated Liver Enzymes Refer to 5.3 Hepatotoxicity. For recommended modifications [see Dosage and Administration (2.8)]. Lipid Abnormalities Treatment with tocilizumab products was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol [see Adverse Reactions (6.1, 6.2)]. – Assess lipid parameters approximately 4 to 8 weeks following initiation of TYENNE therapy. – Subsequently, manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia. Patients with Polyarticular and Systemic Juvenile Idiopathic Arthritis A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with tocilizumab products treatment in the PJIA and SJIA populations. Monitor neutrophils, platelets, ALT and AST at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Monitor lipids as above for approved adult indications [see Dosage and Administration (2.8)]. 5.5 Immunosuppression The impact of treatment with tocilizumab products on the development of malignancies is not known but malignancies were observed in clinical studies [see Adverse Reactions (6.1)]. TYENNE is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies. 5.6 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis, have been reported in association with tocilizumab products and anaphylactic events with a fatal outcome have been reported with intravenous infusion of tocilizumab products. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous tocilizumab, 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1465) of patients in the subcutaneous all- Reference ID: 5495671 12 exposure population. In the SJIA controlled trial with intravenous tocilizumab, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous tocilizumab, 0 out of 188 patients (0%) in the tocilizumab all-exposure population experienced hypersensitivity reactions that required treatment discontinuation. Reactions that required treatment discontinuation included generalized erythema, rash, and urticaria. Injection site reactions were categorized separately [see Adverse Reactions (6)]. In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous tocilizumab products, with or without concomitant therapies. Events have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of tocilizumab products [see Adverse Reactions (6.9)]. In addition, serious cutaneous reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported in patients with autoinflammatory conditions treated with tocilizumab products. TYENNE for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. For TYENNE subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If a hypersensitivity reaction occurs, immediately discontinue TYENNE, treat promptly and monitor until signs and symptoms resolve. 5.7 Demyelinating Disorders The impact of treatment with tocilizumab products on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of TYENNE in patients with preexisting or recent onset demyelinating disorders. 5.8 Active Hepatic Disease and Hepatic Impairment Treatment with TYENNE is not recommended in patients with active hepatic disease or hepatic impairment [see Adverse Reactions (6.1), Use in Specific Populations (8.6)]. 5.9 Vaccinations Avoid use of live vaccines concurrently with TYENNE as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab products. No data are available on the effectiveness of vaccination in patients receiving tocilizumab products. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly pediatric or elderly patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating TYENNE therapy. The interval between live vaccinations and initiation of TYENNE therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: • Serious Infections [see Warnings and Precautions (5.1)] • Gastrointestinal Perforations [see Warnings and Precautions (5.2)] • Laboratory Parameters [see Warnings and Precautions (5.4)] • Immunosuppression [see Warnings and Precautions (5.5)] • Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.6)] 13 Reference ID: 5495671 • Demyelinating Disorders [see Warnings and Precautions (5.7)] • Active Hepatic Disease and Hepatic Impairment [see Warnings and Precautions (5.8)] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. 6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (tocilizumab-IV) The tocilizumab-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of tocilizumab-IV 8 mg per kg monotherapy (288 patients), tocilizumab­IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or tocilizumab-IV 4 mg per kg in combination with methotrexate (774 patients). The all exposure population includes all patients in registration studies who received at least one dose of tocilizumab-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years. All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian. The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1)]. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with tocilizumab-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT. The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking tocilizumab-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of tocilizumab-IV were increased hepatic transaminase values (per protocol requirement) and serious infections. Overall Infections In the 24 week, controlled clinical studies, the rate of infections in the tocilizumab-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 133 and 127 events per 100 patient- years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis. The overall rate of infections with tocilizumab-IV in the all exposure population remained consistent with rates in the controlled periods of the studies. Serious Infections In the 24 week, controlled clinical studies, the rate of serious infections in the tocilizumab-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group. In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported [see Warnings and Precautions (5.1)]. In the cardiovascular outcomes Study WA25204, the rate of serious infections in the tocilizumab 8 mg/kg IV every 4 weeks group, with or without DMARD, was 4.5 per 100 patient-years, and the rate in the etanercept Reference ID: 5495671 14 50 mg weekly SC group, with or without DMARD, was 3.2 per 100 patient-years [see Clinical Studies (14.1)]. Gastrointestinal Perforations During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with tocilizumab-IV therapy. In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti- inflammatory medications (NSAIDs), corticosteroids, or methotrexate [see Warnings and Precautions (5.2)]. The relative contribution of these concomitant medications versus tocilizumab-IV to the development of GI perforations is not known. Infusion Reactions In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting. Anaphylaxis Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with tocilizumab-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of tocilizumab-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction [see Warnings and Precautions 5.6)]. Laboratory Abnormalities Neutropenia In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm3 occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm3 occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm3 and the occurrence of serious infections. In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.4)]. Thrombocytopenia In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm3 occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events. In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions 5.4)]. Elevated Liver Enzymes Reference ID: 5495671 15 Liver enzyme abnormalities are summarized in Table 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tocilizumab-IV, or reduction in tocilizumab-IV dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration (2.1)]. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency [see Warnings and Precautions (5.3, 5.4)]. Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V* Tocilizumab 8 mg per kg MONOTHERAPY N = 288 (%) Methotrexate N = 284 (%) Tocilizumab 4 mg per kg + DMARDs N = 774 (%) Tocilizumab 8 mg per kg + DMARDs N = 1582 (%) Placebo + DMARDs N = 1170 (%) AST (U/L) > ULN to 3x ULN 22 26 34 41 17 > 3x ULN to 5x ULN 0.3 2 1 2 0.3 > 5x ULN 0.7 0.4 0.1 0.2 < 0.1 ALT (U/L) > ULN to 3x ULN 36 33 45 48 23 > 3x ULN to 5x ULN 1 4 5 5 1 > 5x ULN 0.7 1 1.3 1.5 0.3 ULN = Upper Limit of Normal *For a description of these studies, see Section 14, Clinical Studies. In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials. In Study WA25204, of the 1538 patients with moderate to severe RA [see Clinical Studies (14.1)] and treated with tocilizumab, elevations in ALT or AST >3 x ULN occurred in 5.3% and 2.2% patients, respectively. One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with tocilizumab. Lipids Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of tocilizumab-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below: – Mean LDL increased by 13 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 20 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 25 mg per dL in tocilizumab 8 mg per kg monotherapy. – Mean HDL increased by 3 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 5 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 4 mg per dL in tocilizumab 8 mg per kg monotherapy. – Mean LDL/HDL ratio increased by an average of 0.14 in the tocilizumab 4 mg per kg+DMARD arm, 0.15 in the tocilizumab 8 mg per kg+DMARD, and 0.26 in tocilizumab 8 mg per kg monotherapy. – ApoB/ApoA1 ratios were essentially unchanged in tocilizumab-treated patients. – Elevated lipids responded to lipid lowering agents. In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials. Reference ID: 5495671 16 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of tocilizumab or of other tocilizumab products. In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies. Malignancies During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving tocilizumab-IV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the tocilizumab-IV groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years). In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period [see Warnings and Precautions (5.5)]. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg tocilizumab-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2. Table 2 Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per kg Tocilizumab plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD 24 Week Phase 3 Controlled Study Population Preferred Term Tocilizumab 8 mg per kg MONOTHERAPY N = 288 (%) Methotrexate N = 284 (%) Tocilizumab 4 mg per kg + DMARDs N = 774 (%) Tocilizumab 8 mg per kg + DMARDs N = 1582 (%) Placebo + DMARDs N = 1170 (%) Upper Respiratory Tract Infection 7 5 6 8 6 Nasopharyngitis 7 6 4 6 4 Headache 7 2 6 5 3 Hypertension 6 2 4 4 3 ALT increased 6 4 3 3 1 Dizziness 3 1 2 3 2 Bronchitis 3 2 4 3 3 Rash 2 1 4 3 1 Mouth Ulceration 2 2 1 2 1 Abdominal Pain Upper 2 2 3 3 2 Gastritis 1 2 1 2 1 Transaminase increased 1 5 2 2 1 Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with tocilizumab-IV in controlled trials were: Infections and Infestations: oral herpes simplex Gastrointestinal disorders: stomatitis, gastric ulcer Investigations: weight increased, total bilirubin increased Blood and lymphatic system disorders: leukopenia General disorders and administration site conditions: edema peripheral Reference ID: 5495671 17 Respiratory, thoracic, and mediastinal disorders: dyspnea, cough Eye disorders: conjunctivitis Renal disorders: nephrolithiasis Endocrine disorders: hypothyroidism 6.2 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Subcutaneous Tocilizumab (tocilizumab-SC) The tocilizumab-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously and 8 mg/kg intravenously every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo- controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week subcutaneously or placebo in 656 patients. All patients in both studies received background non-biologic DMARDs. The safety observed for tocilizumab-SC administered subcutaneously was consistent with the known safety profile of intravenous tocilizumab, with the exception of injection site reactions (ISRs), which were more common with tocilizumab-SC compared with placebo SC injections (IV arm). Injection Site Reactions In the 6-month control period, in SC-I, the frequency of ISRs was 10.1% (64/631) and 2.4% (15/631) for the weekly tocilizumab-SC and placebo SC (IV-arm) groups, respectively. In SC-II, the frequency of ISRs was 7.1% (31/437) and 4.1% (9/218) for the every other week tocilizumab-SC and placebo groups, respectively. These ISRs (including erythema, pruritus, pain and hematoma) were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation. Immunogenicity In the 6-month control period in SC-I, 0.8% (5/625) in the tocilizumab-SC arm and 0.8% (5/627) in the IV arm developed anti-tocilizumab antibodies; of these, all developed neutralizing antibodies. In SC-II, 1.6% (7/434) in the tocilizumab-SC arm compared with 1.4 % (3/217) in the placebo arm developed anti-tocilizumab antibodies; of these, 1.4% (6/434) in the tocilizumab-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies. A total of 1454 (>99%) patients who received tocilizumab-SC in the all exposure group have been tested for anti­ tocilizumab antibodies. Thirteen patients (0.9%) developed anti-tocilizumab antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies. The rate is consistent with previous intravenous experience. No correlation of antibody development to adverse events or loss of clinical response was observed. Laboratory Abnormalities Neutropenia During routine laboratory monitoring in the 6-month controlled clinical trials, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% and 3.7% of patients receiving tocilizumab-SC weekly and every other week, respectively. There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections. Thrombocytopenia During routine laboratory monitoring in the tocilizumab-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤ 50,000/mm3. Elevated Liver Enzymes During routine laboratory monitoring in the 6-month controlled clinical trials, elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively, receiving tocilizumab-SC weekly and 3.4% and 0.7% Reference ID: 5495671 18 receiving tocilizumab-SC every other week. Lipid Parameters Elevations During routine laboratory monitoring in the tocilizumab-SC 6-month clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and 10.2% of patients on placebo experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l (160 mg/dL) receiving tocilizumab-SC weekly, every other week and placebo, respectively. 6.3 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Subcutaneous Tocilizumab (tocilizumab-SC) The safety of subcutaneous tocilizumab has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the tocilizumab-SC GCA all exposure population was 138.5 patient years during the 12-month double blind, placebo-controlled phase of the study. The overall safety profile observed in the tocilizumab-SC treatment groups was generally consistent with the known safety profile of tocilizumab. There was an overall higher incidence of infections in GCA patients relative to RA patients. The rate of infection/serious infection events was 200.2/9.7 events per 100 patient years in the tocilizumab-SC weekly group and 160.2/4.4 events per 100 patient years in the tocilizumab-SC every other week group as compared to 156.0/4.2 events per 100 patient years in the placebo + 26 week prednisone taper and 210.2/12.5 events per 100 patient years in the placebo + 52 week taper groups. 6.4 Clinical Trials Experience in Giant Cell Arteritis Patients Treated With Intravenous Tocilizumab (tocilizumab-IV) The safety of tocilizumab-IV was studied in an open label PK-PD and safety study in 24 patients with GCA who were in remission on tocilizumab-IV at time of enrollment. Patients received tocilizumab 7 mg/kg every 4 weeks for 20 weeks, followed by 6 mg/kg every 4 weeks for 20 weeks. The total patient years exposure to treatment was 17.5 years. The overall safety profile observed for tocilizumab administered intravenously in GCA patients was consistent with the known safety profile of tocilizumab. 6.5 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Intravenous Tocilizumab (tocilizumab-IV) The safety of tocilizumab-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the tocilizumab-IV all exposure population (defined as patients who received at least one dose of tocilizumab-IV) was 184.4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients [see Adverse Reactions (6.1 and 6.7)]. Infections The rate of infections in the tocilizumab-IV all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%). Infusion Reactions In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the tocilizumab-IV all exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were Reference ID: 5495671 19 similar in nature to those seen in RA and SJIA patients [see Adverse Reactions (6.1 and 6.7)]. No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported. Immunogenicity One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study. Laboratory Abnormalities Neutropenia During routine laboratory monitoring in the tocilizumab-IV all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 3.7% of patients. There was no clear relationship between decreases in neutrophils below 1 x 109 per L and the occurrence of serious infections. Thrombocytopenia During routine laboratory monitoring in the tocilizumab-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50,000 per mm3 without associated bleeding events. Elevated Liver Enzymes During routine laboratory monitoring in the tocilizumab-IV all exposure population, elevation in ALT or AST at or greater than 3 x ULN occurred in 4% and less than 1% of patients, respectively. Lipids During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol greater than 1.5-2 x ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 x ULN occurred in one patient (0.5%). 6.6 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Subcutaneous Tocilizumab (tocilizumab-SC) The safety of tocilizumab-SC was studied in 52 pediatric patients 1 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the PJIA tocilizumab-SC population (defined as patients who received at least one dose of tocilizumab-SC and accounting for treatment discontinuation) was 49.5 patient years. In general, the safety observed for tocilizumab administered subcutaneously was consistent with the known safety profile of intravenous tocilizumab, with the exception of injection site reactions (ISRs), and neutropenia. Injection Site Reactions During the 1-year study, a frequency of 28.8% (15/52) ISRs was observed in tocilizumab-SC treated PJIA patients. These ISRs occurred in a greater proportion of patients at or above 30 kg (44.0%) compared with patients below 30 kg (14.8%). All ISRs were mild in severity and none of the ISRs required patient withdrawal from treatment or dose interruption. A higher frequency of ISRs was observed in tocilizumab-SC treated PJIA patients compared to what was seen in adult RA or GCA patients [see Adverse Reactions (6.2 and 6.3)]. Immunogenicity Three patients, 1 patient below 30 kg and 2 patients at or above 30 kg, developed positive anti-tocilizumab antibodies with neutralizing potential without developing a serious or clinically significant hypersensitivity reaction. One patient subsequently withdrew from the study. Neutropenia During routine laboratory monitoring in the tocilizumab-SC all exposure population, a decrease in neutrophil Reference ID: 5495671 20 counts below 1 × 109 per L occurred in 15.4% of patients, and was more frequently observed in the patients less than 30 kg (25.9%) compared to patients at or above 30 kg (4.0%). There was no clear relationship between decreases in neutrophils below 1 x 109 per L and the occurrence of serious infections. 6.7 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (tocilizumab-IV) The data described below reflect exposure to tocilizumab-IV in one randomized, double-blind, placebo-controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy. At baseline, approximately half of the patients were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension. In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with tocilizumab­IV (8 or 12 mg per kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated with tocilizumab-IV in the open-label extension phase. The most common adverse events (at least 5%) seen in tocilizumab-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea. Infections In the 12 week controlled phase, the rate of all infections in the tocilizumab-IV group was 345 per 100 patient- years and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years. In the 12 week controlled phase, the rate of serious infections in the tocilizumab-IV group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media. Macrophage Activation Syndrome In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with tocilizumab-IV. One patient in the placebo group escaped to tocilizumab-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had tocilizumab-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the tocilizumab-IV SJIA clinical development experience; however no definitive conclusions can be made. Infusion Reactions Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA. Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of tocilizumab-IV and 0% of placebo treated patients experienced events occurring during infusion. One event (angioedema) was considered serious and life- threatening, and the patient was discontinued from study treatment. Within 24 hours after infusion, 16% of patients in the tocilizumab-IV treatment group and 5% of patients in the placebo group experienced an event. In the tocilizumab-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious. Anaphylaxis Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with tocilizumab-IV during the controlled and open label extension study [see Warnings and Precautions (5.6)]. Immunogenicity Reference ID: 5495671 21 All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti­ tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study. Laboratory Abnormalities Neutropenia During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 × 109 per L occurred in 7% of patients in the tocilizumab-IV group, and in no patients in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the tocilizumab-IV group. There was no clear relationship between decrease in neutrophils below 1 x 109 per L and the occurrence of serious infections. Thrombocytopenia During routine monitoring in the 12 week controlled phase, 1% of patients in the tocilizumab-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100,000 per mm3. In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the tocilizumab-IV group, with no associated bleeding. Elevated Liver Enzymes During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3x ULN occurred in 5% and 3% of patients, respectively in the tocilizumab-IV group and in 0% of placebo patients. In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3x ULN occurred in 13% and 5% of tocilizumab-IV treated patients, respectively. Lipids During routine laboratory monitoring in the 12 week controlled phase, elevation in total cholesterol greater than 1.5x ULN – 2x ULN occurred in 1.5% of the tocilizumab-IV group and in 0% of placebo patients. Elevation in LDL greater than 1.5x ULN – 2x ULN occurred in 1.9% of patients in the tocilizumab-IV group and 0% of the placebo group. In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data. 6.8 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Subcutaneous Tocilizumab (tocilizumab-SC) The safety profile of tocilizumab-SC was studied in 51 pediatric patients 1 to 17 years of age with SJIA who had an inadequate clinical response to NSAIDs and corticosteroids. In general, the safety observed for tocilizumab administered subcutaneously was consistent with the known safety profile of intravenous tocilizumab, with the exception of ISRs where a higher frequency was observed in tocilizumab-SC treated SJIA patients compared to PJIA patients and adult RA or GCA patients [see Adverse Reactions (6.2, 6.3 and 6.6)]. Injection Site Reactions (ISRs) A total of 41.2% (21/51) SJIA patients experienced ISRs to tocilizumab-SC. The most common ISRs were erythema, pruritus, pain, and swelling at the injection site. The majority of ISRs reported were Grade 1 events and all ISRs reported were non-serious and none required patient withdrawal from treatment or dose interruption. Immunogenicity Forty-six of the 51 (90.2%) patients who were tested for anti-tocilizumab antibodies at baseline had at least one post-baseline screening assay result. No patient developed positive anti-tocilizumab antibodies post-baseline. 6.9 Postmarketing Experience Reference ID: 5495671 22 The following adverse reactions have been identified during post-approval use of tocilizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Hypersensitivity Reactions: Fatal anaphylaxis, Stevens-Johnson Syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)] • Pancreatitis • Drug-induced liver injury, Hepatitis, Hepatic failure, Jaundice [see Warnings and Precautions (5.3)] 7 DRUG INTERACTIONS 7.1 Concomitant Drugs for Treatment of Adult Indications In RA patients, population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non- steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. Concomitant administration of a single intravenous dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. Tocilizumab products have not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration (2.2)]. In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed. 7.2 Interactions with CYP450 Substrates Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab products may restore CYP450 activities to higher levels than those in the absence of tocilizumab products leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effect on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of tocilizumab, respectively. The effect of tocilizumab products on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of TYENNE, in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise caution when coadministering TYENNE with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab products on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12.3)]. 7.3 Live Vaccines Avoid use of live vaccines concurrently with TYENNE [see Warnings and Precautions (5.9)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The available data with tocilizumab products from a pregnancy exposure registry, retrospective cohort study, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. These studies had methodological limitations, including small sample size of tocilizumab exposed groups, missing exposure and outcomes information, and lack of adjustment for cofounders. Monoclonal antibodies, such as tocilizumab products, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant [see Clinical Considerations]. In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg Reference ID: 5495671 23 per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition [see Data]. Based on the animal data, there may be a potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to TYENNE in utero [see Warnings and Precautions 5.9)]. Disease-associated Maternal Risk Published data suggest that the risk of adverse pregnancy outcomes in women with rheumatoid arthritis is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Data Animal Data An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring. Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery. 8.2 Lactation Risk Summary No information is available on the presence of tocilizumab products in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab products are transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab products are unknown. The lack of clinical data during lactation precludes clear determination of the risk of tocilizumab products to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TYENNE and the potential adverse effects on the breastfed child from TYENNE or from the underlying maternal condition. 8.4 Pediatric Use TYENNE by intravenous use is indicated for the treatment of pediatric patients with: 24 Reference ID: 5495671 • Active systemic juvenile idiopathic arthritis in patients 2 years of age and older • Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older TYENNE by subcutaneous use is indicated for the treatment of pediatric patients with: • Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older • Active systemic juvenile idiopathic arthritis in patients 2 years of age and older The safety and effectiveness of TYENNE in pediatric patients with conditions other than PJIA or SJIA have not been established. The safety and effectiveness in pediatric patients below the age of 2 have not been established in PJIA or SJIA. Systemic Juvenile Idiopathic Arthritis – Intravenous Use A multicenter, open-label, single arm study to evaluate the PK, safety and exploratory PD and efficacy of tocilizumab over 12-weeks in SJIA patients (N=11) under 2 years of age was conducted. Patients received intravenous tocilizumab 12 mg/kg every two weeks. Concurrent use of stable background treatment with corticosteroids, MTX, and/or non-steroidal anti-inflammatory drugs was permitted. Patients who completed the 12-week period could continue to the optional extension period (a total of 52-weeks or until the age of 2 years, whichever was longer). The primary PK endpoints (Cmax, Ctrough and AUC2weeks) of tocilizumab at steady-state in this study were within the ranges of these parameters observed in patients with SJIA aged 2 to 17 years. The safety and immunogenicity of tocilizumab for patients with SJIA under 2 years of age was assessed descriptively. SAEs, AEs leading to discontinuation, and infectious AEs were reported by 27.3%, 36.4%, and 81.8% of patients. Six patients (54.5%) experienced hypersensitivity reactions, defined as all adverse events occurring during or within 24 hours after an infusion considered related to tocilizumab. Three of these patients experienced serious hypersensitivity reactions and were withdrawn from the study. Three patients with hypersensitivity reactions (two with serious hypersensitivity reactions) developed treatment induced anti­ tocilizumab antibodies after the event. There were no cases of MAS based on the protocol-specified criteria, but 2 cases of suspected MAS based on Ravelli criteria1. 8.5 Geriatric Use Of the 2644 patients who received tocilizumab in Studies I to V [see Clinical Studies (14)], a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. Of the 1069 patients who received tocilizumab-SC in studies SC-I and SC-II there were 295 patients 65 years of age and older, including 41 patients 75 years and older. The frequency of serious infection among tocilizumab treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly. 8.6 Hepatic Impairment The safety and efficacy of tocilizumab products have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology [see Warnings and Precautions 5.8)]. 8.7 Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. Tocilizumab products have not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. 9 DRUG ABUSE AND DEPENDENCE 1 Ravelli A, Minoia F, Davì S on behalf of the Paediatric Rheumatology International Trials Organisation, the Childhood Arthritis and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis. Annals of the Rheumatic Diseases 2016;75:481-489. 25 Reference ID: 5495671 No studies on the potential for tocilizumab products to cause dependence have been performed. However, there is no evidence from the available data that tocilizumab products treatment results in dependence. 10 OVERDOSAGE There are limited data available on overdoses with tocilizumab products. One case of accidental overdose was reported with intravenous tocilizumab in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment. 11 DESCRIPTION Tocilizumab-aazg is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H2L2 polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids (excluding the C-terminal lysine), respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. Tocilizumab-aazg has a molecular weight of approximately 148 kDa. The antibody is produced in mammalian (Chinese hamster ovary) cells. Intravenous Infusion TYENNE (tocilizumab-aazg) injection is a sterile, clear and colorless to pale yellow, histidine buffered preservative-free solution with a pH of approximately 6 for further dilution prior to intravenous infusion. Each single-dose vial is available at a concentration of 20 mg/mL containing 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL of TYENNE. Each mL of solution contains arginine (17.4 mg), histidine (3.1 mg), lactic acid (0.9 mg), polysorbate 80 (0.2 mg), sodium chloride (0.6 mg), and Water for Injection, USP. Hydrochloric acid and sodium hydroxide are added to adjust the pH. Subcutaneous Injection TYENNE (tocilizumab-aazg) injection is a sterile, clear, colorless to pale yellow, preservative-free, histidine buffered solution with a pH of approximately 6 for subcutaneous use. It is supplied in a ready-to-use, single-dose 0.9 mL prefilled syringe (PFS) with a needle safety device or in a ready­to-use, single-dose 0.9 mL autoinjector that delivers 162 mg tocilizumab-aazg, arginine (16.7 mg), histidine (2.0 mg), lactic acid (0.9 mg), polysorbate 80 (0.2 mg), sodium chloride (0.6 mg), and Water for Injection, USP. Hydrochloric acid and sodium hydroxide are added to adjust the pH. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tocilizumab products bind to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and have been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis. 12.2 Pharmacodynamics Reference ID: 5495671 26 In clinical studies in RA patients with the 4 mg per kg and 8 mg per kg intravenous doses or the 162 mg weekly and every other weekly subcutaneous doses of tocilizumab, decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A, fibrinogen and increases in hemoglobin) with doses, however the greatest improvements were observed with 8 mg per kg tocilizumab. Pharmacodynamic changes were also observed to occur after tocilizumab administration in GCA, PJIA, and SJIA patients (decreases in CRP, ESR, and increases in hemoglobin). The relationship between these pharmacodynamic findings and clinical efficacy is not known. In healthy subjects administered tocilizumab in doses from 2 to 28 mg per kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to the nadir 3 to 5 days following tocilizumab administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis and GCA patients demonstrated a similar pattern of absolute neutrophil counts following tocilizumab administration [see Warnings and Precautions (5.4)]. 12.3 Pharmacokinetics PK of tocilizumab is characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of tocilizumab elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies. Rheumatoid Arthritis – Intravenous and Subcutaneous Administration The pharmacokinetics in healthy subjects and RA patients suggest that PK is similar between the two populations. The population PK model was developed from an analysis dataset composed of an IV dataset of 1793 patients from Study I, Study III, Study IV, and Study V, and from an IV and SC dataset of 1759 patients from Studies SC-I and SC-II. Cmean is included in place of AUCtau, since for dosing regimens with different inter-dose intervals, the mean concentration over the dosing period characterizes the comparative exposure better than AUCtau. At high serum concentrations, when total clearance of tocilizumab is dominated by linear clearance, a terminal half-life of approximately 21.5 days was derived from the population parameter estimates. For doses of 4 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab at steady state were 86.1 (44.8–202) mcg/mL, 0.1 (0.0–14.6) mcg/mL, and 18.0 (8.9– 50.7) mcg/mL, respectively. For doses of 8 mg/kg tocilizumab given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 176 (75.4–557) mcg/mL, 13.4 (0.1–154) mcg/mL, and 54.0 (17–260) mcg/mL, respectively. Cmax increased dose-proportionally between doses of 4 and 8 mg/kg IV every 4 weeks, while a greater than dose-proportional increase was observed in Cmean and Ctrough. At steady-state, Cmean and Ctrough were 3.0 and 134 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively. The accumulation ratios for AUC and Cmax after multiple doses of 4 and 8 mg/kg IV Q4W are low, while the accumulation ratios for Ctrough are higher (2.62 and 2.47, respectively). For Cmax, greater than 90% of the steady- state value was reached after the 1st IV infusion. For AUCtau and Cmean, 90% of the steady-state value was reached after the 1st and 3rd infusion for 4 mg/kg and 8 mg/kg IV, while for Ctrough, approximately 90% of the steady- state value was reached after the 4th IV infusion after both doses. For doses of 162 mg given every other week subcutaneously, the estimated median (range) steady-state Cmax, Ctrough, and Cmean of tocilizumab were 12.1 (0.4–49.3) mcg/mL, 4.1 (0.0–34.2) mcg/mL, and 9.2 (0.2– 43.6) mcg/mL, respectively. For doses of 162 mg given every week subcutaneously, the estimated median (range) steady-state Cmax, Ctrough, Reference ID: 5495671 27 and Cmean of tocilizumab were 49.8 (3–150) mcg/mL, 42.9 (1.3–144) mcg/mL, and 47.3 (2.4–147) mcg/mL, respectively. Exposures after the 162 mg SC QW regimen were greater by 5.1 (Cmean) to 10.5 fold (Ctrough) compared to the 162 mg SC Q2W regimen. Accumulation ratios after multiple doses of either SC regimen were higher than after IV regimen with the highest ratios for Ctrough (6.02 and 6.30, for 162 mg SC Q2W and 162 mg SC QW, respectively). The higher accumulation for Ctrough was expected based on the nonlinear clearance contribution at lower concentrations. For Cmax, greater than 90% of the steady-state value was reached after the 5th SC and the 12th SC injection with the Q2W and QW regimens, respectively. For AUCtau and Cmean, 90% of the steady-state value was reached after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens, respectively. For Ctrough, approximately 90% of the steady- state value was reached after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens, respectively. Population PK analysis identified body weight as a significant covariate impacting the pharmacokinetics of tocilizumab. When given IV on a mg/kg basis, individuals with body weight ≥ 100 kg are predicted to have mean steady-state exposures higher than mean values for the patient population. Therefore, tocilizumab doses exceeding 800 mg per infusion are not recommended in patients with RA [see Dosage and Administration (2.2)]. Due to the flat dosing employed for SC administration of tocilizumab, no modifications are necessary by this dosing route. Giant Cell Arteritis – Subcutaneous and Intravenous Administration The pharmacokinetics of tocilizumab S C in GCA patients was determined using a population pharmacokinetic analysis on a dataset composed of 149 GCA patients treated with 162 mg subcutaneously every week or with 162 mg subcutaneously every other week. For the 162 mg every week dose, the estimated median (range) steady-state Cmax, Ctrough and Cmean of tocilizumab SC were 72.1 (12.2–151) mcg/mL, 67.2 (10.7–145) mcg/mL, and 70.6 (11.7–149) mcg/mL, respectively. The accumulation ratios for Cmean or AUCtau, Ctrough, and Cmax were 10.9, 9.6, and 8.9, respectively. Steady state was reached after 17 weeks. For the 162 mg every other week dose, the estimated median (range) steady-state Cmax, Ctrough, and Cmean of tocilizumab were 17.2 (1.1–56.2) mcg/mL, 7.7 (0.1–37.3) mcg/mL, and 13.7 (0.5– 49) mcg/mL, respectively. The accumulation ratios for Cmean or AUCtau, Ctrough, and Cmax were 2.8, 5.6, and 2.3 respectively. Steady-state was reached after 14 weeks. The pharmacokinetics of tocilizumab IV in GCA patients was characterized by a non-compartmental pharmacokinetic analysis which included 22 patients treated with 6 mg/kg intravenously every 4 weeks for 20 weeks. The median (range) Cmax, Ctrough and Cmean of tocilizumab at steady state were 178 (115-320) mcg/mL, 22.7 (3.38-54.5) mcg/mL and 57.5 (32.9-110) mcg/mL, respectively. Steady state trough concentrations were within the range observed in GCA patients treated with 162 mg TCZ SC administered every week or every other week. Based on pharmacokinetic exposure and extrapolation between RA and GCA patients, when given IV on a mg/kg basis, tocilizumab doses exceeding 600 mg per infusion are not recommended in patients with GCA [see Dosage and Administration (2.3)]. Polyarticular Juvenile Idiopathic Arthritis – Intravenous and Subcutaneous Administration The pharmacokinetics of tocilizumab (TCZ) in PJIA patients was characterized by a population pharmacokinetic analysis which included 188 patients who were treated with TCZ IV or 52 patients treated with TCZ SC. For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab at steady state were 181 (114– 331) mcg/mL, 3.28 (0.02–35.4) mcg/mL, and 38.6 (22.2–83.8) mcg/mL, respectively. For doses of 10 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 4 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 167 (125–220) mcg/mL, 0.35 (0– 11.8) mcg/mL, and 30.8 (16.0–48.0) mcg/mL, respectively. The accumulation ratios were 1.05 and 1.16 for AUC4weeks, and 1.43 and 2.22 for Ctrough for 10 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. No accumulation for Cmax was Reference ID: 5495671 28 observed. Following 10 mg/kg and 8 mg/kg TCZ IV every 4 weeks doses in PJIA patients (aged 2 to 17 years), steady state concentrations (trough and average) were within the range of exposures in adult RA patients following 4 mg/kg and 8 mg/kg every 4 weeks, and steady state peak concentrations in PJIA patients were comparable to those following 8 mg/kg every 4 weeks in adult RA patients. For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks subcutaneously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 29.7 (7.56–50.3) mcg/mL, 12.7 (0.19–23.8) mcg/mL, and 23.0 (3.86–36.9) mcg/mL, respectively. For doses of 162 mg tocilizumab (patients with a body weight less than 30 kg) given every 3 weeks subcutaneously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 62.4 (39.4–121) mcg/mL, 13.4 (0.21–52.3) mcg/mL, and 35.7 (17.4– 91.8) mcg/mL, respectively. The accumulation ratios were 1.46 and 2.04 for AUC4weeks, 2.08 and 3.58 for Ctrough, and 1.32 and 1.72 for Cmax, for 162 mg given every 3 weeks (BW less than 30 kg) and 162 mg given every 2 weeks (BW at or above 30 kg) subcutaneous doses, respectively. Following subcutaneous dosing, steady state Ctrough was comparable for patients in the two body weight groups, while steady-state Cmax and Cmean were higher for patients in the less than 30 kg group compared to the group at or above 30 kg. All patients treated with TCZ SC had steady-state Ctrough at or higher than that achieved with TCZ IV across the spectrum of body weights. The average and trough concentrations in patients after subcutaneous dosing were within the range of those achieved in adult patients with RA following the subcutaneous administration of the recommended regimens. Systemic Juvenile Idiopathic Arthritis – Intravenous and Subcutaneous Administration The pharmacokinetics of tocilizumab (TCZ) in SJIA patients was characterized by a population pharmacokinetic analysis which included 89 patients who were treated with TCZ IV or 51 patients treated with TCZ SC. For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 2 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 253 (120–404) mcg/mL, 70.7 (5.26–127) mcg/mL, and 117 (37.6–199) mcg/mL, respectively. For doses of 12 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks intravenously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 274 (149–444) mcg/mL, 65.9 (19.0–135) mcg/mL, and 124 (60–194) mcg/mL, respectively. The accumulation ratios were 1.95 and 2.01 for AUC4weeks, and 3.41 and 3.20 for Ctrough for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. Accumulation data for Cmax were 1.37 and 1.42 for 12 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) intravenous doses, respectively. Following every other week dosing with tocilizumab IV, steady state was reached by 8 weeks for both body weight groups. Mean estimated tocilizumab exposure parameters were similar between the two dose groups defined by body weight. For doses of 162 mg tocilizumab (patients with a body weight at or above 30 kg) given every week subcutaneously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 89.8 (26.4– 190) mcg/mL, 72.4 (19.5–158) mcg/mL, and 82.4 (23.9–169) mcg/mL, respectively. For doses of 162 mg tocilizumab (patients with a body weight less than 30 kg) given every 2 weeks subcutaneously, the estimated median (range) Cmax, Ctrough, and Cmean of tocilizumab were 127 (51.7–266) mcg/mL, 64.2 (16.6–136) mcg/mL, and 92.7 (38.5–199) mcg/mL, respectively. The accumulation ratios were 2.27 and 4.28 for AUC4weeks, 3.21 and 4.39 for Ctrough, and 1.88 and 3.66 for Cmax, for 162 mg given every 2 weeks (BW less than 30 kg) and 162 mg given every week (BW at or above 30 kg) subcutaneous doses, respectively. Following subcutaneous dosing, steady state was reached by 12 weeks for both body weight groups. All patients treated with tocilizumab SC had steady-state Cmax lower than that achieved with tocilizumab IV across the spectrum of body weights. Trough and mean concentrations in patients after SC dosing were similar to those achieved with tocilizumab IV across body weights. Reference ID: 5495671 29 Absorption Following subcutaneous dosing, the absorption half-life was around 4 days in RA and GCA patients. The bioavailability for the subcutaneous formulation was 80%. Following subcutaneous dosing in PJIA patients, the absorption half-life was around 2 days, and the bioavailability for the subcutaneous formulation in PJIA patients was 96%. Following subcutaneous dosing in SJIA patients, the absorption half-life was around 2 days, and the bioavailability for the SC formulation in SJIA patients was 95%. In RA patients the median values of Tmax were 2.8 days after the tocilizumab every week dose and 4.7 days after the tocilizumab every other week dose. In GCA patients, the median values of Tmax were 3 days after the tocilizumab every week dose and 4.5 days after the tocilizumab every other week dose. Distribution Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L. In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution was 3.37 L resulting in a volume of distribution at steady state of 7.46 L. In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L. In pediatric patients with SJIA, the central volume of distribution was 1.87 L, the peripheral volume of distribution was 2.14 L resulting in a volume of distribution at steady state of 4.01 L. Elimination Tocilizumab is eliminated by a combination of linear clearance and nonlinear elimination. The concentration- dependent nonlinear elimination plays a major role at low tocilizumab concentrations. Once the nonlinear pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance. The saturation of the nonlinear elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies. The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA patients, 6.7 mL per h in GCA patients, 5.8 mL per h in pediatric patients with PJIA, and 5.7 mL per h in pediatric patients with SJIA. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. For intravenous administration in RA patients, the concentration-dependent apparent t1/2 is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For subcutaneous administration in RA patients, the concentration-dependent apparent t1/2 is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state. In GCA patients at steady state, the effective t1/2 of tocilizumab varied between 18.3 and 18.9 days for 162 mg subcutaneously every week dosing regimen and between 4.2 and 7.9 days for 162 mg subcutaneously every other week dosing regimen. For intravenous administration in GCA patients, the TCZ concentration-dependent apparent t1/2 was 13.2 days following 6 mg/kg every 4 weeks. Reference ID: 5495671 30 The t1/2 of tocilizumab in children with PJIA is up to 17 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg or 10 mg/kg for body weight below 30 kg) during a dosing interval at steady state. For subcutaneous administration, the t1/2 of tocilizumab in PJIA patients is up to 10 days for the two body weight categories (every other week regimen for body weight at or above 30 kg or every 3 week regimen for body weight less than 30 kg) during a dosing interval at steady state. The t1/2 of tocilizumab intravenous in pediatric patients with SJIA is up to 16 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg and 12 mg/kg for body weight below 30 kg every other week) during a dosing interval at steady-state. Following subcutaneous administration, the effective t1/2 of tocilizumab subcutaneous in SJIA patients is up to 14 days for both the body weight categories (162 mg every week for body weight at or above 30 kg and 162 mg every two weeks for body weight below 30 kg) during a dosing interval at steady state. Specific Populations Population pharmacokinetic analyses in adult rheumatoid arthritis patients and GCA patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. In RA patients, the body weight-based dose (8 mg per kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg. There was an inverse relationship between tocilizumab exposure and body weight for flat dose subcutaneous regimens. In GCA patients treated with tocilizumab-SC, higher exposure was observed in patients with lower body weight. For the 162 mg every week subcutaneous dosing regimen, the steady-state Cmean was 51% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. For the 162 mg every other week subcutaneous regimen, the steady-state Cmean was 129% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. There is limited data for patients above 100 kg (n=7). Patients with Hepatic Impairment No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted. Patients with Renal Impairment No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted. Most of the RA and GCA patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance less than 80 mL per min and at or above 50 mL per min based on Cockcroft-Gault formula) did not impact the pharmacokinetics of tocilizumab. Approximately one-third of the patients in the tocilizumab-SC GCA clinical trial had moderate renal impairment at baseline (estimated creatinine clearance of 30-59 mL/min). No impact on tocilizumab exposure was noted in these patients. No dose adjustment is required in patients with mild or moderate renal impairment. Drug Interaction Studies In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of TYENNE, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when TYENNE is coadministered with drugs where decrease in effectiveness is Reference ID: 5495671 31 undesirable, e.g., oral contraceptives (CYP3A4 substrates) [see Drug Interactions (7.2)]. Simvastatin Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with tocilizumab, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of tocilizumab (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of tocilizumab in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of TYENNE (due to normalization of CYP3A4) or higher exposures after discontinuation of TYENNE. Omeprazole Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after tocilizumab infusion (8 mg per kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects. Dextromethorphan Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of tocilizumab (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after tocilizumab infusion. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab products. Literature indicates that the IL-6 pathway can mediate anti-tumor responses by promoting increased immune cell surveillance of the tumor microenvironment. However, available published evidence also supports that IL-6 signaling through the IL-6 receptor may be involved in pathways that lead to tumorigenesis. The malignancy risk in humans from an antibody that disrupts signaling through the IL-6 receptor, such as tocilizumab, is presently unknown. Fertility and reproductive performance were unaffected in male and female mice that received a murine analogue of tocilizumab administered by the intravenous route at a dose of 50 mg/kg every three days. 14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis – Intravenous Administration The efficacy and safety of intravenously administered tocilizumab was assessed in five randomized, double-blind, multicenter studies in patients greater than 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. Tocilizumab was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V). Study I (NCT00109408) evaluated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 24 weeks prior to randomization, or who had not discontinued previous methotrexate treatment as a result of clinically important toxic effects or lack of response. In this study, 67% of patients were Reference ID: 5495671 32 MTX-naïve, and over 40% of patients had rheumatoid arthritis less than 2 years. Patients received tocilizumab 8 mg per kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly). The primary endpoint was the proportion of tocilizumab patients who achieved an ACR 20 response at Week 24. Study II (NCT00106535) was a 104-week study with an optional 156-week extension phase that evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). Upon completion of 52-weeks, patients received open-label treatment with tocilizumab 8 mg per kg through 104 weeks or they had the option to continue their double-blind treatment if they maintained a greater than 70% improvement in swollen/tender joint count. Two pre-specified interim analyses at week 24 and week 52 were conducted. The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At weeks 52 and 104, the primary endpoints were change from baseline in modified total Sharp-Genant score and the area under the curve (AUC) of the change from baseline in HAQ-DI score. Study III (NCT00106548) evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Study IV (NCT00106574) evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received tocilizumab 8 mg per kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Study V (NCT00106522) evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomization. Patients received tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24. Clinical Response The percentages of intravenous tocilizumab-treated patients achieving ACR 20, 50 and 70 responses are shown in Table 3. In all intravenous studies, patients treated with 8 mg per kg tocilizumab had higher ACR 20, ACR 50, and ACR 70 response rates versus MTX- or placebo-treated patients at week 24. During the 24 week controlled portions of Studies I to V, patients treated with tocilizumab at a dose of 4 mg per kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with tocilizumab 8 mg per kg. Reference ID: 5495671 33 Table 3 Clinical Response at Weeks 24 and 52 in Active and Placebo Controlled Trials of Intravenous Tocilizumab (Percent of Patients) Percent of Patients Study I Study II Study III Study IV Study V Response Rate Tocilizumab MTX 8 mg per kg N=284 N=286 Tocilizumab Tocilizumab Placebo + 4 mg per kg 8 mg per kg MTX + MTX + MTX N=393 N=399 N=398 Tocilizumab Tocilizumab Placebo + 4 mg per kg 8 mg per kg MTX + MTX + MTX N=204 N=213 N=205 Tocilizumab Placebo + 8 mg per kg DMARDs + DMARDs N=413 N=803 Tocilizumab Tocilizumab Placebo + 4 mg per kg 8 mg per kg MTX + MTX + MTX N=158 N=161 N=170 (95% CI)a (95% CI)a (95% CI)a (95% CI)a (95% CI)a (95% CI)a (95% CI)a (95% CI)a ACR 20 Week 24 53% 70% 27% 51% 56% 27% 48% 59% 24% 61% 10% 30% 50% (0.11, 0.27) (0.17, 0.29) (0.23, 0.35) (0.15, 0.32) (0.23, 0.41) (0.30, 0.40) (0.15, 0.36) (0.36, 0.56) Week 52 N/A N/A 25% 47% 56% N/A N/A N/A N/A N/A N/A N/A N/A ACR 50 (0.15, 0.28) (0.25, 0.38) Week 24 34% 44% 10% 25% 32% 11% 32% 44% 9% 38% 4% 17% 29% (0.04, 0.20) (0.09, 0.20) (0.16, 0.28) (0.13, 0.29) (0.25, 0.41) (0.23, 0.33) (0.05, 0.25) (0.21, 0.41) Week 52 N/A N/A 10% 29% 36% N/A N/A N/A N/A N/A N/A N/A N/A ACR 70 (0.14, 0.25) (0.21, 0.32) Week 24 15% 28% 2% 11% 13% 2% 12% 22% 3% 21% 1% 5% 12% (0.07, 0.22) (0.03, 0.13) (0.05, 0.15) (0.04, 0.18) (0.12, 0.27) (0.13, 0.21) (-0.06, 0.14) (0.03, 0.22) Week 52 N/A N/A 4% 16% 20% N/A N/A N/A N/A N/A N/A N/A N/A Major Clinical b Responses (0.08, 0.17) (0.12, 0.21) Week 52 N/A N/A 1% 4% 7% N/A N/A N/A N/A N/A N/A N/A N/A (0.01, 0.06) (0.03, 0.09) a CI: 95% confidence interval of the weighted difference to placebo adjusted for site (and disease duration for Study I only) b Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week period Reference ID: 5495671 34 In study II, a greater proportion of patients treated with 4 mg per kg and 8 mg per kg tocilizumab + MTX achieved a low level of disease activity as measured by a DAS 28-ESR less than 2.6 compared with placebo+ MTX treated patients at week 52. The proportion of tocilizumab-treated patients achieving DAS 28-ESR less than 2.6, and the number of residual active joints in these responders in Study II are shown in Table 4. Table 4 Proportion of Patients with DAS28-ESR Less Than 2.6 with Number of Residual Active Joints in Trials of Intravenous Tocilizumab Study II Placebo + MTX N = 393 Tocilizumab 4 mg per kg + MTX N = 399 Tocilizumab 8 mg per kg + MTX N = 398 DAS28-ESR less than 2.6 Proportion of responders at week 52 (n) 95% confidence interval 3% (12) 18% (70) 0.10, 0.19 32% (127) 0.24, 0.34 Of responders, proportion with 0 active joints (n) 33% (4) 27% (19) 21% (27) Of responders, proportion with 1 active joint (n) 8% (1) 19% (13) 13% (16) Of responders, proportion with 2 active joints (n) 25% (3) 13% (9) 20% (25) Of responders, proportion with 3 or more active joints (n) 33% (4) 41% (29) 47% (59) *n denotes numerator of all the percentage. Denominator is the intent-to-treat population. Not all patients received DAS28 assessments at Week 52. The results of the components of the ACR response criteria for Studies III and V are shown in Table 5. Similar results to Study III were observed in Studies I, II and IV. Table 5 Components of ACR Response at Week 24 in Trials of Intravenous Tocilizumab Study III Study V Tocilizumab 4 mg per kg + MTX N=213 Tocilizumab 8 mg per kg + MTX N=205 Placebo + MTX N=204 Tocilizumab 4 mg per kg + MTX N=161 Tocilizumab 8 mg per kg + MTX N=170 Placebo + MTX N=158 Component (mean) Baseline a Week 24 Baseline a Week 24 Baseline Week 24 Baseline a Week 24 Baseline a Week 24 Baseline Week 24 Number of tender joints (0-68) 33 19 -7.0 (-10.0, -4.1) 32 14.5 -9.6 (-12.6, -6.7) 33 25 31 21 -10.8 (-14.6, -7.1) 32 17 -15.1 (-18.8, -11.4) 30 30 Number of swollen joints (0-66) 20 10 -4.2 (-6.1, -2.3) 19.5 8 -6.2 (-8.1, -4.2) 21 15 19.5 13 -6.2 (-9.0, -3.5) 19 11 -7.2 (-9.9, -4.5) 19 18 b Pain 61 33 -11.0 (-17.0, -5.0) 60 30 -15.8 (-21.7, -9.9) 57 43 63.5 43 -12.4 (-22.1, -2.1) 65 33 -23.9 (-33.7, -14.1) 64 48 Patient global b assessment 66 34 -10.9 (-17.1, -4.8) 65 31 -14.9 (-20.9, -8.9) 64 45 70 46 -10.0 (-20.3, 0.3) 70 36 -17.4 (-27.8, -7.0) 71 51 Physician global b assessment 64 26 -5.6 (-10.5, -0.8) 64 23 -9.0 (-13.8, -4.2) 64 32 66.5 39 -10.5 (-18.6, -2.5) 66 28 -18.2 (-26.3, -10.0) 67.5 43 Disability index c (HAQ) 1.64 1.01 -0.18 (-0.34, -0.02) 1.55 0.96 -0.21 (-0.37, -0.05) 1.55 1.21 1.67 1.39 -0.25 (-0.42, -0.09) 1.75 1.34 -0.34 (-0.51, -0.17) 1.70 1.58 CRP (mg per dL) 2.79 1.17 -1.30 (-2.0, -0.59) 2.61 0.25 -2.156 (-2.86, -1.46) 2.36 1.89 3.11 1.77 -1.34 (-2.5, -0.15) 2.80 0.28 -2.52 (-3.72, -1.32) 3.705 3.06 a Data shown is mean at week 24, difference in adjusted mean change from baseline compared with placebo + MTX at week 24 and 95% confidence interval for that difference b Visual analog scale: 0 = best, 100 = worst c Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities The percent of ACR 20 responders by visit for Study III is shown in Figure 1. Similar response curves were observed in studies I, II, IV, and V. Reference ID: 5495671 35 100 95 90 B5 80 75 70 Ii] ~ 65 ! I! 60 ' Ii Q. 55 ' ac 2 50 ,:,: <J <( - 45 Q l CJ 40 1 § 35 ., ... 30 25 20 15 10 5 0 \'It<:'! Wt<4 M((I • • • • • • D □ D Figure 1 Percent of ACR 20 Responders by Visit for Study III (Inadequate Response to MTX)* Placebo + MTX Tocilizumab 8 mg/kg + MTX Tocilizumab 4 mg/kg + MTX Treatment Group (N=204) (N=205) (N=213) *The same patients may not have responded at each timepoint. Radiographic Response In Study II, structural joint damage was assessed radiographically and expressed as change in total Sharp-Genant score and its components, the erosion score and joint space narrowing score. Radiographs of hands/wrists and forefeet were obtained at baseline, 24 weeks, 52 weeks, and 104 weeks and scored by readers unaware of treatments group and visit number. The results from baseline to week 52 are shown in Table 6. Tocilizumab 4 mg per kg slowed (less than 75% inhibition compared to the control group) and tocilizumab 8 mg per kg inhibited (at least 75% inhibition compared to the control group) the progression of structural damage compared to placebo plus MTX at week 52. Reference ID: 5495671 36 Table 6 Mean Radiographic Change from Baseline to Week 52 in Study II Placebo + MTX N=294 Tocilizumab 4 mg per kg + MTX N=343 Tocilizumab 8 mg per kg + MTX N=353 Week 52* Total Sharp-Genant Score, Mean (SD) 1.17 (3.14) 0.33 (1.30) 0.25 (0.98) Adjusted Mean difference** (95%CI) -0.83 (-1.13, -0.52) -0.90 (-1.20, -0.59) Erosion Score, Mean (SD) 0.76 (2.14) 0.20 (0.83) 0.15 (0.77) Adjusted Mean difference** (95%CI) -0.55 (-0.76, -0.34) -0.60 (-0.80, -0.39) Joint Space Narrowing Score, Mean (SD) 0.41 (1.71) 0.13 (0.72) 0.10 (0.49) Adjusted Mean difference** (95%CI) -0.28 (-0.44, -0.11) -0.30 (-0.46, -0.14) * Week 52 analysis employs linearly extrapolated data for patients after escape, withdrawal, or loss to follow up. ** Difference between the adjusted means (tocilizumab + MTX – Placebo + MTX) SD = standard deviation The mean change from baseline to week 104 in Total Sharp-Genant Score for the tocilizumab 4 mg per kg groups was 0.47 (SD = 1.47) and for the 8 mg per kg groups was 0.34 (SD = 1.24). By the week 104, most patients in the control (placebo + MTX) group had crossed over to active treatment, and results are therefore not included for comparison. Patients in the active groups may have crossed over to the alternate active dose group, and results are reported per original randomized dose group. In the placebo group, 66% of patients experienced no radiographic progression (Total Sharp-Genant Score change ≤ 0) at week 52 compared to 78% and 83% in the tocilizumab 4 mg per kg and 8 mg per kg, respectively. Following 104 weeks of treatment, 75% and 83% of patients initially randomized to tocilizumab 4 mg per kg and 8 mg per kg, respectively, experienced no progression of structural damage compared to 66% of placebo treated patients. Health Related Outcomes In Study II, physical function and disability were assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI). Both dosing groups of tocilizumab demonstrated a greater improvement compared to the placebo group in the AUC of change from baseline in the HAQ-DI through week 52. The mean change from baseline to week 52 in HAQ-DI was 0.6, 0.5, and 0.4 for tocilizumab 8 mg per kg, tocilizumab 4 mg per kg, and placebo treatment groups, respectively. Sixty-three percent (63%) and sixty percent (60%) of patients in the tocilizumab 8 mg per kg and tocilizumab 4 mg per kg treatment groups, respectively, achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) at week 52 compared to 53% in the placebo treatment group. Other Health-Related Outcomes General health status was assessed by the Short Form Health Survey (SF-36) in Studies I – V. Patients receiving tocilizumab demonstrated greater improvement from baseline compared to placebo in the Physical Component Summary (PCS), Mental Component Summary (MCS), and in all 8 domains of the SF-36. Cardiovascular Outcomes Reference ID: 5495671 37 Study WA25204 (NCT01331837) was a randomized, open-label (sponsor-blinded), 2-arm parallel-group, multicenter, non-inferiority, cardiovascular (CV) outcomes trial in patients with a diagnosis of moderate to severe RA. This CV safety study was designed to exclude a moderate increase in CV risk in patients treated with tocilizumab compared with a TNF inhibitor standard of care (etanercept). The study included 3,080 seropositive RA patients with active disease and an inadequate response to non- biologic disease-modifying anti-rheumatic drugs, who were aged ≥50 years with at least one additional CV risk factor beyond RA. Patients were randomized 1:1 to IV tocilizumab 8 mg/kg Q4W or SC etanercept 50 mg QW and followed for an average of 3.2 years. The primary endpoint was the comparison of the time-to-first occurrence of any component of a composite of major adverse CV events (MACE; non-fatal myocardial infarction, non-fatal stroke, or CV death), with the final intent-to-treat analysis based on a total of 161 confirmed CV events (83/1538 [5.4%] for tocilizumab; 78/1542 [5.1%] for etanercept) reviewed by an independent and blinded adjudication committee. Non-inferiority of tocilizumab to etanercept for cardiovascular risk was determined by excluding >80% relative increase in the risk of MACE. The estimated hazard ratio (HR) for the risk of MACE comparing tocilizumab to etanercept was 1.05; 95% CI (0.77, 1.43). 14.2 Rheumatoid Arthritis – Subcutaneous Administration The efficacy and safety of subcutaneously administered tocilizumab was assessed in two double-blind, controlled, multicenter studies in patients with active RA. One study, SC-I (NCT01194414), was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously to 8 mg per kg intravenously every four weeks. The second study, SC-II (NCT01232569), was a placebo-controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week subcutaneously to placebo. Both SC-I and SC-II required patients to be >18 years of age with moderate to severe active rheumatoid arthritis diagnosed according to ACR criteria who had at least 4 tender and 4 swollen joints at baseline (SC-I) or at least 8 tender and 6 swollen joints at baseline (SC-II), and an inadequate response to their existing DMARD therapy, where approximately 20% also had a history of inadequate response to at least one TNF inhibitor. All patients in both SC studies received background non-biologic DMARD(s). In SC-I, 1262 patients were randomized 1:1 to receive tocilizumab-SC 162 mg every week or intravenous tocilizumab 8 mg/kg every four weeks in combination with DMARD(s). In SC-II, 656 patients were randomized 2:1 to tocilizumab-SC 162 mg every other week or placebo, in combination with DMARD(s). The primary endpoint in both studies was the proportion of patients who achieved an ACR20 response at Week 24. The clinical response to 24 weeks of tocilizumab-SC therapy is shown in Table 7. In SC-I, the primary outcome measure was ACR20 at Week 24. The pre-specified non-inferiority margin was a treatment difference of 12%. The study demonstrated non-inferiority of tocilizumab with respect to ACR20 at Week 24; ACR50, ACR70, and DAS28 responses are also shown in Table 7. In SC-II, a greater portion of patients treated with tocilizumab 162 mg subcutaneously every other week achieved ACR20, ACR50, and ACR70 responses compared to placebo-treated patients (Table 7). Further, a greater proportion of patients treated with tocilizumab 162 mg subcutaneously every other week achieved a low level of disease activity as measured by a DAS28-ESR less than 2.6 at Week 24 compared to those treated with placebo (Table 7). Reference ID: 5495671 38 Table 6 Clinical Response at Week 24 in Trials of Subcutaneous Tocilizumab (Percent of Patients) SC-Ia SC-IIb TCZ SC 162 mg every week + DMARD TCZ IV 8mg/kg + DMARD TCZ SC 162 mg every other week + DMARD Placebo + DMARD N=558 N=537 N=437 N=219 ACR20 Week 24 69% 73.4% 61% 32% Weighted difference (95% CI) -4% (-9.2, 1.2) 30% (22.0, 37.0) ACR50 Week 24 47% 49% 40% 12% Weighted difference (95% CI) -2% (-7.5, 4.0) 28% (21.5, 34.4) ACR70 Week 24 24% 28% 20% 5% Weighted difference (95% CI) -4% (-9.0, 1.3) 15% (9.8, 19.9) Change in DAS28 [Adjusted mean] Week 24 -3.5 -3.5 -3.1 -1.7 Adjusted mean difference (95% CI) 0 (-0.2, 0.1) -1.4 (-1.7; -1.1) DAS28 < 2.6 Week 24 38.4% 36.9% 32.0% 4.0% Weighted difference (95% CI) 0.9 (-5.0, 6.8) 28.6 (22.0, 35.2) TCZ = tocilizumab a Per Protocol Population b Intent To Treat Population The results of the components of the ACR response criteria and the percent of ACR20 responders by visit for tocilizumab-SC in Studies SC-I and SC-II were consistent with those observed for tocilizumab-IV. Radiographic Response In study SC-II, the progression of structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde modified total Sharp score (mTSS). At week 24, significantly less radiographic progression was observed in patients receiving tocilizumab-SC every other week plus DMARD(s) compared to placebo plus DMARD(s); mean change from baseline in mTSS of 0.62 vs. 1.23, respectively, with an adjusted mean difference of -0.60 (-1.1, -0.1). These results are consistent with those observed in patients treated with intravenous tocilizumab. Health Related Outcomes In studies SC-I and SC-II, the mean decrease from baseline to week 24 in HAQ-DI was 0.6, 0.6, 0.4 and 0.3, and the proportion of patients who achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) was 65%, 67%, 58% and 47%, for the subcutaneous every week, intravenous 8 mg/kg, subcutaneous every other week, and placebo treatment groups, respectively. Other Health-Related Outcomes General health status was assessed by the SF-36 in Studies SC-I and SC-II. In Study SC-II, patients receiving tocilizumab every other week demonstrated greater improvement from baseline compared to placebo in the PCS, MCS, and in all 8 domains of the SF-36. In Study SC-I, improvements in these scores were similar between tocilizumab-SC every week and tocilizumab-IV 8 mg/kg. 14.3 Giant Cell Arteritis – Subcutaneous Administration The efficacy and safety of subcutaneously administered tocilizumab was assessed in a single, randomized, double- blind, multicenter study in patients with active GCA. In Study WA28119 (NCT01791153), 251 screened patients with new-onset or relapsing GCA were randomized to one of four treatment arms. Two subcutaneous doses of tocilizumab (162 mg every week and 162 mg every other week) were compared to two different placebo control groups (pre-specified prednisone-taper regimen over 26 weeks and 52 weeks) randomized 2:1:1:1. The study consisted of a 52-week blinded period, followed by a 104-week open-label extension. Reference ID: 5495671 39 All patients received background glucocorticoid (prednisone) therapy. Each of the tocilizumab-treated groups and one of the placebo-treated groups followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 26 weeks, while the second placebo-treated group followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 52 weeks designed to be more in keeping with standard practice. The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Sustained remission was defined by a patient attaining a sustained (1) absence of GCA signs and symptoms from Week 12 through Week 52, (2) normalization of erythrocyte sedimentation rate (ESR) (to < 30 mm/hr without an elevation to ≥ 30 mm/hr attributable to GCA) from Week 12 through Week 52, (3) normalization of C-reactive protein (CRP) (to < 1 mg/dL, with an absence of successive elevations to ≥ 1mg/dL) from Week 12 through Week 52, and (4) successful adherence to the prednisone taper defined by not more than 100 mg of excess prednisone from Week 12 through Week 52. Tocilizumab 162 mg weekly and 162 mg every other week + 26 weeks prednisone taper both showed superiority in achieving sustained remission from Week 12 through Week 52 compared with placebo + 26 weeks prednisone taper (Table 8). Both tocilizumab treatment arms also showed superiority compared to the placebo + 52 weeks prednisone taper (Table 8). Table 7 Efficacy Results from Study WA28119 PBO + 26 weeks prednisone taper N=50 PBO + 52 weeks prednisone taper N=51 TCZ 162mg SC QW + 26 weeks prednisone taper N=100 TCZ 162 mg SC Q2W + 26 weeks prednisone taper N=49 Sustained remission a Responders, n (%) 7 (14.0%) 9 (17.6%) 56 (56.0%) 26 (53.1%) Unadjusted difference in proportions vs PBO + 26 weeks taper (99.5% CI) N/A N/A 42.0% (18.0, 66.0) 39.1% (12.5 , 65.7) Unadjusted difference in proportions vs PBO + 52 weeks taper (99.5% CI) N/A N/A 38.4% (14.4, 62.3) 35.4% (8.6, 62.2) Components of Sustained Remission Sustained absence of GCA signs and symptomsb , n (%) Sustained ESR<30 mm/hrc , n (%) Sustained CRP normalizationd , n (%) Successful prednisone taperinge , n (%) 20 (40.0%) 20 (40.0%) 17 (34.0%) 10 (20.0%) 23 (45.1%) 22 (43.1%) 13 (25.5%) 20 (39.2%) 69 (69.0%) 83 (83.0%) 72 (72.0%) 60 (60.0%) 28 (57.1%) 37 (75.5%) 34 (69.4%) 28 (57.1%) a Sustained remission was achieved by a patient meeting all of the following components: absence of GCA signs and symptomsb, normalization of ESRc, normalization of CRPd and adherence to the prednisone taper regimene. B Patients who did not have any signs or symptoms of GCA recorded from Week 12 up to Week 52. C Patients who did not have an elevated ESR ≥30 mm/hr which was classified as attributed to GCA from Week 12 up to Week 52. D Patients who did not have two or more consecutive CRP records of ≥ 1mg/dL from Week 12 up to Week 52. E Patients who did not enter escape therapy and received ≤ 100mg of additional concomitant prednisone from Week 12 up to Week 52. Patients not completing the study to week 52 were classified as non-responders in the primary and key secondary analysis: PBO+26: 6 (12.0%), PBO+52: 5 (9.8%), TCZ QW: 15 (15.0%), TCZ Q2W: 9 (18.4%). CRP = C-reactive protein ESR = erythrocyte sedimentation rate PBO = placebo Q2W = every other week dose QW = every week dose TCZ = tocilizumab The estimated annual cumulative prednisone dose was lower in the two tocilizumab dose groups (medians of 1887 mg and 2207 mg on tocilizumab QW and Q2W, respectively) relative to the placebo arms (medians of 3804 mg Reference ID: 5495671 40 and 3902 mg on placebo + 26 weeks prednisone and placebo + 52 weeks prednisone taper, respectively). 14.4 Giant Cell Arteritis – Intravenous Administration Intravenously administered tocilizumab in patients with GCA was assessed in WP41152 (NCT03923738), an open-label PK-PD and safety study to determine the appropriate intravenous dose of tocilizumab that achieved comparable PK-PD profiles to the tocilizumab-SC regimen. At enrollment, all patients (n=24) were in remission on tocilizumab-IV. In Period 1, all patients received open label tocilizumab-IV 7 mg/kg every 4 weeks for 20 weeks. Patients who completed Period 1 and remained in remission (n=22) were eligible to enter Period 2, and received open-label tocilizumab-IV 6 mg/kg every 4 weeks for 20 weeks. The efficacy of intravenous tocilizumab 6 mg/kg in adult patients with GCA is based on pharmacokinetic exposure and extrapolation to the efficacy established for subcutaneous tocilizumab in patients with GCA [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. 14.5 Polyarticular Juvenile Idiopathic Arthritis – Intravenous Administration The efficacy of tocilizumab was assessed in a three-part study, WA19977 (NCT00988221), including an open- label extension in children 2 to 17 years of age with active polyarticular juvenile idiopathic arthritis (PJIA), who had an inadequate response to methotrexate or inability to tolerate methotrexate. Patients had at least 6 months of active disease (mean disease duration of 4.2 ± 3.7 years), with at least five joints with active arthritis (swollen or limitation of movement accompanied by pain and/or tenderness) and/or at least 3 active joints having limitation of motion (mean, 20 ± 14 active joints). The patients treated had subtypes of JIA that at disease onset included Rheumatoid Factor Positive or Negative Polyarticular JIA, or Extended Oligoarticular JIA. Treatment with a stable dose of methotrexate was permitted but was not required during the study. Concurrent use of disease modifying antirheumatic drugs (DMARDs), other than methotrexate, or other biologics (e.g., TNF antagonists or T cell costimulation modulator) were not permitted in the study. Part I consisted of a 16-week active tocilizumab treatment lead-in period (n=188) followed by Part II, a 24-week randomized double-blind placebo-controlled withdrawal period, followed by Part III, a 64-week open-label period. Eligible patients weighing at or above 30 kg received tocilizumab at 8 mg/kg intravenously once every four weeks. Patients weighing less than 30 kg were randomized 1:1 to receive either tocilizumab 8 mg/kg or 10 mg/kg intravenously every four weeks. At the conclusion of the open-label Part I, 91% of patients taking background MTX in addition to tocilizumab and 83% of patients on tocilizumab monotherapy achieved an ACR 30 response at week 16 compared to baseline and entered the blinded withdrawal period (Part II) of the study. The proportions of patients with JIA ACR 50/70 responses in Part I were 84.0%, and 64%, respectively for patients taking background MTX in addition to tocilizumab and 80% and 55% respectively for patients on tocilizumab monotherapy. In Part II, patients (ITT, n=163) were randomized to tocilizumab (same dose received in Part I) or placebo in a 1:1 ratio that was stratified by concurrent methotrexate use and concurrent corticosteroid use. Each patient continued in Part II of the study until Week 40 or until the patient satisfied JIA ACR 30 flare criteria (relative to Week 16) and qualified for escape. The primary endpoint was the proportion of patients with a JIA ACR 30 flare at week 40 relative to week 16. JIA ACR 30 flare was defined as 3 or more of the 6 core outcome variables worsening by at least 30% with no more than 1 of the remaining variables improving by more than 30% relative to Week 16. Tocilizumab treated patients experienced significantly fewer disease flares compared to placebo-treated patients (26% [21/82] versus 48% [39/81]; adjusted difference in proportions -21%, 95% CI: -35%, -8%). During the withdrawal phase (Part II), more patients treated with tocilizumab showed JIA ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo. Reference ID: 5495671 41 14.6 Polyarticular Juvenile Idiopathic Arthritis – Subcutaneous Administration Subcutaneously administered tocilizumab in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA) was assessed in WA28117 (NCT01904279), a 52-week, open-label, multicenter, PK-PD and safety study to determine the appropriate subcutaneous dose of tocilizumab that achieved comparable PK/PD profiles to the tocilizumab-IV regimen. PJIA patients aged 1 to 17 years with an inadequate response or inability to tolerate MTX, including patients with well-controlled disease on treatment with tocilizumab-IV and tocilizumab-naïve patients with active disease, were treated with subcutaneous tocilizumab based on body weight. Patients weighing at or above 30 kg (n = 25) were treated with 162 mg of tocilizumab-SC every 2 weeks and patients weighing less than 30 kg (n = 27) received 162 mg of tocilizumab-SC every 3 weeks for 52 weeks. Of these 52 patients, 37 (71%) were naïve to tocilizumab and 15 (29%) had been receiving tocilizumab-IV and switched to tocilizumab-SC at baseline. The efficacy of subcutaneous tocilizumab in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of intravenous tocilizumab in polyarticular JIA patients and subcutaneous tocilizumab in patients with RA [see Clinical Pharmacology (12.3) and Clinical Studies (14.2 and 14.6)]. 14.7 Systemic Juvenile Idiopathic Arthritis - Intravenous Administration The efficacy of tocilizumab for the treatment of active SJIA was assessed in WA18221 (NCT00642460), a 12­week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients treated with or without MTX, were randomized (tocilizumab:placebo = 2:1) to one of two treatment groups: 75 patients received tocilizumab infusions every two weeks at either 8 mg per kg for patients at or above 30 kg or 12 mg per kg for patients less than 30 kg and 37 were randomized to receive placebo infusions every two weeks. Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR 70 response. After 12 weeks or at the time of escape, due to disease worsening, patients were treated with tocilizumab in the open-label extension phase at weight appropriate dosing. The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set (JIA ACR 30 response) at Week 12 and absence of fever (no temperature at or above 37.5°C in the preceding 7 days). JIA ACR (American College of Rheumatology) responses are defined as the percentage improvement (e.g., 30%, 50%, 70%) in 3 of any 6 core outcome variables compared to baseline, with worsening in no more than 1 of the remaining variables by 30% or more. Core outcome variables consist of physician global assessment, parent per patient global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability (childhood health assessment questionnaire-CHAQ). Primary endpoint result and JIA ACR response rates at Week 12 are shown in Table 9. Reference ID: 5495671 42 Table 8 Efficacy Findings at Week 12 Tocilizumab N=75 Placebo N=37 Primary Endpoint: JIA ACR 30 response + absence of fever Responders 85% 24% Weighted difference (95% CI) 62 (45, 78) - JIA ACR Response Rates at Week 12 JIA ACR 30 Responders Weighted differencea (95% CI)b 91% 67 (51, 83) 24% - JIA ACR 50 Responders Weighted differencea (95% CI) b 85% 74 (58, 90) 11% - JIA ACR 70 Responders Weighted differencea (95% CI) b 71% 63 (46, 80) 8% - aThe weighted difference is the difference between the tocilizumab and Placebo response rates, adjusted for the stratification factors (weight, disease duration, background oral corticosteroid dose and background methotrexate use). b CI: confidence interval of the weighted difference. The treatment effect of tocilizumab was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks). Systemic Features Of patients with fever or rash at baseline, those treated with tocilizumab had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to 5 out of 24 (21%) of placebo-treated patients, and 14 out of 22 (64%) became free of rash compared to 2 out of 18 (11%) of placebo-treated patients. Responses were consistent in the open label extension (data available through 44 weeks). Corticosteroid Tapering Of the patients receiving oral corticosteroids at baseline, 8 out of 31 (26%) placebo and 48 out of 70 (69%), tocilizumab patients achieved a JIA ACR 70 response at week 6 or 8 enabling corticosteroid dose reduction. Seventeen (24%) tocilizumab patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR 30 flare or occurrence of systemic symptoms to week 12. In the open label portion of the study, by week 44, there were 44 out of 103 (43%) tocilizumab patients off oral corticosteroids. Of these 44 patients 50% were off corticosteroids 18 weeks or more. Health Related Outcomes Physical function and disability were assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). Seventy-seven percent (58 out of 75) of patients in the tocilizumab treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of ≥ 0.13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group. 14.8 Systemic Juvenile Idiopathic Arthritis - Subcutaneous Administration Subcutaneously administered tocilizumab in pediatric patients with systemic juvenile idiopathic arthritis (SJIA) was assessed in WA28118 (NCT01904292), a 52-week, open-label, multicenter, PK-PD and safety study to determine the appropriate subcutaneous dose of tocilizumab that achieved comparable PK/PD profiles to the tocilizumab-IV regimen. Reference ID: 5495671 43 Eligible patients received tocilizumab subcutaneously dosed according to body weight, with patients weighing at or above 30 kg (n = 26) dosed with 162 mg of tocilizumab every week and patients weighing below 30 kg (n = 25) dosed with 162 mg of tocilizumab every 10 days (n=8) or every 2 weeks (n=17) for 52 weeks. Of these 51 patients, 26 (51%) were naïve to subcutaneous tocilizumab and 25 (49%) had been receiving tocilizumab intravenously and switched to subcutaneous tocilizumab at baseline. The efficacy of subcutaneous tocilizumab in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of the established efficacy of intravenous tocilizumab in systemic JIA patients [see Clinical Pharmacology (12.3) and Clinical Studies (14.8)]. 16 HOW SUPPLIED/STORAGE AND HANDLING TYENNE (tocilizumab-aazg) injection is a preservative-free, sterile clear and colorless to pale yellow solution. The following packaging configurations are available: For Intravenous Infusion TYENNE Single-Dose Vial Each TYENNE carton contains one vial. Each vial is supplied as 80 mg/4 mL (20 mg/mL) (NDC 65219-590-04), 200 mg/10 mL (20 mg/mL) (NDC 65219-592-10), and 400 mg/20 mL (20 mg/mL) (NDC 65219-594-20) TYENNE solution for further dilution prior to intravenous infusion. The vial stopper is not made with natural rubber latex. For Subcutaneous Injection TYENNE Prefilled Syringe Each TYENNE carton contains a single-dose prefilled syringe delivering 162 mg/0.9 mL of TYENNE. The syringe plunger stopper and needle cover are not made with natural rubber latex. The NDC number is 65219-586-04. TYENNE Autoinjector Each TYENNE carton contains a single-dose autoinjector delivering 162 mg/0.9 mL of TYENNE. The syringe plunger stopper and needle cover are not made with natural rubber latex. The NDC number is 65219-584-01. Storage and Handling: Do not use beyond expiration date on the container, package, prefilled syringe, or autoinjector. TYENNE must be refrigerated at 36°F to 46°F (2ºC to 8ºC). Do not freeze. A single prefilled syringe (or autoinjector) may be stored at room temperature at or below 77°F (25°C) for a single period of up to 14 days. Protect the vials, syringes and autoinjectors from light by storage in the original package until time of use, and keep syringes and autoinjectors dry. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). • Serious Infections Inform patients that TYENNE may lower their resistance to infections [see Warnings and Precautions (5.1)]. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment. • Gastrointestinal Perforation Inform patients that some patients who have been treated with TYENNE have had serious side effects in the stomach and intestines [see Warnings and Precautions (5.2)]. Instruct the patient of the importance of contacting their doctor immediately when symptoms of fever, severe, persistent abdominal pain, and change in bowel habits appear to assure rapid evaluation and appropriate treatment. • Hypersensitivity and Serious Allergic Reactions Reference ID: 5495671 44 Inform patients that some patients who have been treated with TYENNE have developed serious allergic reactions, including anaphylaxis, as well as serious skin reactions [see Warnings and Precautions (5.6)]. Advise patients to stop taking TYENNE and seek immediate medical attention if they experience any symptom of serious allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing). Instruction on Injection Technique Assess patient suitability for home use for subcutaneous injection. Perform the first injection under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer subcutaneous TYENNE, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous TYENNE and the suitability for home use [See Instructions for Use]. Prior to use, remove the prefilled syringe (PFS) or autoinjector from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes (PFS) or 45 minutes (autoinjector), out of the reach of children. Do not warm TYENNE in any other way. Advise patients to consult their healthcare provider if the full dose is not received. A puncture-resistant container for disposal of needles, syringes and autoinjectors should be used and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper needle, syringe and autoinjector disposal, and caution against reuse of these items. Pregnancy Inform female patients of reproductive potential that TYENNE may cause fetal harm and to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)]. TYENNE (tocilizumab-aazg) Manufactured by: Fresenius Kabi USA, LLC Lake Zurich, IL 60047, U.S.A. U.S. License Number: 2146 Reference ID: 5495671 45 Medication Guide TYENNE® (tye en’) (tocilizumab-aazg) injection for intravenous use TYENNE® (tye en’) (tocilizumab-aazg) injection for subcutaneous use What is the most important information I should know about TYENNE? TYENNE can cause serious side effects including: 1. Serious Infections. TYENNE is a medicine that affects your immune system. TYENNE can lower the ability of your immune system to fight infections. Some people have serious infections while taking TYENNE, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections. Your healthcare provider should assess you for TB before starting TYENNE. Your healthcare provider should monitor you closely for signs and symptoms of TB during and after treatment with TYENNE. • You should not start taking TYENNE if you have any kind of infection unless your healthcare provider says it is okay. Before starting TYENNE, tell your healthcare provider if you: • think you have an infection or have symptoms of an infection, with or without a fever, such as: o sweating or chills o feel very tired o cough o shortness of breath o muscle aches o weight loss o warm, red, or painful skin or o blood in phlegm o burning when you urinate or sores on your body o diarrhea or stomach urinating more often than pain normal • are being treated for an infection. • get a lot of infections or have infections that keep coming back. • have diabetes, HIV, or a weak immune system. People with these conditions have a higher chance for infections. • have TB or have been in close contact with someone with TB. • live or have lived or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections (histoplasmosis, coccidiomycosis, or blastomycosis). These infections may happen or become more severe if you use TYENNE. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common. • have or have had hepatitis B. After starting TYENNE, call your healthcare provider right away if you have any symptoms of an infection. TYENNE can make you more likely to get infections or make worse any infection that you have. 2. Tears (perforation) of the stomach or intestines. • Tell your healthcare provider if you have had diverticulitis (inflammation in parts of the large intestine) or ulcers in your stomach or intestines. Some people taking TYENNE get tears in their stomach or intestine. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. • Tell your healthcare provider right away if you have fever and new onset stomach-area pain that does not go away, and a change in your bowel habits. 3. Liver problems (Hepatotoxicity): Some people have experienced serious life-threatening liver problems, which required a liver transplant or led to death. Your healthcare provider may tell you to stop taking TYENNE if you develop new or worse liver problems during treatment with TYENNE. Tell your healthcare provider right away if you have any of the following symptoms: Reference ID: 5495671 o feeling tired (fatigue) o weakness o lack of appetite for several days or longer o nausea and vomiting (anorexia) o yellowing of your skin or the whites of your eyes o confusion (jaundice) o abdominal swelling and pain on the right side of o dark “tea-colored” urine your stomach-area o light colored stools 4. Changes in certain laboratory test results. Your healthcare provider should do blood tests before you start receiving TYENNE. If you have rheumatoid arthritis (RA) or giant cell arteritis (GCA) your healthcare provider should do blood tests every 4 to 8 weeks after you start receiving TYENNE for the first 6 months and then every 3 months after that. If you have polyarticular juvenile idiopathic arthritis (PJIA) you will have blood tests done every 4 to 8 weeks during treatment. If you have systemic juvenile idiopathic arthritis (SJIA) you will have blood tests done every 2 to 4 weeks during treatment. These blood tests are to check for the following side effects of TYENNE: • low neutrophil count. Neutrophils are white blood cells that help the body fight off bacterial infections. • low platelet count. Platelets are blood cells that help with blood clotting and stop bleeding. • increase in certain liver function tests. • increase in blood cholesterol levels. You may also have changes in other laboratory tests, such as your blood cholesterol levels. Your healthcare provider should do blood tests to check your cholesterol levels 4 to 8 weeks after you start receiving TYENNE. Your healthcare provider will determine how often you will have follow-up blood tests. Make sure you get all your follow-up blood tests done as ordered by your healthcare provider. You should not receive TYENNE if your neutrophil or platelet counts are too low, or your liver function tests are too high. Your healthcare provider may stop your TYENNE treatment for a period of time or change your dose of medicine if needed because of changes in these blood test results. 5. Cancer. TYENNE may increase your risk of certain cancers by changing the way your immune system works. Tell your healthcare provider if you have ever had any type of cancer. See “What are the possible side effects with TYENNE?” for more information about side effects. What is TYENNE? TYENNE is a prescription medicine called an Interleukin-6 (IL-6) receptor antagonist. TYENNE is used: • To treat adults with moderately to severely active rheumatoid arthritis (RA), after at least one other medicine called a Disease-Modifying Anti-Rheumatic Drug (DMARD) has been used and did not work well. • To treat adults with giant cell arteritis (GCA). • To treat people with active PJIA ages 2 and above. • To treat people with active SJIA ages 2 and above. It is not known if TYENNE is safe and effective in children with PJIA or SJIA under 2 years of age or in children with conditions other than PJIA or SJIA. Do not take TYENNE: if you are allergic to tocilizumab products, or any of the ingredients in TYENNE. See the end of this Medication Guide for a complete list of ingredients in TYENNE. Before you receive TYENNE, tell your healthcare provider about all of your medical conditions, including if you: • have an infection. See “What is the most important information I should know about TYENNE?” • have liver problems. • have any stomach-area (abdominal) pain or been diagnosed with diverticulitis or ulcers in your stomach or intestines. • have had a reaction to tocilizumab products or any of the ingredients in TYENNE before. • have or had a condition that affects your nervous system, such as multiple sclerosis. • have recently received or are scheduled to receive a vaccine: o All vaccines should be brought up-to-date before starting TYENNE, unless urgent treatment initiation is required. o People who take TYENNE should not receive live vaccines. o People taking TYENNE can receive non-live vaccines. Reference ID: 5495671 • plan to have surgery or a medical procedure. • are pregnant or plan to become pregnant. TYENNE may harm your unborn baby. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with TYENNE. • are breastfeeding or plan to breastfeed. It is not known if TYENNE passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take TYENNE. Tell your healthcare provider about all of the medicines you take, including prescription, over-the-counter medicines, vitamins, and herbal supplements. TYENNE and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take: • any other medicines to treat your RA. Taking TYENNE with these medicines may increase your risk of infection. • medicines that affect the way certain liver enzymes work. Ask your healthcare provider if you are not sure if your medicine is one of these. Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. How will I receive TYENNE? Into a vein (IV or intravenous infusion) for Rheumatoid Arthritis, Giant Cell Arteritis, PJIA or SJIA: • If your healthcare provider prescribes TYENNE as an IV infusion, you will receive TYENNE from a healthcare provider through a needle placed in a vein in your arm. The infusion will take about 1 hour to give you the full dose of medicine. • For rheumatoid arthritis, giant cell arteritis or PJIA you will receive a dose of TYENNE about every 4 weeks. • For SJIA you will receive a dose of TYENNE about every 2 weeks. • While taking TYENNE, you may continue to use other medicines that help treat your rheumatoid arthritis, PJIA, or SJIA such as methotrexate, non-steroidal anti-inflammatory drugs (NSAIDs) and prescription steroids, as instructed by your healthcare provider. • Keep all of your follow-up appointments and get your blood tests as ordered by your healthcare provider. Under the skin (SC or subcutaneous injection) for Rheumatoid Arthritis, Giant Cell Arteritis, PJIA or SJIA: • See the Instructions for Use at the end of this Medication Guide for instructions about the right way to prepare and give your TYENNE injections at home. • TYENNE is available as a single-dose prefilled syringe or single-dose prefilled autoinjector. • You may also receive TYENNE as an injection under your skin (subcutaneous). If your healthcare provider decides that you or a caregiver can give your injections of TYENNE at home, you or your caregiver should receive training on the right way to prepare and inject TYENNE. Do not try to inject TYENNE until you have been shown the right way to give the injections by your healthcare provider. • For PJIA or SJIA, you may self-inject with the prefilled syringe or prefilled autoinjector, or your caregiver can give you TYENNE, if both your healthcare provider and parent/legal guardian find it appropriate. • Your healthcare provider will tell you how much TYENNE to use and when to use it. What are the possible side effects with TYENNE? TYENNE can cause serious side effects, including: • See “What is the most important information I should know about TYENNE?” • Hepatitis B infection in people who carry the virus in their blood. If you are a carrier of the hepatitis B virus (a virus that affects the liver), the virus may become active while you use TYENNE. Your healthcare provider may do blood tests before you start treatment with TYENNE and while you are using TYENNE. Tell your healthcare provider if you have any of the following symptoms of a possible hepatitis B infection: o feel very tired o skin or eyes look yellow o little or no appetite o vomiting o clay-colored bowel movements o fevers o chills o stomach discomfort o muscle aches o dark urine o skin rash • Serious Allergic Reactions. Serious allergic reactions, including death, can happen with TYENNE. These reactions can happen with any infusion or injection of TYENNE, even if they did not occur with an earlier infusion or injection. Stop taking TYENNE, contact your healthcare provider, and get emergency help right away if you have any of the following signs of a serious allergic reaction: o swelling of your face, lips, mouth, or tongue o trouble breathing Reference ID: 5495671 o wheezing o severe itching o skin rash, hives, redness, or swelling outside of the injection site area o dizziness or fainting o fast heartbeat or pounding in your chest (tachycardia) o sweating • Nervous system problems. While rare, Multiple Sclerosis has been diagnosed in people who take TYENNE. It is not known what effect TYENNE may have on some nervous system disorders. The most common side effects of TYENNE include: • upper respiratory tract infections (common cold, sinus infections) • headache • increased blood pressure (hypertension) • injection site reactions Tell your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of TYENNE. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Fresenius Kabi USA, LLC at 1-800-551-7176. General information about the safe and effective use of TYENNE. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not give TYENNE to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TYENNE that is written for health professionals. For more information go to www.TYENNE.com or you can enroll in a patient support program by calling 1-833-522-4227 or visiting the patient support program website: www.kabicare.com. What are the ingredients in TYENNE? Active ingredient: tocilizumab-aazg. Inactive ingredients of Intravenous and Subcutaneous TYENNE: arginine, histidine, hydrochloric acid, lactic acid, polysorbate 80, sodium chloride, sodium hydroxide and Water for Injection. TYENNE is a registered trademark of Fresenius Kabi Manufactured by: Fresenius Kabi USA LLC, Lake Zurich, IL 60047, U.S.A U.S License Number 2146 This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 12/2024 Reference ID: 5495671
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2025-02-12T15:47:45.459127
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BRIDION safely and effectively. See full prescribing information for BRIDION. BRIDION® (sugammadex) Injection, for intravenous use Initial U.S. Approval: 2015 ---------------------------RECENT MAJOR CHANGES --------------------------­ Indication and Usage (1) 12/2024 ----------------------------INDICATIONS AND USAGE---------------------------­ BRIDION is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adult and pediatric patients undergoing surgery. (1) ----------------------- DOSAGE AND ADMINISTRATION ----------------------­ • Dosing is based on actual body weight (2.1) • Monitor for twitch responses to determine the timing and dose for BRIDION administration. (2.1) • Administer as a single bolus injection. (2.1) For rocuronium and vecuronium: • 4 mg/kg is recommended if spontaneous recovery of the twitch response has reached 1 to 2 post-tetanic counts (PTC) and there are no twitch responses to train-of-four (TOF) stimulation. (2.2) • 2 mg/kg is recommended if spontaneous recovery has reached the reappearance of the second twitch in response to TOF stimulation. (2.2) For rocuronium only: • 16 mg/kg is recommended if there is a clinical need to reverse neuromuscular blockade soon (approximately 3 minutes) after administration of a single dose of 1.2 mg/kg of rocuronium. Immediate reversal in pediatric patients has not been studied. (2.2) ---------------------DOSAGE FORMS AND STRENGTHS --------------------­ • 200 mg/2 mL (100 mg/mL) in a single-dose vial for bolus injection (3) • 500 mg/5 mL (100 mg/mL) in a single-dose vial for bolus injection (3) -------------------------------CONTRAINDICATIONS------------------------------­ Known hypersensitivity to sugammadex or any of its components. (4) ----------------------- WARNINGS AND PRECAUTIONS------------------------ Anaphylaxis: Be prepared for hypersensitivity reactions (including anaphylactic reactions) and take necessary precautions. (5.1) Marked Bradycardia: Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after administration. Monitor for hemodynamic changes and administer anticholinergic agents such as atropine if clinically significant bradycardia is observed. (5.2) Respiratory Function Monitoring: Ventilatory support is mandatory until adequate spontaneous respiration is restored and the ability to maintain a patent airway is assured. Provide adequate ventilation if neuromuscular blockade persists after BRIDION or recurs following extubation. (5.3, 5.4) Waiting Times for Re-Administration of Neuromuscular Blocking Agents: If re-administration of a neuromuscular blocking agent is required after reversal with BRIDION, waiting times should be based on the dose of BRIDION and the renal function of the patient. Consider use of a nonsteroidal neuromuscular blocking agent. (5.5) ------------------------------ ADVERSE REACTIONS -----------------------------­ • Most common adverse reactions (reported in ≥10% of adult patients at a 2, 4, or 16 mg/kg BRIDION dose and higher than the placebo rate): vomiting, pain, nausea, hypotension, and headache. (6.1) • Most common adverse reactions (reported in ≥10% of pediatric patients 2 to <17 years of age at BRIDION doses of 2 or 4 mg/kg) were pain, vomiting, and nausea. (6.1) • Most common adverse reaction (reported in ≥10% of pediatric patients from birth to <2 years of age at BRIDION doses of 2 or 4 mg/kg) was procedural pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------- Toremifene: Concomitant use can delay recovery. (7.2) Hormonal contraceptives: Patients must use an additional, non- hormonal method of contraception for 7 days following BRIDION administration. (5.6, 7.3) ----------------------- USE IN SPECIFIC POPULATIONS ----------------------­ • Severe Renal Impairment: Not recommended. (8.6) See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosing and Administration Information 2.2 Recommended Dosing 2.3 Drug Compatibility 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Anaphylaxis and Hypersensitivity 5.2 Marked Bradycardia 5.3 Respiratory Function Monitoring During Recovery 5.4 Risk of Prolonged Neuromuscular Blockade 5.5 Waiting Times for Re-Administration of Neuromuscular Blocking Agents for Intubation Following Reversal with BRIDION 5.6 Interactions Potentially Affecting the Efficacy of Other Drugs 5.7 Risk of Recurrence of Neuromuscular Blockade Due to Displacement Interactions 5.8 Risk of Recurrence of Neuromuscular Blockade with Lower Than Recommended Dosing 5.9 Risk of Recurrence of Neuromuscular Blockade Due to the Administration of Drugs that Potentiate Neuromuscular Blockade 5.10 Risk of Coagulopathy and Bleeding 5.11 Renal Impairment 5.12 Light Anesthesia 5.13 Reversal after Rocuronium or Vecuronium Administration in the ICU 5.14 Reversal of Neuromuscular Blocking Agents Other Than Rocuronium or Vecuronium 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-Marketing Experience 7 DRUG INTERACTIONS 7.1 Summary 7.2 Interactions Potentially Affecting the Efficacy of BRIDION 7.3 Interaction Potentially Affecting the Efficacy of Hormonal Contraceptives 7.4 Interference with Laboratory Tests 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 8.8 Cardiac Patients 8.9 Pulmonary Patients 8.10 Obese Patients with a BMI ≥40 kg/m2 8.11 American Society of Anesthesiologists Class 3 or 4 Patients 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics Reference ID: 5494299 13 12.3 Pharmacokinetics NONCLINICAL TOXICOLOGY 16 17 HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION 14 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology CLINICAL STUDIES *Sections or subsections omitted from the full prescribing information are not listed. 14.1 Controlled Clinical Studies FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE BRIDION® is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adult and pediatric patients undergoing surgery. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosing and Administration Information BRIDION dosing is based on actual body weight. BRIDION (sugammadex) injection, for intravenous use, should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Doses and timing of BRIDION administration should be based on monitoring for twitch responses and the extent of spontaneous recovery that has occurred. Administer BRIDION intravenously as a single bolus injection. The bolus injection may be given over 10 seconds, into an existing intravenous line. BRIDION has only been administered as a single bolus injection in clinical trials. From the time of BRIDION administration until complete recovery of neuromuscular function, monitor the patient to assure adequate ventilation and maintenance of a patent airway. Satisfactory recovery should be determined through assessment of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation. The recommended dose of BRIDION does not depend on the anesthetic regimen. Preparation of dilution for pediatric use: BRIDION 100 mg/mL may be diluted to a concentration of 10 mg/mL, using 0.9% sodium chloride injection, USP, to increase the accuracy of dosing in the pediatric population. • To prepare the required dose, aseptically transfer all the contents of the 2 mL vial of BRIDION 2­ mL single-dose vials containing 200 mg sugammadex (100 mg/mL) to a bottle (or intravenous bag) containing 18 mL of 0.9% sodium chloride injection, to achieve a final concentration of 10 mg/mL sugammadex. The diluted solution should be used immediately. • BRIDION injection is a single-dose sterile solution without preservatives. Discard any unused portion from the vial. 2.2 Recommended Dosing BRIDION can be used to reverse different levels of rocuronium- or vecuronium-induced neuromuscular blockade. For rocuronium and vecuronium: • A dose of 4 mg/kg BRIDION is recommended if spontaneous recovery of the twitch response has reached 1 to 2 post-tetanic counts (PTC) and there are no twitch responses to train-of-four (TOF) stimulation following rocuronium- or vecuronium-induced neuromuscular blockade [see Warnings and Precautions (5.8)]. Reference ID: 5494299 • A dose of 2 mg/kg BRIDION is recommended if spontaneous recovery has reached the reappearance of the second twitch (T2) in response to TOF stimulation following rocuronium- or vecuronium-induced neuromuscular blockade [see Warnings and Precautions (5.8)]. For rocuronium only: • A dose of 16 mg/kg BRIDION is recommended if there is a clinical need to reverse neuromuscular blockade soon (approximately 3 minutes) after administration of a single dose of 1.2 mg/kg of rocuronium. The efficacy of the 16 mg/kg dose of BRIDION following administration of vecuronium has not been studied. Immediate reversal in pediatric patients has not been studied [see Clinical Studies (14.1)]. 2.3 Drug Compatibility May inject BRIDION into the intravenous line of a running infusion with the following intravenous solutions: • 0.9% sodium chloride • 5% dextrose • 0.45% sodium chloride and 2.5% dextrose • 5% dextrose in 0.9% sodium chloride • isolyte P with 5% dextrose • Ringer’s lactate solution • Ringer’s solution Ensure the infusion line is adequately flushed (e.g., with 0.9% sodium chloride) between administration of BRIDION and other drugs. Do not mix BRIDION with other products except those listed above. BRIDION is physically incompatible with verapamil, ondansetron, and ranitidine. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever the solution and container permit. 3 DOSAGE FORMS AND STRENGTHS BRIDION (sugammadex) injection is a sterile, clear, colorless to slightly yellow-brown, non-pyrogenic aqueous solution intended for intravenous infusion. BRIDION is available as follows: • 200 mg/2 mL (100 mg/mL) in a single-dose vial for bolus injection • 500 mg/5 mL (100 mg/mL), in a single-dose vial for bolus injection 4 CONTRAINDICATIONS BRIDION is contraindicated in patients with known hypersensitivity to sugammadex or any of its components. Hypersensitivity reactions that occurred varied from isolated skin reactions to serious systemic reactions (i.e., anaphylaxis, anaphylactic shock) and have occurred in patients with no prior exposure to sugammadex [see Warnings and Precautions (5.1), Adverse Reactions (6)]. 3 Reference ID: 5494299 5 WARNINGS AND PRECAUTIONS 5.1 Anaphylaxis and Hypersensitivity Clinicians should be prepared for the possibility of drug hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions [see Contraindications (4), Adverse Reactions (6.1)]. Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with BRIDION. The nature and frequency of anaphylaxis and hypersensitivity associated with BRIDION administration were evaluated in a randomized, double-blind, placebo-controlled, parallel-group, repeat- dose study in which 375 subjects were randomized to receive 3 doses of BRIDION IV with a 5-week washout period: 151 subjects received 4 mg/kg, 148 received 16 mg/kg and 76 received placebo. The frequency of anaphylaxis for the 299 healthy volunteers treated with intravenous BRIDION was 0.3% (n=1 in the BRIDION 16 mg/kg group on the first dose). Signs and symptoms included conjunctival edema, urticaria, erythema, swelling of the uvula and reduction in peak expiratory flow within 5 minutes of dose administration. The most common hypersensitivity adverse reactions reported were nausea, pruritus and urticaria and showed a dose response relationship, occurring more frequently in the 16 mg/kg group compared to the 4 mg/kg and placebo groups. Anaphylaxis has also been reported in the post-marketing setting, including at doses less than 16 mg/kg. The most commonly described clinical features in reports of anaphylaxis were dermatologic symptoms (including urticaria, rash, erythema, flushing and skin eruption); and clinically important hypotension often requiring the use of vasopressors for circulatory support. In addition, prolonged hospitalization and/or the use of additional respiratory support until full recovery (re-intubation, prolonged intubation, manual or mechanical ventilation) have been noted in a number of the anaphylaxis reports. 5.2 Marked Bradycardia Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of BRIDION [see Adverse Reactions (6.2)]. Patients should be closely monitored for hemodynamic changes during and after reversal of neuromuscular blockade. Treatment with anticholinergic agents, such as atropine, should be administered if clinically significant bradycardia is observed. 5.3 Respiratory Function Monitoring During Recovery Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored and the ability to maintain a patent airway is assured. Even if recovery from neuromuscular blockade is complete, other drugs used in the peri- and post-operative period could depress respiratory function and therefore ventilatory support might still be required. Should neuromuscular blockade persist after BRIDION administration or recur following extubation, take appropriate steps to provide adequate ventilation. 5.4 Risk of Prolonged Neuromuscular Blockade In clinical trials, a small number of patients experienced a delayed or minimal response to the administration of BRIDION [see Clinical Studies (14.1)]. Thus, it is important to monitor ventilation until recovery occurs. 5.5 Waiting Times for Re-Administration of Neuromuscular Blocking Agents for Intubation Following Reversal with BRIDION A minimum waiting time is necessary before administration of a steroidal neuromuscular blocking agent after administration of BRIDION. 4 Reference ID: 5494299 Table 1: Re-administration of Rocuronium or Vecuronium after Reversal (up to 4 mg/kg BRIDION) Minimum Waiting Time NMBA and Dose to be Administered 5 minutes 1.2 mg/kg rocuronium 4 hours 0.6 mg/kg rocuronium or 0.1 mg/kg vecuronium When rocuronium 1.2 mg/kg is administered within 30 minutes after reversal with BRIDION, the onset of neuromuscular blockade may be delayed up to approximately 4 minutes and the duration of neuromuscular blockade may be shortened up to approximately 15 minutes. The recommended waiting time in patients with mild or moderate renal impairment for re-use of 0.6 mg/kg rocuronium or 0.1 mg/kg vecuronium after reversal with up to 4 mg/kg BRIDION should be 24 hours. If a shorter waiting time is required, the rocuronium dose for a new neuromuscular blockade should be 1.2 mg/kg. For re-administration of rocuronium or administration of vecuronium after reversal of rocuronium with 16 mg/kg BRIDION, a waiting time of 24 hours is suggested. If neuromuscular blockade is required before the recommended waiting time has elapsed, use a nonsteroidal neuromuscular blocking agent. The onset of a depolarizing neuromuscular blocking agent might be slower than expected, because a substantial fraction of postjunctional nicotinic receptors can still be occupied by the neuromuscular blocking agent. 5.6 Interactions Potentially Affecting the Efficacy of Other Drugs Due to the administration of BRIDION, certain drugs, including hormonal contraceptives, could become less effective due to a lowering of the (free) plasma concentrations. In this situation, consider the re- administration of the other drug, the administration of a therapeutically equivalent drug (preferably from a different chemical class), and/or non-pharmacological interventions as appropriate [see Drug Interactions (7.3)]. 5.7 Risk of Recurrence of Neuromuscular Blockade Due to Displacement Interactions Recurrence of neuromuscular blockade may occur due to displacement of rocuronium or vecuronium from BRIDION by other drugs [see Drug Interactions (7.2)]. In this situation the patient may require mechanical ventilation. Administration of the drug which caused displacement should be stopped in case of an infusion. The risk of displacement reactions will be the highest in the time period equivalent to 3 times the half-life of BRIDION [see Clinical Pharmacology (12.3)]. 5.8 Risk of Recurrence of Neuromuscular Blockade with Lower Than Recommended Dosing The use of lower than recommended doses of BRIDION may lead to an increased risk of recurrence of neuromuscular blockade after initial reversal and is not recommended [see Dosage and Administration (2.2), Adverse Reactions (6.1)]. 5.9 Risk of Recurrence of Neuromuscular Blockade Due to the Administration of Drugs that Potentiate Neuromuscular Blockade When drugs which potentiate neuromuscular blockade are used in the post-operative phase, special attention should be paid to the possibility of recurrence of neuromuscular blockade. Refer to the package insert for rocuronium or vecuronium for a list of the specific drugs which potentiate neuromuscular blockade. In case recurrence of neuromuscular blockade is observed, the patient may require mechanical ventilation. 5 Reference ID: 5494299 5.10 Risk of Coagulopathy and Bleeding BRIDION doses up to 16 mg/kg were associated with increases in the coagulation parameters activated partial thromboplastin time (aPTT) and prothrombin time/international normalized ratio [PT(INR)] of up to 25% for up to 1 hour in healthy volunteers. In patients undergoing major orthopedic surgery of the lower extremity who were concomitantly treated with heparin or low molecular weight heparin for thromboprophylaxis, increases in aPTT and PT(INR) of 5.5% and 3.0%, respectively, were observed in the hour following BRIDION 4 mg/kg administration. This clinical trial did not demonstrate an increased blood loss or anemia incidence with BRIDION compared with usual treatment. The rate of adjudicated bleeding events within 24 hours was 2.9% for sugammadex and 4.1% for usual care. The rate of post-operative anemia was 21% for sugammadex and 22% for usual care. The mean 24-hour drainage volume was 0.46 L for sugammadex and 0.48 L for usual care. The need for any post-operative transfusion was 37% for sugammadex and 39% for usual care. In vitro experiments demonstrated additional aPTT and PT(INR) prolongations for sugammadex in combination with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban, and dabigatran up to ~25% and ~50% at Cmax levels of sugammadex corresponding to 4 mg/kg and 16 mg/kg doses, respectively. Since bleeding risk has been studied systematically with only heparin and low molecular weight heparin thromboprophylaxis and 4 mg/kg doses of sugammadex coagulation parameters should be carefully monitored in patients with known coagulopathies, being treated with therapeutic anticoagulation, receiving thromboprophylaxis drugs other than heparin and low molecular weight heparin, or receiving thromboprophylaxis drugs and who then receive a dose of 16 mg/kg sugammadex. 5.11 Renal Impairment BRIDION is not recommended for use in patients with severe renal impairment, including those requiring dialysis [see Use in Specific Populations (8.6)]. With regard to the recommended waiting time for re- administration in patients with mild or moderate renal impairment, see Waiting Times for Re-Administration of Neuromuscular Blocking Agents for Intubation Following Reversal with BRIDION [see Warnings and Precautions (5.5)]. 5.12 Light Anesthesia When neuromuscular blockade was reversed intentionally in the middle of anesthesia in clinical trials, e.g., when investigating urgent reversal, signs of light anesthesia were noted occasionally (movement, coughing, grimacing and suckling of the tracheal tube). 5.13 Reversal after Rocuronium or Vecuronium Administration in the ICU BRIDION has not been studied for reversal following rocuronium or vecuronium administration in the ICU. 5.14 Reversal of Neuromuscular Blocking Agents Other Than Rocuronium or Vecuronium Do not use BRIDION to reverse blockade induced by nonsteroidal neuromuscular blocking agents such as succinylcholine or benzylisoquinolinium compounds. Do not use BRIDION to reverse neuromuscular blockade induced by steroidal neuromuscular blocking agents other than rocuronium or vecuronium. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Anaphylaxis and Hypersensitivity [see Contraindications (4), Warnings and Precautions (5.1)] • Marked Bradycardia [see Warnings and Precautions (5.2)] 6 Reference ID: 5494299 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Patients The data described below reflect 2914 subjects exposed to 2, 4, or 16 mg/kg BRIDION and 544 to placebo in pooled Phase 1-3 studies. The population was 18 to 92 years old, 47% male and 53% female, 34% ASA (American Society of Anesthesiologists) Class 1, 51% ASA Class 2, and 14% ASA Class 3, and 82% Caucasian. Most subjects received a single dose of BRIDION 2 mg/kg or 4 mg/kg. Adverse reactions reported in ≥10% of patients at a 2, 4, or 16 mg/kg BRIDION dose with a rate higher than the placebo rate are: vomiting, pain, nausea, hypotension, and headache. All adverse reactions occurring in ≥2% of subjects treated with BRIDION and more often than placebo for adult subjects who received anesthesia and/or neuromuscular blocking agent in pooled Phase 1 to 3 studies are presented in Table 2. Table 2: Percent of Subject Exposures in Pooled Phase 1 to 3 Studies with Adverse Reactions Incidence ≥2% Sugammadex Placebo Body System Preferred Term 2 mg/kg (N=895) n (%) 4 mg/kg (N=1921) n (%) 16 mg/kg (N=98) n (%) (N=544) n (%) Injury, poisoning and procedural complications Incision site pain 58 (6) 106 (6) 4 (4) 6 (1) Procedural complication 13 (1) 27 (1) 8 (8) 3 (1) Airway complication of anesthesia 11 (1) 13 (1) 9 (9) 0 Anesthetic complication 8 (1) 14 (1) 9 (9) 1 (<1) Wound hemorrhage 5 (1) 38 (2) 0 8 (1) Recurrence of neuromuscular blockade 0 1 (<1) 2 (2) 0 Gastrointestinal disorders Nausea* 208 (23) 503 (26) 23 (23) 127 (23) Vomiting* 98 (11) 236 (12) 15 (15) 57 (10) Abdominal pain* 48 (5) 68 (4) 6 (6) 17 (3) Flatulence 17 (2) 51 (3) 1 (1) 10 (2) Dry mouth 9 (1) 5 (<1) 2 (2) 0 General disorders and administration site conditions Pain* 434 (48) 993 (52) 35 (36) 207 (38) 7 Reference ID: 5494299 Sugammadex Placebo Body System Preferred Term 2 mg/kg (N=895) n (%) 4 mg/kg (N=1921) n (%) 16 mg/kg (N=98) n (%) (N=544) n (%) Pyrexia 77 (9) 109 (6) 5 (5) 17 (3) Chills 30 (3) 61 (3) 7 (7) 27 (5) Nervous system disorders Headache 61 (7) 99 (5) 10 (10) 42 (8) Dizziness 44 (5) 67 (3) 6 (6) 13 (2) Hypoesthesia 12 (1) 24 (1) 3 (3) 9 (2) Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 42 (5) 66 (3) 5 (5) 27 (5) Cough 13 (1) 49 (3) 8 (8) 11 (2) Musculoskeletal and connective tissue disorders Pain in extremity 13 (1) 35 (2) 6 (6) 15 (3) Musculoskeletal pain 16 (2) 33 (2) 1 (1) 6 (1) Myalgia 5 (1) 17 (1) 2 (2) 3 (1) Psychiatric disorders Insomnia 20 (2) 103 (5) 5 (5) 22 (4) Anxiety 14 (2) 19 (1) 3 (3) 1 (<1) Restlessness 3 (<1) 17 (1) 2 (2) 2 (<1) Depression 2 (<1) 5 (<1) 2 (2) 0 Investigations Red blood cell count decreased* 13 (1) 34 (2) 1 (1) 2 (<1) Electrocardiogram QT interval abnormal* 13 (1) 7 (<1) 6 (6) 4 (1) Blood creatine phosphokinase increased 9 (1) 14 (1) 2 (2) 1 (<1) Vascular disorders Hypertension* 48 (5) 96 (5) 9 (9) 38 (7) Hypotension* 33 (4) 102 (5) 13 (13) 20 (4) Skin and subcutaneous tissue disorders Pruritus 17 (2) 50 (3) 2 (2) 9 (2) Erythema 5 (1) 31 (2) 0 6 (1) 8 Reference ID: 5494299 Sugammadex Placebo Body System Preferred Term 2 mg/kg (N=895) n (%) 4 mg/kg (N=1921) n (%) 16 mg/kg (N=98) n (%) (N=544) n (%) Metabolism and nutrition disorders Hypocalcemia 15 (2) 12 (1) 0 4 (1) Cardiac disorders Tachycardia* 17 (2) 29 (2) 5 (5) 4 (1) Bradycardia* 9 (1) 21 (1) 5 (5) 6 (1) Surgical and medical procedures Hysterectomy 0 0 2 (2) 0 * Combinations of preferred terms are as follows: Nausea includes preferred terms nausea and procedural nausea Vomiting includes preferred terms vomiting and procedural vomiting Abdominal pain includes preferred terms abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, and epigastric discomfort Pain includes preferred terms pain and procedural pain Red blood cell count decreased includes preferred terms red blood cell count decreased, hemoglobin decreased, and hematocrit decreased Electrocardiogram QT interval abnormal includes preferred terms electrocardiogram QT interval abnormal and electrocardiogram QT interval prolonged Hypertension includes preferred terms hypertension, procedural hypertension, and blood pressure increased Hypotension includes preferred terms hypotension, procedural hypotension, and blood pressure decreased Tachycardia includes preferred terms tachycardia and heart rate increased Bradycardia includes preferred terms bradycardia and heart rate decreased Pediatric Patients 2 to <17 years of age The safety of BRIDION has been assessed in a randomized, active-controlled study of pediatric patients 2 to <17 years of age, with 242 receiving treatment with BRIDION. Adverse events occurring in ≥5% of pediatric patients are presented in Table 3. The safety profile was generally consistent with that observed in adults. 9 Reference ID: 5494299 Table 3: Pediatric Patients (2 to <17 years of age) with Adverse Events Incidence ≥5% in One or More Treatment Groups Up to 7 Days Post-Treatment Sugammadex 2 mg/kg Sugammadex 4 mg/kg n (%) n (%) Subjects in population with one or more specific adverse events with no specific adverse events Cardiac disorders Bradycardia* Eye disorders Gastrointestinal disorders Nausea Vomiting Injury, poisoning and procedural complications Incision site pain Procedural nausea Procedural pain Procedural vomiting 51 40 11 5 5 3 8 1 4 34 3 4 30 3 (78) (22) (10) (10) (6) (16) (2) (8) (67) (6) (8) (59) (6) 191 143 48 16 13 1 35 12 20 121 6 9 111 5 (75) (25) (8) (7) (1) (18) (6) (10) (63) (3) (5) (58) (3) *Combines preferred terms of bradycardia and sinus bradycardia Every subject is counted a single time for each applicable row and column. A system organ class or specific adverse event appears in this table only if its incidence in one or more of the columns meets the incidence criterion in the table title, after rounding. Birth to <2 years of age The safety of BRIDION has been assessed in a randomized, double-blinded, active comparator-controlled study of pediatric patients from birth to <2 years of age, with 107 receiving treatment with BRIDION. Adverse events occurring in ≥5% of pediatric patients are presented in Table 4. The safety profile was generally consistent with that observed in pediatric patients from 2 to <17 years of age and adults. 10 Reference ID: 5494299 Table 4: Pediatric Participants (Birth to <2 Years) with Specific Adverse Events Incidence ≥ 5% in One or More Treatment Groups Up to 7 Days Post-Treatment Sugammadex 2 mg/kg Sugammadex 4 mg/kg n (%) n (%) Participants in population 44 63 with one or more specific adverse events 30 (68.2) 43 (68.3) with no specific adverse events 14 (31.8) 20 (31.7) Cardiac disorders 3 (6.8) 0 (0.0) Gastrointestinal disorders 6 (13.6) 4 (6.3) Vomiting 4 (9.1) 1 (1.6) General disorders and administration site conditions 5 (11.4) 6 (9.5) Pyrexia 3 (6.8) 3 (4.8) Infections and infestations 3 (6.8) 0 (0.0) Injury, poisoning and procedural complications 19 (43.2) 35 (55.6) Procedural pain 18 (40.9) 34 (54.0) Procedural vomiting 3 (6.8) 1 (1.6) Metabolism and nutrition disorders 3 (6.8) 2 (3.2) Respiratory, thoracic and mediastinal disorders 5 (11.4) 3 (4.8) Every participant is counted a single time for each applicable row and column. A system organ class or specific adverse event appears in this table only if its incidence in one or more of the columns meets the incidence criterion in the table title, after rounding. Anaphylaxis and Hypersensitivity Hypersensitivity reactions, including anaphylaxis, have occurred in both premarketing clinical trials and in post-marketing spontaneous reports. In a dedicated hypersensitivity study in healthy volunteers, the frequency of anaphylaxis was 0.3% [see Warnings and Precautions (5.1)]. These reactions varied from isolated skin reactions to serious systemic reactions (i.e., anaphylaxis, anaphylactic shock) and have occurred in patients with no prior exposure to sugammadex. Symptoms associated with these reactions can include: flushing, urticaria, erythematous rash, (severe) hypotension, tachycardia, swelling of tongue, swelling of pharynx, bronchospasm and pulmonary obstructive events. Severe hypersensitivity reactions can be fatal. A randomized, double-blind study examined the incidence of drug hypersensitivity reactions in healthy volunteers given up to 3 doses of placebo (N=76), sugammadex 4 mg/kg (N=151) or sugammadex 16 mg/kg (N=148). Reports of suspected hypersensitivity were adjudicated by a blinded committee. The incidence of adjudicated hypersensitivity was 1%, 7% and 9% in the placebo, sugammadex 4 mg/kg and sugammadex 16 mg/kg groups, respectively. There were no reports of anaphylaxis after placebo or sugammadex 4 mg/kg. There was a single case of adjudicated anaphylaxis after the first dose of sugammadex 16 mg/kg. The frequency of anaphylaxis for the 299 healthy volunteers treated with intravenous sugammadex was 0.3%. There was no evidence of increased frequency or severity of hypersensitivity with repeat dosing. In a previous study of similar design, there were three adjudicated cases of anaphylaxis, all after sugammadex 16 mg/kg (incidence 1% in the 298 healthy volunteers treated with sugammadex). Recurrence of Neuromuscular Blockade In clinical studies with subjects treated with rocuronium or vecuronium, where BRIDION was administered using a dose labeled for the depth of neuromuscular blockade (N=2022), an incidence of <1% was observed 11 Reference ID: 5494299 for recurrence of neuromuscular blockade as based on neuromuscular monitoring or clinical evidence [see Warnings and Precautions (5.8)]. Bronchospasm In one dedicated clinical trial and in post-marketing data, in patients with a history of pulmonary complications [see Use in Specific Populations (8.9)], bronchospasm was reported as a possibly related adverse event. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of BRIDION. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: Cases of marked bradycardia and bradycardia with cardiac arrest have been observed within minutes after administration of sugammadex [see Warnings and Precautions (5.2)]. Other cardiac rhythm abnormalities have included atrial fibrillation, atrioventricular block, cardiac/cardiorespiratory arrest, electrocardiographic (ECG) ST segment changes, supraventricular tachycardia/extrasystoles, tachycardia, ventricular fibrillation, and ventricular tachycardia. Anaphylaxis associated with ECG ST segment changes (elevation or depression) consistent with myocardial ischemia or coronary spasm has also been reported. General Disorders and Administration Site Conditions: Cases of BRIDION not having the intended effect. Immune System Disorders: Hypersensitivity events including anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, and Type 1 hypersensitivity have been reported [see Warnings and Precautions (5.1)]. Respiratory, Thoracic, and Mediastinal Disorders: Events of laryngospasm, dyspnea, wheezing, pulmonary edema, and respiratory arrest have been reported. 7 DRUG INTERACTIONS 7.1 Summary The information reported in sections 7.2 – 7.4 is based on binding affinity between BRIDION and other drugs, preclinical experiments, clinical studies and simulations of a pharmacokinetic-pharmacodynamic (PK-PD) model. Based on these considerations, no clinically significant pharmacodynamic interactions with other drugs are expected, with the exception of toremifene and hormonal contraceptives. 7.2 Interactions Potentially Affecting the Efficacy of BRIDION Toremifene For toremifene, which has a relatively high binding affinity for sugammadex and for which relatively high plasma concentrations might be present, some displacement of vecuronium or rocuronium from the complex with BRIDION could occur. The recovery to TOF ratio to 0.9 could therefore be delayed in patients who have received toremifene on the same day of surgery. 7.3 Interaction Potentially Affecting the Efficacy of Hormonal Contraceptives In vitro binding studies indicate that BRIDION may bind to progestogen, thereby decreasing progestogen exposure. Therefore, the administration of a bolus dose of BRIDION is considered to be equivalent to missing dose(s) of oral contraceptives containing an estrogen or progestogen. If an oral contraceptive is taken on the same day that BRIDION is administered, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception (such as condoms and spermicides) for the next 7 days. In the case of non-oral hormonal contraceptives, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception (such as condoms and spermicides) for the next 7 days. 12 Reference ID: 5494299 7.4 Interference with Laboratory Tests BRIDION may interfere with the serum progesterone assay. Interference with this test was observed at sugammadex plasma concentrations of 100 mcg/mL, which may be observed for up to 30 minutes after a 16 mg/kg dose. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no clinical trial data on BRIDION use in pregnant women to inform any drug-associated risks. The available data from the pharmacovigilance safety database and published literature on BRIDION use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of malformations following daily intravenous administration of sugammadex to rats and rabbits during organogenesis at exposures of up to 6 and 8 times, respectively, the maximum recommended human dose (MRHD) of 16 mg/kg. However, there was an increase in the incidence of incomplete ossification of the sternebra and reduced fetal body weights in the rabbit study at 8 times the MRHD, which is a dose level in which maternal toxicity was also observed. In a pre- and postnatal development study, sugammadex treatment resulted in an increase in early postnatal loss, which correlated with maternal behavior (increased incidence of pup cannibalism), at exposures equivalent to the MRHD and higher (see Data). The background risk of major birth defects and miscarriage for the indicated population are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15­ 20% of clinically recognized pregnancies. Data Animal Data In an embryofetal development study in rats, pregnant animals received daily intravenous administration of sugammadex at 0, 20, 100, and 500 mg/kg (0.2, 1, and 6 times the MRHD of 16 mg/kg/day, respectively, based on AUC comparison) during organogenesis (Gestational Days 6-17). No treatment-related maternal and embryofetal changes were observed. In another embryofetal development study, pregnant New Zealand white rabbits received daily intravenous administration of sugammadex at 0, 20, 65, 200 mg/kg (0.6, 2, and 8 times the MRHD, respectively, based on AUC comparison) during organogenesis (Gestational Days 6-18). Fetal body weight decreases (10 and 14%, respectively) were observed in the offspring at maternal doses of 65 mg/kg and 200 mg/kg. In addition, incomplete ossification of sternebra, and unossified 1st metacarpal were noted at a maternal dose of 200 mg/kg/day. Maternal toxicity was also observed at 200 mg/kg. Considering the observed effects of sugammadex on bone [see Nonclinical Toxicology (13.2)], it is possible that these findings may be attributable to drug. There was no evidence of malformations at any dose. In a prenatal and postnatal development study, pregnant rats were administered sugammadex intravenously at 0, 30, 120, and 500 mg/kg (0.3, 1, and 6 times the MRHD, respectively, based on AUC comparison) from Gestational Day (GD) 6 to Postnatal Day (PND) 21 (corresponding to the beginning of organogenesis through parturition and subsequent pup weaning). Postnatal loss during PND 1-4 was noted across control litters and treated litters from dams receiving sugammadex as a result of pup cannibalization by dams. Overall incidence of affected litters was 2, 1, 4, and 3 litters, respectively, at 0, 30, 120, or 500 mg/kg/day. The reason for the increased cannibalization is not known. An effect of sugammadex on steroidal hormones and/or pheromones cannot be ruled out. In addition, there were no drug-related effects on parturition in rats during evaluations for prenatal or postnatal development. 8.2 Lactation Risk Summary No data are available regarding the presence of sugammadex in human milk, the effects of sugammadex on the breast fed infant, or the effects of sugammadex on milk production. However, sugammadex is present in rat milk (see Data). The developmental and health benefits of breastfeeding should be 13 Reference ID: 5494299 considered along with the mother’s clinical need for BRIDION and any potential adverse effects on the breastfed infant from BRIDION or from the underlying maternal condition. Data In a milk excretion study in rat dams following single intravenous dose of 20 mg/kg sugammadex on Postnatal Day 9, the maximum drug level was achieved at about 30 minutes after dosing with a ratio of milk to plasma level approximately 1:1. The oral exposure via milk did not induce effects on survival, body weight and physical or the behavioral developmental parameters monitored in rats in the prenatal and postnatal development studies [see Use in Specific Populations (8.1)]. 8.3 Females and Males of Reproductive Potential Contraception Upon administration of BRIDION, the efficacy of hormonal contraceptives may be reduced for up to 7 days. Advise female patients of reproductive potential using hormonal contraceptives to use an additional, non- hormonal contraceptive for the next 7 days following BRIDION administration [see Drug Interactions (7.3)]. 8.4 Pediatric Use The safety and effectiveness of BRIDION for reversal of neuromuscular blockade induced by rocuronium bromide or vecuronium bromide have been established in pediatric patients from birth and older. Use of BRIDION in these age groups is supported by evidence from adequate and well-controlled studies of BRIDION [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. In pediatric patients, the safety profile is generally consistent with that observed in adults [see Adverse Reactions (6.1)]. Juvenile Animal Studies In a bone deposition study, sugammadex concentrations were significantly higher in juvenile rats compared to adult rats (13% vs. 3% of the administered dose, respectively) following a single intravenous (IV) dose at 30 mg/kg (0.3 times the MRHD based on adult AUC comparison). In a juvenile animal bone toxicity study, 7-day old rats were dosed intravenously once daily for 28 days with 0, 30, 120, and 500 mg/kg sugammadex (approximately 0.1, 0.6, and 3 times the MRHD, respectively, by adult AUC comparison). Sugammadex at 120 and 500 mg/kg decreased ulna and femur bone lengths by approximately 3%, which did not recover after an 8-week treatment-free period. Reversible whitish discoloration and disturbance of enamel formation were also observed in the incisors at these dose levels. In molars, this effect was only observed at 500 mg/kg. The no-observed-effect-level (NOEL) was 30 mg/kg. In a second juvenile animal bone toxicity study, 7-day old rats were dosed once weekly for 8 weeks with 0, 7.5, 30, and 120 mg/kg (up to 1.2 times the MRHD of 16 mg/kg based on adult AUC comparison). No adverse effects on bone or teeth were noted. 8.5 Geriatric Use BRIDION has been administered in a dedicated clinical study to a total 102 geriatric patients that compared the time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of 2 mg/kg BRIDION given at the reappearance of T2 in 65-74 year-olds (N=62) and ≥75 year-olds (N=40) compared with 18-64 year-olds (N=48). The median time to recovery of the TOF (T4/T1) ratio to 0.9 in 18-64 year-olds was 2.2 minutes; in 65-74 year-olds it was 2.5 minutes, and in ≥75 year-olds it was 3.6 minutes. For time to recovery from neuromuscular blockade induced by rocuronium following administration of 4 mg/kg BRIDION given at 1-2 PTCs, results across clinical trials revealed a median recovery of 2.5 minutes for geriatric patients (≥65 years, N=63) versus 2.0 minutes, for adults aged 18-64 years (N=359). Hence no dose adjustment is necessary in geriatric patients with normal organ function [see Dosage and Administration (2.2)]. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 14 Reference ID: 5494299 8.6 Renal Impairment This drug is known to be substantially excreted by the kidney. Effect of mild or moderate renal impairment (creatinine clearance ≥30 and ≤80 mL/min) on sugammadex PK and PD was obtained from a study in elderly patients [see Use in Specific Populations (8.5)]. Although clearance of drug decreased in elderly subjects with mild and moderate renal impairment, there was no significant difference in the ability of sugammadex to reverse the pharmacodynamic effect of rocuronium. Hence, no dosage adjustment is necessary for mild and moderate renal impairment. BRIDION is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min) due to insufficient safety information combined with the prolonged and increased overall exposure in these patients [see Warnings and Precautions (5.11), Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment BRIDION is not metabolized nor excreted by the liver; therefore, dedicated trials in patients with hepatic impairment have not been conducted. Exercise caution when administering BRIDION to patients with hepatic impairment accompanied by coagulopathy or severe edema [see Warnings and Precautions (5.10, 5.14)]. 8.8 Cardiac Patients One trial of 76 patients who were diagnosed with or have a history of cardiac disease (e.g., patients with ischemic heart disease, chronic heart failure, or arrhythmia) of primarily NYHA (New York Heart Association) Class II investigated time to recovery from neuromuscular blockade induced by rocuronium 0.6 mg/kg following administration of 2 mg/kg or 4 mg/kg BRIDION given at the reappearance of T2. The trial showed that the median time to recovery of the T4/T1 ratio to 0.9 was 1.7 minutes and 1.3 minutes, respectively, in the 2 mg/kg and 4 mg/kg BRIDION dose groups. This is similar to the median values observed in the other trials; therefore, no dosage adjustment is necessary [see Dosage and Administration (2.2)]. 8.9 Pulmonary Patients One trial of 77 patients who were diagnosed with or have a history of pulmonary complications investigated the time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of 2 mg/kg or 4 mg/kg BRIDION given at the first signs of recovery (reappearance of T2). The trial showed that for these patients the median time to recovery of the T4/T1 ratio to 0.9 was 2.1 minutes after a dose of 2 mg/kg BRIDION and 1.9 minutes after a dose of 4 mg/kg BRIDION. This is similar to the median values observed in the other trials; therefore, no dosage adjustment is necessary. [See Dosage and Administration (2.2), Adverse Reactions (6.1).] 8.10 Obese Patients with a BMI ≥40 kg/m2 A trial of 188 obese patients, with a body mass index ≥40 kg/m2, investigated the time to recovery from moderate or deep neuromuscular blockade induced by rocuronium or vecuronium. Patients received 2 mg/kg or 4 mg/kg BRIDION, as appropriate for level of block, dosed according to either actual body weight (ABW) or ideal body weight (IBW) in random, double-blinded fashion. Pooled across depth of block and neuromuscular blocking agent, the median time to recover to a train-of-four (TOF) ratio ≥0.9 in patients dosed by ABW (1.8 minutes) was statistically significantly faster compared to patients dosed by IBW (3.3 minutes). The adverse reaction profile was generally similar to the profile in adult patients in pooled Phase 1 to 3 studies [see Adverse Reactions (6.1)]. No dosage adjustment is necessary [see Dosage and Administration (2.2)]. 8.11 American Society of Anesthesiologists Class 3 or 4 Patients One trial of 331 patients who were assessed as ASA Class 3 or 4 investigated the incidence of treatment- emergent arrhythmias (sinus bradycardia, sinus tachycardia, or other cardiac arrhythmias) after administration of sugammadex. In patients receiving sugammadex (2 mg/kg, 4 mg/kg, or 16 mg/kg), the number (%) of patients with treatment-emergent sinus bradycardia (up to 35 minutes post-administration of sugammadex) was 1/105 15 Reference ID: 5494299 (1.0%) in the 2 mg/kg sugammadex treatment group, 2/107 (1.9%) in the 4 mg/kg sugammadex treatment group, and 5/68 (7.4%) in the 16 mg/kg sugammadex treatment group, compared to 4/51 (7.8%) in the neostigmine (50 µg/kg up to 5 mg maximum dose) + glycopyrrolate (10 µg/kg up to 1 mg maximum dose) treatment group. The number of patients with treatment-emergent sinus tachycardia (up to 35 minutes post- administration of sugammadex) was 7/105 (6.7%) in the 2 mg/kg sugammadex treatment group, 10/107 (9.3%) in the 4 mg/kg sugammadex treatment group, and 6/68 (8.8%) in the 16 mg/kg sugammadex treatment group, compared to 11/51 (21.6%) in the neostigmine + glycopyrrolate treatment group. The number of other treatment-emergent arrhythmias (up to 35 minutes post administration of sugammadex) was 1/105 (1.0%) in the 2 mg/kg sugammadex treatment group, 0/107 (0%) in the 4 mg/kg sugammadex treatment group, and 1/68 (1.5%) in the 16 mg/kg sugammadex treatment group, compared to 1/51 (2.0%) in the neostigmine + glycopyrrolate treatment group. The adverse reaction profiles in ASA Class 3 and 4 patients were generally similar to those in adult patients in pooled Phase 1 to 3 studies; therefore, no dosage adjustment is necessary [see Dosage and Administration (2.1), Adverse Reactions (6.1)]. 10 OVERDOSAGE In premarketing clinical trials, one case of accidental overdose with 40 mg/kg BRIDION was reported without significant effects. BRIDION can be removed using hemodialysis with a high-flux filter, but not with a low-flux filter. Based upon clinical studies, BRIDION concentrations in plasma are reduced with a high-flux filter by about 70% after a 3- to 6-hour dialysis session. 11 DESCRIPTION BRIDION (sugammadex) injection, for intravenous use, contains sugammadex sodium, a modified gamma cyclodextrin chemically designated as 6A,6B,6C,6D,6E,6F,6G,6H-Octakis-S-(2-carboxyethyl)­ 6A,6B,6C,6D,6E,6F,6G,6H-octathio-γ-cyclodextrin sodium salt (1:8) with a molecular weight of 2178.01. The structural formula is: BRIDION is supplied as a sterile, non-pyrogenic aqueous solution that is clear, colorless to slightly yellow- brown for intravenous injection only. Each mL contains 100 mg sugammadex, which is equivalent to 108.8 mg sugammadex sodium. The aqueous solution is adjusted to a pH of between 7 and 8 with hydrochloric acid and/or sodium hydroxide. The osmolality of the product is between 300 and 500 mOsmol/kg. BRIDION may contain up to 7 mg/mL of the mono OH-derivative of sugammadex [see Clinical Pharmacology (12.2)]. This derivative is chemically designated as 6A,6B,6C,6D,6E,6F,6G-Heptakis-S-(2­ carboxyethyl)-6A,6B,6C,6D,6E,6F,6G-heptathio-γ-cyclodextrin sodium salt (1:7) with a molecular weight of 2067.90. The structural formula is: 16 Reference ID: 5494299 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action BRIDION is a modified gamma cyclodextrin. It forms a complex with the neuromuscular blocking agents rocuronium and vecuronium, and it reduces the amount of neuromuscular blocking agent available to bind to nicotinic cholinergic receptors in the neuromuscular junction. This results in the reversal of neuromuscular blockade induced by rocuronium and vecuronium. 12.2 Pharmacodynamics BRIDION has been administered in doses ranging from 0.5 mg/kg to 16 mg/kg in dose response trials of rocuronium-induced blockade (0.6, 0.9, 1 and 1.2 mg/kg with and without maintenance doses) and vecuronium-induced blockade (0.1 mg/kg with or without maintenance doses) at different time points/depths of block. In these trials a clear dose-response relationship was observed. BRIDION may contain up to 7% of the mono OH-derivative of sugammadex. In preclinical pharmacology studies, the mono OH-derivative was demonstrated to have ~50% of the affinity as sugammadex for rocuronium and vecuronium and that product with up to 7% of the mono OH-derivative has nearly similar efficacy in reversing rocuronium- or vecuronium-induced blockade. Although sugammadex has greatest affinity for aminosteroid neuromuscular blocking agents such as rocuronium and vecuronium, plasma levels of endogenous or exogenous compounds with a similar steroidal structure, such as some hormones, hormonal contraceptives, and pheromones may also be reduced following administration of sugammadex [see Drug Interactions (7.3)]. Cardiac Electrophysiology At a dose 2 times the maximum recommended dose, sugammadex does not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics The sugammadex pharmacokinetic parameters were calculated from the total sum of non-complex-bound and complex-bound concentrations of sugammadex. Pharmacokinetic parameters as clearance and volume of distribution are assumed to be the same for non-complex-bound and complex-bound sugammadex in anesthetized patients. Distribution The observed steady-state volume of distribution of sugammadex is approximately 11 to 14 liters in adult patients with normal renal function (based on conventional, non-compartmental pharmacokinetic analysis). Neither sugammadex nor the complex of sugammadex and rocuronium binds to plasma proteins or erythrocytes, as was shown in vitro using male human plasma and whole blood. Sugammadex exhibits linear kinetics in the dosage range of 1 to 16 mg/kg when administered as an IV bolus dose. 17 Reference ID: 5494299 In nonclinical drug distribution studies, sugammadex is retained in sites of active mineralization, such as bone and teeth, with a mean half-life of 172 and 8 days, respectively [see Use in Specific Populations (8.4), Nonclinical Toxicology (13.2)]. Metabolism In clinical studies, no metabolites of sugammadex have been observed and only renal excretion of the unchanged product was observed as the route of elimination. Elimination In adult anesthetized patients with normal renal function, the elimination half-life (t1/2) of sugammadex is about 2 hours and the estimated plasma clearance is about 88 mL/min (based on compartmental pharmacokinetic analysis). A mass balance study demonstrated that >90% of the dose was excreted within 24 hours. Ninety-six percent (96%) of the dose was excreted in urine, of which at least 95% could be attributed to unchanged sugammadex. Excretion via feces or expired air was less than 0.02% of the dose. Administration of BRIDION to healthy volunteers resulted in increased renal elimination of rocuronium in complex. Patients with Renal Impairment Sugammadex is known to be substantially excreted by the kidney. The half-life of sugammadex in patients with mild, moderate and severe renal impairment is 4, 6, and 19 hours, respectively. In one study, exposure to sugammadex was prolonged, leading to 17-fold higher overall exposure in patients with severe renal impairment. Low concentrations of sugammadex are detectable for at least 48 hours post-dose in patients with severe renal impairment. In a second study comparing subjects with moderate or severe renal impairment to subjects with normal renal function, sugammadex clearance progressively decreased and t1/2 was progressively prolonged with declining renal function. Exposure was 2-fold and 5-fold higher in subjects with moderate and severe renal impairment, respectively. Sugammadex concentrations were no longer detectable beyond 7 days post- dose in subjects with severe renal impairment. Geriatric Patients Geriatric patients may have mild or moderate renal impairment. Population pharmacokinetic analysis indicated that, beyond the effects of a decreased creatinine clearance, increased age has limited impact on sugammadex PK parameters [see Use in Specific Populations (8.5, 8.6)]. Pediatric Patients The pharmacokinetics of sugammadex in pediatric patients have been evaluated in 2 clinical studies following administration of intravenous doses of 2 or 4 mg/kg sugammadex administered for reversal of moderate or deep neuromuscular blockade, respectively. In one study, sugammadex pharmacokinetic parameters were estimated in pediatric patients 2 to <17 years of age with patients enrolled into 3 age groups (2 to <6, 6 to <12 and 12 to <17 years of age). In a second study, sugammadex pharmacokinetic parameters were estimated in pediatric patients birth to <2 years of age with patients enrolled into 4 age groups (birth to 27 days, 28 days to <3 months, 3 months to <6 months and 6 months to < 2 years). Sugammadex exposure (AUC0-inf and Cmax) increased in a dose-dependent, linear manner following administration of 2 or 4 mg/kg across patients birth to <17 years of age. Sugammadex exposure was approximately 40% lower in patients <6 years of age following administration of 2 or 4 mg/kg sugammadex compared to older pediatric patients (6 to <17 years) and adults; however, this difference was not clinically relevant [see Clinical Studies (14.1)]. Both clearance and volume of distribution increase with increasing age in pediatric patients, whereas elimination half-life is generally similar across pediatric patients. As a result, the observed steady-state volume of distribution of sugammadex is approximately 3 to 10 liters and clearance is approximately 38 to 95 mL/min resulting in a half-life of approximately 1-2 hours in pediatric patients 2 to <17 years of age. By 18 Reference ID: 5494299 comparison, observed steady-state volume of distribution of sugammadex is approximately 1 to 3 liters and clearance is approximately 38 to 95 mL/min with a half-life of approximately 1-2 hours in pediatric patients birth to <2 years of age. Sex No pharmacokinetic differences between male and female subjects were observed. Race In a study in healthy Japanese and Caucasian subjects no clinically relevant differences in pharmacokinetic parameters were observed. Limited data do not indicate differences in pharmacokinetic parameters in Black or African Americans. Obesity In one clinical study of obese patients with a body mass index ≥40 kg/m2, sugammadex 2 mg/kg and 4 mg/kg was dosed according to ABW (n=76) or IBW (n=74). Sugammadex exposure increased in a dose- dependent, linear manner following administration according to ABW or IBW. No clinically relevant differences in pharmacokinetic parameters were observed between obese patients and the general population, when dosed according to ABW. [See Use in Specific Populations (8.10).] Systemic exposure of sugammadex is approximately 50% lower with IBW dosing compared to ABW. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term animal studies to evaluate the carcinogenic potential of sugammadex have not been conducted. Mutagenesis Sugammadex and its mono OH-derivative tested negatively in in vitro bacterial reverse mutation assays (Ames test), in vitro chromosomal aberration assays in human peripheral blood lymphocytes, and in vivo micronucleus assays in mice and rats. Impairment of Fertility A fertility and early embryonic development study in Sprague-Dawley rats in which male rats were treated daily for 29 days prior to mating and through the mating period and female rats were treated daily for 14 days prior to mating to Day 5 post-coitum via intravenous administration of sugammadex at 20, 100, and 500 mg/kg (0.2, 1, and 6 times the MRHD of 16 mg/kg, respectively, based on AUC comparison) did not show adverse effects on fertility. 13.2 Animal Toxicology and/or Pharmacology Bone and teeth retention of sugammadex occurred in rats after intravenous injection, with mean half-lives of 172 and 8 days, respectively. Sugammadex bound to hydroxyapatite in an in vitro study and distributed in the bone formation area where hydroxyapatite is present for mineralization in vivo. In adult rat bone toxicity studies, a single dose of sugammadex at 2000 mg/kg (approximately 24 times the maximum recommended human dose (MRHD) of 16 mg/kg by AUC comparison) administered to adult rats caused a slight increase in bone resorption, but had no effect on teeth color. No adverse bone effects were seen following a single dose of sugammadex at 500 mg/kg (4 times the MRHD dose of 16 mg/kg based on plasma AUC comparison). In a bone repair study, adult rats were treated with intravenous sugammadex weekly for 6 weeks at 0, 30, 120, and 500 mg/kg (approximately 0.4, 1, and 6 times the MRHD, respectively, by AUC comparison). Based on histological data, high dose animals with post-fracture treatment, showed a statistically significant increase in callus formation and decrease in bone formation, suggesting a potential for a slight delay in the bone healing process. However, there were no statistically significant effects on bone volume or bone mineral density. 19 Reference ID: 5494299 In juvenile animal studies, bone and teeth deposition was significantly higher in juvenile rats compared to adults. In addition, sugammadex administered to juvenile rats daily for 4 weeks caused slight bone length decrease (approximately 3%), which did not recover after an 8-week treatment-free period, and reversible whitish discoloration of the teeth at a dose approximately 0.6 times the MRHD, while weekly administration for 8 weeks did not produce similar changes in bone and teeth at doses up to 1.2 times the MRHD [see Use in Specific Populations (8.4)]. 14 CLINICAL STUDIES 14.1 Controlled Clinical Studies Comparative Study of BRIDION versus Neostigmine as a Reversal Agent for Neuromuscular Blockade Induced by Rocuronium or Vecuronium at Reappearance of T2 (Moderate Blockade) A multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded study comparing BRIDION and neostigmine enrolled 189 patients (87 women and 102 men, 95% were ASA class 1 and 2 and 99% were Caucasian, median weights were 72 kg and 76 kg and median ages were 50 years and 51 years in the rocuronium and vecuronium groups, respectively). Patients were randomly assigned to the rocuronium or vecuronium group and underwent elective surgical procedures under general anesthesia that required endotracheal intubation and maintenance of neuromuscular blockade. The surgical procedures were mainly endocrine, ocular, ENT, abdominal (gynecological, colorectal, urological), orthopedic, vascular, or dermatological. At the reappearance of T2, after the last dose of rocuronium or vecuronium, 2 mg/kg BRIDION or 50 mcg/kg neostigmine was administered in a randomized order as a single bolus injection. The time from start of administration of BRIDION or neostigmine to recovery of the TOF (T4/T1) ratio to 0.9 was assessed. Generally, a T4/T1 ratio ≥0.9 correlates with recovery from neuromuscular blockade. Return of the T4/T1 ratio to 0.9 after the reappearance of T2 was overall faster with BRIDION 2 mg/kg as compared to neostigmine 50 mcg/kg in the setting of rocuronium or vecuronium-induced neuromuscular blockade (Figures 1 and 2). 20 Reference ID: 5494299 ~I _I Figure 1: Time (Minutes) from Administration of BRIDION or Neostigmine at the Reappearance of T2 after Rocuronium to Recovery of the T4/T1 Ratio to 0.9 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative Recovery Rate Median (Q1, Q3)§ of Recovery Times: sugammadex 1.4 min (1.2, 1.7) neostigmine 21.5 min (9.8, 42.0) 0 10 20 30 40 50 60 70 80 90 100 110 120 Time to Recovery (Minutes) Rocuronium plus: sugammadex 2 mg/kg (N=48) neostigmine 0.05 mg/kg (N=48) § Medians and quartiles (Q1, Q3) based on product-limit estimates + Censored observations 21 Reference ID: 5494299 r ,.r .. ,r r r-r J ,.. r ~ ,..r 1 ~ - ,--------- ,.r---J ____ J -----+ __ r _I i Figure 2: Time (Minutes) from Administration of BRIDION or Neostigmine at the Reappearance of T2 after Vecuronium to Recovery of the T4/T1 Ratio to 0.9 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative Recovery Rate Median (Q1, Q3)§ of Recovery Times: sugammadex 2.1 min (1.8, 3.4) neostigmine 29.0 min (12.2, 76.2) 0 10 20 30 40 50 60 70 80 90 100 110 120 Time to Recovery (Minutes) Vecuronium plus: sugammadex 2 mg/kg (N=48) neostigmine 0.05 mg/kg (N=45) § Medians and quartiles (Q1, Q3) based on product-limit estimates + Censored observations Comparative Study of BRIDION versus Neostigmine as a Reversal Agent for Neuromuscular Blockade Induced by Rocuronium or Vecuronium at 1 to 2 PTCs (Deep Blockade) A multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded study comparing BRIDION and neostigmine enrolled 157 patients (86 women and 71 men; 8% ASA class 1, 71% class 2, and 21% class 3; 79% Caucasian; median weights of 81 kg and 84 kg, and median ages of 54 years and 56 years in the rocuronium and vecuronium groups, respectively). Patients were randomly assigned to the rocuronium or vecuronium group and underwent elective surgical procedures under general anesthesia that required endotracheal intubation and maintenance of neuromuscular blockade. The surgical procedures were mainly abdominal (gynecological, colorectal, urological), orthopedic, reconstructive, or neurological. At 1 to 2 PTCs, after the last dose of rocuronium or vecuronium, 4 mg/kg BRIDION or 70 mcg/kg neostigmine was administered in a randomized order as a single bolus injection. The time from start of administration of BRIDION or neostigmine to recovery of the TOF (T4/T1) ratio to 0.9 was assessed, although neostigmine was not expected to reverse neuromuscular blockade at a depth of 1 to 2 PTCs. Generally, a T4/T1 ratio ≥0.9 correlates with recovery from neuromuscular blockade. Return of the T4/T1 ratio to 0.9 in patients with 1 to 2 PTCs with BRIDION 4 mg/kg had a wider range of recovery times but the median time to recovery was comparable to the study of reversal at T2 (2.7 minutes with 25th and 75th percentiles of 2.1 and 4.3 minutes for rocuronium [N=37], and 3.3 minutes with 25th and 75th percentiles of 2.3 and 6.6 minutes for vecuronium [N=47]). There were 7 and 6 censored observations in the rocuronium and vecuronium groups, respectively. Reversal of Neuromuscular Blockade 3 Minutes after Rocuronium 1.2 mg/kg Time to recovery from neuromuscular blockade induced by succinylcholine compared with recovery from neuromuscular blockade induced by rocuronium followed 3 minutes later with BRIDION was assessed in a multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded study. The study was conducted in 110 patients (64 women and 46 men, ASA class 1 and 2, 78% were Caucasian, median weight was 70 kg, median age was 43 years). Patients underwent elective surgical procedures under general anesthesia that required endotracheal intubation and a short duration of neuromuscular relaxation. 22 Reference ID: 5494299 The laparoscopic or open surgical procedures were mainly gynecological, orthopedic, or reconstructive. Return of the first twitch in a TOF (T1) to 10% of baseline was compared between BRIDION 16 mg/kg for reversal of rocuronium 1.2 mg/kg versus spontaneous recovery from succinylcholine 1 mg/kg. Recovery to T1 of 10% of baseline (relative to the time of administration of rocuronium or succinylcholine) was overall faster in the rocuronium/BRIDION group compared with succinylcholine alone (Table 5). Table 5: Time (minutes) from Start of Administration of Rocuronium or Succinylcholine to Recovery of T1 to 10% of Baseline Treatment Regimen Rocuronium (1.2 mg/kg) and BRIDION (16 mg/kg) Succinylcholine (1 mg/kg) N Mean (SD) Median (Range) 55 4.4 (0.7) 4.2 (3.5 – 7.7) 55 7.1 (1.6) 7.1 (3.8 – 10.5) Comparative Studies of BRIDION versus Neostigmine as a Reversal Agent for Neuromuscular Blockade Induced by Rocuronium or Vecuronium in Pediatric Patients 2 to <17 Years of Age Time to recovery from neuromuscular blockade induced by rocuronium or vecuronium followed by administration of BRIDION or neostigmine was assessed in a randomized, double-blind, active comparator- controlled study. The study was conducted in 288 randomized pediatric patients 2 to <17 years of age, of which 276 patients received treatment (153 boys and 123 girls; ASA class 1, 2, and 3; 89.5% were Caucasian; median weight was 25 kg; median age was 7 years). The primary efficacy objective was to evaluate the effect of BRIDION compared to neostigmine for reversal of moderate neuromuscular blockade as measured by time to recovery to a TOF ratio of ≥0.9. Recovery to a TOF ratio of ≥0.9 was statistically significantly faster in pediatric patients 2 to <17 years of age dosed with BRIDION 2 mg/kg (N=33) compared with neostigmine (N=34) for reversal of moderate block based on a geometric mean of 1.7 minutes for BRIDION 2 mg/kg and 7.4 minutes for neostigmine (ratio of geometric means was 0.22, 95% CI (0.16, 0.32)). These effects were consistent across age cohorts studied (2 to <6; 6 to <12; 12 to <17 years of age) and neuromuscular blocking agent (rocuronium and vecuronium). Birth to <2 Years of Age Time to recovery from neuromuscular blockade induced by rocuronium or vecuronium followed by administration of BRIDION or neostigmine was assessed in a randomized, double-blind, active comparator- controlled study. The study was conducted in 145 randomized pediatric patients from birth to <2 years of age, of which 138 patients received treatment (92 boys and 46 girls; ASA class 1, 2, and 3; 68% were White; median weight was 5.8 kg; median age was 100.5 days). The primary efficacy objective was to evaluate the time to neuromuscular recovery of BRIDION in comparison to neostigmine for the reversal of moderate neuromuscular blockade. Time to neuromuscular recovery was statistically significantly faster in participants dosed with BRIDION 2 mg/kg (N=29) compared with neostigmine (N=31) (median of 1.4 minutes for BRIDION 2 mg/kg and 4.4 minutes for neostigmine; hazard ratio=2.40, 95% CI: 1.37, 4.18). BRIDION 4 mg/kg achieved neuromuscular recovery with a median of 1.1 minutes. These effects were consistent across age cohorts studied (birth to 27 days, 28 days to <3 months, 3 months to <6 months, 6 months to <2 years of age). 16 HOW SUPPLIED/STORAGE AND HANDLING BRIDION (sugammadex) injection is a clear, colorless to slightly yellow-brown, non-pyrogenic aqueous solution intended for intravenous infusion. BRIDION is available in the following presentations: 23 Reference ID: 5494299 • BRIDION 2-mL single-dose vials containing 200 mg sugammadex (100 mg/mL) Box of 10 NDC 0006-5423-12 • BRIDION 5-mL single-dose vials containing 500 mg sugammadex (100 mg/mL) Box of 10 NDC 0006-5423-15, NDC 0006-5425-15 The packaging of this product is not made with natural rubber latex. Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature). Protect from light. When not protected from light, the vial should be used within 5 days. Discard unused portion. 17 PATIENT COUNSELING INFORMATION • Advise females of reproductive potential using hormonal contraceptives that BRIDION may reduce the contraceptive effect. Instruct females to use an additional, non-hormonal method of contraception for the next 7 days following BRIDION administration [see Drug Interactions (7.3)]. Distributed by: Merck Sharp & Dohme LLC Rahway, NJ 07065, USA For patent information: www.msd.com/research/patent Copyright © 2015-2024 Merck & Co., Inc., Rahway, NJ, USA, and its affiliates. All rights reserved. uspi-mk8616-soi-2412r010 24 Reference ID: 5494299
custom-source
2025-02-12T15:47:45.554498
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VTAMA® cream safely and effectively. See full prescribing information for VTAMA cream. VTAMA (tapinarof) cream, for topical use Initial U.S. Approval: 2022 -----------------------------RECENT MAJOR CHANGES------------------------­ Indications and Usage (1.2) MM/YYYY -----------------------------INDICATIONS AND USAGE-------------------------­ VTAMA cream, 1% is an aryl hydrocarbon receptor agonist indicated for: • the topical treatment of plaque psoriasis in adults. (1.1) • the topical treatment of atopic dermatitis in adults and pediatric patients 2 years of age and older. (1.2) ------------------------DOSAGE AND ADMINISTRATION---------------------­ • Apply a thin layer of VTAMA cream to affected areas once daily. (2) • VTAMA cream is not for oral, ophthalmic, or intravaginal use. (2) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ Cream, 1% (3) Each gram of VTAMA cream contains 10 mg of tapinarof. (3) -----------------------------CONTRAINDICATIONS------------------------------­ None. (4) -------------------------------ADVERSE REACTIONS-----------------------------­ • In plaque psoriasis, the most common adverse reactions (incidence ≥ 1%) were folliculitis, nasopharyngitis, contact dermatitis, headache, pruritus, and influenza. (6.1) • In atopic dermatitis, the most common adverse reactions (incidence ≥ 1%) were upper respiratory tract infection, folliculitis, lower respiratory tract infection, headache, asthma, vomiting, ear infection, pain in extremity, and abdominal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dermavant Sciences, Inc. at 1-8DERMAVANT or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Plaque Psoriasis 1.2 Atopic Dermatitis 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Plaque Psoriasis 14.2 Atopic Dermatitis 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5495185 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Plaque Psoriasis VTAMA® cream is indicated for the topical treatment of plaque psoriasis in adults. 1.2 Atopic Dermatitis VTAMA cream is indicated for the topical treatment of atopic dermatitis in adults and pediatric patients 2 years of age and older. 2 DOSAGE AND ADMINISTRATION Apply a thin layer of VTAMA cream to affected areas once daily. Wash hands after application, unless VTAMA cream is for treatment of the hands. VTAMA cream is not for oral, ophthalmic, or intravaginal use. 3 DOSAGE FORMS AND STRENGTHS Cream, 1% Each gram of VTAMA cream contains 10 mg of tapinarof in a white to off-white cream. 4 CONTRAINDICATIONS None. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Plaque Psoriasis Clinical Trials In two randomized, double-blind, multicenter, vehicle-controlled clinical trials (PSOARING 1 and PSOARING 2), 1025 adults with plaque psoriasis were treated with VTAMA cream or received vehicle cream once daily for up to 12 weeks. Subjects ranged in age from 18 to 75 years, with an overall median age of 51 years. The majority of subjects were White (85%) and male (57%); and 85% identified as non-Hispanic or Latino. Table 1 presents adverse reactions that occurred in at least 1% of subjects treated with VTAMA cream, and for which the rate exceeded the rate for vehicle. Reference ID: 5495185 Table 1: Adverse Reactions Occurring in ≥1% of Adult Subjects with Plaque Psoriasis (and More Frequently than Vehicle) in the 12-week PSOARING 1 and PSOARING 2 Clinical Trials Adverse Reaction VTAMA cream N=683 n (%) Vehicle cream N=342 n (%) Folliculitisa 140 (20) 3 (1) Nasopharyngitisb 73 (11) 31 (9) Contact dermatitisc 45 (7) 2 (1) Headached 26 (4) 5 (1) Prurituse 20 (3) 2 (1) Influenzaf 14 (2) 2 (1) a Folliculitis includes application site folliculitis and folliculitis b Nasopharyngitis includes nasopharyngitis, nasal congestion, pharyngitis, respiratory tract infection (RTI) viral, rhinorrhea, sinus congestion, upper RTI, and viral upper RTI c Contact dermatitis includes dermatitis, contact dermatitis, hand dermatitis, and rash d Headache includes headache, migraine, and tension headache e Pruritus includes application site pruritus, pruritus, generalized pruritus, and genital pruritus f Influenza includes influenza and influenza-like illness Two (0.3%) subjects using VTAMA cream developed urticaria. Adverse reactions leading to treatment discontinuation in >1% of subjects who received VTAMA cream were contact dermatitis (2.9%) and folliculitis (2.8%). In an open label safety trial (PSOARING 3), 763 subjects were treated for up to an additional 40 weeks after completing PSOARING 1 or PSOARING 2. In addition to the adverse reactions reported in the 12-week PSOARING 1 and PSOARING 2 clinical trials, the following adverse reactions were reported: urticaria (1.0%) and drug eruption (0.7%). Atopic Dermatitis Clinical Trials In two randomized, double-blind, multicenter, vehicle-controlled clinical trials (ADORING 1 and ADORING 2), 811 adult and pediatric subjects 2 years of age and older with atopic dermatitis were treated with VTAMA cream or received vehicle cream once daily for up to 8 weeks. Subjects ranged in age from 2 to 81 years, with an overall median age of 11 years. The majority (51%) of subjects were White, 31% were Black, 12% were Asian; 54% were female; and 78% of subjects identified as non-Hispanic or Latino. Table 2 presents adverse reactions that occurred in at least 1% of subjects treated with VTAMA cream, and for which the rate exceeded the rate for vehicle. Table 2: Adverse Reactions Occurring in ≥1% of Adult and Pediatric Subjects 2 Years and Older with Atopic Dermatitis (and More Frequently than Vehicle) in the 8 week ADORING 1 and ADORING 2 Clinical Trials Adverse Reaction VTAMA cream N=541 n (%) Vehicle cream N=270 n (%) Upper respiratory tract infectiona 66 (12) 15 (6) Folliculitisb 51 (9) 3 (1) Lower respiratory tract infectionc 25 (5) 6 (2) Reference ID: 5495185 Headache 23 (4) 3 (1) Asthmad 12 (2) 1 (0) Vomiting 10 (2) 2 (1) Ear infectione 10 (2) 1 (0) Pain in extremityf 9 (2) 1 (0) Abdominal paing 6 (1) 0 (0) a Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, nasal congestion, sinusitis, pharyngitis streptococcal, cough, oropharyngeal pain, pharyngitis, acute sinusitis, streptococcal infection, streptococcus test positive, viral upper respiratory tract infection, viral infection, rhinorrhea, sinus congestion b Folliculitis includes folliculitis, application site folliculitis, keratosis pilaris, follicular eczema c Lower respiratory tract infection includes lower respiratory tract infection, COVID-19, influenza, bronchitis, pneumonia d Asthma includes asthma, wheezing e Ear infection includes ear infection, otitis media, otitis externa, otitis media acute f Pain in extremity includes pain in extremity, arthralgia g Abdominal pain includes abdominal pain and abdominal pain upper Application site reactions were reported in 19 (3.5%) subjects treated with VTAMA cream and 9 (3.3%) subjects receiving vehicle. The adverse reactions observed in pediatric subjects 2 years of age and older were generally consistent with those observed in adults with atopic dermatitis. Adverse reactions occurring more frequently in pediatric subjects compared to adults were upper respiratory tract infection (16.3% in subjects ages 2-6 years of age and 11.2% in subjects ages 7-17 years of age vs. 9.5% in subjects 18 years and older) and ear infection (5.7% in subjects ages 2-6 years of age and 1.4% in subjects ages 7-11 years of age vs. 0% in subjects 12 years and older). In an open label safety trial (ADORING 3), 728 subjects (124 adult and 604 pediatric subjects 2 years of age and older) were treated for up to 48 weeks. This included 624 subjects completing either ADORING 1 or ADORING 2, 28 subjects completing the maximal usage trial, and 76 subjects treated only in ADORING 3. The safety profile with long term use was generally consistent with the safety profile observed at Week 8. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The available data on VTAMA cream use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, subcutaneous administration of tapinarof to pregnant rats and rabbits during the period of organogenesis resulted in no significant adverse effects at doses 264 and 16 times, respectively, the maximum recommended human dose (MRHD) (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Reference ID: 5495185 In an embryofetal development study in rats, tapinarof was administered by subcutaneous injection to pregnant animals at doses of 1.2, 6.9 and 34 mg/kg/day during the period of organogenesis. Tapinarof was not associated with embryofetal lethality or fetal malformations. Tapinarof increased the incidence of skeletal variations (incomplete ossification of nasal bones) at the dose of 34 mg/kg/day (264 times the MRHD based on AUC comparisons). In an embryofetal development study in rabbits, tapinarof was administered by subcutaneous injection to pregnant animals twice daily at doses of 0.3, 1, and 3 mg/kg/day during the period of organogenesis. Maternal toxicity as evidenced by decreased maternal body weight gain and associated increased post-implantation loss (embryolethality) was observed at 3 mg/kg/day. In addition, fetal skeletal variations were observed at 3 mg/kg/day. Tapinarof was not associated with embryofetal lethality or fetal malformations at doses up to 1 mg/kg/day (16 times the MRHD based on AUC comparison) or fetal malformations at doses up to 3 mg/kg/day (30 times the MRHD based on AUC comparison). In a second embryofetal development study in rabbits, tapinarof was administered by continuous subcutaneous infusion to pregnant animals at doses of 1, 2 and 3 mg/kg/day during the period of organogenesis. Tapinarof was not associated with embryofetal lethality or fetal malformations at doses up to 3 mg/kg/day (20 times the MRHD based on AUC comparison). In a prenatal and postnatal development study, tapinarof was administered by subcutaneous injection to pregnant rats at doses of 1, 6 and 30 mg/kg/day beginning on gestation day 6 through lactation day 20. Maternal toxicity associated with decreases in body weight gain and food consumption was noted at 30 mg/kg/day (264 times the MRHD based on AUC comparisons). Tapinarof decreased fetal survival and viability that resulted in reduced litter sizes and decreased fetal weights at doses greater than or equal to 6 mg/kg/day (44 times the MRHD based on AUC comparisons). No tapinarof-related effects on fetal survival and viability were noted at a dose of 1 mg/kg/day (6 times the MRHD based on AUC comparisons). No tapinarof-related effects on postnatal development, neurobehavioral or reproductive performance of offspring were noted at doses up to 30 mg/kg/day (264 times the MRHD based on AUC comparison). 8.2 Lactation Risk Summary No data are available regarding the presence of tapinarof in human milk or the effects of tapinarof on the breastfed infant, or on milk production. Tapinarof was detected in rat offspring following subcutaneous administration to pregnant female rats which suggests that tapinarof was transferred into the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VTAMA cream and any potential adverse effects on the breastfed infant from VTAMA cream or from the underlying maternal condition. Data In a prenatal and postnatal development study, tapinarof was administered by subcutaneous injection to pregnant rats at doses of 1, 6, and 30 mg/kg/day from gestation day 6 through lactation day 20. Tapinarof was quantifiable in offspring plasma samples on postnatal day 10 at doses of 6 and 30 mg/kg/day, suggesting that tapinarof is present in animal milk. 8.4 Pediatric Use Plaque Psoriasis The safety and efficacy of VTAMA cream for the topical treatment of plaque psoriasis have not been established in pediatric patients. Reference ID: 5495185 Atopic Dermatitis The safety and efficacy of VTAMA cream for the topical treatment of atopic dermatitis have been established in pediatric patients 2 years of age and older. Use of VTAMA cream for this indication is supported by evidence from two adequate and well-controlled trials (ADORING 1 and ADORING 2), which included 654 pediatric subjects 2 years of age and older (436 of whom received VTAMA cream) with moderate to severe atopic dermatitis. Adverse reactions occurring more frequently in pediatric subjects compared to adults were upper respiratory tract infection and ear infection [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. The safety and efficacy of VTAMA cream for the topical treatment of atopic dermatitis have not been established in pediatric patients younger than 2 years of age. Juvenile Animal Toxicity Data In a juvenile animal toxicity study, tapinarof was administered by subcutaneous injection to juvenile rats at doses of 1, 10 and 20 mg/kg/day from postnatal day (PND) 7 to 21 and at doses of 1.5, 15, and 30 mg/kg/day from PND 22 to 77. The dose escalation conducted at PND 22 was implemented to maintain consistent systemic exposure across the duration of the dosing period. Renal pelvic dilatation was observed at doses greater than or equal to 15 mg/kg/day (165 times the MRHD based on AUC comparisons). No adverse effects in juvenile animals were noted at 1.5 mg/kg/day (11 times the MRHD based on AUC comparisons). 8.5 Geriatric Use Plaque Psoriasis Of the 683 subjects exposed to VTAMA cream in the PSOARING 1 or PSOARING 2 clinical trials, 99 (14.5%) were 65 years of age and older, including 8 (1.2%) subjects who were 75 years of age and older. No overall differences in efficacy, safety, or tolerability of VTAMA cream were observed between subjects 65 years of age and older and younger adult subjects. Atopic Dermatitis Of the 541 subjects exposed to VTAMA cream in the ADORING 1 or ADORING 2 clinical trials, 20 (3.7%) were 65 years of age and older, including 4 (0.7%) subjects who were 75 years of age and older. No overall differences in efficacy, safety, or tolerability were observed between subjects 65 years of age and older and younger adult subjects. 11 DESCRIPTION VTAMA (tapinarof) cream contains tapinarof as the active ingredient. Tapinarof is an aryl hydrocarbon receptor agonist. Tapinarof is a white to pale brown powder. Chemically, tapinarof is 3, 5-dihydroxy-4-isopropyl-trans­ stilbene, also known as (E)-2-isopropyl-5-styrylbenzene-1,3-diol, with the empirical formula C17H18O2, a molecular weight of 254.32, and the following structural formula. Reference ID: 5495185 Each gram of VTAMA cream for topical use contains 10 mg of tapinarof in a white to off-white cream. VTAMA cream also contains the following inactive ingredients: benzoic acid, butylated hydroxytoluene, citric acid monohydrate, diethylene glycol monoethyl ether, edetate disodium, emulsifying wax, medium-chain triglycerides, polyoxyl 2 stearyl ether, polyoxyl 20 stearyl ether, polysorbate 80, propylene glycol, purified water, and sodium citrate dihydrate. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tapinarof is an aryl hydrocarbon receptor (AhR) agonist. The specific mechanisms by which VTAMA cream exerts its therapeutic actions are unknown. 12.2 Pharmacodynamics Pharmacodynamics of VTAMA cream are unknown. Cardiac Electrophysiology At the approved recommended dosage, VTAMA cream does not prolong the QTc interval to any clinically relevant extent. 12.3 Pharmacokinetics The plasma concentrations of tapinarof were higher in pediatric subjects 2 years of age and older with atopic dermatitis when compared to adult subjects with plaque psoriasis. Absorption Adults with Plaque Psoriasis No accumulation was observed with repeat topical application. Plasma concentration of tapinarof was below the quantifiable limits (BQL) of the assay (lower limit of quantification was 50 pg/mL) in 68% of the PK samples. On Day 1, mean ± SD values of Cmax and AUC0-last were 0.90 ± 1.4 ng/mL and 4.1 ± 6.3 ng.h/mL, respectively, following a mean daily dose of 5.23 g applied to a mean body surface area (BSA) involvement of 27.2% (range 21 to 46%) in 21 subjects with moderate to severe plaque psoriasis. On Day 29, the mean ± SD Cmax and AUC0­ last were 0.12 ± 0.15 ng/mL and 0.61 ± 0.65 ng.h/mL, respectively. Pediatric Subjects with Atopic Dermatitis The PK of VTAMA cream were investigated in 36 pediatric subjects 2 years of age and older with moderate to severe atopic dermatitis and a mean ± SD BSA involvement of 43% ± 15% (range 26% to 90%). In this study, subjects applied approximately 3.2 g/day for 27 days. Plasma concentrations were BQL in 25% of PK samples on Day 1 and 76% of PK samples on Day 28. On Day 1, the mean ± SD Cmax and AUC0-last were 2.4 ± 3.9 ng/mL and 4.7 ± 5.6 ng.h/mL, respectively in the overall Reference ID: 5495185 pediatric population with atopic dermatitis. The mean ± SD Cmax and AUC0-last on Day 1 in pediatric subjects with atopic dermatitis stratified by age is shown in Table 3. Table 3: Pharmacokinetic Parameters of Tapinarof by Age Group in Pediatric Subjects with Atopic Dermatitis PK Parameter (Mean ± SD) 2 – 6 Years 7 – 11 Years 12 – 17 Years Day 1 Cmax (ng/mL) 3.8 ± 5.87 2.2 ± 2.5 1.3 ± 1.8 AUC0-t (ng.h/mL) 5.5 ± 6.2 5.2 ± 5.9 3.3 ± 4.8 Day 28 Cꚍ (ng/mL) 0.046 ± 0.107 0.089 ± 0.130 0.125 ± 0.413 Cꚍ: concentration at the end of 24 h dosing interval on Day 28. Distribution Human plasma protein binding of tapinarof is approximately 99% in vitro. Elimination Metabolism Tapinarof is metabolized in the liver by multiple pathways including oxidation, glucuronidation, and sulfation in vitro. Drug Interaction Studies In Vitro Studies Cytochrome P450 (CYP) Enzymes: Tapinarof is not an inhibitor of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5. Tapinarof is not an inducer of CYP1A2, CYP2B6 or CYP3A4. Transporter Systems: Tapinarof is not an inhibitor of BCRP, MATE1, MATE-2K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, or P-gp. Tapinarof is not a substrate for BCRP, OATP1B1, OATP1B3, or P-gp. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies were conducted in mice (daily topical administration at doses of 0.5, 1.5 and 3% tapinarof cream) and in rats (subcutaneous administration at doses of 0.1, 0.3, and 1 mg/kg/day tapinarof). No drug-related neoplasms were noted in mice after 98 (females) to 102 (males) weeks of daily topical administration at doses up to 3% tapinarof cream (44 times the MRHD based on AUC comparisons). No drug- related neoplasms were noted in female rats after 83 weeks of daily subcutaneous administration at doses up to 1 mg/kg/day tapinarof (9 times the MRHD based on AUC comparisons). Tapinarof revealed no evidence of mutagenicity or clastogenicity in an Ames assay, an in vitro mammalian chromosomal aberration assay, an in vitro mouse lymphoma assay and two in vivo micronucleus assays in mice and rats. Tapinarof did not impair female fertility at subcutaneous doses up to 30 mg/kg/day (264 times the MRHD based on AUC comparisons). Reference ID: 5495185 14 CLINICAL STUDIES 14.1 Plaque Psoriasis Two multicenter, randomized, double-blind, vehicle-controlled trials were conducted to evaluate the safety and efficacy of VTAMA cream for the treatment of adults with plaque psoriasis (PSOARING 1 [NCT03956355] and PSOARING 2 [NCT03983980]). These trials were conducted in a total of 1025 subjects randomized 2:1 to VTAMA cream or vehicle cream applied once daily for 12 weeks to any lesion regardless of anatomic location. Baseline disease severity was graded using the 5-point Physician’s Global Assessment (PGA). The majority of subjects had “Moderate” disease (82%), while 10% had “Mild” disease, and 8% had “Severe” disease at baseline. The extent of disease involvement assessed by mean body surface area (BSA), excluding the scalp, palms, and soles, was 8% (range 3 to 20%). Subjects ranged in age from 18 to 75 years, with a median age of 51 years. Overall, 57% of the subjects were male and 85% were White. The primary efficacy endpoint in both studies was the proportion of subjects who achieved treatment success, defined as a PGA score of “Clear” (0) or “Almost Clear” (1) and at least a 2-grade improvement from baseline. Efficacy results from the two trials are summarized in Table 4. Table 4: Clinical Response at Week 12 in PSOARING 1 and PSOARING 2 in Adults with Plaque Psoriasis (Intent-to-Treat; Multiple Imputation) Clinical Response PSOARING 1 PSOARING 2 VTAMA cream N=340 Vehicle cream N=170 VTAMA cream N=343 Vehicle cream N=172 PGA Treatment Success a 36% 6% 40% 6% Difference (95% CI) 29% (22%, 36%) 34% (27%, 41%) a Treatment success was defined as a PGA score of “Clear” or “Almost Clear” and at least a 2-grade improvement from baseline. Following 12 weeks of treatment, 73 subjects randomized to VTAMA achieved complete disease clearance (PGA 0) and had VTAMA withdrawn. These subjects were followed for up to 40 additional weeks with a median time to first worsening (PGA ≥ 2 [“Mild”]) of 114 days (95% CI: 85, 142). 14.2 Atopic Dermatitis Two multicenter, randomized, double-blind, vehicle-controlled trials were conducted to evaluate the safety and efficacy of VTAMA cream for the treatment of adult and pediatric subjects 2 years of age and older with atopic dermatitis (ADORING 1 [NCT05014568] and ADORING 2 [NCT05032859]). These trials were conducted in a total of 813 subjects (80% of subjects were 2 to 17 years of age) randomized 2:1 to VTAMA cream or vehicle cream applied once daily for 8 weeks to any lesion regardless of anatomic location. Baseline disease severity was graded using the 5-point validated Investigator’s Global Assessment (vIGA- AD™). The majority of subjects had “Moderate” disease (87%), while 13% had “Severe” disease at baseline. The extent of disease involvement assessed by mean affected BSA, excluding the scalp, was 16.8% (range 5 to 44%). The mean baseline Eczema Area and Severity Index (EASI) score was 12.9 (range 4.4 to 36.0). The mean baseline Peak Pruritus Numeric Rating Scale (PP-NRS) score for subjects 12 years of age and older was 6.4 on a scale of 0-10. Subjects ranged in age from 2 to 81 years, with a median age of 11 years. Overall, 54% of the subjects were female, 51% were White, 31% were Black, and 12% were Asian. For ethnicity, 78% of subjects identified as non-Hispanic or Latino. The primary efficacy endpoint in both trials was the proportion of subjects who achieved treatment success, defined as a vIGA-AD score of “Clear” (0) or “Almost Clear” (1) and at least a 2-grade improvement from Reference ID: 5495185 baseline. Efficacy was also assessed using a ≥ 4-point improvement in PP-NRS score in subjects 12 years of age and older. Efficacy results from the two trials are summarized in Table 5. Table 5: Clinical Response at Week 8 in ADORING 1 and ADORING 2 in Adult and Pediatric Subjects with Atopic Dermatitis (Intent-to-Treat; Multiple Imputation) ADORING 1 ADORING 2 VTAMA cream Vehicle cream VTAMA cream Vehicle cream Number of subjects randomized 270 137 271 135 vIGA-AD Treatment Successa,b Difference from Vehicle (95% CI) 45% 32% (23%, 40%) 14% 46% 29% (19%, 38%) 18% Number of subjects ≥12 years of age with baseline PP-NRS score ≥4 103 54 126 64 ≥ 4-point improvement in PP-NRSc Difference from Vehicle (95% CI) 56% 22% (5%, 38%) 34% 53% 29% (15%, 43%) 24% a Based on number of subjects randomized. b Treatment success was defined as a vIGA-AD score of “Clear” or “Almost Clear” and at least a 2-grade improvement from baseline. c Based on number of subjects 12 years of age and older whose baseline PP-NRS score was ≥4. Of the 431 subjects randomized to VTAMA who completed 8 weeks of treatment in ADORING 1 and ADORING 2 and elected to continue follow-up, 51 subjects achieved complete disease clearance (vIGA-AD = 0) and had VTAMA withdrawn. These subjects were followed for up to 48 additional weeks with a median time to first worsening (vIGA-AD ≥ 2 [“Mild”]) of 57 days (95% CI: 30, 79). 16 HOW SUPPLIED/STORGAGE AND HANDLING VTAMA (tapinarof) cream, 1% is a white to off-white cream. Each gram of VTAMA cream contains 10 mg of tapinarof. It is supplied in the following size: 60 g laminated tubes: NDC 81672-5051-1 Storage and Handling: - Store at 20°C to 25°C (68°F to 77°F) excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. - Do not freeze. - Protect from exposure to excessive heat. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Administration Instructions [see Dosage and Administration (2)] Reference ID: 5495185 • Instruct patients to apply VTAMA cream once daily to affected skin lesions only and avoid unaffected areas of skin. • Advise patients to wash hands after application unless VTAMA cream is for treatment of the hands. • Advise patients that VTAMA cream is for external use only. Marketed by: Dermavant Sciences Inc., 3780 Kilroy Airport Way, Long Beach, CA 90806 VTAMA is a registered trademark of Dermavant Sciences, GmbH or its affiliates. vIGA-AD is the trademark of Eli Lilly and Co. U.S. Patents: www.dermavant.com/patents Reference ID: 5495185 PATIENT INFORMATION VTAMA® (Vee-TAM-uh) (tapinarof) cream, for topical use Important information: VTAMA cream is for use on the skin (topical use) only. Do not use VTAMA cream in your eyes, mouth, or vagina. What is VTAMA cream? VTAMA cream is a prescription medicine used on the skin (topical) to treat: • plaque psoriasis in adults. • atopic dermatitis in adults and children 2 years of age and older. It is not known if VTAMA cream is safe and effective for the topical treatment of plaque psoriasis in children. It is not known if VTAMA cream is safe and effective for the topical treatment of atopic dermatitis in children under 2 years of age. Before using VTAMA cream, tell your healthcare provider about all of your medical conditions, including if you: • are pregnant or plan to become pregnant. It is not known if VTAMA cream will harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if VTAMA cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with VTAMA cream. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I use VTAMA cream? • Use VTAMA cream exactly as your healthcare provider tells you to use it. • Apply a thin layer of VTAMA cream only to the affected skin areas 1 time a day. Avoid applying VTAMA cream to unaffected areas of your skin. • Wash your hands after applying VTAMA cream unless you are using it to treat your hands. • If someone else applies VTAMA cream for you, they should wash their hands after application. What are the possible side effects of VTAMA cream? The most common side effects of VTAMA cream in people treated for plaque psoriasis include: • red raised bumps around the hair pores (folliculitis) • headache • pain or swelling in the nose and throat (nasopharyngitis) • flu • skin rash or irritation including itching and redness, peeling, burning, or stinging The most common side effects of VTAMA cream in people treated for atopic dermatitis include: • upper and lower respiratory tract infections • vomiting • red raised bumps around the hair pores (folliculitis) • ear infection • headache • pain in extremity • asthma • stomach-area (abdominal) pain VTAMA cream can also cause skin reactions at the treatment site. Tell your healthcare provider if you have itching, irritation, pain, redness, burning or changes in skin color at the treatment site. These are not all the possible side effects of VTAMA cream. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store VTAMA cream? • Store VTAMA cream at room temperature between 68°F to 77°F (20°C to 25°C). • Do not freeze VTAMA cream. • Protect VTAMA cream from exposure to excessive heat. Keep VTAMA cream and all medicines out of the reach of children. General information about the safe and effective use of VTAMA cream. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use VTAMA cream for a condition for which it was not prescribed. Do not give VTAMA cream to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VTAMA cream that is written for health professionals. What are the ingredients in VTAMA cream? Active ingredient: tapinarof Inactive ingredients: benzoic acid, butylated hydroxytoluene, citric acid monohydrate, diethylene glycol monoethyl ether, edetate disodium, emulsifying wax, medium-chain triglycerides, polyoxyl 2 stearyl ether, polyoxyl 20 stearyl ether, polysorbate 80, propylene glycol, purified water, and sodium citrate dihydrate. Marketed by: Dermavant Sciences Inc., 3780 Kilroy Airport Way, Long Beach, CA 90806 VTAMA is a registered trademark of Dermavant Sciences, GmbH or its affiliates. U.S. Patents: www.dermavant.com/patents Reference ID: 5495185 For more information, go to www.VTAMA.com or call 1-833-762-8268 (1-8DERMAVANT). This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 12/2024 Reference ID: 5495185
custom-source
2025-02-12T15:47:45.844783
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Bayer, the Bayer Cross, Claritin and the Claritin Vista are registered trademarks of Bayer. © 2023 Bayer. Dist by: Bayer HealthCare LLC Whippany, NJ 07981 Made in India. Pat.: patents.livewell.bayer.com Bayer, the Bayer Cross, Claritin and the Claritin Vista are registered trademarks of Bayer. © 2023 Bayer. Dist by: Bayer HealthCare LLC Whippany, NJ 07981 Made in India. Pat.: patents.livewell.bayer.com 000000000 Drug Facts Active ingredient Purpose (in each 5 mL) Loratadine 5 mg ............................... Antihistamine Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: ■ runny nose ■ itchy, watery eyes ■ sneezing ■ itching of the nose or throat Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients. Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. When using this product do not take more than directed. Taking more than directed may cause drowsiness. Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Directions ■ use only with enclosed dosing cup ■ mL = milliliter Drug Facts (continued) adults and children 10 mL daily; do not take 6 years and over more than 10 mL in 24 hours children 2 to under 5 mL daily; do not take 6 years of age more than 5 mL in 24 hours children under 2 years ask a doctor of age consumers with liver ask a doctor or kidney disease Other information ■ each 5 mL contains: sodium 5.5 mg ■ do not use if tape imprinted with “SEALED FOR YOUR PROTECTION” on top and bottom flaps of carton is not intact ■ store between 20° to 25°C (68° to 77°F) Inactive ingredients edetate disodium, flavors, glycerin, maltitol, menthol, phosphoric acid, propylene glycol, purified water, sodium benzoate, sodium phosphate, sorbitol, sucralose Questions or comments? 1-800-CLARITIN (1-800-252-7484) 00000000 LOT: EXP: • Sneezing • Runny Nose • Itchy, Watery Eyes • Itchy Throat or Nose Indoor and Outdoor Allergies loratadine oral solution 5 mg/5 mL antihistamine 1 FL OZ (30 mL) 1 FL OZ (30 mL) *When taken as directed. When taken as directed. See Drug Facts Panel. See Drug Facts Panel. SAMPLE NOT FOR SALE Cooling Honey Flavored Cooling Honey Flavored • 24 Hour Relief • Dye-Free • No Added Alcohol • No Added Sugar NO TEXT ZONE NO COLOR ZONE NO TEXT ZONE NO COLOR ZONE NO TEXT ZONE NO COLOR ZONE NO TEXT ZONE NO COLOR ZONE NO TEXT ZONE NO COLOR ZONE NO TEXT ZONE NO COLOR ZONE NO TEXT ZONE NO COLOR ZONE NO TEXT ZONE NO COLOR ZONE Reference ID: 5385353 00000000 Active ingredient (in each 5 mL) Purpose Loratadine 5 mg.........................................Antihistamine Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: ■ runny nose ■ itchy, watery eyes ■ sneezing ■ itching of the nose or throat Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients. Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. When using this product do not take more than directed. Taking more than directed may cause drowsiness. Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Directions ■ use only with enclosed dosing cup ■ mL = milliliter adults and children 6 years and over: 10 mL daily, do not take more than 10 mL in 24 hours; children 2 to under 6 years of age: 5 mL daily, do not take more than 5 mL in 24 hours; children under 2 years of age: ask a doctor Other information ■ each 5 mL contains: sodium 5.5 mg ■ do not use if tape imprinted with “SEALED FOR YOUR PROTECTION” on top and bottom flaps of carton is not intact ■ store between 20° to 25°C (68° to 77°F) Inactive ingredients edetate disodium, flavors, glycerin, maltitol, menthol, phosphoric acid, propylene glycol, purified water, sodium benzoate, sodium phosphate, sorbitol, sucralose Questions or comments? 1-800-CLARITIN (1-800-252-7484) © 2023 Bayer. Dist by: Bayer HealthCare LLC, Whippany, NJ 07981 00000000 1 FL OZ (30 mL) 1 FL OZ (30 mL) *When taken as directed. When taken as directed. See Drug Facts Panel. See Drug Facts Panel. Sample-Not for sale loratadine oral solution 5 mg/5 mL antihistamine loratadine oral solution 5 mg/5 mL antihistamine Cooling Honey Flavored Indoor & Outdoor Allergies Reference ID: 5385353 00000000 Drug Facts Active ingredient (in each 5 mL) Purpose Loratadine 5 mg ...................................................... Antihistamine Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: ■ runny nose ■ itchy, watery eyes ■ sneezing ■ itching of the nose or throat Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients. Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. When using this product do not take more than directed. Taking more than directed may cause drowsiness. Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Drug Facts (continued) Directions ■ use only with enclosed dosing cup ■ mL = milliliter Other information ■ each 5 mL contains: sodium 5.5 mg ■ do not use if tape imprinted with “SEALED FOR YOUR PROTECTION” on top and bottom flaps of carton is not intact ■ store between 20° to 25°C (68° to 77°F) Inactive ingredients edetate disodium, flavors, glycerin, maltitol, menthol, phosphoric acid, propylene glycol, purified water, sodium benzoate, sodium phosphate, sorbitol, sucralose Questions or comments? 1-800-CLARITIN (1-800-252-7484) adults and children 6 years and over children 2 to under 6 years of age consumers with liver or kidney disease 10 mL daily; do not take more than 10 mL in 24 hours 5 mL daily; do not take more than 5 mL in 24 hours ask a doctor children under 2 years of age ask a doctor Bayer, the Bayer Cross, Claritin and the Claritin Vista are registered trademarks of Bayer. © 2023 Bayer. 00000000 Pat.: patents.livewell.bayer.com Dist by: Bayer HealthCare LLC, Whippany, NJ 07981 Made in India. LOT: EXP: • Sneezing • Runny Nose • Itchy, Watery Eyes • Itchy Throat or Nose Indoor and Outdoor Allergies 2.7 FL OZ (80 mL) 2.7 FL OZ (80 mL) *When taken as directed. When taken as directed. See Drug Facts Panel. See Drug Facts Panel. loratadine oral solution 5 mg/5 mL antihistamine Cooling Honey Flavored Cooling Honey Flavored • 24 Hour Relief • Dye-Free • No Added Alcohol • No Added Sugar Reference ID: 5385353 00000000 Active ingredient (in each 5 mL) Purpose Loratadine 5 mg..................................Antihistamine Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: ■ runny nose ■ itchy, watery eyes ■ sneezing ■ itching of the nose or throat Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients. Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. When using this product do not take more than directed. Taking more than directed may cause drowsiness. Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Directions ■ use only with enclosed dosing cup ■ mL = milliliter adults and children 6 years and over: 10 mL daily, do not take more than 10 mL in 24 hours; children 2 to under 6 years of age: 5 mL daily, do not take more than 5 mL in 24 hours; children under 2 years of age: ask a doctor Other information ■ each 5 mL contains: sodium 5.5 mg ■ do not use if tape imprinted with “SEALED FOR YOUR PROTECTION” on top and bottom flaps of carton is not intact ■ store between 20° to 25°C (68° to 77°F) Inactive ingredients edetate disodium, flavors, glycerin, maltitol, menthol, phosphoric acid, propylene glycol, purified water, sodium benzoate, sodium phosphate, sorbitol, sucralose Questions or comments? 1-800-CLARITIN (1-800-252-7484) © 2023 Bayer. Dist by: Bayer HealthCare LLC, Whippany, NJ 07981 00000000 LOT: EXP: Cooling Honey Flavored loratadine oral solution 5 mg/5 mL antihistamine loratadine oral solution 5 mg/5 mL antihistamine Indoor & Outdoor Allergies 2.7 FL OZ (80 mL) 2.7 FL OZ (80 mL) *When taken as directed. When taken as directed. See Drug Facts Panel. See Drug Facts Panel. Reference ID: 5385353 LOT: EXP: Bayer, the Bayer Cross, Claritin and the Claritin Vista are registered trademarks of Bayer. © 2023 Bayer. 00000000 Dist by: Bayer HealthCare LLC Whippany, NJ 07981 Made in India. Pat.: patents.livewell.bayer.com 00000000 Drug Facts Active ingredient (in each 5 mL) Purpose Loratadine 5 mg ............................................................................. Antihistamine Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: ■ runny nose ■ itchy, watery eyes ■ sneezing ■ itching of the nose or throat Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients. Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. When using this product do not take more than directed. Taking more than directed may cause drowsiness. Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Drug Facts (continued) Directions ■ use only with enclosed dosing cup ■ mL = milliliter adults and children 6 years and over 10 mL daily; do not take more than 10 mL in 24 hours children 2 to under 6 years of age 5 mL daily; do not take more than 5 mL in 24 hours children under 2 years of age ask a doctor consumers with liver or kidney disease ask a doctor Other information ■ each 5 mL contains: sodium 5.5 mg ■ do not use if tape imprinted with “SEALED FOR YOUR PROTECTION” on top and bottom flaps of carton is not intact ■ store between 20° to 25°C (68° to 77°F) Inactive ingredients edetate disodium, flavors, glycerin, maltitol, menthol, phosphoric acid, propylene glycol, purified water, sodium benzoate, sodium phosphate, sorbitol, sucralose Questions or comments? 1-800-CLARITIN (1-800-252-7484) Indoor and Outdoor Allergies • Sneezing • Runny Nose • Itchy, Watery Eyes • Itchy Throat or Nose 8 FL OZ (240 mL) 8 FL OZ (240 mL) *When taken as directed. When taken as directed. See Drug Facts Panel. See Drug Facts Panel. loratadine oral solution 5 mg/5 mL antihistamine Cooling Honey Flavored Cooling Honey Flavored • 24 Hour Relief • Dye-Free • No Added Alcohol • No Added Sugar Cooling Honey Flavored Cooling Honey Flavored Indoor and Outdoor Allergies • Sneezing • Runny Nose • Itchy, Watery Eyes • Itchy Throat or Nose Cooling Honey Flavored Cooling Honey Flavored Reference ID: 5385353 Active ingredient Purpose (in each 5 mL) Loratadine 5 mg..............Antihistamine Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: ■ runny nose ■ itchy, watery eyes ■sneezing ■ itching of the nose or throat Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients. Ask a doctor before use if you have liver or kidney disease. Your doctor should determine if you need a different dose. When using this product do not take more than directed. Taking more than directed may cause drowsiness. Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Directions ■use only with enclosed dosing cup ■ mL = milliliter adults and children 6 years and over: 10 mL daily, do not take more than 10 mL in 24 hours; children 2 to under 6 years of age: 5 mL daily, do not take more than 5 mL in 24 hours; children under 2 years of age: ask a doctor Other information ■ each 5 mL contains: sodium 5.5 mg ■ do not use if tape imprinted with “SEALED FOR YOUR PROTECTION” on top and bottom flaps of carton is not intact ■ store between 20° to 25°C (68° to 77°F) Inactive ingredients edetate disodium, flavors, glycerin, maltitol, menthol, phosphoric acid, propylene glycol, purified water, sodium benzoate, sodium phosphate, sorbitol, sucralose Questions or comments? 1-800-CLARITIN (1-800-252-7484) 00000000 © 2023 Bayer. Dist by: Bayer HealthCare LLC Whippany, NJ 07981 00000000 LOT: EXP: Cooling Honey Flavored loratadine oral solution 5 mg/5 mL antihistamine loratadine oral solution 5 mg/5 mL antihistamine Indoor & Outdoor Allergies 8 FL OZ (240 mL) 8 FL OZ (240 mL) *When taken as directed. When taken as directed. See Drug Facts Panel. See Drug Facts Panel. Reference ID: 5385353 NDA 20-641 2010 AR Section 3.1.7 Page 1 of 1 NDA 20-641 2010 AR Section 3.1.7 Page 1 of 1 NDA 20-641 2010 AR Section 3.1.7 Page 1 of 1 Reference ID: 5385353 1.09" Lower Width 1.41" Height 1.66" Upper Width Reference ID: 5385353 10 mL 10 mL 10 mL 10 mL 5 mL 5 mL 5 mL 5 mL 10 mL 10 mL 10 mL 10 mL 5 mL 5 mL 5 mL 5 mL READ LABEL DIRECTIONS READ LABEL DIRECTIONS HAND WASH AFTER USING HAND WASH AFTER USING 31000309 C8514 9pt Helvetica-Roman 9pt Helvetica-Roman 9pt Helvetica-Roman 9pt Helvetica-Roman 11pt Helvetica-Bold 11pt Helvetica-Bold 11pt Helvetica-Bold 11pt Helvetica-Bold 7pt OCRA-Med 7pt OCRA-Med 1.25" (+/- .010") Lower Width 1.53" (+/- .010") Upper Width 1.325"(+/- .010") Height Reference ID: 5385353
custom-source
2025-02-12T15:47:46.387729
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use VEOZAH safely and effectively. See full prescribing information for VEOZAH. VEOZAH® (fezolinetant) tablets, for oral use Initial U.S. Approval: 2023 WARNING: RISKS OF HEPATOTOXICITY See full prescribing information for complete boxed warning. Hepatotoxicity has occurred with the use of VEOZAH in the postmarketing setting (5.1). • Perform hepatic laboratory tests prior to initiation of treatment to evaluate for hepatic function and injury. Do not start VEOZAH if either aminotransferase is ≥ 2 x ULN or if the total bilirubin is ≥ 2 x ULN for the evaluating laboratory. • Perform follow-up hepatic laboratory testing monthly for the first 3 months, at 6 months, and 9 months of treatment (2.1, 5.1). • Advise patients to discontinue VEOZAH immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury (new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain) (2.1, 5.1). • Discontinue VEOZAH if transaminase elevations are > 5 x ULN, or if transaminase elevations are > 3 x ULN and the total bilirubin level is > 2 x ULN. • If transaminase elevations > 3 x ULN occur, perform more frequent follow-up hepatic laboratory tests until resolution (5.1). -------------------------- RECENT MAJOR CHANGES -------------------------­ Boxed Warning, Hepatotoxicity 12/2024 Dosage and Administration, Recommended Dosage (2.1) 12/2024 Warnings and Precautions, Hepatotoxicity (5.1) 12/2024 --------------------------- INDICATIONS AND USAGE -------------------------­ VEOZAH is a neurokinin 3 (NK3) receptor antagonist indicated for the treatment of moderate to severe vasomotor symptoms due to menopause. (1) ---------------------- DOSAGE AND ADMINISTRATION ---------------------­ One 45 mg tablet orally once daily with or without food. Perform baseline hepatic laboratory tests to evaluate for hepatic function and injury before beginning VEOZAH. While using VEOZAH, perform follow-up hepatic laboratory tests monthly for the first 3 months, at 6 months, and 9 months after initiation of therapy or when signs or symptoms suggest liver injury. (2.1) --------------------- DOSAGE FORMS AND STRENGTHS -------------------­ Tablets: 45 mg (3) ------------------------------ CONTRAINDICATIONS ----------------------------­ • Known cirrhosis (4, 5.1) • Severe renal impairment or end-stage renal disease (4, 8.6) • Concomitant use with CYP1A2 inhibitors (4, 7.1) ----------------------- WARNINGS AND PRECAUTIONS ---------------------- Hepatotoxicity: Cases of hepatotoxicity and jaundice have been reported in the postmarketing setting. Perform hepatic laboratory tests prior to initiation of VEOZAH to evaluate for hepatic function and injury. Perform follow-up hepatic laboratory tests monthly for the first 3 months, at 6 months, and 9 months after initiation of therapy. Advise patients to discontinue VEOZAH immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury (new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain). (5.1) ------------------------------ ADVERSE REACTIONS ----------------------------­ The most common adverse reactions with VEOZAH [at least 2% in VEOZAH 45 mg and greater than placebo] are: abdominal pain, diarrhea, insomnia, back pain, hot flush, and hepatic transaminase elevation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 10 OVERDOSAGE 2 DOSAGE AND ADMINISTRATION 11 DESCRIPTION 2.1 Recommended Dosage 12 CLINICAL PHARMACOLOGY 3 DOSAGE FORMS AND STRENGTHS 12.1 Mechanism of Action 4 CONTRAINDICATIONS 12.2 Pharmacodynamics 5 WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics 5.1 Hepatotoxicity 13 NONCLINICAL TOXICOLOGY 6 ADVERSE REACTIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 6.1 Clinical Trials Experience 13.2 Animal Toxicology and/or Pharmacology 6.2 Postmarketing Experience 14 CLINICAL STUDIES 7 DRUG INTERACTIONS 14.1 Effects on Vasomotor Symptoms in Postmenopausal Women 7.1 Effect of Other Drugs on VEOZAH 14.2 Effects on Endometrium in Postmenopausal Women 8 USE IN SPECIFIC POPULATIONS 16 HOW SUPPLIED/STORAGE AND HANDLING 8.1 Pregnancy 16.1 How Supplied 8.2 Lactation 16.2 Storage and Handling 8.4 Pediatric Use 17 PATIENT COUNSELING INFORMATION 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 5497306 FULL PRESCRIBING INFORMATION WARNING: RISKS OF HEPATOTOXICITY Hepatotoxicity has occurred with the use of VEOZAH in the postmarketing setting (5.1). • Perform hepatic laboratory tests prior to initiation of treatment to evaluate for hepatic function and injury. Do not start VEOZAH if either aminotransferase is ≥ 2 x the upper limit of normal (ULN) or if the total bilirubin is ≥ 2 x ULN for the evaluating laboratory. • Perform follow-up hepatic laboratory testing monthly for the first 3 months, at 6 months, and 9 months of treatment (2.1, 5.1). • Advise patients to discontinue VEOZAH immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury (new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain) (2.1, 5.1). • Discontinue VEOZAH if transaminase elevations are > 5 x ULN, or if transaminase elevations are > 3 x ULN and the total bilirubin level is > 2 x ULN. • If transaminase elevations > 3 x ULN occur, perform more frequent follow-up hepatic laboratory tests until resolution (5.1). 1 INDICATIONS AND USAGE VEOZAH® is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage Take a single 45 mg VEOZAH tablet orally once daily with or without food. Take VEOZAH with liquids and swallow whole. Do not cut, crush, or chew tablets. Administer VEOZAH orally at about the same time each day. If a dose of VEOZAH is missed or not taken at the usual time, administer the missed dose as soon as possible, unless there is less than 12 hours before the next scheduled dose. Return to the regular schedule the following day. Perform baseline hepatic laboratory tests to evaluate for hepatic function and injury [including serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), serum alkaline phosphatase (ALP), and serum bilirubin (total and direct)] before initiating treatment with VEOZAH. Do not start VEOZAH if ALT or AST is ≥ 2 x ULN or if the total bilirubin is ≥ 2 x ULN for the evaluating laboratory. While using VEOZAH, perform follow-up hepatic laboratory tests monthly for the first 3 months, at 6 months, and 9 months after initiation of therapy. Advise patients to discontinue VEOZAH immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury [see Warnings and Precautions (5.1)]. 3 DOSAGE FORMS AND STRENGTHS Tablets: 45 mg, round, light red, film-coated tablets, debossed with the Astellas logo and ‘645’ on the same side. 2 Reference ID: 5497306 4 CONTRAINDICATIONS VEOZAH is contraindicated in women with any of the following conditions: • Known cirrhosis [see Warnings and Precautions (5.1), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]. • Severe renal impairment or end-stage renal disease [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. • Concomitant use with CYP1A2 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity In three clinical trials, elevations in serum transaminase [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] levels > 3 x the upper limit of normal (ULN) occurred in 2.3% [exposure adjusted incidence rate (EAIR) of 2.7 per 100 person-years] of women receiving VEOZAH and 0.9% (EAIR of 1.5 per 100 person-years) of women receiving placebo. No elevations in serum total bilirubin (> 2 x ULN) occurred. Women with ALT or AST elevations were generally asymptomatic. Transaminase levels returned to pretreatment levels (or close to these) without sequelae with dose continuation, and upon dose interruption, or discontinuation. Women with cirrhosis were not studied [see Adverse Reactions (6.1)]. In the postmarketing setting, cases of drug-induced liver injury with elevations of ALT, AST, alkaline phosphatase (ALP), and total bilirubin occurred within 40 days of starting VEOZAH. Patients reported a general sense of feeling unwell and symptoms of fatigue, nausea, pruritus, jaundice, pale feces, and dark urine. The patients’ signs and symptoms gradually resolved after discontinuation of VEOZAH [see Adverse Reactions (6.2)]. Perform baseline hepatic laboratory tests to evaluate for hepatic function and injury [including serum ALT, serum AST, serum ALP, and serum bilirubin (total and direct)] prior to VEOZAH initiation. Do not start VEOZAH if ALT or AST is ≥ 2 x ULN or if the total bilirubin is ≥ 2 x ULN for the evaluating laboratory. Perform follow-up hepatic laboratory tests monthly for the first 3 months, at 6 months, and 9 months after initiation of therapy. Advise patients to discontinue VEOZAH immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury: • new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain. Discontinue VEOZAH if: • transaminase elevations are > 5 x ULN. • transaminase elevations are > 3 x ULN and total bilirubin is > 2 x ULN. If transaminase elevations > 3 x ULN occur, perform more frequent follow-up hepatic laboratory tests until resolution. Exclude alternative causes of hepatic laboratory test elevations. 3 Reference ID: 5497306 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hepatic Transaminase Elevation and Hepatotoxicity [see Warnings and Precautions (5.1)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of VEOZAH was evaluated in three 52-week clinical trials [see Clinical Studies (14)]. Across the three clinical trials, a total of 1100 women received VEOZAH. Trials 1 and 2 were placebo-controlled for the first 12 weeks, followed by re-randomization of women previously receiving placebo to VEOZAH (women on VEOZAH remained on VEOZAH) for an additional 40 weeks of uncontrolled treatment. Trial 3 was a randomized, placebo-controlled, double-blind safety study evaluating the safety of VEOZAH for 52 weeks. The adverse reactions reported in at least 2% in VEOZAH 45 mg and greater than placebo in Trial 3 are presented in Table 1. Table 1: Adverse Reactions Reported in at Least 2% in VEOZAH 45 mg and Greater Than Placebo in a Placebo- Controlled, Double-Blind 52-Week Trial (Trial 3) Adverse Reaction VEOZAH 45 mg (n=609) Total Person-Years=504.2 n (%, EAIR1) Placebo (n=610) Total Person-Years=475.0 n (%, EAIR1) Abdominal pain2 26 (4.3%, 5.2) 13 (2.1%, 2.7) Diarrhea 24 (3.9%, 4.8) 16 (2.6%, 3.4) Insomnia 24 (3.9%, 4.8) 11 (1.8%, 2.3) Back pain 18 (3.0%, 3.6) 13 (2.1%, 2.7) Hot flush 15 (2.5%, 3.0) 10 (1.6%, 2.1) Hepatic transaminase elevation3 14 (2.3%, 2.8) 5 (0.8%, 1.1) 1. EAIR = Number of individuals experiencing an adverse event divided by exposure time (total person-years) x 100. 2. Abdominal pain (including Abdominal pain, Abdominal pain lower, Abdominal pain upper). 3. Hepatic transaminase elevations (including Alanine aminotransferase abnormal, Alanine aminotransferase increased, Aspartate aminotransferase abnormal, Aspartate aminotransferase increased). In the pooled laboratory data of Trials 1, 2, and 3, elevated hepatic transaminases (> 3 x ULN) occurred in 25 women (2.3%, 2.7 EAIR) exposed to VEOZAH 45 mg (n=1100, 912.1 total person-years) as compared to 8 women (0.9%, 1.5 EAIR) exposed to placebo (n=952, 549.1 total person-years). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of VEOZAH. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatic: Cases of serious drug-induced hepatotoxicity occurred within 40 days of starting VEOZAH. Patients experienced elevated transaminases (up to 50 x ULN at peak elevation), elevated alkaline phosphatase (up to 4 x ULN at peak elevation), and bilirubin (up to 5 x ULN at peak elevation) coupled with symptoms of fatigue, nausea, pruritus, jaundice, pale feces, and dark urine. After discontinuation of VEOZAH, these abnormalities gradually resolved. 4 Reference ID: 5497306 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on VEOZAH CYP1A2 Inhibitors VEOZAH is a substrate of CYP1A2. Concomitant use of VEOZAH with drugs that are weak, moderate, or strong CYP1A2 inhibitors, increase the plasma Cmax and AUC of VEOZAH [see Clinical Pharmacology (12.3)]. VEOZAH is contraindicated in individuals using CYP1A2 inhibitors. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no data on VEOZAH use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In embryo-fetal toxicity animal studies with fezolinetant, embryo-lethality occurred at high doses above the human therapeutic dose in rats and rabbits, but no teratogenicity was observed. In the pre- and post-natal development animal study, delayed parturition and embryo-lethality occurred at high doses above the human therapeutic dose in rats. Additionally, in the male offspring delayed male reproductive maturation was observed, characterized by incomplete preputial separation, which affected male fertility at doses above the human therapeutic dose in rats [see Data]. In the U.S. general population, the estimated background risk of major birth defects or miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Animal Data In embryo-fetal development toxicity studies in rats and rabbits, embryo-lethality was noted at the highest doses (128- and 174-fold the human AUC24 at the human therapeutic dose for rats and rabbits, respectively). The no observed adverse effect level (NOAEL) for embryo-fetal development was 50 mg/kg/day in rats and 45 mg/kg/day in rabbits (62- and 16­ fold the human AUC24 at the human therapeutic dose for rats and rabbits, respectively). Fezolinetant showed no effects on fertility and early embryonic development in rats [see Nonclinical Toxicology (13.1)]. In the pre- and post-natal development study in rats, the NOAEL for maternal and fetal toxicity was 30 mg/kg/day (36­ fold the human AUC24 at the human therapeutic dose) based on delayed parturition and embryo-lethality at 100 mg/kg/day. The NOAEL for F1 generation development was determined to be 100 mg/kg/day for females (204-fold the human AUC24 at the human therapeutic dose) and 10 mg/kg/day for males (11-fold the human AUC24 at the human therapeutic dose). The F1 male showed delayed male reproductive maturation, characterized as incomplete balanopreputial separation at time of mating, at doses of greater than or equal to 30 mg/kg/day (36-fold the human AUC24 at the human therapeutic dose), which affected male fertility [see Nonclinical Toxicology (13.1)]. 8.2 Lactation Risk Summary There are no data on the presence of fezolinetant in human milk, the effects on the breastfed child, or the effects on milk production. It is not known if fezolinetant is present in human milk. Data Animal Data Following administration of radiolabeled fezolinetant to lactating rats, the radioactivity concentration in milk was higher than that in the plasma at all time points, indicating that fezolinetant-derived components transferred to the tissues in infant rats via breast milk. 5 Reference ID: 5497306 F 0 /,1/ (N'y' ,,,,CH, N~N _N/ H3C~- N,.,..S 8.4 Pediatric Use The efficacy and safety of VEOZAH in individuals less than 18 years of age have not been established. 8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical trials utilizing VEOZAH to determine whether those over 65 years of age differ from younger women in their response to VEOZAH. 8.6 Renal Impairment VEOZAH is contraindicated in individuals with severe (eGFR 15 to less than 30 mL/min/1.73 m2) renal impairment or end-stage renal disease (eGFR less than 15 mL/min/1.73 m2) [see Clinical Pharmacology (12.3)]. No dose adjustment of VEOZAH is recommended for individuals with mild (eGFR 60 to less than 90 mL/min/1.73 m2) or moderate (eGFR 30 to less than 60 mL/min/1.73 m2) renal impairment. 8.7 Hepatic Impairment Child-Pugh Class A or B hepatic impairment increased the exposure of VEOZAH [see Clinical Pharmacology (12.3)]. VEOZAH has not been studied in individuals with Child-Pugh Class C hepatic impairment. VEOZAH is contraindicated in individuals with cirrhosis [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Treatment of overdose consists of discontinuation of VEOZAH therapy with institution of appropriate symptomatic care. 11 DESCRIPTION VEOZAH (fezolinetant) is a small-molecule NK3 receptor antagonist. The chemical name of fezolinetant is (4-Fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6­ dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone having a molecular formula of C16H15FN6OS and a molecular weight of 358.39. The structural formula of fezolinetant is: Fezolinetant is a white powder. It is very slightly soluble in water (0.29 mg/mL). Each VEOZAH (fezolinetant) tablet for oral use contains 45 mg of fezolinetant and the following inactive ingredients: ferric oxide, hydroxypropyl cellulose, hypromellose, low-substituted hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide. 6 Reference ID: 5497306 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action VEOZAH is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center. Fezolinetant has high affinity for the NK3 receptor (Ki value of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than binding affinity to NK1 or NK2 receptors. 12.2 Pharmacodynamics Treatment with fezolinetant did not show any clear trends in sex hormones measured (follicle-stimulating hormone, testosterone, estrogen, and dehydroepiandrosterone sulfate) in menopausal women. Transient decrease of luteinizing hormone (LH) levels was observed at peak concentrations of fezolinetant. Cardiac Electrophysiology At a dose 20 times the maximum approved recommended dose, fezolinetant does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics In healthy women, fezolinetant Cmax and AUC increased proportionally over a dosage range from 20 to 60 mg once daily (0.44 to 1.33 times the approved recommended dosage). Steady-state plasma concentrations of fezolinetant were reached after two once daily doses, with minimal fezolinetant accumulation. Absorption The median (range) time to reach fezolinetant Cmax is 1.5 (1 to 4) hours in healthy women. Effect of Food No clinically significant differences in fezolinetant pharmacokinetics were observed following administration with a high- calorie, high-fat meal containing approximately 1000 calories (500-600 calories from fat, 250 calories from carbohydrates, and 150 calories from protein). Distribution The mean apparent volume of distribution (Vz/F) of fezolinetant is 189 L. The plasma protein binding of fezolinetant is 51%. The blood-to-plasma ratio is 0.9. Elimination The effective half-life (t1/2) of fezolinetant is 9.6 hours in women with vasomotor symptoms. The apparent clearance at steady-state of fezolinetant is 10.8 L/h. Metabolism Fezolinetant is primarily metabolized by CYP1A2 and to a lesser extent by CYP2C9 and CYP2C19. A major metabolite of fezolinetant, ES259564, was identified in plasma. ES259564 is approximately 20-fold less potent than the parent. The metabolite-to-parent ratio ranges from 0.7 to 1.8. Excretion Following oral administration of fezolinetant, 76.9% of the dose was excreted in urine (1.1% unchanged) and 14.7% in feces (0.1% unchanged). 7 Reference ID: 5497306 Specific Populations There were no substantive differences in the pharmacokinetics of VEOZAH based on race and body weight (93 to 278 pounds). Women with Renal Impairment Following single-dose administration of 30 mg fezolinetant, there was no effect on VEOZAH exposure (Cmax and AUC) in women with mild (eGFR 60 to less than 90 mL/min/1.73 m2) to severe (eGFR 15 to less than 30 mL/min/1.73 m2) renal impairment. The AUC of ES259564 (a major metabolite of fezolinetant) in women with moderate (eGFR 30 to less than 60 mL/min/1.73 m2) and severe (eGFR 15 to less than 30 mL/min/1.73 m2) renal impairment increased by approximately 75% and 380%, respectively. VEOZAH has not been studied in individuals with end-stage renal disease (eGFR less than 15 mL/min/1.73 m2). Women with Hepatic Impairment Following single-dose administration of 30 mg fezolinetant in women with mild Child-Pugh Class A cirrhosis, the mean Cmax increased by 23% and AUCinf increased by 56%, relative to women with normal hepatic function. In women with moderate Child-Pugh Class B cirrhosis, the mean Cmax of fezolinetant decreased by 15% and AUCinf increased by 96%. The Cmax of ES259564 decreased in both mild and moderate cirrhosis while AUCinf and AUClast increased less than 15%. VEOZAH has not been studied in individuals with severe Child-Pugh Class C cirrhosis. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong CYP1A2 Inhibitors: Fezolinetant Cmax increased by 80% and AUC increased by 840% following concomitant use with fluvoxamine (strong CYP1A2 inhibitor). Moderate CYP1A2 Inhibitors: Fezolinetant Cmax increased by 40% and AUC increased by 360% following concomitant use with mexiletine (moderate CYP1A2 inhibitor) 400 mg every 8 hours. Weak CYP1A2 Inhibitors: Fezolinetant Cmax increased by 30% and AUC increased by 100% following concomitant use with cimetidine (weak CYP1A2 inhibitor) 300 mg every 6 hours. No clinically significant differences in fezolinetant exposure were observed in smokers (moderate CYP1A2 inducer). In Vitro Studies Cytochrome P450 (CYP) Enzymes: Fezolinetant and ES259564 are not inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Fezolinetant and ES259564 are not inducers of CYP1A2, CYP2B6, and CYP3A4. Transporter Systems Fezolinetant is not a substrate nor an inhibitor of P-glycoprotein (P-gp). ES259564 is a substrate of P-gp, but not an inhibitor of P-gp. Both fezolinetant and ES259564 are not a substrate of BCRP, OATP1B1, and OATP1B3. In addition, ES259564 is not a substrate of OAT1, OAT3, OCT2, MATE1, and MATE2-K. 8 Reference ID: 5497306 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 2-year female rat carcinogenicity study and a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 186-fold and 47-fold the human AUC24 at the human therapeutic dose of 45 mg, respectively. Mutagenesis Fezolinetant showed no genotoxic potential by the bacterial reverse mutation test, chromosomal aberration test, or in vivo micronucleus test. Impairment of Fertility Fezolinetant had no effect on female fertility or early embryonic development up to 100 mg/kg/day in rats (143-fold the human AUC24 at the human therapeutic dose). In the pre- and post-natal development study in rats, the F1 male showed incomplete balanopreputial separation at doses greater than or equal to 30 mg/kg/day (36-fold the human AUC24 at the human therapeutic dose), which delayed male reproductive maturation and affected fertility. These effects were not observed following dosing at 10 mg/kg/day (11-fold the human AUC24 at the human therapeutic dose) [see Use in Specific Populations (8.1)]. 13.2 Animal Toxicology and/or Pharmacology Repeat dose toxicity studies were conducted in intact female rats and cynomolgus monkeys. In female rats, daily administration of fezolinetant for 26 weeks at doses equal to or greater than 30 mg/kg/day (56-fold the human AUC24 at the human therapeutic dose) showed uterine atrophy and epithelial mucification of the vagina and cervix. In female cynomolgus monkeys, daily administration for 39 weeks at doses equal to or greater than 10 mg/kg/day (19-fold the human AUC24 at the human therapeutic dose) showed reduced ovarian activity. 14 CLINICAL STUDIES 14.1 Effects on Vasomotor Symptoms in Postmenopausal Women The efficacy of VEOZAH for the treatment of moderate to severe vasomotor symptoms due to menopause was evaluated in the first 12-week, randomized, placebo-controlled, double-blind portion of each of two phase 3 clinical trials. In each of these two trials, after the first 12 weeks, women on placebo were then re-randomized to VEOZAH for a 40-week extension to evaluate safety for up to 52 weeks total exposure. In Trials 1 (NCT04003155) and 2 (NCT04003142), 1022 women (522 in Trial 1 and 500 in Trial 2) who had a minimum average of 7 moderate to severe vasomotor symptoms per day were randomized to one of two doses of fezolinetant (including the 45 mg dosage strength) or placebo. Randomization was stratified by smoking status. The mean age of the postmenopausal women was 54 years. Women self-identified as Caucasian (81%), African American (17%), Asian (1%), and Hispanic/Latina ethnicity (24%). The study population included menopausal women with one or more of the following: prior hysterectomy (32.1%), prior oophorectomy (21.6%), or prior hormone therapy use (19.9%). Those who were on prior hormone therapy underwent a wash-out period prior to trial participation. The co-primary efficacy endpoints for both trials were the mean change from baseline in moderate to severe vasomotor symptoms frequency and severity to Weeks 4 and 12. Data from each trial demonstrated statistically significant and clinically meaningful (≥ 2 hot flashes over 24 hours) reduction from baseline in the frequency of moderate to severe vasomotor symptoms for VEOZAH 45 mg compared to placebo at Weeks 4 and 12. Data from each trial also demonstrated a statistically significant reduction from baseline in the severity of moderate to severe vasomotor symptoms (over 24 hours) at Weeks 4 and 12 for VEOZAH 45 mg compared to placebo. 9 Reference ID: 5497306 Results of the co-primary endpoint for change from baseline to Weeks 4 and 12 in mean frequency of moderate to severe vasomotor symptoms over 24 hours from Trials 1 and 2 are shown in Table 2. Table 2: Mean Baseline and Change from Baseline to Weeks 4 and 12 for Mean Frequency of Moderate to Severe Vasomotor Symptoms over 24 Hours in Women Treated with VEOZAH in Trials 1 and 2 Parameter Trial 1 Trial 2 VEOZAH 45 mg (n=174) Placebo (n=175) VEOZAH 45 mg (n=167) Placebo (n=167) Baseline Mean (SD) 10.4 (3.92) 10.5 (3.79) 11.8 (8.26) 11.6 (5.02) Change from Baseline to Week 4 LS Mean (SE) Difference vs Placebo (95% CI) P-value -5.4 (0.30) -2.1 (-2.9, -1.3) < 0.0011 -3.3 (0.29) -- -­ -6.3 (0.33) -2.6 (-3.5, -1.6) < 0.0011 -3.7 (0.33) -- -­ Change from Baseline to Week 12 LS Mean (SE) Difference vs Placebo (95% CI) P-value -6.4 (0.31) -2.6 (-3.4, -1.7) < 0.0011 -3.9 (0.31) -- -­ -7.5 (0.39) -2.5 (-3.6, -1.5) < 0.0011 -5.0 (0.39) -- -­ 1. Statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment. LS Mean: Least Squares Mean estimated from a mixed model for repeated measures analysis of covariance; SD: Standard Deviation; SE: Standard Error. Results of the co-primary endpoint for change from baseline to Weeks 4 and 12 in mean severity of moderate to severe vasomotor symptoms over 24 hours from Trials 1 and 2 are shown in Table 3. Table 3: Mean Baseline and Change from Baseline to Weeks 4 and 12 for Mean Severity of Moderate to Severe Vasomotor Symptoms over 24 Hours in Women Treated with VEOZAH in Trials 1 and 2 Parameter Trial 1 Trial 2 VEOZAH 45 mg (n=174) Placebo (n=175) VEOZAH 45 mg (n=167) Placebo (n=167) Baseline Mean (SD) 2.4 (0.35) 2.4 (0.35) 2.4 (0.34) 2.4 (0.32) Change from Baseline to Week 4 LS Mean (SE) Difference vs Placebo (95% CI) P-value -0.5 (0.04) -0.2 (-0.3, -0.1) 0.0021 -0.3 (0.04) -- -­ -0.6 (0.05) -0.3 (-0.4, -0.2) < 0.0011 -0.3 (0.05) -- -­ Change from Baseline to Week 12 LS Mean (SE) Difference vs Placebo (95% CI) P-value -0.6 (0.05) -0.2 (-0.4, -0.1) 0.0071 -0.4 (0.05) -- -­ -0.8 (0.06) -0.3 (-0.5, -0.1) < 0.0011 -0.5 (0.06) -- -­ 1. Statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment. LS Mean: Least Squares Mean estimated from a mixed model for repeated measures analysis of covariance; SD: Standard Deviation; SE: Standard Error. 10 Reference ID: 5497306 14.2 Effects on Endometrium in Postmenopausal Women In the VEOZAH 45 mg dose group across Trials 1, 2, and 3, endometrial biopsy assessments identified one case of endometrial hyperplasia and one case of endometrial malignancy. The rate of these events in the VEOZAH 45 mg dose group was ≤ 1% with the upper bound of the one-sided 95% confidence limit being ≤ 4%. Table 4: Incidence of Endometrial Hyperplasia or Carcinoma after 12 Months of Treatment in Trials 1, 2, and 3 Final Diagnosis VEOZAH 45 mg (n=350) Placebo (n=186) Endometrial Hyperplasia and Carcinoma, n (%) One-sided upper limit of 95% CI - Simple hyperplasia without atypia - Endometrial adenocarcinoma 2 (0.6%) 1.8% 1 1 0 1.6% 0 0 Five cases of disordered proliferative endometrium were reported in women receiving VEOZAH 45 mg and four cases were reported in women receiving placebo across the three clinical trials. The EAIR was 1.4 per 100 person-years in VEOZAH 45 mg versus 2.0 per 100 person-years in the placebo group. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied VEOZAH (fezolinetant) 45 mg tablets are supplied as round, light red, film-coated tablets, debossed with the Astellas logo and ‘645’ on the same side. VEOZAH tablets are available in the following package sizes: • Bottles of 30 tablets with child resistant closure and desiccant, (NDC 0469-2660-30) • Bottles of 90 tablets with child resistant closure and desiccant, (NDC 0469-2660-90) 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F) with excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 11 Reference ID: 5497306 17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Patient Information). Evaluation of Hepatic Injury During Treatment with VEOZAH Inform patients that they will have to have a blood test to evaluate their liver function before beginning VEOZAH and while using VEOZAH monthly for the first 3 months, at 6 months, and 9 months after initialization of therapy. Advise patients to discontinue VEOZAH immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver abnormalities such as new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain [see Warnings and Precautions (5.1)]. Serious Adverse Reactions with VEOZAH Inform patients of possible serious adverse reactions of VEOZAH including hepatic transaminase elevation and liver injury [see Warnings and Precautions (5.1)]. Common Adverse Reactions with VEOZAH Inform patients of possible less serious but common adverse reactions of VEOZAH including abdominal pain, diarrhea, insomnia, back pain, and hot flush [see Adverse Reactions (6.1)]. Drug Interactions Advise patients to report their use of any other prescription or nonprescription medications or dietary supplements [see Drug Interactions (7.1)]. Distributed by: Astellas Pharma US, Inc. Northbrook, IL 60062 © 2024 Astellas Pharma US, Inc. or its affiliates 432095-VEO-USA 12 Reference ID: 5497306 PATIENT INFORMATION VEOZAH® (vee-O-zah) (fezolinetant) tablets, for oral use What is the most important information I should know about VEOZAH? VEOZAH can cause serious side effects, including: • Liver Problems. Your healthcare provider will do a blood test to check your liver before you start taking VEOZAH. Your healthcare provider will also do this blood test monthly for the first 3 months, at month 6, and month 9 after you start taking VEOZAH or if you have signs or symptoms that suggest liver problems. If your liver blood test values are elevated, your healthcare provider may advise you to stop treatment or request additional liver blood tests. Stop VEOZAH right away and call your healthcare provider if you have the following signs or symptoms of liver problems: • feeling more tired than you do usually • yellowing of the eyes or skin (jaundice) • decreased appetite • pale feces • nausea • dark urine • vomiting • pain in the stomach (abdomen) • itching See “What are the possible side effects of VEOZAH?” for more information about side effects. What is VEOZAH? VEOZAH is a prescription medicine used to reduce moderate to severe vasomotor symptoms due to menopause. VEOZAH is not a hormone. Vasomotor symptoms are the feelings of warmth in the face, neck, and chest, or sudden intense feelings of heat and sweating (“hot flashes” or “hot flushes”). Do not use VEOZAH if you: • have cirrhosis. • have severe kidney problems or kidney failure. • are taking certain medicines called CYP1A2 inhibitors. Ask your healthcare provider if you are not sure. Before you use VEOZAH, tell your healthcare provider about all of your medical conditions, including if you: • have liver disease or liver problems. • have kidney problems. • have any medical conditions that may become worse while you are using VEOZAH. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VEOZAH may affect the way other medicines work, and other medicines may affect how VEOZAH works. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take VEOZAH? • Take VEOZAH exactly as your healthcare provider tells you to take it. • Take 1 VEOZAH tablet by mouth with or without food at about the same time each day. • Swallow the VEOZAH tablet whole with liquid. Do not cut, crush, or chew the tablet. • If you miss a dose of VEOZAH, take the missed dose as soon as possible on the same day, with at least 12 hours before the next scheduled dose. Return to your normal schedule the following day. What are the possible side effects of VEOZAH? VEOZAH can cause serious side effects, including: • See “What is the most important information I should know about VEOZAH?” Common side effects of VEOZAH include: • stomach (abdominal) pain • diarrhea • difficulty sleeping (insomnia) • back pain • hot flashes or hot flushes Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of VEOZAH. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. 1 Reference ID: 5497306 How should I store VEOZAH? • Store VEOZAH at room temperature between 68°F to 77°F (20°C to 25°C). • Dispose of the unused medicine through a take-back option, if available. See www.fda.gov/drugdisposal for more information. • Keep VEOZAH and all medicines out of the reach of children. General information about the safe and effective use of VEOZAH. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use VEOZAH for a condition for which it was not prescribed. Do not give VEOZAH to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about VEOZAH. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about VEOZAH that is written for healthcare professionals. What are the ingredients in VEOZAH? Active ingredient: fezolinetant Inactive ingredients: ferric oxide, hydroxypropyl cellulose, hypromellose, low-substituted hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide Distributed by: Astellas Pharma US, Inc. Northbrook, IL 60062 © 2024 Astellas Pharma US, Inc. or its affiliates 432095-VEO-USA For more information, go to www.VEOZAH.com or call 1-800-727-7003. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 12/2024 2 Reference ID: 5497306
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2025-02-12T15:47:46.683854
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DEPO-SUBQ PROVERA 104® safely and effectively. See full prescribing information for DEPO-SUBQ PROVERA 104. DEPO-SUBQ PROVERA 104 (medroxyprogesterone acetate) injectable suspension, for subcutaneous use Initial U.S. Approval: 1959 WARNING: LOSS OF BONE MINERAL DENSITY See full prescribing information for complete boxed warning. • Women who use depo-subQ provera 104 may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. (5.1) • It is unknown if use of depo-subQ provera 104 during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. (5.1) • Depo-subQ provera 104 is not recommended as a long-term (i.e., longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate. (1, 5.1) ---------------------------RECENT MAJOR CHANGES --------------------------­ Warnings and Precautions, Injection Site Reactions (5.10) 12/2024 --------------------------- INDICATIONS AND USAGE---------------------------­ Depo-subQ provera 104 is a progestin that is indicated in females of reproductive age for: • Prevention of pregnancy. (1) • Management of endometriosis-associated pain. (1) Limitations of Use: Use of depo-subQ provera 104 is not recommended as a long-term (i.e., longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate. (1, 5.1) -----------------------DOSAGE AND ADMINISTRATION ----------------------­ • Only for healthcare professional administration. (2.1) • Prior to first injection, confirm the patient is not pregnant. (2.1) • Administer 104 mg of depo-subQ provera 104 by subcutaneous injection into the anterior thigh or abdomen, once every 12 to 14 weeks. (2.1) • See Full Prescribing Information for recommendations on switching from another contraceptive method to depo-subQ provera 104. (2.2) • See Full Prescribing Information for important preparation and administration instructions. (2.3) --------------------- DOSAGE FORMS AND STRENGTHS---------------------­ Injectable suspension: 104 mg/0.65 mL (3) ------------------------------ CONTRAINDICATIONS -----------------------------­ • Active thrombophlebitis, or current or history of thromboembolic disorders, or cerebral vascular disease. (4) • Known, suspected, or past malignancy of the breast. (4) • Significant liver disease. (4) • Known hypersensitivity to medroxyprogesterone acetate or any of the ingredients of depo-subQ provera 104. (4) • Undiagnosed vaginal bleeding. (4) ----------------------- WARNINGS AND PRECAUTIONS ----------------------­ • Thromboembolic disorders: Discontinue depo-subQ provera 104 in patients who develop arterial or venous thrombosis. (5.2) • Breast cancer risks: Monitor women with a family history of breast cancer or a significant risk of breast cancer carefully. (5.3) • Ectopic pregnancy: Consider ectopic pregnancy if a woman becomes pregnant or complains of severe abdominal pain. (5.4) • Anaphylaxis: Provide emergency medical treatment. (5.5) • Injection site reactions (e.g., persistent atrophy, dimpling/indentation, lump/nodule and discoloration) have been reported. (5.10) • Diabetics may be at greater risk of hyperglycemia. (5.12) • Jaundice and elevated transaminase: Discontinue depo-subQ provera 104 if jaundice or elevated transaminase levels develop. (5.13) ------------------------------ ADVERSE REACTIONS -----------------------------­ Most common adverse reactions (incidence >5%) are dysfunctional uterine bleeding, headache, increased weight, amenorrhea, and injection site reactions. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS------------------------------­ Strong CYP3A inhibitors and inducers: Avoid concomitant use. (7) ----------------------- USE IN SPECIFIC POPULATIONS ----------------------­ • Pregnancy: Discontinue if pregnancy occurs. (8.1) • Lactation: Detectable amounts of drug have been identified in the milk of mothers receiving depot-medroxyprogesterone acetate. (8.2) • Pediatric patients (after menarche): Bone loss is a particular concern. (8.4) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 12/2024 1 Reference ID: 5495121 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: LOSS OF BONE MINERAL DENSITY 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions 2.2 Switching from Another Method of Contraception 2.3 Preparation and Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Loss of Bone Mineral Density 5.2 Arterial and Venous Thromboembolic Disorders 5.3 Cancer Risks 5.4 Ectopic Pregnancy 5.5 Anaphylaxis 5.6 Fluid Retention 5.7 Weight Gain 5.8 Delayed Return of Ovulation or Fertility 5.9 Depression 5.10 Injection Site Reactions 5.11 Bleeding Irregularities 5.12 Risk of Hyperglycemia in Patients with Diabetes 5.13 Jaundice and Elevated Transaminase 5.14 Protection Against Sexually Transmitted Infections 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on depo-SubQ provera 104 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Contraception Studies 14.2 Endometriosis Studies 14.3 Bone Mineral Density in Women Treated with Depo-medroxyprogesterone acetate for Contraception 14.4 Bone Mineral Density Changes in Adolescent Females (12 to 18 years of age) Treated with DMPA-IM 14.5 Bone Fracture Incidence in Women Treated with Depo-medroxyprogesterone acetate for Contraception 14.6 Bone Mineral Density in Women Treated with depo-SubQ provera 104 for Endometriosis 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 2 Reference ID: 5495121 FULL PRESCRIBING INFORMATION WARNING: LOSS OF BONE MINERAL DENSITY • Women who use depo-subQ provera 104 may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible [see Warnings and Precautions (5.1)]. • It is unknown if use of depo-subQ provera 104 during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life [see Warnings and Precautions (5.1)]. • Depo-subQ provera 104 is not recommended as a long-term (i.e., longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate [see Indications and Usage (1) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE Depo-subQ provera 104 is indicated in females of reproductive age for: • Prevention of pregnancy and • Management of endometriosis-associated pain. Limitations of Use: The use of depo-subQ provera 104 is not recommended as a long-term (i.e., longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)]. 2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Instructions Depo-subQ provera 104 is only for subcutaneous administration and is only to be administered by a healthcare professional. Use for longer than 2 years is not recommended (unless other birth control methods or medical therapies for endometriosis-associated pain are considered inadequate) due to the impact of long-term depo-subQ provera 104 treatment on bone mineral density (BMD) [see Warnings and Precautions (5.1)]. Prior to the first injection confirm that the patient is not pregnant. For women who are sexually active and who have regular menses, administer the first injection only during the first 5 days of a normal menstrual period. For women who are breast-feeding, administer the first injection during or after the sixth post-partum week. The recommended dosage of depo-subQ provera 104 is 104 mg given subcutaneously every 12 to 14 weeks. If more than 14 weeks elapse between injections, confirm that the patient is not pregnant before the next injection. Instruct the patient that if they are unable to receive an injection within 12-14 weeks, another contraceptive method should be used until the next depo-subQ provera 104 injection. The dosage does not need to be adjusted for body weight. Inject the entire contents of the pre-filled syringe using strict aseptic technique into the upper anterior thigh or abdomen, rotating the sites with every injection [see Dosage and Administration (2.3)]. 2.2 Switching from Another Method of Contraception When switching from another contraceptive method to depo-subQ provera 104, administer depo-subQ provera 104 in a manner that ensures continuous contraceptive coverage. Follow the respective recommendations when switching from the contraceptive methods listed below: • Combined hormonal contraceptives: administer the first injection of depo-subQ provera 104 within 7 days after the last day of using the combined hormonal contraceptive method (i.e., within 7 days after taking the last active pill). 3 Reference ID: 5495121 Prefilled syringe Safety shield (needle guard} Needle= 3/8' length Needle with safety shield • An implant: administer the first injection of depo-subQ provera 104 on the day of implant removal. • A contraceptive vaginal ring or transdermal system: administer the first injection of depo-subQ provera 104 on the day the patient would have inserted the next ring or applied the next transdermal system. • An Intrauterine Device (IUD) or Intrauterine System (IUS): administer the first injection of depo-subQ provera 104 on the day of IUD/IUS removal. If the IUD/IUS is not removed on the first day of the patient’s menstrual cycle, instruct patients to use a non-hormonal back-up method of birth control for the first 7 days after administration of depo-subQ provera 104. • Depot medroxyprogesterone acetate injectable suspension for intramuscular use (DMPA-IM): inject depo-subQ provera 104 12 to 14 weeks after the last dose of DMPA-IM. 2.3 Preparation and Administration Instructions Prior to injection: • Ensure all the components in Figure A are available and that depo-subQ provera 104 is at room temperature. • Shake the pre-filled syringe vigorously prior to injection to ensure appropriate viscosity of the suspension. • Inspect depo-subQ provera 104 visually for particulate matter and discoloration. Figure A. Components in the Package 4 Reference ID: 5495121 C) ,, oYo Step 1: Select & Prepare the Injection Area • Select a preferred injection area, i.e., the left or right upper thigh or the abdomen (see shaded areas, Figure B). • Avoid selection of bony areas and the umbilicus. • Clean the skin in the injection area you have chosen with a clean cotton pad or clean paper tissue. • Rotate the injection site by injecting into a different puncture site than used for the previous injection. Figure B. Preferred injection areas: Left or right upper thigh or abdomen Step 2: Prepare Syringe • Carefully remove the needle and syringe from the packaging. • Hold the syringe firmly by the barrel, with the barrel pointing upward. • Shake the syringe vigorously for at least 1 minute to mix thoroughly (Figure C). Figure C. Shake vigorously for 1 minute • While holding the syringe barrel firmly, remove the protective cap from the tip of the syringe barrel by unscrewing it (Figure D). Figure D. 5 Reference ID: 5495121 • While holding the syringe barrel firmly, attach the needle to the barrel of the syringe firmly by pushing the plastic needle cover down fully and firmly with a slight twisting movement (Figure E). Figure E. • Move the safety shield away from the needle and toward the syringe barrel. The safety shield will remain in an open 45- to 90­ degree position (Figure F). Figure F. • While holding the syringe barrel firmly, remove the plastic needle cover from the needle without twisting, ensuring the needle is still firmly attached to the syringe (Figure G). Figure G. • While holding the syringe with the needle pointing upward, gently push in the plunger until the liquid is up to the top of the syringe (Figure H). There should be no air within the barrel. Figure H. 6 Reference ID: 5495121 Step 3: Injecting depo-Sub Q provera 104 • Gently grasp and squeeze a large area of skin in the chosen injection area between the thumb and forefinger, pulling it away from the body (Figure I). • Insert the needle at a 45-degree angle so that most of the needle is in the fatty tissue. • The plastic hub of the needle should be nearly or almost touching the skin. Figure I. Inject slowly until the syringe is empty (Figure J). • This should take about 5 to 7 seconds. • It is important that the entire dose is given. Figure J. Inject slowly (5-7 seconds) Step 4: Remove the Needle and Activate the Safety Shield • After completing the injection, remove the needle from the skin and activate the safety shield as follows: o While positioning the shield about 40°- 45°, and with a firm quick motion, press down against a flat surface until a click is heard or felt (Figure K). o If uncertain that the safety shield is fully engaged, repeat this step. Figure K. 7 Reference ID: 5495121 • Use a clean cotton pad to press lightly on the injection area for a few seconds (Figure L). • Do not rub the area. Figure L. 3 DOSAGE FORMS AND STRENGTHS Injectable suspension (104 mg/0.65 mL) in a single-dose pre-filled syringe, packaged with a 26-gauge × 3/8-inch Terumo SurGuard® needle. 4 CONTRAINDICATIONS The use of depo-subQ provera 104 is contraindicated in the following conditions: • Active thrombophlebitis, or current or history of thromboembolic disorders, or cerebral vascular disease [see Warnings and Precautions (5.2)]. • Known, suspected, or past malignancy of the breast [see Warnings and Precautions (5.3)]. • Significant liver disease [see Warnings and Precautions (5.13)]. • Known hypersensitivity to medroxyprogesterone acetate or any of the ingredients in depo-subQ provera 104 [see Warnings and Precautions (5.5)]. • Undiagnosed vaginal bleeding [see Warnings and Precautions (5.11)]. 5 WARNINGS AND PRECAUTIONS 5.1 Loss of Bone Mineral Density Use of depo-subQ provera 104 reduces serum estrogen levels and is associated with significant loss of bone mineral density (BMD). This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if use of depo-subQ provera 104 by younger women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. A study to assess the reversibility of loss of BMD in adolescents was conducted with DMPA-IM. After discontinuing DMPA-IM in these adolescents, mean BMD loss at the total hip and femoral neck did not fully recover by 5 years (60 months) post-treatment in the sub-group of adolescents who were treated for more than 2 years [see Clinical Studies (14.4)]. Similarly, in adults, there was only partial recovery of mean BMD at the total hip, femoral neck, and lumbar spine towards baseline by 2 years post-treatment [see Clinical Studies (14.3)]. The use of depo-subQ provera 104 is not recommended as a long-term (i.e., longer than 2 years) birth control method or medical therapy for endometriosis-associated pain unless other options are considered inadequate. BMD should be evaluated when a woman needs to continue to use depo-subQ provera 104 long-term. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. Other birth control methods or therapies for endometriosis-associated pain should be considered in the risk/benefit analysis for the use of depo-subQ provera 104 in women with osteoporosis risk factors. Depo-subQ provera 104 can pose 8 Reference ID: 5495121 an additional risk in patients with risk factors for osteoporosis (e.g., metabolic bone disease, chronic alcohol and/or tobacco use, anorexia nervosa, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids). 5.2 Arterial and Venous Thromboembolic Disorders There have been reports of serious arterial and venous thrombotic events in women treated with DMPA-IM. Women with a history of thromboembolic disorders were not studied in clinical trials of depo-subQ provera 104. Although no causal relationship between the use of depo-subQ provera 104 and thrombotic events has been clearly established, patients who develop arterial or venous thrombosis while taking depo-subQ provera 104 should discontinue treatment. Do not re-administer depo-subQ provera 104 pending examination if there is a sudden onset of a suspected vascular ocular event (e.g., partial or complete loss of vision, proptosis, or diplopia) or migraine. Do not re-administer depo-subQ provera 104 if examination reveals papilledema or retinal vascular lesions. 5.3 Cancer Risks Breast Cancer The use of hormonal contraceptives, including depo sub-Q provera 104, is contraindicated in women who have or have had breast cancer because breast cancer may be sensitive to hormones [see Contraindications (4)]. Women who have a family history of breast cancer or a significant risk of breast cancer should be monitored. The results of five large case-control studies assessing the association between DMPA-IM use and the risk of breast cancer are summarized in Figure M. Three of the studies suggest a slightly increased risk of breast cancer in the overall population of users; these increased risks were statistically significant in one study. One US study1 evaluated the timing and duration of use and found a statistically significant increased risk of breast cancer in recent DMPA-IM users (defined as last use within the past five years) who used DMPA-IM for 12 months or longer; this is consistent with results of a previous study2. 9 Reference ID: 5495121 Lee et al. (1987) ■ 2.6 [ 1.4 , 4.7 ] Paul et al. (1989) 1.0 [ o.8 , 1.3 l WHO (1991 ) ■ I 1.2 [ 1.0 , 1.5 l Shapiro et al. (2000) I ■ o.9 [ o.7 , 1.2 l Li et al. (2012): All Subjects I ■ 1.2 [ o.9 , 1.6 l DMPA use>= 12 mos. ■ 2.2 [ 1.2 , 4.2 l 0.6 1.0 1.6 2.7 4.5 7.4 Odds Ratio (ratio > 1 indicates increased risk for DMPA) Figure M. Risk Estimates of Breast Cancer in DMPA-IM Users Odds Ratio [95% confidence interval (CI)] displayed on logarithmic scale Odds ratio estimates were adjusted for the following covariates: Lee et al. (1987): age, parity, and socioeconomic status. Paul et al. (1989): age, parity, ethnic group, and year of interview. WHO (1991): age, center, and age at first live birth. Shapiro et al. (2000): age, ethnic group, socioeconomic status, and any combined estrogen/progestogen oral contraceptive use. Li et al. (2012): age, year, BMI, duration of OC use, number of full-term pregnancies, family history of breast cancer, and history of screening mammography. Based on the published SEER-18 2015 incidence rate (age-adjusted to the 2000 US Standard Population) of breast cancer for US women, all races, age 20 to 49 years, a doubling of risk would increase the incidence of breast cancer in women who use DMPA-IM from about 73 to about 146 cases per 100,000 women. Other Cancers The relative rate of invasive squamous-cell cervical cancer in women who ever used DMPA-IM was estimated to be 1.11 (95% CI: 0.96 to 1.29). No trends in risk with duration of use or times since initial or most recent exposure were observed. Long-term, case-controlled surveillance of users of DMPA-IM found no overall increased risk of ovarian or liver cancer. 5.4 Ectopic Pregnancy Healthcare professionals should be alert to the possibility of an ectopic pregnancy among women using depo-subQ provera 104 who become pregnant or complain of severe abdominal pain. 10 Reference ID: 5495121 5.5 Anaphylaxis Serious anaphylactic reactions have been reported in women using depo-subQ provera 104. If an anaphylactic reaction occurs, appropriate emergency medical treatment should be administered. 5.6 Fluid Retention Because progestational drugs including depo-subQ provera 104 may cause fluid retention, monitor patients with conditions that might be affected by fluid retention. 5.7 Weight Gain Weight gain is a common occurrence in women using depo-subQ provera 104. In three large clinical trials using depo-subQ provera 104, the mean weight gain was 3.5 lb (1.6 kg) in the first year of use. In a small, two-year study comparing depo-subQ provera 104 to DMPA-IM, the mean weight gain observed for women using depo-subQ provera 104 [7.5 lb (3.4 kg)] was similar to the mean weight gain for women using DMPA-IM [7.6 lb (3.5 kg)]. Although there are no data related to weight gain beyond 2 years for depo-subQ provera 104, the data on DMPA-IM may be relevant. In a clinical study, after five years, 41 women using Depo-Provera CI (150 mg) had a mean weight gain of 11.2 lb (5.1 kg), while 114 women using non-hormonal contraception had a mean weight gain of 6.4 lb (2.9 kg). 5.8 Delayed Return of Ovulation or Fertility Return to ovulation is likely to be delayed after stopping depo-subQ provera 104, as demonstrated in a study of 15 women who received multiple doses of depo-subQ provera 104: • Median time to ovulation was 10 months after the last injection. • Earliest return to ovulation was 6 months after the last injection. • 12 women (80%) ovulated within 1 year of the last injection. However, ovulation has occurred as early as 14 weeks after a single dose of depo-subQ provera 104; therefore, administer the next depo-subQ provera 104 12 to 14 weeks after the last injection. Return to fertility also is likely to be delayed after stopping therapy. Among 28 women using depo-subQ provera 104 for contraception who stopped treatment to become pregnant, 7 women were lost to follow-up. One woman became pregnant within one year of her last injection and another woman became pregnant 443 days after her last injection. The remaining 19 women had not become pregnant; it is not known if these 19 women were still attempting to become pregnant or if they had started a new contraceptive method. 5.9 Depression Depression (3% of depo-subQ provera 104-treated patients) and other mood disorders have been reported in clinical trials of depo-subQ provera 104 [see Adverse Reactions (6.1)]. Patients with a history of depression or who are on treatment for depression may be at increased risk for depression recurrence or exacerbation and for associated mood disorders while receiving depo-subQ provera 104. Therefore, patients should be monitored for symptoms of depression and mood changes. 5.10 Injection Site Reactions In five clinical studies of depo-subQ provera 104 involving 2325 women (282 treated for up to 6 months, 1780 treated for up to 1 year, and 263 women treated for up to 2 years), 5% of women reported injection site reactions (such as pain/tenderness, nodule/lump, lipodystrophy, discoloration), and 1% had persistent atrophy/indentation/dimpling [see Adverse Reactions (6.1)]. These injection site reactions have also been reported in post-marketing experience. 5.11 Bleeding Irregularities Most women using depo-subQ provera 104 experienced changes in menstrual bleeding patterns, such as amenorrhea, irregular unpredictable spotting or bleeding, prolonged spotting or bleeding, or heavy bleeding [see Adverse Reactions (6.1)]. Fewer women experienced irregular bleeding and more experienced amenorrhea with longer term use of depo-subQ provera 104, consistent with expected endometrial thinning effects. 11 Reference ID: 5495121 6 In three contraception trials, 39% of 2053 depo-subQ provera 104-treated women experienced amenorrhea during Month 6, and 57% experienced amenorrhea during Month 12. In two endometriosis trials using depo-subQ provera 104, 24% of 289 women experienced amenorrhea during Month 6 [see Adverse Reactions (6.1)]. If abnormal bleeding is persistent or severe, evaluate the patient for underlying pathology or pregnancy. 5.12 Risk of Hyperglycemia in Patients with Diabetes Some patients receiving progestins may exhibit a decrease in glucose tolerance; therefore, patients with diabetes may be at greater risk of hyperglycemia. 5.13 Jaundice and Elevated Transaminase Discontinue depo-subQ provera 104 if jaundice or elevated transaminase levels develop. Depo-subQ provera 104 may be resumed after both the jaundice and elevated transaminase levels resolve, and the healthcare professional determines that depo-subQ provera 104 did not cause the abnormalities. 5.14 Protection Against Sexually Transmitted Infections Patients should be counseled that this product does not protect against HIV infection (including AIDS) and other sexually transmitted infections. ADVERSE REACTIONS The following important adverse reactions are described in more detail in other sections of the prescribing information: • Loss of bone mineral density [see Warnings and Precautions (5.1)] • Arterial and venous thromboembolic disorders [see Warnings and Precautions (5.2)] • Anaphylaxis [see Warnings and Precautions (5.5)] • Fluid retention [see Warnings and Precautions (5.6)] • Delayed return of ovulation or fertility [see Warnings and Precautions (5.8)] • Depression [see Warnings and Precautions (5.9)] • Injection site reactions [see Warnings and Precautions (5.10)] • Bleeding irregularities [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Clinical trials are conducted under widely varying conditions, therefore adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to depo-subQ provera 104 in five clinical trials involving 2325 women including 2043 women who received treatment for contraception (1780 treated up to 1 year and 263 treated for up to 2 years) and 282 women for endometriosis for up to 6 months. In these pooled trials, 9% of women discontinued treatment due to an adverse reaction and the most common reason for discontinuation was dysfunctional uterine bleeding (3%). Adverse Reactions in the Contraception Adult Studies Table 1 presents frequently reported adverse reactions (>1%) in the contraception pooled studies. In these studies, the most frequently reported adverse reactions (>5%) were dysfunctional uterine bleeding (e.g., irregular, increased, decreased, or spotting), headache, increased weight, amenorrhea, and injection site reactions (e.g., pain/tenderness, nodule/lump, persistent atrophy/indentation/dimpling or lipodystrophy). The frequency reported is based on the all-causality incidence in the pooled results of the three contraception studies. Closely related “Adverse Reaction” terms were grouped but individual patients reporting two or more grouped events were only counted once. 12 Reference ID: 5495121 - - ... ~ ... - ... ... ... ... ... ... - ~ ~ Table 1. Frequently Reported Adverse Reactions in the Contraception Studies (>1%) Adverse Reaction Frequency Dysfunctional uterine bleeding (irregular, increase, decrease, spotting) 18% Headache 9% Increased weight (see below) 7% Amenorrhea 6% Injection site reactions (such as pain/tenderness, nodule/lump, persistent atrophy/indentation/dimpling, lipodystrophy, discoloration) 6% Vaginitis, including candidiasis and bacterial 5% Abdominal pain 4% Urinary tract infections 4% Acne 4% Depression 3% Decreased libido 3% Nausea 3% Back pain 3% Breast pain/tenderness 2% Fatigue 2% Anxiety 1% Irritability 1% Dizziness 1% Dysfunctional Uterine Bleeding The extent of bleeding and spotting in the three contraception trials is presented in Figure N; data from the endometriosis trials are presented in Figure O [see Warnings and Precautions (5.1)]. Figure N. Mean Number of Bleeding or Spotting Days in the Subgroup of Women with Bleeding or Spotting Among Women Treated with depo-subQ provera 104 in Contraception Studies 0 5 10 15 20 25 30 1 N:1758 2 1439 3 1353 4 1053 5 1022 6 1030 7 724 8 761 9 734 10 537 11 580 12 554 Month Mean (25th, 75th Percentiles) Number of Days Bleeding and/or Spotting N=Number of subjects with bleeding or spotting during indicated month. 13 Reference ID: 5495121 _._ ~- Figure O. Mean Number of Bleeding or Spotting Days in the Subgroup of Women with Bleeding or Spotting Among Women Treated with depo-subQ provera 104 in Endometriosis Studies 0 5 10 15 20 25 30 1 N:226 2 199 3 190 4 158 5 156 6 131 Month Mean (25th, 75th Percentiles) Number of Days Bleeding and/or Spotting N=Number of subjects with bleeding or spotting during indicated month. Weight Gain In three large clinical trials, the mean weight gain in depo-subQ provera 104 treated patients was 3.5 lb (1.6 kg) in the first year of use. Half (50%) of women remained within 4.9 lb (2.2 kg) of their initial body weight; 12% of women lost more than 4.9 lb (2.2 kg), and 38% of women gained more than 5.1 lb (2.3 kg). In a small, 2-year study comparing depo-subQ provera 104 to DMPA-IM, the mean weight gain observed for women using depo-subQ provera 104 [7.5 lb (3.4 kg)] was similar to the mean weight gain for women using DMPA-IM [7.7 lb (3.5 kg)]. Other Adverse Reactions Observed in Contraception Clinical Trials with depo-subQ provera 104 Other adverse reactions occurring at an incidence of <1% in women who received depo-subQ provera 104 were as follows: • Neoplasms benign, malignant and unspecified (including cysts and polyps): breast lump • Blood and lymphatic system disorders: anemia • Immune system disorders: drug hypersensitivity • Metabolism and nutrition disorders: weight decreased, fluid retention • Nervous system disorders: facial palsy, syncope, paresthesia, somnolence • Cardiac disorders: tachycardia • Vascular disorders: hot flushes • Respiratory, thoracic and mediastinal disorders: asthma, dyspnea • Gastrointestinal disorders: diarrhea, abdominal distension • Skin and subcutaneous tissue disorders: urticaria, pruritus, dry skin • Reproductive system and breast disorders: dysmenorrhea, galactorrhea, dyspareunia • General disorders and administration site conditions: chest pain Adverse Reactions in the Endometriosis Adult Studies The safety profile of depo-subQ provera 104 in endometriosis clinical trials was similar to the safety profile of depo-subQ provera 104 in the contraception studies with the exception of the following adverse reactions which were more frequently reported in patients with endometriosis: abdominal pain, diarrhea, nausea, and back pain. 14 Reference ID: 5495121 In endometriosis studies, subjects recorded daily the occurrence and severity of hot flushes. Of the depo-subQ provera 104 users, 29% reported experiencing moderate or severe hot flushes at baseline, 36% at Month 3, and 27% at Month 6. Of the leuprolide users, 33% reported experiencing moderate or severe hot flushes at baseline, 74% at Month 3, and 69% at Month 6. Adverse Reactions in the Adolescent Contraception Study Depo-sub-Q provera 104 and DMPA-IM clinical trials reported similar safety profiles in adult study populations (see Table 1 above). Accordingly, a similar safety profile is expected for adolescents receiving depo-subQ provera 104 as for adolescents receiving DMPA-IM. The safety profile of DMPA-IM for prevention of pregnancy in adolescents was observed to be generally similar to the safety profile of adult women using DMPA-IM for prevention of pregnancy, with the exception of the following adverse reactions which were reported more frequently by adolescents: abdominal pain, diarrhea, back pain, weight increased, depression, headache, and dysmenorrhea. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of DMPA-IM. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: • Immune system disorders: anaphylactic reaction, anaphylactoid reaction, angioedema • Vascular disorders: pulmonary embolism, deep vein thrombosis, thrombophlebitis • Musculoskeletal and connective tissue disorders: osteoporosis (including osteoporotic fractures) • Reproductive system and breast disorders: prolonged anovulation, unexpected pregnancy, uterine hyperplasia • Respiratory, thoracic and mediastinal disorders: hoarseness • Skin and subcutaneous tissue disorders: increased body odor • Gastrointestinal disorders: gastrointestinal disturbances • General disorders and administration site conditions: axillary swelling, chills, thirst 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on depo-SubQ provera 104 Moderate or Strong CYP3A Inducers Concomitant use with moderate or strong CYP3A inducers may decrease concentrations of medroxyprogesterone acetate which may reduce depo-subQ provera 104 efficacy. This effect is based upon the primary metabolism of medroxyprogesterone acetate by CYP3A and was not confirmed by a clinical study. Avoid coadministration of depo-subQ provera 104 with moderate or strong CYP3A inducers. Some examples of moderate CYP3A inducers are bosentan, efavirenz, etravirine, and modafinil. Some examples of strong CYP3A inducers are rifampin, carbamazepine, phenytoin, phenobarbital, mitotane, and St. John’s wort (the CYP3A4 induction effect of St. John’s wort varies widely and is preparation dependent). These examples are a guide and do not represent a comprehensive list of all possible drugs that may fit these categories. The use of CYP3A inducers may require using a back-up or alternate contraceptive method. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, depo-subQ provera 104 should be discontinued during pregnancy. 15 Reference ID: 5495121 Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to progestins before conception or during early pregnancy. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 8.2 Lactation Risk Summary Although medroxyprogesterone acetate is detectable in the milk of mothers receiving DMPA-IM, milk composition, quality, and amount do not appear to be adversely affected. Effects on milk production and lactation initiation/duration remain unclear when administered before 6 weeks after delivery, therefore, in mothers who exclusively breastfeed, initiate depo-subQ provera 104 during or after the sixth post-partum week [see Dosage and Administration (2.1)]. No adverse effects in breastfed infants would be expected with maternal use of progestins. Neonates and infants exposed to medroxyprogesterone acetate from breast milk have been studied and no adverse effects have been noted. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for depo-subQ provera 104 and any potential adverse effects on the breastfed child from depo-subQ provera 104 or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Depo-subQ provera 104 is indicated for the prevention of pregnancy and would therefore be expected to impair female fertility until cessation of treatment. Women may experience a delay in return to ovulation and fertility (conception) following discontinuation of depo-subQ provera 104 [see Warnings and Precautions (5.8)]. 8.4 Pediatric Use Depo-subQ provera 104 is indicated for the prevention of pregnancy and management of endometriosis-associated pain in females of reproductive age. Efficacy is expected to be the same for post-menarchal females under the age of 17 as for users 17 years and older. Use of depo-subQ provera 104 is associated with significant loss of bone mineral density (BMD). This loss of BMD is of particular concern during adolescence, a critical period of bone accretion. It is unknown if use of depo-subQ provera 104 by female adolescents will reduce peak bone mass and increase the risk for osteoporotic fractures in later life. In a study of adolescent females (12-18 years of age) receiving DMPA-IM for contraception, mean BMD 2 years after starting DMPA-IM decreased 1.9% (spine), 4.3% (total hip), and 4.2% (femoral neck). In those adolescents who used DMPA-IM for more than 2 years, mean BMD at total hip and femoral neck did not return to baseline within 5 years. Depo-subQ provera 104 is not indicated before menarche. 8.5 Geriatric Use Depo-subQ provera 104 is not indicated in post-menopausal women. 11 DESCRIPTION Depo-subQ provera 104 contains medroxyprogesterone acetate (MPA), a derivative of progesterone, as its active ingredient. MPA is a white to off-white, odorless crystalline powder that is stable in air and that melts between 205ºC and 209ºC. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water. 16 Reference ID: 5495121 The chemical name for MPA is 17-hydroxy-6α-methylpregn-4-ene-3,20-dione 17-acetate. The structural formula is as follows: H3C O CH3 O O O CH3 CH3 CH3 Depo-subQ provera 104 for subcutaneous use is available in pre-filled syringes, each containing 0.65 mL (104 mg) of sterile medroxyprogesterone acetate injectable suspension. Each 0.65 mL contains the following inactive ingredients: Methylparaben 1.040 mg Propylparaben 0.098 mg Sodium Chloride 5.200 mg Polyethylene Glycol 18.688 mg Polysorbate 80 1.950 mg Monobasic Sodium Phosphate H2O 0.451 mg Dibasic Sodium Phosphate 12H2O 0.382 mg Methionine 0.975 mg Povidone 3.250 mg Water for Injection qs When necessary, the pH is adjusted with sodium hydroxide or hydrochloric acid, or both. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Depo-subQ provera 104 inhibits the secretion of gonadotropins, which primarily prevents follicular maturation and ovulation and causes thickening of cervical mucus. These actions contribute to its contraceptive effect. Suppression of serum estradiol concentrations is likely to be responsible for the therapeutic effect on endometriosis-associated pain. 12.2 Pharmacodynamics The following laboratory tests are expected to be affected by progestins including depo-subQ provera 104: • Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol). • Gonadotropin levels are decreased. • Sex-hormone-binding-globulin concentrations are decreased. • Histology specimens may demonstrate changes consistent with progestin effects. The following laboratory tests may be affected by depo-subQ provera 104, however the clinical significance is unknown: • Protein-bound iodine and butanol extractable protein-bound iodine may increase. • T3-uptake values may decrease. • Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase. • Sulfobromophthalein and other liver function test values may be increased. 17 Reference ID: 5495121 Time (Days) • The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies. 12.3 Pharmacokinetics The pharmacokinetic parameters of MPA following a single subcutaneous injection of depo-subQ provera 104 in healthy women (n=42) are shown in Table 2 and Figure P. Table 2. Pharmacokinetic Parameters of MPA after a Single Subcutaneous Injection of depo-subQ provera 104 in Healthy Women Cmax (ng/mL) Tmax (day) C91 (ng/mL) AUC0–91 (ng·day/mL) AUC0–∞ (ng·day/mL) t½ (day) Mean 1.56 8.8 0.402 66.98 92.84 43 Min 0.53 2.0 0.133 20.63 31.36 16 Max 3.08 80.0 0.733 139.79 162.29 114 Abbreviations: Cmax=peak serum concentration; Tmax=time when Cmax is observed; C91=serum concentration at 91 days; AUC0– 91 and AUC0–∞=area under the concentration-time curve over 91 days or infinity, respectively; t½=terminal half-life. Following subcutaneous administration of single depo-subQ provera 104 doses ranging from 50 to 150 mg (0.48 and 1.4 times the recommended dose, respectively), the AUC and Cmin (Day 91) increased with higher doses, but there was considerable overlap across dose levels. Serum MPA concentrations at Day 91 increased in a dose proportional manner but Cmax did not appear to increase proportionally with increasing dose. The AUC data were suggestive of dose linearity. Absorption Following a single subcutaneous injection of depo-subQ provera 104 in healthy women, serum MPA concentrations reached ≥0.2 ng/mL within 24 hours. The mean Tmax was attained approximately 1 week after injection. Figure P. Serum Concentration-Time Profile of MPA Mean (SD) after a Single Injection of depo-subQ provera 104 to Healthy Women In a study to assess accumulation and the achievement of steady state following multiple subcutaneous administrations, trough concentrations of MPA were determined after 6, 12, and 24 months, and in a subset of 8 subjects, bi-weekly concentrations were determined within one dosing interval in the second year of administration. The mean (SD) MPA trough concentrations were 0.67 (0.36) ng/mL (n=157), 0.79 (0.36) ng/mL (n=144), and 0.87 (0.33) ng/mL (n=106) at 6, 12, and 24 months, respectively. Depo-subQ provera 104 was administered subcutaneously into the anterior thigh or the abdomen to evaluate effects of injection site location on the MPA concentration-time profile. MPA trough concentrations (Cmin; Day 91) were similar for the two injection site locations. 18 Reference ID: 5495121 Distribution Plasma protein binding of MPA averages 86%. MPA binding occurs primarily to serum albumin. No binding of MPA occurs with sex-hormone-binding globulin (SHBG). Elimination Metabolism MPA is extensively metabolized in the liver by P450 enzymes. Its metabolism primarily involves ring A and/or side-chain reduction, loss of the acetyl group, hydroxylation in the 2-, 6-, and 21-positions or a combination of these positions, resulting in more than 10 metabolites. Excretion Residual MPA concentrations at the end of the first dosing interval (12 to 14 weeks) of depo-subQ provera 104 were generally below 0.5 ng/mL, consistent with its apparent terminal half-life of ~40 days after subcutaneous administration. Most MPA metabolites were excreted in the urine as glucuronide conjugates with only small amounts excreted as sulfates. Specific Populations Racial Groups There were no significant differences in the pharmacokinetics and/or pharmacodynamics of MPA after subcutaneous administration of depo-subQ provera 104 in African-American, Caucasian, and Asian women. Effect of Body Weight Although total MPA exposure was lower in obese women, no dosage adjustment of depo-subQ provera 104 is necessary based on body weight. The effect of body weight on the pharmacokinetics of MPA following a single dose was assessed in a subset of women [n=42, body mass index (BMI) ranged from 18.2 to 46.7 kg/m2]. The AUC0–91 values for MPA were 71.6, 67.9, and 46.3 ng·day/mL in women with BMI categories of ≤28 kg/m2, >28-38 kg/m2, and >38 kg/m2, respectively. The mean MPA Cmax was 1.74 ng/mL in women with BMI ≤28 kg/m2, 1.53 ng/mL in women with BMI >28–38 kg/m2, and 1.02 ng/mL in women with BMI >38 kg/m2, respectively. The MPA trough (Cmin) concentrations had a tendency to be lower in women with BMI >38 kg/m2. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility [See Warnings and Precautions (5.3, 5.8)] 14 CLINICAL STUDIES 14.1 Contraception Studies In three open label clinical studies, depo-SubQ provera 104 (104 mg given every three months subcutaneously), was administered to healthy, sexually-active, nonpregnant women 18 to 49 years of age who desired long-term contraception. In these three studies, no pregnancies were detected among 2042 women treated with depo-subQ provera 104 for up to 1 year. In women less than 36 years of age (at baseline), the Pearl Index pregnancy rate in cycles in which no other contraceptive methods were used, was 0 pregnancies per 100 women-years of use (upper 95% CI = 0.25). 14.2 Endometriosis Studies The efficacy of depo-subQ provera 104 in the reduction of endometriosis-associated pain in women with the signs and symptoms of endometriosis was demonstrated in two active comparator-controlled studies in pre-menopausal women 18 to 49 years of age with laparoscopically diagnosed endometriosis and persistent endometriosis pain symptoms (i.e., Studies 268 and 270). Each study assessed endometriosis-associated pain over 6 months of treatment and recurrence of symptoms for 12-months post treatment. Subjects were treated for six months with depo-subQ provera 104 [104 mg given subcutaneously every 3 months (2 injections)] or leuprolide [11.25 mg given subcutaneously every 3 months (2 injections) or 3.75 mg given subcutaneously every month (6 injections)]. Study 268 was conducted in the U.S. and Canada and enrolled 274 subjects (136 subjects received depo-subQ provera 104 and 138 subjects received leuprolide). Study 270 was conducted in 19 Reference ID: 5495121 - C: a, ~ a, a. ■study 268: depo-subQ provera 104 (N=136) ~Study 268:leuprolide (N=138) □Study 270:depo-subQ provera 104 (N=153) mlStudy 270:leuprolide (N=146) 100 ---,-----------------------, 90 80 70 60 50 40 30 20 10 0 ----~-'--......-""-----.-J---aaL-~---L----~..1-"'----'---.......... ...,_---'--'""'-! South America, Europe, and Asia, and enrolled 299 subjects (153 subjects received depo-subQ provera 104 and 146 subjects received leuprolide). Reduction in endometriosis pain was evaluated using a modified Biberoglu and Behrman scale that consisted of three patient-reported symptoms (i.e., dysmenorrhea, dyspareunia, and pelvic pain not related to menses) and two signs assessed during pelvic examination (i.e., pelvic tenderness and induration). For each category, a favorable response was defined as improvement of at least 1 unit (severity was assessed on a scale of 0 to 3) relative to baseline score (Figure Q). Figure Q. Responders at End of Treatment (Month 6 or Last Assessment if Earlier) in Patients with Endometriosis in Studies 268 and 270 Favorable Response = reduction in severity of symptom or sign of >1 point on a scale of 0 to 3, as compared to baseline. Additionally, scores from each of the five categories were combined into a composite score that was considered a global measurement of overall disease improvement. For subjects with baseline scores for each of the 5 categories, a mean decrease of 4 points relative to baseline was considered a clinically meaningful improvement. Across both studies, the mean changes in the composite score met the protocol-defined criterion for improvement for the depo-subQ provera 104 and leuprolide treatment groups. In the clinical trials, treatment with depo-subQ provera 104 was limited to six months. Data on the persistence of benefit with longer treatment are not available. 14.3 Bone Mineral Density in Women Treated with Depo-medroxyprogesterone acetate for Contraception In a study that compared changes in bone mineral density (BMD) in adult women using depo-subQ provera 104 or DMPA-IM for contraception, both treatments showed BMD reductions in the lumbar spine, total hip, and femoral neck. Mean percent changes in BMD in depo-subQ provera 104-treated women are shown in Table 3. 20 Reference ID: 5495121 Table 3. BMD Mean Percent Change from Baseline in Women Using depo-subQ provera 104 for Contraception Time on Lumbar Spine Total Hip Femoral Neck Treatment Mean % Change (95% CI) Mean % Change (95% CI) Mean % Change (95% CI) 1 year (n=166) -2.7 (-3.1 to -2.3) -1.7 (-2.1 to -1.3) -1.9 (-2.5 to -1.4) 2 years (n=106) - 4.1 (-4.6 to -3.5) -3.5 (-4.2 to -2.7) -3.5 (-4.3 to -2.6) BMD Recovery Post-Treatment in Women Given the similar effects on BMD from depo-subQ provera 104 and DMPA-IM described above, BMD recovery post-treatment is also expected to be similar. In a controlled clinical study that compared changes in BMD in adult women using DMPA-IM for contraception or no hormonal contraception, the 2-year post-treatment follow-up demonstrated incomplete recovery of BMD following the last injection of DMPA-IM. Table 4 shows the change in BMD in women after 5 years of treatment with DMPA-IM and in the control group, as well as the extent of BMD recovery in the subset of women for whom 2-year post-treatment data were available. Table 4. BMD Mean Percent Change from Baseline in Women by Skeletal Site and Cohort (5 Years of Treatment and 2 Years of Follow-Up) Time in Study Spine Total Hip Femoral Neck DMPA-IM* Control** DMPA-IM* Control** DMPA-IM* Control** 5 years -5.38% n=33 0.43% n=105 -5.16% n=21 0.19% n=65 -6.12% n=34 -0.27% n=106 7 years -3.13% n=12 0.53% n=60 -1.34% n=7 0.94% n=39 -5.38% n=13 -0.11% n=63 * Women who received DMPA-IM for 5 years and were then followed for 2 years post-treatment (total time in study of 7 years). ** Women who did not use hormonal contraception and were followed for 7 years. 14.4 Bone Mineral Density Changes in Adolescent Females (12 to 18 years of age) Treated with DMPA-IM The effect of DMPA-IM on BMD in adolescents is described below, and the effect of depo-subQ provera 104 on BMD in adolescents is expected to be similar. The impact of DMPA-IM use for up to 240 weeks (4.6 years) was evaluated in an open-label non-randomized clinical study in 389 adolescent females (12 to 18 years of age). Use of DMPA-IM was associated with a significant decline from baseline in BMD. Partway through the trial, DMPA-IM administration was stopped (at 120 weeks). The mean number of injections per DMPA-IM user was 9.3. Table 5 summarizes the study findings. The decline in BMD at total hip and femoral neck was greater with longer duration of use. The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%). Adolescents in the untreated cohort had an increase in BMD during the period of growth following menarche. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD, and other factors that influence the rate of acquisition of BMD. 21 Reference ID: 5495121 Table 5. BMD Mean Percent Change from Baseline in Adolescents Receiving ≥4 Injections per 60-week Period, by Skeletal Site and Cohort Duration of Treatment DMPA-IM (150 mg) Unmatched, Untreated Cohort N Mean % Change N Mean % Change Total Hip BMD Week 60 (1.2 years) Week 120 (2.3 years) Week 240 (4.6 years) 113 73 28 -2.75 -5.40 -6.40 166 109 84 1.22 2.19 1.71 Femoral Neck BMD Week 60 Week 120 Week 240 113 73 28 -2.96 -5.30 -5.40 166 108 84 1.75 2.83 1.94 Lumbar Spine BMD Week 60 Week 120 Week 240 114 73 27 -2.47 -2.74 -2.11 167 109 84 3.39 5.28 6.40 BMD Recovery Post-Treatment in Adolescents Longer duration of treatment and smoking were associated with less recovery of BMD following the last injection of DMPA-IM. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescents who received DMPA-IM for two years or less compared to more than two years. Post-treatment follow-up showed that, in adolescents treated for more than two years, only lumbar spine BMD recovered to baseline levels after treatment was discontinued. Adolescents treated with DMPA-IM for more than two years did not recover to their baseline BMD level at the femoral neck and total hip even up to 60 months post-treatment. Adolescents in the untreated cohort gained BMD throughout the trial period [see Warnings and Precautions (5.1)]. Table 6. BMD Recovery (Months Post-Treatment) in Adolescents by Years of DMPA-IM Use (2 Years or Less vs. More than 2 Years) Duration of Treatment (Months) 2 Years or Less More than 2 Years N Mean % Change from baseline N Mean % Change from baseline Total Hip BMD End of Treatment 49 -1.5% 49 -6.2% 12 M post-treatment 33 -1.4% 24 -4.6% 24 M post-treatment 18 0.3% 17 -3.6% 36 M post-treatment 12 2.1% 11 -4.6% 48 M post-treatment 10 1.3% 9 -2.5% 60 M post-treatment 3 0.2% 2 -1.0% Femoral Neck BMD End of Treatment 49 -1.6% 49 -5.8% 12 M post-treatment 33 -1.4% 24 -4.3% 24 M post-treatment 18 0.5% 17 -3.8% 36 M post-treatment 12 1.2% 11 -3.8% 48 M post-treatment 10 2.0% 9 -1.7% 60 M post-treatment 3 1.0% 2 -1.9% Lumbar Spine BMD End of Treatment 49 -0.9% 49 -3.5% 12 M post-treatment 33 0.4% 23 -1.1% 24 M post-treatment 18 2.6% 17 1.9% 36 M post-treatment 12 2.4% 11 0.6% 48 M post-treatment 10 6.5% 9 3.5% 60 M post-treatment 3 6.2% 2 5.7% 22 Reference ID: 5495121 14.5 Bone Fracture Incidence in Women Treated with Depo-medroxyprogesterone acetate for Contraception A retrospective cohort study to assess the association between DMPA-IM injection and the incidence of bone fractures was conducted in 312,395 female contraceptive users in the UK. The incidence rates of fracture were compared between DMPA-IM users and contraceptive users who had no recorded use of DMPA-IM. The Incident Rate Ratio (IRR) for any fracture during the follow-up period (mean=5.5 years) was 1.41 (95% CI 1.35, 1.47). It is not known if this is due to DMPA-IM use or to other related lifestyle factors that have a bearing on fracture rate. In the study, when cumulative exposure to DMPA-IM was calculated, the fracture rate in users who received fewer than 8 injections was higher than that in women who received 8 or more injections. However, it is not clear that cumulative exposure, which may include periods of intermittent use separated by periods of non-use, is a useful measure of risk, as compared to exposure measures based on continuous use. There were very few osteoporotic fractures (fracture sites known to be related to low BMD) in the study overall, and the incidence of osteoporotic fractures was not found to be higher in DMPA-IM users compared to non-users. Importantly, this study could not determine whether use of DMPA-IM has an effect on fracture rate later in life. Given the similar effects on BMD from depo-subQ provera 104 and DMPA-IM described above, bone fracture incidence may also be expected to be similar. 14.6 Bone Mineral Density in Women Treated with depo-SubQ provera 104 for Endometriosis In two clinical studies of 573 adult women with endometriosis, the BMD effects of 6 months of depo-subQ provera 104 treatment (104 mg subcutaneously every 3 months) were compared to 6 months of leuprolide treatment (either 11.25 mg given subcutaneously every 3 months or 3.75 mg given subcutaneously every month). Subjects were then observed after treatment completion, for an additional 12 months. See Table 7 for the results. Table 7. BMD Mean Percent Change from Baseline after Therapy for Endometriosis with depo-subQ provera 104 or Leuprolide for 6 Months, and 6- and 12-Months Post-Therapy (Studies 268 and 270 Combined) Time of BMD Lumbar Spine Total Hip Measurement depo-subQ provera 104 Leuprolide depo-subQ provera 104 Leuprolide N Mean % Change N Mean % Change N Mean % Change N Mean % Change Month 6 of treatment (End of Treatment) 208 -1.20 229 -4.10 207 -0.03 227 -1.83 6 months post-treatment 168 -1.06 180 -2.75 169 -0.05 181 -1.59 12 months post-treatment 124 -0.54 133 -1.48 125 0.39 134 -1.15 15. REFERENCES 1. Li CI, Beaber EF, Tang MCT et al. Effect of Depo-Medroxyprogesterone Acetate on Breast Cancer Risk among Women 20 to 44 years of Age. Cancer Research 2012; 72:2028-2035. 2. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med J 1989; 299:759-62. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Depo-subQ provera 104 medroxyprogesterone acetate injectable suspension (104 mg/0.65 mL) is available in a single dose, disposable pre-filled syringe and is packaged with a 26-gauge × 3/8-inch Terumo SurGuard® needle. NDC 0009-4709-13 16.2 Storage Store at controlled room temperature 20º C to 25º C (68º F to 77ºF) [see USP]. Do not refrigerate. 23 Reference ID: 5495121 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Loss of Bone Mineral Density Advise the patient that the use of depo-subQ provera 104 decreases BMD [see Warnings and Precautions (5.1)]. Arterial and Venous Thromboembolic Disorders Advise the patient that serious arterial and venous thrombotic events have been seen in women treated with depot medroxyprogesterone acetate (DMPA) [see Warnings and Precautions (5.2)]. Anaphylaxis Counsel patients on the importance of seeking urgent medical attention if they experience symptoms of anaphylaxis [see Warnings and Precautions (5.5)]. Ectopic Pregnancy Advise patients to tell their healthcare professional right away if they become pregnant or experience severe abdominal pain to exclude a diagnosis of ectopic pregnancy [see Warnings and Precautions (5.4)]. Bleeding Irregularities Advise patients at the beginning of treatment that their menstrual cycle may be disrupted, resulting in irregular and unpredictable bleeding or spotting. Explain that bleeding and spotting irregularities usually decrease to the point of amenorrhea as treatment with depo-subQ provera 104 continues, and does not require other therapy [see Warnings and Precautions (5.11)]. Delayed Return of Ovulation and Fertility Advise patients that return to ovulation and fertility is likely to be delayed after stopping depo-subQ provera 104 [see Warnings and Precautions (5.8)]. Risks of Breast Cancer Counsel patients about the possible increased risk of breast cancer in women who use depo-subQ provera 104 [see Warnings and Precautions (5.3)]. Depression Counsel patients about the possible risk of depression and mood disorders. Advise patients with a history of depression or who are receiving treatment for depression to be alert to any mood changes or worsening of their depression. Counsel patients to follow up with their healthcare professional accordingly [see Warnings and Precautions (5.9)]. Risk of Hyperglycemia in Patients with Diabetes Advise diabetic patients that some patients receiving progestins may exhibit a decrease in glucose tolerance and hyperglycemia [see Warnings and Precautions (5.12)]. Liver Dysfunction Advise patients to seek medical advice if they experience symptoms of liver problems such as jaundice [see Warnings and Precautions (5.13)]. Fluid Retention Counsel patients with conditions that may be influenced by fluid retention to inform their healthcare professional if they experience symptoms of fluid retention [see Warnings and Precautions (5.6)]. Injection Site Reactions Counsel patients that injection site reactions including site dimpling, scarring or discoloration may occur [see Warnings and Precautions (5.10)]. 24 Reference ID: 5495121 ~Pfizer Distributed by Pharmacia & Upjohn Company LLC A subsidiary of Pfizer Inc. New York, NY 10001 Sexually Transmitted Infections Counsel patients that depo-subQ provera 104 does not protect against HIV infection (AIDS) and other sexually transmitted infections [see Warnings and Precautions (5.14)]. Drug Interactions Counsel patients to contact their healthcare professional if they start a medication that is a CYP3A enzyme inducer [see Drug Interactions (7)]. Advise patients that taking a medication that is a CYP3A enzyme inducer may require using a back-up or alternate contraceptive method. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. LAB-0295-17.2b 25 Reference ID: 5495121 PATIENT INFORMATION DEPO-SUBQ PROVERA 104® (deh-poh’ sub-cue’ pro-ver-ah’ one-oh-four) (medroxyprogesterone acetate injectable suspension) for subcutaneous use WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT depo-subQ provera 104? Use of depo-subQ provera 104 may cause you to lose calcium stored in your bones. The longer you use depo-subQ provera 104 the more calcium you are likely to lose. The calcium may not return completely once you stop using depo-subQ provera 104. Loss of calcium may cause weak, porous bones (osteoporosis) that could increase the risk that your bones might break, especially after menopause. It is not known whether your risk of developing osteoporosis may be greater if you are a teenager when you start to use depo-subQ provera 104. You should use depo-subQ provera 104 long-term (for example, more than 2 years) only if other methods of birth control or other treatments for endometriosis pain are not right for you. Depo-subQ provera 104 does not protect you from HIV (AIDS) and other sexually transmitted infections (STIs). WHAT IS depo-subQ provera 104? Depo-subQ provera 104 is a drug for birth control. It also helps relieve pain related to endometriosis (en-do-ME-tree­ OH-sis). Symptoms of endometriosis arise when cells normally inside your uterus grow outside the uterus. The cells respond to menstrual cycle hormones, and may cause painful periods, pelvic pain, and painful sex. Depo-subQ provera 104 contains a hormone called medroxyprogesterone acetate (MPA). It is given as a shot (injection) every 3 months. Three months is the same as 12 to 14 weeks. HOW WELL DOES depo-subQ provera 104 WORK FOR PREVENTING PREGNANCY? When you use depo-subQ provera 104 correctly, the chance of getting pregnant is very low. In studies, no women became pregnant during the year they used depo-subQ provera 104 injection. The list below estimates the chances of getting pregnant using different types of birth control. The numbers are based on typical use. Typical use includes people who use the method correctly and people who use the method incorrectly. The list shows the number of women out of 100 women who will likely get pregnant if they use the method for 1 year. Method Typical Chance of Getting Pregnant in 1 year (Number of pregnancies in 100 women) Shot Implant Female sterilization Male sterilization IUD (copper IUD and levonorgestrel IUD) Less than 1 Pill 5 Condom alone (male) 14 Withdrawal 19 Diaphragm with spermicides 20 Condom alone (female) 21 Periodic abstinence 25 Spermicides alone 26 Vaginal sponge or Cervical cap with spermicide 20 to 40 26 Reference ID: 5495121 HOW WILL I GET depo-subQ provera 104? Depo-subQ provera 104 is given as a shot just under the skin on your thigh or belly. You get it once every 3 months. For Birth Control First shot: Your healthcare professional will want to be sure that you are not pregnant before you get your first shot. Normally, you get the shot by the 5th day from the START of your menstrual period. You get it whether or not you are still bleeding. If you are breast-feeding, you may have your first shot as early as 6 weeks after you deliver your baby. After the first shot: It is very important to keep getting depo-subQ provera 104 every 3 months. If you wait more than 14 weeks between shots, you could become pregnant. Your healthcare professional must make sure you are not pregnant before you get your next shot. When you get your shot, make an appointment for your next shot. Mark it on your calendar. If you need a birth control method for more than two years, your healthcare professional may ask you to have a test of your bones or ask you to switch to another birth control method before continuing depo-subQ provera 104, especially if you have other risks for weak bones. For Endometriosis If you have regular periods, you will get depo-subQ provera 104 the same way as described above for birth control. If your periods have stopped or are not regular, your healthcare professional must test to make sure you are not pregnant before you get your first shot. It is not recommended that you receive depo-subQ provera 104 for treatment of endometriosis for longer than 2 years. If your painful symptoms return after stopping treatment, your healthcare professional should ask you to have a test of your bones before restarting treatment. WHAT IF I MISS A SHOT? If you miss a shot, or wait longer than 14 weeks between shots, you could get pregnant. The longer you wait, the greater the risk of getting pregnant. Talk with your healthcare professional to find out when to restart depo-subQ provera 104. You should be tested to be sure you are not pregnant. Use another kind of non-hormonal birth control, such as condoms, until you start depo-subQ provera 104 again. DO NOT TAKE depo-subQ provera 104 IF YOU… • Have any unexplained vaginal bleeding • Have or have ever had breast cancer or think you have breast cancer • Ever had serious blood clots, such as blood clots in your legs (deep venous thrombophlebitis), lungs (pulmonary embolism), heart (heart attack), or head (stroke) • Have liver disease • Are allergic to anything in depo-subQ provera 104. There is a list of what is in depo-subQ provera 104 at the end of this leaflet. BEFORE TAKING depo-subQ provera 104 Your healthcare professional may do a physical examination and check your blood and urine. 27 Reference ID: 5495121 Tell your healthcare professional about all your medical conditions. Most importantly, tell your healthcare professional if you: • Are pregnant or might be pregnant. You should not get depo-subQ provera 104 if you are pregnant. • Plan to become pregnant in the next year. After you stop getting depo-subQ provera 104, it takes time for your body to be able to get pregnant. It can be as early as 1 week after the last shot wears off. Most likely it will take up to 1 year or longer for you to get pregnant. • Have or have ever had breast cancer, or think you have breast cancer • Have breast cancer in your family • Have an abnormal mammogram (breast X-ray), lumps in your breast, or bleeding from your nipples • Have irregular, light, or heavy menstrual periods • Have or had any of the following medical problems: o Kidney problems o High blood pressure o Migraine headaches o Asthma o Seizures o Diabetes, or if it runs in your family o Depression o Heart attack, stroke, or blood clots o Bone disease o Anorexia nervosa (an eating disorder) o A strong family history of osteoporosis o Use of a drug that can lower the amount of calcium in bones (drugs for epilepsy or steroids) o Drinking a lot of alcohol or smoking a lot It is important to see your healthcare professional regularly if you have any of these conditions. Some medicines may make depo-subQ provera 104 less effective at preventing pregnancy, including those listed below: • Bosentan (used to treat pulmonary arterial hypertension) • Efavirenz, etravirine (HIV medicines) • Modafinil (used to improve wakefulness) • Mitotane (used to treat adrenal cortical carcinoma) • Phenytoin, carbamazepine, phenobarbital (used to treat seizures) • Rifampin (an antibiotic) • St. John’s Wort (herbal medicinal product) Tell your healthcare professional about all the medicines you take. This includes prescription and over-the-counter medicines, vitamins, and herbal products. WHAT ELSE SHOULD I KNOW ABOUT TAKING depo-subQ provera 104? Other Birth Control. If you can’t take birth control pills or can’t use a birth control patch or ring, you may be able to use depo-subQ provera 104. Ask your healthcare professional. Pregnancy. When you take depo-subQ provera 104 every 3 months, your chance of getting pregnant is very low. You could miss a period or have a light period and not be pregnant. If you miss 1 or 2 periods and think you might be pregnant, see your healthcare professional as soon as possible. You should not use depo-subQ provera 104 if you are pregnant. However, depo-subQ provera 104 taken by accident during pregnancy does not seem to cause birth defects. Pregnancy in your fallopian tubes (Ectopic Pregnancy). If you have severe pain low in your belly, tell your healthcare professional right away. Infrequently, a baby may start to grow outside the uterus, most often in the tubes. 28 Reference ID: 5495121 Nursing a baby. Wait at least 6 weeks after your baby is born to start depo-subQ provera 104. You can use depo-subQ provera 104 if you are nursing. It does not lower the amount of milk you can make. It can pass through breast milk into your baby, but it is not harmful. Blood or urine tests. Depo-subQ provera 104 may affect blood or urine test results. Tell your healthcare professional you are taking depo-subQ provera 104 if you are going to have blood or urine tests. Liver problems. Your healthcare professional may stop depo-subQ provera 104 if you have liver problems. Some signs of liver problems are yellow skin or eyes, feeling like you have the flu, feeling more tired than usual, and itching. Tell your healthcare professional if you have these symptoms. WHAT ARE THE MOST SERIOUS RISKS OF depo-subQ provera 104? Losing calcium from your bones. Depo-subQ provera 104 use may decrease the amount of calcium in your bones. The longer you use depo-subQ provera 104, the more calcium you are likely to lose. This increases the risk of your bones weakening if you use depo-subQ provera 104 continuously for a long time (for example, if you use depo-subQ provera 104 for more than 2 years). The loss of calcium may increase your risk of osteoporosis and broken bones, particularly after your menopause. Calcium is generally added to the bones during teenage years. The decrease of calcium in your bones is of most concern if you are a teenager or have the following risk factors: • Bone disease • Anorexia nervosa (an eating disorder) • A strong family history of osteoporosis • Using a drug that can lower the amount of calcium in bones (drugs for epilepsy or steroids), or • Drinking a lot of alcohol or smoking a lot If you need a birth control method for more than 2 years, your healthcare professional may ask you to have a test of your bones or ask you to switch to another birth control method before continuing depo-subQ provera 104, especially if you have other risks for weak bones. When depo-subQ provera 104 is stopped, the calcium in your bones begins to come back. The lost calcium may not return completely once you stop using depo-subQ provera 104. Abnormal or very heavy bleeding. If you start having very heavy or very long periods, tell your healthcare professional. Allergic reaction. Allergic reactions to depo-subQ provera 104 have been reported. If you have hives, problems breathing, swelling of the face, mouth, tongue, or neck, or just do not feel right after your shot, call your healthcare professional or go to the Emergency Room right away. Serious blood clots. Call your healthcare professional immediately if you: • Have sharp chest pain, cough blood, or suddenly have trouble breathing • Have a sudden severe headache with vomiting, blindness or trouble talking, weakness, or numbness in an arm or leg, or get dizzy or faint • Have swelling or severe pain in your leg Depression. If you suffer from depression or have a history of depression, inform your healthcare professional if you notice any worsening of your depression while taking depo-subQ provera 104. WHAT ARE COMMON SIDE EFFECTS OF depo-subQ provera 104? The most common side effects are: • Changes in your monthly periods. You may not know when you will bleed, your periods may not be regular, you may have heavy bleeding, or you may have spotting. You may have more days of bleeding during the first 2 or 3 months after you start depo-subQ provera 104. Over time, you may have less and less bleeding. Many women stop 29 Reference ID: 5495121 ~Pfizer Distributed by Pharmacia & Upjohn Company LLC A subsidiary of Pfizer Inc. New York, NY 10001 having periods by the end of 1 year. Your periods will come back eventually after you stop using depo-subQ provera 104. • Headache. • Weight gain. In studies, women gained an average of 3 to 4 pounds during the first year they used depo-subQ provera 104. After 2 years of using depo-subQ provera 104, women gained an average of 7 to 8 pounds. Some women gained more, some gained less, some lost, and some stayed the same. Weight changes beyond 2 years of use with depo-subQ provera 104 have not been studied. Women who used a similar birth control product for 5 years gained on average 5 pounds more than women who did not use a hormone contraceptive product. • Skin reaction where you got the shot. Lumps, skin dimpling, or pain may occur. Scarring and discoloration are uncommon, but may happen. If there is swelling or your skin gets hot, has pus or looks bruised 1 or more days after your shot, call your healthcare professional. Women using depo-subQ provera 104 for birth control or endometriosis had these less common side effects: Vaginal inflammation, vaginal thrush, abdominal pain, urinary tract infections, acne, depression, less sex drive, nausea, back pain, breast pain/tenderness, fatigue, anxiety, being irritable, dizziness, hot flushes and fluid retention. If you feel you are having other side effects, talk with your healthcare professional. DOES depo-subQ provera 104 CAUSE CANCER? There have been several studies of women who use birth control like depo-subQ provera 104. • Women who use depo-subQ provera 104 may have a slightly increased risk of breast cancer compared to non-users. • The risk of cancer of the ovary, liver, or cervix did not change. WHAT IF I WANT TO BECOME PREGNANT? Plan ahead. The effect of depo-subQ provera 104 can last for a long time after you stop getting shots. Although you may be able to get pregnant quickly, it is more likely to take a year or longer after your last shot before you get pregnant. It’s best to see your healthcare professional for a pre-pregnancy check-up. Your healthcare professional may also tell you to take a vitamin called folic acid every day if you are planning to become pregnant. GENERAL ADVICE ABOUT depo-subQ provera 104 For more information about depo-subQ provera 104, ask your healthcare professional or pharmacist. WHAT IS IN depo-subQ provera 104? Active ingredient: medroxyprogesterone acetate. Inactive ingredients: methylparaben, propylparaben, sodium chloride, polyethylene glycol, polysorbate 80, monobasic sodium phosphate⋅H2O, dibasic sodium phosphate⋅12H2O, methionine, povidone, water for shot. When necessary, the pH is adjusted with sodium hydroxide or hydrochloric acid, or both. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. LAB-0298-10.3 Revised December 2024 Reference ID: 5495121 30 NDA 021583/S-043 Page 4 ENCLOSURES: • Content of Labeling o Prescribing Information o Patient Package Insert U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov Reference ID: 5495121
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2025-02-12T15:47:46.950243
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_______________________________________________________________________________________________________________________________________ _______________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AROMASIN safely and effectively. See full prescribing information for AROMASIN. AROMASIN® (exemestane) tablets, for oral use Initial U.S. Approval: 1999 ----------------------------INDICATIONS AND USAGE--------------------------­ AROMASIN is an aromatase inhibitor indicated for: • adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to AROMASIN for completion of a total of five consecutive years of adjuvant hormonal therapy (14.1). • treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy (14.2). ----------------------DOSAGE AND ADMINISTRATION----------------------­ Recommended Dose: One 25 mg tablet once daily after a meal (2.1). ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ Tablets: 25 mg (3) -------------------------------CONTRAINDICATIONS-----------------------------­ Patients with a known hypersensitivity to the drug or to any of the excipients (4). ---------------------WARNINGS AND PRECAUTIONS-----------------------­ • Reductions in bone mineral density (BMD) over time are seen with exemestane use (5.1). • Routine assessment of 25-hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be performed (5.2). • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception (5.6, 8.1, 8.3). ------------------------------ADVERSE REACTIONS------------------------------­ • Early breast cancer: Adverse reactions occurring in ≥10% of patients in any treatment group (AROMASIN vs. tamoxifen) were hot flushes (21% vs. 20%), fatigue (16% vs. 15%), arthralgia (15% vs. 9%), headache (13% vs. 11%), insomnia (12% vs. 9%), and increased sweating (12% vs. 10%). Discontinuation rates due to AEs were similar between AROMASIN and tamoxifen (6% vs. 5%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were AROMASIN 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: AROMASIN 0.4%, tamoxifen 0.3% (6, 6.1). • Advanced breast cancer: Most common adverse reactions were mild to moderate and included hot flushes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for AROMASIN and megestrol acetate, respectively (6, 6.1). To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------­ Strong CYP 3A4 inducers: Concomitant use of strong CYP 3A4 inducers decreases exemestane exposure. Increase the AROMASIN dose to 50 mg (2.2, 7). -----------------------USE IN SPECIFIC POPULATIONS-----------------------­ Lactation: Advise not to breastfeed (8.2). See 17 for PATIENT COUNSELING INFORMATION and FDA – approved patient labeling Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Adjuvant Treatment of Postmenopausal Women 1.2 Advanced Breast Cancer in Postmenopausal Women 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose 2.2 Dose Modifications 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Reductions in Bone Mineral Density (BMD) 5.2 Vitamin D Assessment 5.3 Administration with Estrogen-Containing Agents 5.4 Laboratory Abnormalities 5.5 Use in Premenopausal Women 5.6 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience 6.2 Post-Marketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10OVERDOSAGE 11DESCRIPTION 12CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14CLINICAL STUDIES 14.1 Adjuvant Treatment in Early Breast Cancer 14.2 Treatment of Advanced Breast Cancer 16HOW SUPPLIED/STORAGE AND HANDLING 17PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5496840 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Adjuvant Treatment of Postmenopausal Women AROMASIN is indicated for adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to AROMASIN for completion of a total of five consecutive years of adjuvant hormonal therapy [see Clinical Studies (14.1)]. 1.2 Advanced Breast Cancer in Postmenopausal Women AROMASIN is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy [see Clinical Studies (14.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended dose of AROMASIN in early and advanced breast cancer is one 25 mg tablet once daily after a meal. • adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to AROMASIN for completion of a total of five consecutive years of adjuvant hormonal therapy. • the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy. 2.2 Dose Modifications Concomitant use of strong CYP 3A4 inducers decreases exemestane exposure, For patients receiving AROMASIN with a strong CYP 3A4 inducer such as rifampicin or phenytoin, the recommended dose of AROMASIN is 50 mg once daily after a meal [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS AROMASIN Tablets are round, biconvex, and off-white to slightly gray. Each tablet contains 25 mg of exemestane. The tablets are printed on one side with the number “7663” in black. 4 CONTRAINDICATIONS AROMASIN is contraindicated in patients with a known hypersensitivity to the drug or to any of the excipients. 5 WARNINGS AND PRECAUTIONS 5.1 Reductions in Bone Mineral Density (BMD) Reductions in bone mineral density (BMD) over time are seen with exemestane use. Table 1 describes changes in BMD from baseline to 24 months in patients receiving exemestane compared to patients receiving tamoxifen (IES) or placebo (027). Concomitant use of bisphosphonates, vitamin D supplementation, and calcium was not allowed. Table 1. Percent Change in BMD from Baseline to 24 months, Exemestane vs. Control1 IES 027 BMD Exemestane N=29 Tamoxifen1 N=38 Exemestane N=59 Placebo1 N=65 Lumbar spine (%) -3.1 -0.2 -3.5 -2.4 Femoral neck (%) -4.2 -0.3 -4.6 -2.6 During adjuvant treatment with exemestane, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry at the commencement of treatment. Monitor patients for bone mineral density loss and treat as appropriate. 5.2 Vitamin D Assessment Routine assessment of 25-hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be performed, due to the high prevalence of vitamin D deficiency in women with early breast cancer (EBC). Women with vitamin D deficiency should receive supplementation with vitamin D. 5.3 Administration with Estrogen-Containing Agents AROMASIN should not be coadministered with systemic estrogen-containing agents as these could interfere with its pharmacologic action. Reference ID: 5496840 5.4 Laboratory Abnormalities In patients with early breast cancer, the incidence of hematological abnormalities of Common Toxicity Criteria (CTC) grade ≥1 was lower in the exemestane treatment group, compared with tamoxifen. Incidence of CTC grade 3 or 4 abnormalities was low (approximately 0.1%) in both treatment groups. Approximately 20% of patients receiving exemestane in clinical studies in advanced breast cancer experienced CTC grade 3 or 4 lymphocytopenia. Of these patients, 89% had a pre-existing lower grade lymphopenia. Forty percent of patients either recovered or improved to a lesser severity while on treatment. Patients did not have a significant increase in viral infections, and no opportunistic infections were observed. Elevations of serum levels of AST, ALT, alkaline phosphatase, and gamma glutamyl transferase >5 times the upper value of the normal range (i.e., ≥ CTC grade 3) have been rarely reported in patients treated for advanced breast cancer but appear mostly attributable to the underlying presence of liver and/or bone metastases. In the comparative study in advanced breast cancer patients, CTC grade 3 or 4 elevation of gamma glutamyl transferase without documented evidence of liver metastasis was reported in 2.7% of patients treated with AROMASIN and in 1.8% of patients treated with megestrol acetate. In patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receiving exemestane than either tamoxifen or placebo. Treatment-emergent bilirubin elevations (any CTC grade) occurred in 5% of exemestane patients and 0.8% of tamoxifen patients on the Intergroup Exemestane Study (IES), and in 7% of exemestane treated patients vs. 0% of placebo treated patients in the 027 study. CTC grade 3–4 increases in bilirubin occurred in 0.9% of exemestane treated patients compared to 0.1% of tamoxifen treated patients. Alkaline phosphatase elevations of any CTC grade occurred in 15% of exemestane treated patients on the IES compared to 2.6% of tamoxifen treated patients, and in 14% of exemestane treated patients compared to 7% of placebo treated patients in study 027. Creatinine elevations occurred in 6% of exemestane treated patients and 4.3% of tamoxifen treated patients on the IES and in 6% of exemestane treated patients and 0% of placebo treated patients in study 027. 5.5 Use in Premenopausal Women AROMASIN is not indicated for the treatment of breast cancer in premenopausal women. 5.6 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, AROMASIN can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of exemestane to pregnant rats and rabbits caused increased incidence of abortions and embryo-fetal toxicity. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with AROMASIN and for 1 month after the last dose [see Use in Specific Populations (8.1), (8.3) and Clinical Pharmacology (12.1)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Reductions in Bone Mineral Density (BMD) [see Warnings and Precautions (5.1)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adjuvant Therapy The data described below reflect exposure to AROMASIN in 2325 postmenopausal women with early breast cancer. AROMASIN tolerability in postmenopausal women with early breast cancer was evaluated in two well- controlled trials: the IES study [See Clinical Studies (14.1)] and the 027 study (a randomized, placebo-controlled, double-blind, parallel group study specifically designed to assess the effects of exemestane on bone metabolism, hormones, lipids, and coagulation factors over 2 years of treatment). The median duration of adjuvant treatment was 27.4 months and 27.3 months for patients receiving AROMASIN or tamoxifen, respectively, within the IES study and 23.9 months for patients receiving AROMASIN or placebo within the 027 study. Median duration of observation after randomization for AROMASIN was 34.5 months and for tamoxifen was 34.6 months. Median duration of observation was 30 months for both groups in the 027 study. Certain adverse reactions, which were expected based on the known pharmacological properties and side effect profiles of test drugs, were actively sought through a positive checklist. Signs and symptoms were graded for severity using CTC in both studies. Within the IES study, the presence of some illnesses/conditions was monitored through a positive checklist without assessment of severity. These included myocardial infarction, other cardiovascular disorders, gynecological disorders, osteoporosis, osteoporotic fractures, other primary cancer, and hospitalizations. Reference ID: 5496840 Within the IES study, discontinuations due to adverse reactions occurred in 6% and 5% of patients receiving AROMASIN and tamoxifen, respectively, and in 12% and 4.1% of patients receiving exemestane or placebo respectively within study 027. Deaths due to any cause were reported for 1.3% of the exemestane treated patients and 1.4% of the tamoxifen treated patients within the IES study. There were 6 deaths due to stroke on the exemestane arm compared to 2 on tamoxifen. There were 5 deaths due to cardiac failure on the exemestane arm compared to 2 on tamoxifen. The incidence of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) was 1.6% in exemestane treated patients and 0.6% in tamoxifen treated patients in the IES study. Cardiac failure was observed in 0.4% of exemestane treated patients and 0.3% of tamoxifen treated patients. In the adjuvant treatment of early breast cancer, the most common adverse reactions occurring in ≥10% of patients in any treatment group (AROMASIN vs. tamoxifen) were hot flushes (21% vs. 20%), fatigue (16% vs. 15%), arthralgia (15% vs. 9%), headache (13% vs. 11%), insomnia (12% vs. 9%), and increased sweating (12% vs. 10%). Discontinuation rates due to AEs were similar between AROMASIN and tamoxifen (6% vs. 5%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were AROMASIN 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: AROMASIN 0.4%, tamoxifen 0.3%. Treatment-emergent adverse reactions and illnesses including all causalities and occurring with an incidence of ≥5% in either treatment group of the IES study during or within one month of the end of treatment are shown in Table 2. Table 2. Incidence (%) of Adverse Reactions of all Grades1 and Illnesses Occurring in (≥5%) of Patients in Any Treatment Group in Study IES in Postmenopausal Women with Early Breast Cancer % of patients Body system and Adverse Reaction by MedDRA dictionary AROMASIN 25 mg daily (N=2252) Tamoxifen 20 mg daily2 (N=2280) Eye Visual disturbances3 5 3.8 Gastrointestinal Nausea3 9 9 General Disorders Fatigue3 16 15 Musculoskeletal Arthralgia Pain in limb Back pain Osteoarthritis 15 9 9 6 9 6 7 4.5 Nervous System Headache3 Dizziness3 13 10 11 8 Psychiatric Insomnia3 Depression 12 6 9 6 Skin & Subcutaneous Tissue Increased sweating3 12 10 Vascular Hot flushes3 Hypertension 21 10 20 8 1 Graded according to Common Toxicity Criteria; 2 75 patients received tamoxifen 30 mg daily; 3 Event actively sought. In the IES study, as compared to tamoxifen, AROMASIN was associated with a higher incidence of events in musculoskeletal disorders and in nervous system disorders, including the following events occurring with frequency lower than 5% (osteoporosis [4.6% vs. 2.8%], osteochondrosis [0.3% vs. 0%] and stenosing tenosynovitis (trigger finger) [0.3% vs. 0%], paresthesia [2.6% vs. 0.9%], carpal tunnel syndrome [2.4% vs. 0.2%], and neuropathy [0.6% vs. 0.1%]). Diarrhea was also more frequent in the exemestane group (4.2% vs. 2.2%). Clinical fractures were reported in 94 patients receiving exemestane (4.2%) and 71 patients receiving tamoxifen (3.1%). After a median duration of therapy of about 30 months and a median follow-up of about 52 months, gastric ulcer was observed at a slightly higher frequency in the AROMASIN group compared to tamoxifen (0.7% vs. <0.1%). The majority of patients on AROMASIN with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history. Reference ID: 5496840 Tamoxifen was associated with a higher incidence of muscle cramps [3.1% vs. 1.5%], thromboembolism [2.0% vs. 0.9%], endometrial hyperplasia [1.7% vs. 0.6%], and uterine polyps [2.4% vs. 0.4%]. Common adverse reactions occurring in study 027 are described in Table 3. Table 3. Incidence of Selected Treatment-Emergent Adverse Reactions of all CTC Grades* Occurring in ≥ 5% of Patients in Either Arm in Study 027 Adverse Reaction Exemestane N=73 (% incidence) Placebo N=73 (% incidence) Hot flushes 33 25 Arthralgia 29 29 Increased sweating 18 21 Alopecia 15 4.1 Hypertension 15 7 Insomnia 14 15 Nausea 12 16 Fatigue 11 19 Abdominal pain 11 14 Depression 10 7 Diarrhea 10 1.4 Dizziness 10 10 Dermatitis 8 1.4 Headache 7 4.1 Myalgia 6 4.1 Edema 6 7 * Most events were CTC grade 1–2 Treatment of Advanced Breast Cancer A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. One death was considered possibly related to treatment with exemestane; an 80-year-old woman with known coronary artery disease had a myocardial infarction with multiple organ failure after 9 weeks on study treatment. In the clinical trials program, 3% of the patients discontinued treatment with exemestane because of adverse reactions, 2.7% of patients discontinued exemestane within the first 10 weeks of treatment. In the comparative study, adverse reactions were assessed for 358 patients treated with AROMASIN and 400 patients treated with megestrol acetate. Fewer patients receiving AROMASIN discontinued treatment because of adverse reactions than those treated with megestrol acetate (2% vs. 5%). Adverse reactions that were considered drug related or of indeterminate cause included hot flashes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for AROMASIN and megestrol acetate, respectively. The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with AROMASIN (17% vs. 8%). In the treatment of advanced breast cancer, the most common adverse reactions included hot flushes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for AROMASIN and megestrol acetate, respectively. Table 4 shows the adverse reactions of all CTC grades, regardless of causality, reported in 5% or greater of patients in the study treated either with AROMASIN or megestrol acetate. Reference ID: 5496840 Table 4. Incidence (%) of Adverse Reactions of all Grades* and Causes Occurring in ≥5% of Advanced Breast Cancer Patients In Each Treatment Arm in the Comparative Study Body system and Adverse Reaction by WHO ART dictionary AROMASIN 25 mg once daily (N=358) Megestrol Acetate 40 mg QID (N=400) Autonomic Nervous Increased sweating 6 9 Body as a Whole Fatigue Hot flashes Pain Influenza-like symptoms Edema (includes edema, peripheral edema, leg edema) 22 13 13 6 7 29 6 13 5 6 Cardiovascular Hypertension 5 6 Nervous Depression Insomnia Anxiety Dizziness Headache 13 11 10 8 8 9 9 11 6 7 Gastrointestinal Nausea Vomiting Abdominal pain Anorexia Constipation Diarrhea Increased appetite 18 7 6 6 5 4 3 12 4 11 5 8 5 6 Respiratory Dyspnea Coughing 10 6 15 7 * Graded according to Common Toxicity Criteria Adverse reactions of any cause (from 2% to 5%) reported in the comparative study for patients receiving AROMASIN 25 mg once daily were fever, generalized weakness, paresthesia, pathological fracture, bronchitis, sinusitis, rash, itching, urinary tract infection, and lymphedema. Additional adverse reactions of any cause observed in the overall clinical trials program (N = 1058) in 5% or greater of patients treated with exemestane 25 mg once daily but not in the comparative study included pain at tumor sites (8%), asthenia (6%), and fever (5%). Adverse reactions of any cause reported in 2% to 5% of all patients treated with exemestane 25 mg in the overall clinical trials program but not in the comparative study included chest pain, hypoesthesia, confusion, dyspepsia, arthralgia, back pain, skeletal pain, infection, upper respiratory tract infection, pharyngitis, rhinitis, and alopecia. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of AROMASIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders- hypersensitivity Hepatobiliary disorders- hepatitis including cholestatic hepatitis Nervous system disorders- paresthesia Musculoskeletal and connective tissue disorder- tendon disorders including tendon rupture, tendonitis, and tenosynovitis Skin and subcutaneous tissue disorders- acute generalized exanthematous pustulosis, urticaria, pruritus Reference ID: 5496840 7 DRUG INTERACTIONS Drugs That Induce CYP 3A4 Co-medications that induce CYP 3A4 (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John’s wort) may significantly decrease exposure to exemestane. Dose modification is recommended for patients who are also receiving a strong CYP 3A4 inducer [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action, AROMASIN can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Limited human data from case reports are insufficient to inform a drug-associated risk. In animal reproduction studies, administration of exemestane to pregnant rats and rabbits caused increased incidence of abortions, embryo-fetal toxicity, and prolonged gestation with abnormal or difficult labor [see Data]. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In animal reproduction studies in rats and rabbits, exemestane caused embryo-fetal toxicity, and was abortifacient. Radioactivity related to 14C-exemestane crossed the placenta of rats following oral administration of 1 mg/kg exemestane. The concentration of exemestane and its metabolites was approximately equivalent in maternal and fetal blood. When rats were administered exemestane from 14 days prior to mating until either days 15 or 20 of gestation, and resuming for the 21 days of lactation, an increase in placental weight was seen at 4 mg/kg/day (approximately 1.5 times the recommended human daily dose on a mg/m2 basis). Increased resorptions, reduced number of live fetuses, decreased fetal weight, retarded ossification, prolonged gestation and abnormal or difficult labor was observed at doses equal to or greater than 20 mg/kg/day (approximately 7.5 times the recommended human daily dose on a mg/m2 basis). Daily doses of exemestane, given to rabbits during organogenesis, caused a decrease in placental weight at 90 mg/kg/day (approximately 70 times the recommended human daily dose on a mg/m2 basis) and in the presence of maternal toxicity, abortions, an increase in resorptions, and a reduction in fetal body weight were seen at 270 mg/kg/day. No malformations were noted when exemestane was administered to pregnant rats or rabbits during the organogenesis period at doses up to 810 and 270 mg/kg/day, respectively (approximately 320 and 210 times the recommended human dose on a mg/m2 basis, respectively). 8.2 Lactation Risk Summary There is no information on the presence of exemestane in human milk, or on its effects on the breastfed infant or milk production. Exemestane is present in rat milk at concentrations similar to maternal plasma [see Data]. Because of the potential for serious adverse reactions in breast-fed infants from AROMASIN, advise a woman not to breastfeed during treatment with AROMASIN and for 1 month after the final dose. Data Radioactivity related to exemestane appeared in rat milk within 15 minutes of oral administration of radiolabeled exemestane. Concentrations of exemestane and its metabolites were approximately equivalent in the milk and plasma of rats for 24 hours after a single oral dose of 1 mg/kg 14C-exemestane. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating AROMASIN. Contraception Females AROMASIN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with AROMASIN and for 1 month after the final dose. Reference ID: 5496840 Infertility Based on findings in animals, male and female fertility may be impaired by treatment with AROMASIN [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.6 Hepatic Impairment The AUC of exemestane was increased in subjects with moderate or severe hepatic impairment (Childs-Pugh B or C) [see Clinical Pharmacology (12.3)]. However, based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life-threatening adverse reactions, dosage adjustment does not appear to be necessary. 8.7 Renal Impairment The AUC of exemestane was increased in subjects with moderate or severe renal impairment (creatinine clearance <35 mL/min/1.73 m2) [see Clinical Pharmacology (12.3)]. However, based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life-threatening adverse reactions, dosage adjustment does not appear to be necessary. 10 OVERDOSAGE Clinical trials have been conducted with exemestane given as a single dose to healthy female volunteers at doses as high as 800 mg and daily for 12 weeks to postmenopausal women with advanced breast cancer at doses as high as 600 mg. These dosages were well tolerated. There is no specific antidote to overdosage and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated. A male child (age unknown) accidentally ingested a 25-mg tablet of exemestane. The initial physical examination was normal, but blood tests performed 1 hour after ingestion indicated leucocytosis (WBC 25000/mm3 with 90% neutrophils). Blood tests were repeated 4 days after the incident and were normal. No treatment was given. In mice, mortality was observed after a single oral dose of exemestane of 3200 mg/kg, the lowest dose tested (about 640 times the recommended human dose on a mg/m2 basis). In rats and dogs, mortality was observed after single oral doses of exemestane of 5000 mg/kg (about 2000 times the recommended human dose on a mg/m2 basis) and of 3000 mg/kg (about 4000 times the recommended human dose on a mg/m2 basis), respectively. Convulsions were observed after single doses of exemestane of 400 mg/kg and 3000 mg/kg in mice and dogs (approximately 80 and 4000 times the recommended human dose on a mg/m2 basis), respectively. 11 DESCRIPTION AROMASIN Tablets for oral administration contain 25 mg of exemestane, an irreversible, steroidal aromatase inactivator. Exemestane is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C20H24O2 and its structural formula is as follows: CH3 H O CH3 H H O CH2 The active ingredient is a white to slightly yellow crystalline powder with a molecular weight of 296.41. Exemestane is freely soluble in N, N-dimethylformamide, soluble in methanol, and practically insoluble in water. Each AROMASIN Tablet contains the following inactive ingredients: mannitol, crospovidone, polysorbate 80, hypromellose, colloidal silicon dioxide, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, simethicone, polyethylene glycol 6000, sucrose, magnesium carbonate, titanium dioxide, methylparaben, and polyvinyl alcohol. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Breast cancer cell growth may be estrogen-dependent. Aromatase is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Reference ID: 5496840 Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme, causing its inactivation, an effect also known as “suicide inhibition.” Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme. 12.2 Pharmacodynamics Effect on Estrogens Multiple doses of exemestane ranging from 0.5 to 600 mg/day were administered to postmenopausal women with advanced breast cancer. Plasma estrogen (estradiol, estrone, and estrone sulfate) suppression was seen starting at a 5­ mg daily dose of exemestane, with a maximum suppression of at least 85% to 95% achieved at a 25-mg dose. Exemestane 25 mg daily reduced whole body aromatization (as measured by injecting radiolabeled androstenedione) by 98% in postmenopausal women with breast cancer. After a single dose of exemestane 25 mg, the maximal suppression of circulating estrogens occurred 2 to 3 days after dosing and persisted for 4 to 5 days. Effect on Corticosteroids In multiple-dose trials of doses up to 200 mg daily, exemestane selectivity was assessed by examining its effect on adrenal steroids. Exemestane did not affect cortisol or aldosterone secretion at baseline or in response to ACTH at any dose. Thus, no glucocorticoid or mineralocorticoid replacement therapy is necessary with exemestane treatment. Other Endocrine Effects Exemestane does not bind significantly to steroidal receptors, except for a slight affinity for the androgen receptor (0.28% relative to dihydrotestosterone). The binding affinity of its 17-dihydrometabolite for the androgen receptor, however, is 100 times that of the parent compound. Daily doses of exemestane up to 25 mg had no significant effect on circulating levels of androstenedione, dehydroepiandrosterone sulfate, or 17-hydroxyprogesterone, and were associated with small decreases in circulating levels of testosterone. Increases in testosterone and androstenedione levels have been observed at daily doses of 200 mg or more. A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with daily exemestane doses of 2.5 mg or higher. Slight, nondose-dependent increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been observed even at low doses as a consequence of feedback at the pituitary level. Exemestane 25 mg daily had no significant effect on thyroid function [free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH)]. Coagulation and Lipid Effects In study 027 of postmenopausal women with early breast cancer treated with exemestane (N=73) or placebo (N=73), there was no change in the coagulation parameters activated partial thromboplastin time [APTT], prothrombin time [PT], and fibrinogen. Plasma HDL cholesterol was decreased 6–9% in exemestane treated patients; total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-A1, apolipoprotein-B, and lipoprotein-a were unchanged. An 18% increase in homocysteine levels was also observed in exemestane treated patients compared with a 12% increase seen with placebo. 12.3 Pharmacokinetics Following oral administration to healthy postmenopausal women, plasma concentrations of exemestane decline polyexponentially with a mean terminal half-life of about 24 hours. The pharmacokinetics of exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose. Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng∙h/mL) were about twice those in healthy women (41.4 ng∙h/mL). Absorption Following oral administration, exemestane appeared to be absorbed more rapidly in women with breast cancer than in the healthy women, with a mean tmax of 1.2 hours in the women with breast cancer and 2.9 hours in healthy women. Approximately 42% of radiolabeled exemestane was absorbed from the gastrointestinal tract. A high-fat breakfast increased AUC and Cmax of exemestane by 59% and 39%, respectively, compared to fasted state. Distribution Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and α11-acid glycoprotein both contribute to the binding. The distribution of exemestane and its metabolites into blood cells is negligible. Reference ID: 5496840 Metabolism Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity [see Clinical Pharmacology (12.2)]. Studies using human liver preparations indicate that cytochrome P 450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane. Exemestane is metabolized also by aldoketoreductases. Elimination Following administration of radiolabeled exemestane to healthy postmenopausal women, the cumulative amounts of radioactivity excreted in urine and feces were similar (42 ± 3% in urine and 42 ± 6% in feces over a 1-week collection period). The amount of drug excreted unchanged in urine was less than 1% of the dose. Specific Populations Geriatric: Healthy postmenopausal women aged 43 to 68 years were studied in the pharmacokinetic trials. Age- related alterations in exemestane pharmacokinetics were not seen over this age range. Gender: The pharmacokinetics of exemestane following administration of a single, 25-mg tablet to fasted healthy males (mean age 32 years) were similar to the pharmacokinetics of exemestane in fasted healthy postmenopausal women (mean age 55 years). Race: The influence of race on exemestane pharmacokinetics has not been evaluated. Hepatic Impairment: The pharmacokinetics of exemestane have been investigated in subjects with moderate or severe hepatic impairment (Childs-Pugh B or C). Following a single 25-mg oral dose, the AUC of exemestane was approximately 3 times higher than that observed in healthy volunteers. Renal Impairment: The AUC of exemestane after a single 25-mg dose was approximately 3 times higher in subjects with moderate or severe renal insufficiency (creatinine clearance <35 mL/min/1.73 m2) compared with the AUC in healthy volunteers. Pediatric: The pharmacokinetics of exemestane have not been studied in pediatric patients. Drug Interaction Studies Exemestane does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1, and 3A4. In a pharmacokinetic interaction study of 10 healthy postmenopausal volunteers pretreated with potent CYP 3A4 inducer rifampicin 600 mg daily for 14 days followed by a single dose of exemestane 25 mg, the mean plasma Cmax and AUC 0–∞ of exemestane were decreased by 41% and 54%, respectively [see Dosage and Administration (2.2) and Drug Interactions (7)]. In a clinical pharmacokinetic study, coadministration of ketoconazole, a potent inhibitor of CYP 3A4, has no significant effect on exemestane pharmacokinetics. Although no other formal drug-drug interaction studies with inhibitors have been conducted, significant effects on exemestane clearance by CYP isoenzyme inhibitors appear unlikely. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year carcinogenicity study in mice at doses of 50, 150, and 450 mg/kg/day exemestane (gavage), resulted in an increased incidence of hepatocellular adenomas and/or carcinomas in both genders at the high dose level. Plasma AUC (0–24hr) at the high dose were 2575 ± 386 and 5667 ± 1833 ng.hr/mL in males and females (approx. 34 and 75 fold the AUC in postmenopausal patients at the recommended clinical dose). An increased incidence of renal tubular adenomas was observed in male mice at the high dose of 450 mg/kg/day. Since the doses tested in mice did not achieve an MTD, neoplastic findings in organs other than liver and kidneys remain unknown. A separate carcinogenicity study was conducted in rats at the doses of 30, 100, and 315 mg/kg/day exemestane (gavage) for 92 weeks in males and 2 years in females. No evidence of carcinogenic activity up to the highest dose tested of 315 mg/kg/day was observed in females. The male rat study was inconclusive since it was terminated prematurely at Week 92. At the highest dose, plasma AUC(0–24hr) levels in male (1418 ± 287 ng.hr/mL) and female (2318 ± 1067 ng.hr/mL) rats were 19 and 31 fold higher than those measured in postmenopausal cancer patients receiving the recommended clinical dose. Exemestane was not mutagenic in vitro in bacteria (Ames test) or mammalian cells (V79 Chinese hamster lung cells). Exemestane was clastogenic in human lymphocytes in vitro without metabolic activation but was not Reference ID: 5496840 clastogenic in vivo (micronucleus assay in mouse bone marrow). Exemestane did not increase unscheduled DNA synthesis in rat hepatocytes when tested in vitro. In a pilot reproductive study in rats, male rats were treated with doses of 125–1000 mg/kg/day exemestane, beginning 63 days prior to and during cohabitation. Untreated female rats showed reduced fertility when mated to males treated with ≥500 mg/kg/day exemestane (≥200 times the recommended human dose on a mg/m2 basis). In a separate study, exemestane was given to female rats at 4–100 mg/kg/day beginning 14 days prior to mating and through day 15 or 20 of gestation. Exemestane increased the placental weights at ≥4 mg/kg/day (≥1.5 times the human dose on a mg/m2 basis). Exemestane showed no effects on ovarian function, mating behavior, and conception rate in rats given doses up to 20 mg/kg/day (approximately 8 times the recommended human dose on a mg/m2 basis); however, decreases in mean litter size and fetal body weight, along with delayed ossification were evidenced at ≥20 mg/kg/day. In general toxicology studies, changes in the ovary, including hyperplasia, an increase in the incidence of ovarian cysts, and a decrease in corpora lutea were observed with variable frequency in mice, rats, and dogs at doses that ranged from 3–20 times the human dose on a mg/m2 basis. 14 CLINICAL STUDIES 14.1 Adjuvant Treatment in Early Breast Cancer The Intergroup Exemestane Study 031 (IES) was a randomized, double-blind, multicenter, multinational study comparing exemestane (25 mg/day) vs. tamoxifen (20 or 30 mg/day) in postmenopausal women with early breast cancer. Patients who remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive an additional 3 or 2 years of AROMASIN or tamoxifen to complete a total of 5 years of hormonal therapy. The primary objective of the study was to determine whether, in terms of disease-free survival, it was more effective to switch to AROMASIN rather than continuing tamoxifen therapy for the remainder of five years. Disease- free survival was defined as the time from randomization to time of local or distant recurrence of breast cancer, contralateral invasive breast cancer, or death from any cause. The secondary objectives were to compare the two regimens in terms of overall survival and long-term tolerability. Time to contralateral invasive breast cancer and distant recurrence-free survival were also evaluated. A total of 4724 patients in the intent-to-treat (ITT) analysis were randomized to AROMASIN (exemestane tablets) 25 mg once daily (N = 2352) or to continue to receive tamoxifen once daily at the same dose received before randomization (N = 2372). Demographics and baseline tumor characteristics are presented in Table 5. Prior breast cancer therapy is summarized in Table 6. Reference ID: 5496840 Table 5. Demographic and Baseline Tumor Characteristics from the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population) Parameter Exemestane (N = 2352) Tamoxifen (N = 2372) Age (years): Median age (range) 63.0 (38.0 – 96.0) 63.0 (31.0 – 90.0) Race, n (%): Caucasian 2315 (98.4) 2333 (98.4) Hispanic 13 (0.6) 13 (0.5) Asian 10 (0.4) 9 (0.4) Black 7 (0.3) 10 (0.4) Other/not reported 7 (0.3) 7 (0.3) Nodal status, n (%): Negative 1217 (51.7) 1228 (51.8) Positive 1051 (44.7) 1044 (44.0) 1–3 Positive nodes 721 (30.7) 708 (29.8) 4–9 Positive nodes 239 (10.2) 244 (10.3) >9 Positive nodes 88 (3.7) 86 (3.6) Not reported 3 (0.1) 6 (0.3) Unknown or missing 84 (3.6) 100 (4.2) Histologic type, n (%): Infiltrating ductal 1777 (75.6) 1830 (77.2) Infiltrating lobular 341 (14.5) 321 (13.5) Other 231 (9.8) 213 (9.0) Unknown or missing 3 (0.1) 8 (0.3) Receptor status*, n (%): ER and PgR Positive 1331 (56.6) 1319 (55.6) ER Positive and PgR Negative/Unknown 677 (28.8) 692 (29.2) ER Unknown and PgR Positive**/Unknown 288 (12.2) 291 (12.3) ER Negative and PgR Positive 6 (0.3) 7 (0.3) ER Negative and PgR Negative/Unknown (none positive) 48 (2.0) 58 (2.4) Missing 2 (0.1) 5 (0.2) Tumor Size, n (%): < 0.5 cm 58 (2.5) 46 (1.9) > 0.5 – 1.0 cm 315 (13.4) 302 (12.7) > 1.0 – 2 cm 1031 (43.8) 1033 (43.5) > 2.0 – 5.0 cm 833 (35.4) 883 (37.2) > 5.0 cm 62 (2.6) 59 (2.5) Not reported 53 (2.3) 49 (2.1) Tumor Grade, n (%): G1 397 (16.9) 393 (16.6) G2 977 (41.5) 1007 (42.5) G3 454 (19.3) 428 (18.0) G4 23 (1.0) 19 (0.8) Unknown/Not Assessed/Not reported 501 (21.3) 525 (22.1) * Results for receptor status include the results of the post-randomization testing of specimens from subjects for whom receptor status was unknown at randomization. ** Only one subject in the exemestane group had unknown ER status and positive PgR status. Reference ID: 5496840 Table 6. Prior Breast Cancer Therapy of Patients in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population) Parameter Exemestane (N = 2352) Tamoxifen (N = 2372) Type of surgery, n (%): Mastectomy 1232 (52.4) 1242 (52.4) Breast-conserving 1116 (47.4) 1123 (47.3) Unknown or missing 4 (0.2) 7 (0.3) Radiotherapy to the breast, n (%): Yes 1524 (64.8) 1523 (64.2) No 824 (35.5) 843 (35.5) Not reported 4 (0.2) 6 (0.3) Prior therapy, n (%): Chemotherapy 774 (32.9) 769 (32.4) Hormone replacement therapy 567 (24.1) 561 (23.7) Bisphosphonates 43 (1.8) 34 (1.4) Duration of tamoxifen therapy at randomization (months): Median (range) 28.5 (15.8 – 52.2) 28.4 (15.6 – 63.0) Tamoxifen dose, n (%): 20 mg 2270 (96.5) 2287 (96.4) 30 mg* 78 (3.3) 75 (3.2) Not reported 4 (0.2) 10 (0.4) *The 30 mg dose was used only in Denmark, where this dose was the standard of care. After a median duration of therapy of 27 months and with a median follow-up of 34.5 months, 520 events were reported, 213 in the AROMASIN group and 307 in the tamoxifen group (Table 7). Table 7. Primary Endpoint Events (ITT Population) Event First Events N (%) Exemestane (N = 2352) Tamoxifen (N = 2372) Loco-regional recurrence 34 (1.45) 45 (1.90) Distant recurrence 126 (5.36) 183 (7.72) Second primary – contralateral breast cancer 7 (0.30) 25 (1.05) Death – breast cancer 1 (0.04) 6 (0.25) Death – other reason 41 (1.74) 43 (1.81) Death – missing/unknown 3 (0.13) 5 (0.21) Ipsilateral breast cancer 1 (0.04) 0 Total number of events 213 (9.06) 307 (12.94) Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.69, 95% CI: 0.58, 0.82, P = 0.00003, Table 8, Figure 1] in the AROMASIN arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 85% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.65, 95% CI: 0.53, 0.79, P = 0.00001) in the AROMASIN arm compared to the tamoxifen arm. Consistent results were observed in the subgroups of patients with node negative or positive disease, and patients who had or had not received prior chemotherapy. An overall survival update at 119 months median follow-up showed no significant difference between the two groups, with 467 deaths (19.9%) occurring in the AROMASIN group and 510 deaths (21.5%) in the tamoxifen group. Reference ID: 5496840 1.0 0.9 0.8 Cl C: ·,; 0.7 ·,; :S rn 0.6 C: 0 :e 0.5 0 Q. 0 0.4 a: 0.3 0.2 0.1 0.0 0 HR (95% Cl): 0.69 (0.58-0.82) p (log-rank): 0.00003 Treatment Randomized n Events n Patients Exemestane 213 2352 Tamoxifen 307 2372 10 20 30 40 50 Duration of Disease-free Survival (Months) 60 70 Table 8. Efficacy Results from the IES Study in Postmenopausal Women with Early Breast Cancer ITT Population Hazard Ratio (95% CI) p-value (log-rank test) Disease-free survival Time to contralateral breast cancer Distant recurrence-free survival Overall survival 0.69 (0.58–0.82) 0.32 (0.15–0.72) 0.74 (0.62–0.90) 0.91 (0.81–1.04) 0.00003 0.00340 0.00207 0.16* ER and/or PgR positive Disease-free survival Time to contralateral breast cancer Distant recurrence-free survival Overall survival 0.65 (0.53–0.79) 0.22 (0.08–0.57) 0.73 (0.59–0.90) 0.89 (0.78–1.02) 0.00001 0.00069 0.00367 0.09065* *Not adjusted for multiple testing. Figure 1. Disease-Free Survival in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population) 14.2 Treatment of Advanced Breast Cancer Exemestane 25 mg administered once daily was evaluated in a randomized double-blind, multicenter, multinational comparative study and in two multicenter single-arm studies of postmenopausal women with advanced breast cancer who had disease progression after treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also have received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease. The primary purpose of the three studies was evaluation of objective response rate (complete response [CR] and partial response [PR]). Time to tumor progression and overall survival were also assessed in the comparative trial. Response rates were assessed based on World Health Organization (WHO) criteria, and in the comparative study, were submitted to an external review committee that was blinded to patient treatment. In the comparative study, 769 patients were randomized to receive AROMASIN (exemestane tablets) 25 mg once daily (N = 366) or megestrol acetate 40 mg four times daily (N = 403). Demographics and baseline characteristics are presented in Table 9. Table 9. Demographics and Baseline Characteristics from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy Parameter AROMASIN (N = 366) Megestrol Acetate (N = 403) Median Age (range) 65 (35–89) 65 (30–91) ECOG Performance Status 0 1 2 167 (46%) 162 (44%) 34 (9%) 187 (46%) 172 (43%) 42 (10%) Receptor Status ER and/or PgR + ER and PgR unknown Responders to prior tamoxifen 246 (67%) 116 (32%) 68 (19%) 274 (68%) 128 (32%) 85 (21%) Reference ID: 5496840 Table 9. Demographics and Baseline Characteristics from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy Parameter AROMASIN (N = 366) Megestrol Acetate (N = 403) NE for response to prior tamoxifen 46 (13%) 41 (10%) Site of Metastasis Visceral ± other sites Bone only Soft tissue only Bone & soft tissue 207 (57%) 61 (17%) 54 (15%) 43 (12%) 239 (59%) 73 (18%) 51 (13%) 38 (9%) Measurable Disease 287 (78%) 314 (78%) Prior Tamoxifen Therapy Adjuvant or Neoadjuvant Advanced Disease, Outcome CR, PR, or SD > 6 months SD < 6 months, PD or NE 145 (40%) 179 (49%) 42 (12%) 152 (38%) 210 (52%) 41 (10%) Prior Chemotherapy For advanced disease ± adjuvant Adjuvant only No chemotherapy 58 (16%) 104 (28%) 203 (56%) 67 (17%) 108 (27%) 226 (56%) The efficacy results from the comparative study are shown in Table 10. The objective response rates observed in the two treatment arms showed that AROMASIN was not different from megestrol acetate. Response rates for AROMASIN from the two single-arm trials were 23.4% and 28.1%. Table 10. Efficacy Results from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy Response Characteristics AROMASIN (N=366) Megestrol Acetate (N=403) Objective Response Rate = CR + PR (%) Difference in Response Rate (AR-MA) 95% C.I. 15.0 12.4 2.6 7.5, -2.3 CR (%) PR (%) SD ≥ 24 Weeks (%) Median Duration of Response (weeks) Median TTP (weeks) 2.2 12.8 21.3 76.1 20.3 1.2 11.2 21.1 71.0 16.6 Hazard Ratio (AR-MA) 0.84 Abbreviations: CR = complete response, PR = partial response, SD = stable disease (no change), TTP = time to tumor progression, C.I. = confidence interval, MA = megestrol acetate, AR = AROMASIN There were too few deaths occurring across treatment groups to draw conclusions on overall survival differences. The Kaplan-Meier curve for time to tumor progression in the comparative study is shown in Figure 2. Reference ID: 5496840 LO 0.9 0.8 0.7 i 0.6 {l 0.5 £ 0.4 0.3 0.2 0.1 0.0 AROMASIN (No. of PDB/No. pt.s. = 270/366) Megestrol Acetate (No. of PDB/No. pt.s. = 305/403) -"'\,. _ ---- , Weeks Figure 2. Time to Tumor Progression in the Comparative Study of Postmenopausal Women With Advanced Breast Cancer Whose Disease Had Progressed After Tamoxifen Therapy 16 HOW SUPPLIED/STORAGE AND HANDLING AROMASIN Tablets are round, biconvex, and off-white to slightly gray. Each tablet contains 25 mg of exemestane. The tablets are printed on one side with the number “7663” in black. AROMASIN is packaged in HDPE bottles with a child-resistant screw cap, supplied in packs of 30 tablets. 30-tablet HDPE bottle NDC 0009-7663-04 Store at 25°C (77ºF); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Bone Effects Advise patients that AROMASIN lowers the level of estrogen in the body. This may lead to reduction in bone mineral density (BMD) over time. The lower the BMD, the greater the risk of osteoporosis and fracture [see Warnings and Precautions (5.1)]. Other Estrogen-Containing Agents Advise patients that they should not take estrogen-containing agents while they are taking AROMASIN as these could interfere with its pharmacologic action [see Warnings and Precautions (5.3)]. Use in Premenopausal Women Advise patients that AROMASIN is not for use for the treatment of breast cancer in premenopausal women [see Warnings and Precautions (5.5)]. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential that exposure during pregnancy or within 1 month prior to conception can result in fetal harm. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception while taking AROMASIN and for 1 month after the last dose [see Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment with AROMASIN and for 1 month after the last dose [see Use in Specific Populations (8.2)]. Reference ID: 5496840 ~Pfizer Distributed by Pharmacia & Upjohn Company LLC A subsidiary of Pfizer Inc. New York, NY 10001 LAB-0098-21.3 Reference ID: 5496840 Patient Information AROMASIN (ah ROME ah sin) (exemestane) tablets What is AROMASIN? AROMASIN is used in women who are past menopause for the treatment of: • Early breast cancer (cancer that has not spread outside the breast) in women who: o have cancer that needs the female hormone estrogen to grow, and o have had other treatments for breast cancer, and o have taken tamoxifen for 2 to 3 years, and o are switching to AROMASIN to complete 5 years in a row of hormonal therapy. • Advanced breast cancer (cancer that has spread) after treatment with tamoxifen, and it did not work or is no longer working. It is not known if AROMASIN is safe and effective in children. Do not take AROMASIN if you are allergic to AROMASIN or any of the ingredients in AROMASIN. See the end of this leaflet for a complete list of ingredients in AROMASIN. Before you take AROMASIN, tell your doctor about all your medical conditions, including if you: • are still having menstrual periods (are not past menopause). AROMASIN is only for women who are past menopause. • have weak or brittle bones (osteoporosis) • are pregnant or plan to become pregnant. Taking AROMASIN during pregnancy or within 1 month of becoming pregnant can harm your unborn baby. o Females who are able to become pregnant should have a pregnancy test within 7 days before starting treatment with AROMASIN. o Females who are able to become pregnant should use effective birth control (contraceptive) during treatment with AROMASIN and for 1 month after your last dose of AROMASIN. Tell your doctor right away if you become pregnant or think you may be pregnant. • are breastfeeding or plan to breastfeed. It is not known if AROMASIN passes into your breast milk. Do not breast-feed during treatment with AROMASIN and for 1 month after your last dose of AROMASIN. • Have liver or kidney problems. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Especially tell your doctor if you take medicines that contain estrogen, including other hormone replacement therapy or birth control pills or patches. AROMASIN should not be taken with medicines that contain estrogen as they could affect how well AROMASIN works. How should I take AROMASIN? • Take AROMASIN exactly as your doctor tells you. • Take AROMASIN 1 time each day after a meal. • If you take too much AROMASIN, call your doctor right away or go to nearest hospital emergency room. What are the possible side effects of AROMASIN? AROMASIN may cause serious side effects, including: • Bone loss. AROMASIN decreases the amount of estrogen in your body which may reduce your bone mineral density (BMD) over time. This may increase your risk for bone fractures or weak and brittle bones (osteoporosis). Your doctor may check your bones during treatment with AROMASIN if you have osteoporosis or at risk for osteoporosis. The most common side effects of AROMASIN in women with early breast cancer include: • hot flashes • feeling tired • joint pain • headache • trouble sleeping • increased sweating The most common side effects of AROMASIN in women with advanced breast cancer include: • hot flashes • nausea • feeling tired • increased sweating • increased appetite Your doctor will do blood tests to check your vitamin D level before starting treatment with AROMASIN. AROMASIN may cause decreased fertility in males and females. Talk to your doctor if you have concerns about fertility. These are not all the possible side effects of AROMASIN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Reference ID: 5496840 ~Pfizer Distributed by Pharmacia & Upjohn Company LLC A subsidiary of Pfizer Inc. New York, NY 10001 How should I store AROMASIN? • Store AROMASIN at room temperature 68°F to 77°F (20°C to 25°C). • Keep AROMASIN and all medicines out of the reach of children. General information about the safe and effective use of AROMASIN. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use AROMASIN for a condition for which it was not prescribed. Do not give AROMASIN to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about AROMASIN that is written for health professionals. What is in AROMASIN? Active ingredient: exemestane Inactive ingredients: mannitol, crospovidone, polysorbate 80, hypromellose, colloidal silicon dioxide, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, simethicone, polyethylene glycol 6000, sucrose, magnesium carbonate, titanium dioxide, methylparaben, and polyvinyl alcohol. LAB-0399-9.1 For more information, go to www.AROMASIN.com or call 1-888-AROMASIN (1-888-276-6274). This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 12/2024 Reference ID: 5496840
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2025-02-12T15:47:47.491229
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FEMARA safely and effectively. See full prescribing information for FEMARA. FEMARA (letrozole) tablets, for oral use Initial U.S. Approval: 1997 ----------------------------INDICATIONS AND USAGE--------------------------- Femara is an aromatase inhibitor indicated for: • Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. (1.1) • Extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy. (1.2) • First and second-line treatment of postmenopausal women with hormone receptor positive or unknown advanced breast cancer. (1.3) -------------------------DOSAGE AND ADMINISTRATION--------------------- Femara tablets are taken orally without regard to meals (2): • Recommended dose: 2.5 mg once daily. (2.1) • Patients with cirrhosis or severe hepatic impairment: 2.5 mg every other day. (2.5, 5.3) -----------------------DOSAGE FORMS AND STRENGTHS-------------------­ 2.5 mg tablets. (3) --------------------------------CONTRAINDICATIONS----------------------------­ • Pregnancy. (4) • Known hypersensitivity to the active substance, or to any of the excipients. (4) -----------------------WARNINGS AND PRECAUTIONS----------------------­ • Decreases in bone mineral density may occur. Consider bone mineral density monitoring. (5.1) • Increases in total cholesterol may occur. Consider cholesterol monitoring. (5.2) • Fatigue, dizziness, and somnolence may occur. Exercise caution when operating machinery. (5.4) • Embryo-Fetal Toxicity: Can cause fetal harm when administered to pregnant women. Obtain a pregnancy test in females of reproductive potential. Advise females of reproductive potential to use effective contraception. (5.6, 8.1, 8.3) ------------------------------ADVERSE REACTIONS------------------------------­ The most common adverse reactions (greater than 20%) were hot flashes, arthralgia; flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, bone pain; and musculoskeletal. (6) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA­ 1088 or www.fda.gov/medwatch. ------------------------------USE IN SPECIFIC POPULATIONS----------------­ • Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Adjuvant Treatment of Early Breast Cancer 1.2 Extended Adjuvant Treatment of Early Breast Cancer 1.3 First and Second-Line Treatment of Advanced Breast Cancer 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose 2.2 Use in Adjuvant Treatment of Early Breast Cancer 2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer 2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer 2.5 Use in Hepatic Impairment 2.6 Use in Renal Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Bone Effects 5.2 Cholesterol 5.3 Hepatic Impairment 5.4 Fatigue and Dizziness 5.5 Laboratory Test Abnormalities 5.6 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Updated Adjuvant Treatment of Early Breast Cancer 14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months 14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months 14.4 First-Line Treatment of Advanced Breast Cancer 14.5 Second-Line Treatment of Advanced Breast Cancer 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed Reference ID: 5496852 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Adjuvant Treatment of Early Breast Cancer Femara (letrozole) is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. 1.2 Extended Adjuvant Treatment of Early Breast Cancer Femara is indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of Femara in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival (DFS) in patients treated with Femara for a median of 60 months [see Clinical Studies (14.2, 14.3)]. 1.3 First and Second-Line Treatment of Advanced Breast Cancer Femara is indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Femara is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy [see Clinical Studies (14.4, 14.5)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended dose of Femara is one 2.5 mg tablet administered once a day, without regard to meals. 2.2 Use in Adjuvant Treatment of Early Breast Cancer In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. In both the adjuvant study and the post approval adjuvant study, median treatment duration was 5 years. Treatment should be discontinued at relapse [see Clinical Studies (14.1)]. 2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer In the extended adjuvant setting, the optimal treatment duration with Femara is not known. The planned duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration for Femara was 60 months. Seventy-one percent (71%) of patients were treated for at least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse [see Clinical Studies (14.2)]. 2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer In patients with advanced disease, treatment with Femara should continue until tumor progression is evident [see Clinical Studies (14.4, 14.5)]. 2.5 Use in Hepatic Impairment No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although Femara blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of Femara in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and Precautions (5.3)]. The recommended dose of Femara for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on Femara exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined. 2.6 Use in Renal Impairment No dosage adjustment is required for patients with renal impairment if creatinine clearance is greater than or equal to 10 mL/min [see Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS 2.5 mg tablets: dark yellow, film-coated, round, slightly biconvex, with beveled edges (imprinted with the letters FV on one side and CG on the other side). Reference ID: 5496852 4 CONTRAINDICATIONS • Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations (8.1)]. • Known hypersensitivity to the active substance, or to any of the excipients [see Adverse Reactions (6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bone Effects Use of Femara may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of a safety study to evaluate safety in the adjuvant setting comparing the effect on lumbar spine (L2-L4) BMD of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001) [see Adverse Reactions (6)]. Updated results from the BMD substudy (MA-17B) in the extended adjuvant setting demonstrated that at 2 years patients receiving letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2.0% in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not significantly different [see Adverse Reactions (6)]. In the adjuvant trial (BIG 1-98) the incidence of bone fractures at any time after randomization was 14.7% for letrozole and 11.4% for tamoxifen at a median follow-up of 96 months. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [see Adverse Reactions (6)]. In the extended adjuvant trial (MA-17), the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo at a median follow-up of 62 months. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo [see Adverse Reactions (6)]. 5.2 Cholesterol Consideration should be given to monitoring serum cholesterol. In the adjuvant trial (BIG 1-98), hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. Grade 3-4 hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of greater than or equal to 1.5 x upper limit of normal (ULN) in total cholesterol (generally nonfasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., less than =1.5 x ULN) in 155/1843 (8.4%) patients on letrozole vs 71/1840 (3.9%) patients on tamoxifen Lipid lowering medications were required for 29% of patients on letrozole and 20% on tamoxifen [see Adverse Reactions (6)]. 5.3 Hepatic Impairment Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of Femara experienced approximately twice the exposure to Femara as healthy volunteers with normal liver function [see Clinical Pharmacology (12.3)]. Therefore, a dose reduction is recommended for this patient population. The effect of hepatic impairment on Femara exposure in cancer patients with elevated bilirubin levels has not been determined [see Dosage and Administration (2.5)]. 5.4 Fatigue and Dizziness Because fatigue, dizziness, and somnolence have been reported with the use of Femara, caution is advised when driving or using machinery until it is known how the patient reacts to Femara use. 5.5 Laboratory Test Abnormalities No dose-related effect of Femara on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving Femara 2.5 mg. This depression was transient in about half of those affected. Two patients on Femara developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not was infrequent. 5.6 Embryo-Fetal Toxicity Based on post-marketing reports, findings from animal studies and the mechanism of action, Femara can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects. Letrozole caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were below the maximum recommended human dose (MHRD) on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with Femara and for at least 3 weeks after the last dose [see Adverse Reactions (6.2), Use in Specific Populations (8.1, 8.3), and Clinical Pharmacology (12.1)]. Reference ID: 5496852 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Bone effects [see Warnings and Precautions (5.1)] • Increases in cholesterol [see Warnings and Precautions (5.2)] • Fatigue and Dizziness [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Treatment of Early Breast Cancer In study, BIG 1-98, the median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 96 months for patients receiving Femara and tamoxifen. Certain adverse reactions were prospectively specified for analysis (see Table 1), based on the known pharmacologic properties and side effect profiles of the two drugs. Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported (approximately 75% of patients who reported AEs) were Grade 1 or Grade 2 applying the Common Toxicity Criteria (CTC) Version 2.0/Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0. Table 1 describes adverse reactions (Grades 1-4 and Grades 3-4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population). Table 1: Patients With Adverse Reactions (CTC Grades 1-4) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 96 Months; Median Treatment 60 Months) Grades 1-4 Grades 3-4 Femara Tamoxifen Femara Tamoxifen Adverse Reactions N = 2448 N = 2447 N = 2448 N = 2447 n (%) n (%) n (%) n (%) Patients with any adverse reaction 2309 (94.3) 2212 (90.4) 636 (26.0) 606 (24.8) Hypercholesterolemia* 1280 (52.3) 700 (28.6) 11 (0.4) 6 (0.2) Hot flashes* Arthralgia/arthritis* Bone fractures1 819 621 361 (33.5) (25.4) (14.7) 929 504 280 (38.0) (20.6) (11.4) - 84 - - (3.4) - - 50 - - (2.0) - Night sweats* 356 (14.5) 426 (17.4) - - - - Weight increase* 317 (12.9) 378 (15.4) 27 (1.1) 39 (1.6) Nausea* Bone fractures**2 Fatigue (lethargy, malaise, asthenia)* 284 249 235 (11.6) (10.2) (9.6) 277 175 250 (11.3) (7.2) (10.2) 6 - 6 (0.2) - (0.2) 9 - 7 (0.4) - (0.3) Myalgia* Vaginal bleeding* 221 129 (9.0) (5.3) 212 320 (8.7) (13.1) 18 1 (0.7) (< 0.1) 14 8 (0.6) (0.3) Edema* 164 (6.7) 160 (6.5) 3 (0.1) 1 (< 0.1) Weight decrease Osteoporosis** 140 126 (5.7) (5.1) 129 67 (5.3) (2.7) 8 10 (0.3) (0.4) 5 5 (0.2) (0.2) Back pain 125 (5.1) 136 (5.6) 7 (0.3) 11 (0.4) Bone pain 123 (5.0) 109 (4.5) 6 (0.2) 4 (0.2) Reference ID: 5496852 Grades 1-4 Grades 3-4 Femara Tamoxifen Femara Tamoxifen Adverse Reactions N = 2448 N = 2447 N = 2448 N = 2447 n (%) n (%) n (%) n (%) Depression 119 (4.9) 114 (4.7) 16 (0.7) 14 (0.6) Vaginal irritation* 112 (4.6) 77 (3.1) 2 (< 0.1) 2 (< 0.1) Headache* 105 (4.3) 94 (3.8) 8 (0.3) 4 (0.2) Pain in extremity 103 (4.2) 79 (3.2) 6 (0.2) 4 (0.2) Osteopenia* 87 (3.6) 76 (3.1) 0 - 3 (0.1) Dizziness/light-headedness* 84 (3.4) 80 (3.3) 1 (< 0.1) 6 (0.2) Alopecia 83 (3.4) 84 (3.4) - - - - Vomiting* 80 (3.3) 80 (3.3) 3 (0.1) 5 (0.2) Cataract* 49 (2.0) 54 (2.2) 16 (0.7) 17 (0.7) Constipation* 49 (2.0) 71 (2.9) 3 (0.1) 1 (< 0.1) Myocardial infarction1 42 (1.7) 28 (1.1) - - - - Breast pain* 37 (1.5) 43 (1.8) 1 (< 0.1) - - Anorexia* 20 (0.8) 20 (0.8) 1 (< 0.1) 1 (< 0.1) Endometrial proliferation 14 (0.6) 86 (3.5) 0 - 14 (0.6) disorders* Ovarian cyst* 11 (0.4) 18 (0.7) 4 (0.2) 4 (0.2) Endometrial 11 (0.4) 72 (2.9) - - - - hyperplasia/cancer**1 Endometrial 6/1909 (0.3) 57/194 (2.9) - - - - hyperplasia/cancer**,3 3 Other endometrial disorders* 2 (< 0.1) 3 (0.1) 0 - 0 - Myocardial infarction**2 24 (1.0) 12 (0.5) - - - - Myocardial ischemia 6 (0.2) 9 (0.4) - - - - Cerebrovascular 74 (3.0) 68 (2.8) - - - - accident/TIA**1 Cerebrovascular 51 (2.1) 47 (1.9) - - - - accident/TIA**2 Angina requiring surgery**1 35 (1.4) 33 (1.3) - - - - Angina requiring surgery**2 25 (1.0) 25 (1.0) - - - - Thromboembolic event**1 79 (3.2) 113 (4.6) - - - - Thromboembolic event**2 51 (2.1) 89 (3.6) - - - - Cardiac failure1 39 (1.6) 34 (1.4) - - - - Cardiac failure2 27 (1.1) 15 (0.6) - - - - Hypertension1 160 (6.5) 175 (7.2) - - - - Hypertension2 138 (5.6) 139 (5.7) - - - - Other cardiovascular**1 172 (7.0) 174 (7.1) - - - - Other cardiovascular**2 120 (4.9) 119 (4.9) - - - - Second primary malignancy1 129 (5.3) 150 (6.1) - - - - Second primary malignancy2 54 (2.2) 79 (3.2) - - - - *Target events pre-specified for analysis Reference ID: 5496852 Grades 1-4 Grades 3-4 Femara Tamoxifen Femara Tamoxifen Adverse Reactions N = 2448 N = 2447 N = 2448 N = 2447 n (%) n (%) n (%) n (%) **Events pre-printed on CRF 1At median follow-up of 96 months (i.e., any time after randomization) for Femara (range up to 144 months) and 95 months for tamoxifen (range up to 143 months). 2At median treatment duration of 60 months (i.e. during treatment + 30 days after discontinuation of treatment) for Femara and tamoxifen (range up to 68 months). 3Excluding women who had undergone hysterectomy before study entry. TIA = Transient ischemic attack. Note: Cardiovascular events (including cerebrovascular and thromboembolic events), skeletal and urogenital/endometrial events and second primary malignancies were collected life -long. All of these events were assumed to be of CTC Grade 3 to 5 and were not individually graded. When considering all grades during study treatment, a higher incidence of events was seen for Femara regarding fractures (10.1% vs 7.1%), myocardial infarctions (1.0% vs 0.5%), and arthralgia (25.2% vs 20.4%) (Femara vs tamoxifen respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (2.1% vs 3.6%), endometrial hyperplasia/cancer (0.3% vs 2.9%), and endometrial proliferation disorders (0.3% vs 1.8%) (Femara vs tamoxifen respectively). At a median follow-up of 96 months, a higher incidence of events was seen for Femara (14.7%) than for tamoxifen (11.4%) regarding fractures. A higher incidence was seen for tamoxifen compared to Femara regarding thromboembolic events (4.6% vs 3.2%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs Femara, respectively). Bone Study: Results of a safety trial in 263 postmenopausal women with resected receptor positive early breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2-L4) BMD of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) (P < 0.0001). No patients with a normal BMD at baseline became osteoporotic over the 2 years and only 1 patient with osteopenia at baseline (T score of -1.9) developed osteoporosis during the treatment period (assessment by central review). The results for total hip BMD were similar, although the differences between the two treatments were less pronounced. During the 2 year period, fractures were reported by 4 of 103 patients (4%) in the letrozole arm, and 6 of 97 patients (6%) in the tamoxifen arm. Lipid Study: In a safety trial in 263 postmenopausal women with resected receptor positive early breast cancer at 24 months comparing the effects on lipid profiles of adjuvant letrozole to tamoxifen, 12% of patients on letrozole had at least one total cholesterol value of a higher CTCAE grade than at baseline compared with 4% of patients on tamoxifen. In another postapproval randomized, multicenter, open label, study of letrozole vs anastrozole in the adjuvant treatment of postmenopausal women with hormone receptor and node positive breast cancer (FACE, NCT00248170), the median duration of treatment was 60 months for both treatment arms. Table 2 describes adverse reactions (Grades 1-4 and Grades 3-4) irrespective of relationship to study treatment in the adjuvant study (safety population). Table 2: Adverse Reactions (CTC Grades 1-4), Occurring in at Least 5% of Patients in Either Treatment Arm, by Preferred Term (Safety set) Letrozole Anastrozole N = 2049 N = 2062 Adverse Reactions n (%) n (%) Grade 3/4 All Grades Grade 3/4 All Grades n (%) n (%) n (%) n (%) Patients with at least one AR 628 (30.6) 2049 (100.0) 591 (28.7) 2062 (100.0) Arthralgia 80 (3.9) 987 (48.2) 69 (3.3) 987 (47.9) Hot flush 17 (0.8) 666 (32.5) 9 (0.4) 666 (32.3) Fatigue 8 (0.4) 345 (16.8) 10 (0.5) 343 (16.6) Osteoporosis 5 (0.2) 223 (10.9) 11 (0.5) 225 (10.9) Myalgia 16 (0.8) 233 (11.4) 15 (0.7) 212 (10.3) Back pain 11 (0.5) 212 (10.3) 17 (0.8) 193 (9.4) Osteopenia 4 (0.2) 203 (9.9) 1 (0.0) 173 (8.4) Reference ID: 5496852 Pain in extremity 9 (0.4) 168 (8.2) 3 (0.1) 174 (8.4) Lymphoedema 5 (0.2) 159 (7.8) 2 (0.1) 179 (8.7) Insomnia 7 (0.3) 160 (7.8) 3 (0.1) 149 (7.2) Hypercholesterolaemia 2 (0.1) 155 (7.6) 1 (0.0) 151 (7.3) Hypertension 25 (1.2) 156 (7.6) 20 (1.0) 149 (7.2) Depression 16 (0.8) 147 (7.2) 13 (0.6) 137 (6.6) Bone pain 10 (0.5) 138 (6.7) 9 (0.4) 122 (5.9) Nausea 6 (0.3) 137 (6.7) 5 (0.2) 152 (7.4) Headache 3 (0.1) 130 (6.3) 5 (0.2) 168 (8.1) Alopecia 2 (0.1) 127 (6.2) 0 (0.0) 134 (6.5) Musculoskeletal pain 6 (0.3) 123 (6.0) 9 (0.4) 147 (7.1) Radiation skin injury 11 (0.5) 120 (5.9) 6 (0.3) 88 (4.3) Dyspnea 16 (0.8) 118 (5.8) 10 (0.5) 96 (4.7) Cough 1 (0.0) 106 (5.2) 1 (0.0) 120 (5.8) Musculoskeletal stiffness 2 (0.1) 102 (5.0) 2 (0.1) 84 (4.1) Dizziness 2 (0.2) 94 (4.6) 7 (0.3) 109 (5.3) The following adverse reactions were also identified in less than 5% of the 2049 patients treated with letrozole and not included in the table: fall, vertigo, hyperbilirubinemia, jaundice, and chest pain. Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months In study MA-17, the median duration of extended adjuvant treatment was 24 months and the median duration of follow­ up for safety was 28 months for patients receiving Femara and placebo. Table 3 describes the adverse reactions occurring at a frequency of at least 5% in any treatment group during treatment. Most adverse reactions reported were Grade 1 and Grade 2 based on the CTC Version 2.0. In the extended adjuvant setting, the reported drug-related adverse reactions that were significantly different from placebo were hot flashes, arthralgia/arthritis, and myalgia. Table 3: Adverse Reactions Occurring in at Least 5% of Patients in Either Treatment Arm Number (%) of Patients with Grade 1-4 Adverse Reactions Number (%) of Patients with Grade 3-4 Adverse Reactions Femara Placebo N = 2563 N = 2573 Femara Placebo N = 2563 N = 2573 Any Adverse Reactions 2232 (87.1) 2174 (84.5) 419 (16.3) 389 (15.1) Vascular Disorders 1375 (53.6) 1230 (47.8) 59 (2.3) 74 (2.9) Flushing 1273 (49.7) 1114 (43.3) 3 (0.1) 0 General Disorders 1154 (45) 1090 (42.4) 30 (1.2) 28 (1.1) Asthenia 862 (33.6) 826 (32.1) 16 (0.6) 7 (0.3) Edema NOS 471 (18.4) 416 (16.2) 4 (0.2) 3 (0.1) Musculoskeletal Disorders 978 (38.2) 836 (32.5) 71 (2.8) 50 (1.9) Arthralgia 565 (22) 465 (18.1) 25 (1) 20 (0.8) Arthritis NOS 173 (6.7) 124 (4.8) 10 (0.4) 5 (0.2) Myalgia 171 (6.7) 122 (4.7) 8 (0.3) 6 (0.2) Back Pain 129 (5) 112 (4.4) 8 (0.3) 7 (0.3) Nervous System Disorders 863 (33.7) 819 (31.8) 65 (2.5) 58 (2.3) Headache 516 (20.1) 508 (19.7) 18 (0.7) 17 (0.7) Dizziness 363 (14.2) 342 (13.3) 9 (0.4) 6 (0.2) Skin Disorders 830 (32.4) 787 (30.6) 17 (0.7) 16 (0.6) Sweating Increased 619 (24.2) 577 (22.4) 1 (< 0.1) 0 Gastrointestinal Disorders 725 (28.3) 731 (28.4) 43 (1.7) 42 (1.6) Constipation 290 (11.3) 304 (11.8) 6 (0.2) 2 (< 0.1) Nausea 221 (8.6) 212 (8.2) 3 (0.1) 10 (0.4) Diarrhea NOS 128 (5) 143 (5.6) 12 (0.5) 8 (0.3) Metabolic Disorders 551 (21.5) 537 (20.9) 24 (0.9) 32 (1.2) Hypercholesterolemia 401 (15.6) 398 (15.5) 2 (< 0.1) 5 (0.2) Reference ID: 5496852 Reproductive Disorders Vaginal Hemorrhage Vulvovaginal Dryness Psychiatric Disorders Insomnia Respiratory Disorders Dyspnea Investigations Infections and Infestations Renal Disorders 303 (11.8) 123 (4.8) 137 (5.3) 320 (12.5) 149 (5.8) 279 (10.9) 140 (5.5) 184 (7.2) 166 (6.5) 130 (5.1) 357 (13.9) 171 (6.6) 127 (4.9) 276 (10.7) 120 (4.7) 260 (10.1) 137 (5.3) 147 (5.7) 163 (6.3) 100 (3.9) 9 (0.4) 2 (< 0.1) 0 21 (0.8) 2 (< 0.1) 30 (1.2) 21 (0.8) 13 (0.5) 40 (1.6) 12 (0.5) 8 (0.3) 5 (0.2) 0 16 (0.6) 2 (< 0.1) 28 (1.1) 18 (0.7) 13 (0.5) 33 (1.3) 6 (0.2) Based on a median follow-up of patients for 28 months, the incidence of clinical fractures from the core randomized study in patients who received Femara was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported osteoporosis was higher in patients who received Femara 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received Femara and 18.7% of the patients who received placebo. The incidence of cardiovascular ischemic events from the core randomized study was comparable between patients who received Femara 6.8% (175) and placebo 6.5% (167). A patient-reported measure that captures treatment impact on important symptoms associated with estrogen deficiency demonstrated a difference in favor of placebo for vasomotor and sexual symptom domains. Bone Substudy: [see Warnings and Precautions (5.1)] Lipid Substudy: In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between Femara and placebo in total cholesterol or in any lipid fraction at any time over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed [see Warnings and Precautions (5.2)]. Updated Analysis, Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months The extended adjuvant treatment trial (MA-17) was unblinded early [see Adverse Reactions (6)]. At the updated (final analysis), overall the side effects seen were consistent to those seen at a median treatment duration of 24 months. During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) a higher rate of fractures was observed for Femara (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (Femara 12.2% vs placebo 6.4%). Based on 62 months median duration of follow-up in the randomized letrozole arm in the safety population the incidence of new fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo. During treatment or within 30 days of stopping treatment (median duration of treatment 60 months), the incidence of cardiovascular events was 9.8% for Femara and 7.0% for placebo. Based on 62 months median duration of follow-up in the randomized letrozole arm in the safety population the incidence of cardiovascular disease at any time after randomization was 14.4% for letrozole and 9.8% for placebo. Lipid Substudy: In the extended adjuvant setting (MA-17), based on a median duration of follow-up of 62 months, there was no significant difference between Femara and placebo in total cholesterol or in any lipid fraction over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed [see Warnings and Precautions (5.2)]. First-Line Treatment of Advanced Breast Cancer In study P025 a total of 455 patients were treated for a median time of exposure of 11 months in the Femara arm (median 6 months in the tamoxifen arm). The incidence of adverse reactions was similar for Femara and tamoxifen. The most frequently reported adverse reactions were bone pain, hot flushes, back pain, nausea, arthralgia, and dyspnea. Discontinuations for adverse reactions other than progression of tumor occurred in 10/455 (2%) of patients on Femara and in 15/455 (3%) of patients on tamoxifen. Adverse reactions that were reported in at least 5% of the patients treated with Femara 2.5 mg or tamoxifen 20 mg in the first-line treatment study are shown in Table 4. Table 4: Adverse Reactions Occurring in at Least 5% of Patients in Either Treatment Arm Reference ID: 5496852 Adverse Reactions Femara 2.5 mg (N = 455) % Tamoxifen 20 mg (N = 455) % General Disorders Fatigue 13 13 Chest Pain 8 9 Edema Peripheral 5 6 Pain NOS 5 7 Weakness Investigations 6 4 Weight Decreased Vascular Disorders 7 5 Hot Flushes 19 16 Hypertension Gastrointestinal Disorders 8 4 Nausea 17 17 Constipation 10 11 Diarrhea 8 4 Vomiting Infections/Infestations 7 8 Influenza 6 4 Urinary Tract Infection NOS Injury, Poisoning and Procedural Complications 6 3 Post-Mastectomy Lymphedema Metabolism and Nutrition Disorders 7 7 Anorexia Musculoskeletal and Connective Tissue Disorders 4 6 Bone Pain 22 21 Back Pain 18 19 Arthralgia 16 15 Pain in Limb Nervous System Disorders 10 8 Headache NOS Psychiatric Disorders 8 7 Insomnia Reproductive System and Breast Disorders 7 4 Breast Pain Respiratory, Thoracic and Mediastinal Disorders 7 7 Dyspnea 18 17 Cough 13 13 Chest Wall Pain 6 6 Other less frequent (less than or equal to 2%) adverse reactions considered consequential for both treatment groups, included peripheral thromboembolic events, cardiovascular events, and cerebrovascular events. Peripheral thromboembolic events included venous thrombosis, thrombophlebitis, portal vein thrombosis, and pulmonary embolism. Cardiovascular events included angina, myocardial infarction, myocardial ischemia, and coronary heart disease. Cerebrovascular events included transient ischemic attacks, thrombotic or hemorrhagic strokes, and development of hemiparesis. Second-Line Treatment of Advanced Breast Cancer Study discontinuations in the megestrol acetate comparison study (AR/BC2) for adverse reactions other than progression of tumor were 5/188 (2.7%) on Femara 0.5 mg, in 4/174 (2.3%) on Femara 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both Femara doses than on the megestrol acetate arm (0.6% vs 4.7%). There was also less vaginal bleeding (0.3% vs 3.2%) on Femara than on megestrol acetate. In the aminoglutethimide comparison study (AR/BC3), discontinuations for reasons other than progression occurred in 6/193 (3.1%) on 0.5 mg Femara, 7/185 (3.8%) on 2.5 mg Femara, and 7/178 (3.9%) of patients on aminoglutethimide. Reference ID: 5496852 Comparisons of the incidence of adverse reactions revealed no significant differences between the high and low dose Femara groups in either study. Most of the adverse reactions observed in all treatment groups were mild to moderate in severity and it was generally not possible to distinguish adverse reactions due to treatment from the consequences of the patient’s metastatic breast cancer, the effects of estrogen deprivation, or intercurrent illness. Adverse reactions that were reported in at least 5% of the patients treated with Femara 0.5 mg, Femara 2.5 mg, megestrol acetate, or aminoglutethimide in the two controlled trials AR/BC2 and AR/BC3 are shown in Table 5. Table 5: Adverse Reactions Occurring at a Frequency of at Least 5% of Patients in Either Treatment Arm Adverse Reactions Pooled Femara 2.5 mg (N = 359) % Pooled Femara 0.5 mg (N = 380) % Megestrol Acetate 160 mg (N = 189) % Aminoglutethimide 500 mg (N = 178) % Body as a Whole Chest Pain 6 3 7 3 Peripheral Edema1 5 5 8 3 Asthenia 4 5 4 5 Weight Increase Cardiovascular 2 2 9 3 Hypertension Digestive System 5 7 5 6 Nausea 13 15 9 14 Vomiting 7 7 5 9 Constipation 6 7 9 7 Diarrhea 6 5 3 4 Pain-Abdominal 6 5 9 8 Anorexia 5 3 5 5 Dyspepsia Infections/Infestations 3 4 6 5 Viral Infection Lab Abnormality 6 5 6 3 Hypercholesterolemia Musculoskeletal System 3 3 0 6 Musculoskeletal2 21 22 30 14 Arthralgia Nervous System 8 8 8 3 Headache 9 12 9 7 Somnolence 3 2 2 9 Dizziness Respiratory System 3 5 7 3 Dyspnea 7 9 16 5 Coughing Skin and Appendages 6 5 7 5 Hot Flushes 6 5 4 3 Rash3 5 4 3 12 Pruritus 1 2 5 3 1Includes peripheral edema, leg edema, dependent edema, edema. 2Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain. 3Includes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash. Other less frequent (less than 5%) adverse reactions considered consequential and reported in at least 3 patients treated with Femara, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating, and vertigo. First and Second-Line Treatment of Advanced Breast Cancer In the combined analysis of the first- and second-line metastatic trials and postmarketing experiences other adverse reactions that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, dysesthesia (including hypesthesia/paresthesia), arterial thrombosis, memory impairment, irritability, nervousness, urticaria, increased urinary frequency, leukopenia, stomatitis cancer pain, pyrexia, vaginal discharge, appetite increase, dryness of skin and mucosa (including dry mouth), and disturbances of taste and thirst. Reference ID: 5496852 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Femara. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Eye Disorders: blurred vision • Hepatobiliary Disorders: increased hepatic enzymes, hepatitis • Immune System Disorders: anaphylactic reactions, hypersensitivity reactions • Nervous System Disorders: carpal tunnel syndrome • Pregnancy: spontaneous abortions, congenital birth defects • Skin and subcutaneous disorders: angioedema, toxic epidermal necrolysis, erythema multiforme • Musculoskeletal and connective tissue disorders: tendon disorders including tendon rupture, tendonitis, tenosynovitis, and tenosynovitis stenosans (trigger finger) 7 DRUG INTERACTIONS Tamoxifen Coadministration of Femara and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average (Study P015). Clinical experience in the second-line breast cancer trials (AR/BC2 and AR/BC3) indicates that the therapeutic effect of Femara therapy is not impaired if Femara is administered immediately after tamoxifen. Cimetidine A pharmacokinetic interaction study with cimetidine (Study P004) showed no clinically significant effect on letrozole pharmacokinetics. Warfarin An interaction study (P017) with warfarin showed no clinically significant effect of letrozole on warfarin pharmacokinetics. Other Anticancer Agents There is no clinical experience to date on the use of Femara in combination with other anticancer agents. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on postmarketing reports, findings from animal studies and the mechanism of action, Femara can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform a drug-associated risk [see Contraindications (4), Warnings and Precautions (5.6), Adverse Reactions (6.2), and Clinical Pharmacology (12.1)]. In animal reproduction studies, administration of letrozole to pregnant animals during organogenesis resulted in increased post-implantation pregnancy loss and resorption, fewer live fetuses, and fetal malformation affecting the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily maximum recommended human dose (MRHD) on a mg/m2 basis (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data Reference ID: 5496852 In a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-implantation loss at doses ≥ 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis). In an embryo-fetal developmental toxicity study in rats, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.003 mg/kg (approximately 0.01 time the maximum recommended human dose on a mg/m2 basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies, including absence and shortening of renal papilla, dilation of ureter, edema, and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic to rats at a dose of 0.03 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis) and caused fetal domed head and cervical/centrum vertebral fusion. In the embryo-fetal development toxicity study in rabbits, daily administration of oral letrozole during the period of organogenesis at doses ≥ 0.002 mg/kg (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis) resulted in embryo-fetal toxicity, including intrauterine mortality, increased resorption, increased postimplantation loss and decreased numbers of live fetuses. Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs. 8.2 Lactation Risk Summary It is not known if letrozole is present in human milk. There are no data on the effects of letrozole on the breastfed infant or milk production. Exposure of lactating rats to letrozole was associated with impaired reproductive performance of the male offspring (see Data). Because of the potential for serious adverse reactions in breastfed infants from Femara, advise lactating women not to breastfeed while taking Femara and for at least 3 weeks after the last dose. Data Animal Data In a postnatal developmental toxicity study in lactating rats, letrozole was administered orally at doses of 1, 0.003, 0.03, or 0.3 mg/kg/day on Day 0 through Day 20 of lactation. The reproductive performance of the male offspring was impaired at letrozole dose as low as 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis), as reflected by decreased mating and pregnancy ratios. There were no effects on the reproductive performance of female offspring. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Based on animal studies, Femara can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Females of reproductive potential should have a pregnancy test prior to starting treatment with Femara. Contraception Females Based on animal studies, Femara can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Femara and for at least 3 weeks after the last dose. Infertility Females Based on studies in female animals, Femara may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)]. Males Based on studies in male animals, Femara may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)]. Reference ID: 5496852 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. Letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis. Administration of 0.3 mg/kg/day resulted in AUC values that were similar to the AUC in adult patients receiving the recommended dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. Histopathological changes were not reversible at clinically relevant exposures. 8.5 Geriatric Use The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64-65 years. About 1/3 of the patients were greater than or equal to 70 years old. In the first-line study, patients greater than or equal to 70 years of age experienced longer time to tumor progression and higher response rates than patients less than 70. For the extended adjuvant setting (MA-17), more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In the adjuvant setting (BIG 1-98), more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients. 10 OVERDOSAGE Isolated cases of Femara overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse reactions were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. In single-dose studies, the highest dose used was 30 mg, which was well tolerated; in multiple-dose trials, the largest dose of 10 mg was well tolerated. Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2,000 mg/kg (about 4,000 to 8,000 times the daily maximum recommended human dose on a mg/m2 basis); death was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended human dose on a mg/m2 basis); death was preceded by depressed blood pressure and arrhythmias. 11 DESCRIPTION Femara tablets for oral administration contains 2.5 mg of letrozole, a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4'-(1H-1,2,4-Triazol-1-ylmethylene) dibenzonitrile, and its structural formula is Reference ID: 5496852 12 Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31 g/mol, empirical formula C17H11N5, and a melting range of 184°C to 185°C. Femara is available as 2.5 mg tablets for oral administration. Inactive Ingredients: Colloidal silicon dioxide, ferric oxide, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, maize starch, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc, and titanium dioxide. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women. In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme. Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones. 12.2 Pharmacodynamics In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg Femara (letrozole) suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline with maximal suppression achieved within two-three days. Suppression is dose-related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher. Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17­ hydroxy-progesterone, ACTH or in plasma renin activity among postmenopausal patients treated with a daily dose of Femara 0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary. No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of Femara or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels. 12.3 Pharmacokinetics Absorption and Distribution: Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozole’s terminal elimination half-life is about 2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2-6 Reference ID: 5496852 13 weeks. Plasma concentrations at steady state are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg). Elimination Metabolism and Excretion: Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'-methanol­ bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole. In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole inhibited CYP2A6 and CYP2C19, however, the clinical significance of these findings is unknown. Specific Populations Pediatric, Geriatric and Race: In the study populations (adults ranging in age from 35 to greater than 80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied. Renal Impairment: In a study of volunteers with varying renal function (24-hour creatinine clearance: 9 to 116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of Femara was found. In addition, in a study (AR/BC2) of 347 patients with advanced breast cancer, about half of whom received 2.5 mg Femara and half 0.5 mg Femara, renal impairment (calculated creatinine clearance: 20 to 50 mL/min) did not affect steady-state plasma letrozole concentrations. Hepatic Impairment: In a study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), the mean area under curve (AUC) values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. In a pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included bilirubins about 2-11 times ULN with minimal to severe ascites) had two-fold increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients with normal liver function receiving similar doses of this drug [see Dosage and Administration (2.5)]. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 to 100 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was excluded due to low survival. In a separate study, plasma AUC0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose. The benign ovarian stromal tumors observed in mice and rats were considered to be related to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing hormone resulting from the decrease in circulating estrogen. Femara (letrozole) was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was observed to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats). In a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-implantation loss at doses ≥ 0.03 mg/kg/day (approximately 0.1 times the maximum recommended human dose on a mg/m2 basis). In repeat-dose toxicity studies, Reference ID: 5496852 14 administration of letrozole caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (approximately 1, 0.4, and 0.4 times the daily maximum recommended human dose on a mg/m2 basis, respectively). CLINICAL STUDIES 14.1 Updated Adjuvant Treatment of Early Breast Cancer In a multicenter study (BIG 1-98, NCT00004205) enrolling over 8,000 postmenopausal women with resected, receptor- positive early breast cancer, one of the following treatments was randomized in a double-blind manner: Option 1: A. Tamoxifen for 5 years B. Femara for 5 years C. Tamoxifen for 2 years followed by Femara for 3 years D. Femara for 2 years followed by tamoxifen for 3 years Option 2: A. Tamoxifen for 5 years B. Femara for 5 years The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether Femara for 5 years was superior to Tamoxifen for 5 years (Primary Core Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis). Selected baseline characteristics for the study population are shown in Table 6. The primary endpoint of this trial was DFS (i.e., interval between randomization and earliest occurrence of a local, regional, or distant recurrence, or invasive contralateral breast cancer, or death from any cause). The secondary endpoints were overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer, time to breast cancer recurrence (TBR) and time to distant metastasis (TDM). The Primary Core Analysis (PCA) included all patients and all follow-up in the monotherapy arms in both randomization options, but follow-up in the two sequential treatments arms was truncated 30 days after switching treatments. The PCA was conducted at a median treatment duration of 24 months and a median follow-up of 26 months. Femara was superior to tamoxifen in all endpoints except overall survival and contralateral breast cancer [e.g., DFS: hazard ratio (HR) 0.79; 95% CI (0.68, 0.92); P = 0.002; SDFS: HR 0.83; 95% CI (0.70, 0.97); TDM: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06). In 2005, based on recommendations by the independent Data Monitoring Committee, the tamoxifen arms were unblinded and patients were allowed to complete initial adjuvant therapy with Femara (if they had received tamoxifen for at least 2 years) or to start extended adjuvant treatment with Femara (if they had received tamoxifen for at least 4.5 years) if they remained alive and disease-free. In total, 632 patients crossed to Femara or another aromatase inhibitor. Approximately 70% (448) of these 632 patients crossed to Femara to complete initial adjuvant therapy and most of these crossed in years 3 to 4. All of these patients were in Option 1. A total of 184 patients started extended adjuvant therapy with Femara (172 patients) or with another aromatase inhibitor (12 patients). To explore the impact of this selective crossover, results from analyses censoring follow-up at the date of the selective crossover (in the tamoxifen arm) are presented for the MAA. The PCA allowed the results of Femara for 5 years compared with tamoxifen for 5 years to be reported in 2005 after a median follow-up of only 26 months. The design of the PCA is not optimal to evaluate the effect of Femara after a longer time (because follow-up was truncated in two arms at around 25 months). The MAA (ignoring the two sequential treatment arms) provided follow-up equally as long in each treatment and did not over-emphasize early recurrences as the PCA did. The MAA thus provides the clinically appropriate updated efficacy results in answer to the first primary question, despite the confounding of the tamoxifen reference arm by the selective crossover to Femara. The updated results for the MAA are summarized in Table 7. Median follow-up for this analysis is 73 months. The Sequential Treatments Analysis (STA) addresses the second primary question of the study. The primary analysis for the STA was from switch (or equivalent time-point in monotherapy arms) + 30 days (STA-S) with a two-sided test applied to each pair-wise comparison at the 2.5% level. Additional analyses were conducted from randomization (STA-R) but these comparisons (added in light of changing medical practice) were under-powered for efficacy. Table 6: Adjuvant Study - Patient and Disease Characteristics (ITT Population) Reference ID: 5496852 Primary Core Analysis (PCA) Monotherapy Arms Analysis (MAA) Femara Tamoxifen Femara Tamoxifen N = 4003 N = 4007 N = 2463 N = 2459 Characteristic n (%) n (%) n (%) n (%) Age (median, years) 61 61 61 61 Age range (years) 38-89 39-90 38-88 39-90 Hormone receptor status (%) ER+ and/or PgR+ 99.7 99.7 99.7 99.7 Both unknown 0.3 0.3 0.3 0.3 Nodal status (%) Node negative 52 52 50 52 Node positive 41 41 43 41 Nodal status unknown 7 7 7 7 Prior adjuvant chemotherapy (%) 24 24 24 24 Table 7: Updated Adjuvant Study Results - Monotherapy Arms Analysis (Median Follow-up 73 Months) Femara Tamoxifen Hazard ratio N = 2463 N = 2459 Events 5-year Events 5-year (95% CI) P (%) rate (%) rate Disease-free survival1 ITT 445 (18.1) 87.4 500 (20.3) 84.7 0.87 (0.76, 0.99) 0.03 Censor 445 87.4 483 84.2 0.84 (0.73, 0.95) 0 positive nodes ITT 165 92.2 189 90.3 0.88 (0.72, 1.09) 1-3 positive nodes ITT 151 85.6 163 83.0 0.85 (0.68, 1.06) >=4 positive nodes ITT 123 71.2 142 62.6 0.81 (0.64, 1.03) Adjuvant chemotherapy ITT 119 86.4 150 80.6 0.77 (0.60, 0.98) No chemotherapy ITT 326 87.8 350 86.1 0.91 (0.78, 1.06) Systemic DFS2 ITT 401 88.5 446 86.6 0.88 (0.77,1.01) Time to distant metastasis3 ITT 257 92.4 298 90.1 0.85 (0.72, 1.00) Adjuvant chemotherapy ITT 84 - 109 - 0.75 (0.56-1.00) No chemotherapy ITT 173 - 189 - 0.90 (0.73,1.11) Distant DFS4 ITT 385 89.0 432 87.1 0.87 (0.76,1.00) Contralateral breast cancer ITT 34 99.2 44 98.6 0.76 (0.49, 1.19) Overall survival ITT 303 91.8 343 90.9 0.87 (0.75, 1.02) Censor 303 91.8 338 90.1 0.82 (0.70, 0.96) 0 positive nodes ITT 107 95.2 121 94.8 0.90 (0.69.1.16) 1-3 positive nodes ITT 99 90.8 114 90.6 0.81(0.62,1.06) > = 4 positive nodes ITT 92 80.2 104 73.6 0.86 (0.65, 1.14) Adjuvant chemotherapy ITT 76 91.5 96 88.4 0.79 (0.58, 1.06) No chemotherapy ITT 227 91.9 247 91.8 0.91 (0.76, 1.08) Definition of: 1Disease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without a prior event. 2Systemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event. 3Time to distant metastasis: Interval from randomization to distant metastasis. 4Distant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause. ITT analysis ignores selective crossover in tamoxifen arms. Censored analysis censors follow-up at the date of selective crossover in 632 patients who crossed to Femara or another aromatase inhibitor after the tamoxifen arms were unblinded in 2005. Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis. Reference ID: 5496852 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Patitm.b at ri■k: Letrozole Tamoxi:f'en No. of Patients Events Censored Treatment: 2'39 2430 -- - Letrozole 2469 445 (18.1%) 2018 (81.9%) 12 18 2376 2300 --- --- Tsmoxifen 2459 500 (20.3%) 1959 (79.7%) Letrozole Tunoxifen 24 233B 2302 30 .... 2249 36 Months 2249 2203 42 220B 2159 48 2176 2 116 54 2130 2087 60 1927 1B08 66 1483 1448 72 1290 1245 Figure 1: Disease-Free Survival (Median follow-up 73 months, ITT Approach) DFS events defined as loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death from any cause (i.e., definition excludes second non- breast primary cancers). The medians of overall survival for both arms were not reached for the MAA. There was no statistically significant difference in overall survival. The hazard ratio for survival in the Femara arm compared to the tamoxifen arm was 0.87, with 95% CI (0.75, 1.02) (see Table 7). There were no significant differences in DFS, OS, SDFS, and Distant DFS from switch in the Sequential Treatments Analysis with respect to either monotherapy (e.g., [tamoxifen 2 years followed by] Femara 3 years versus tamoxifen beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [Femara 2 years followed by] tamoxifen 3 years versus Femara beyond 2 years, DFS HR 0.93; 97.5% CI 0.71, 1.22). There were no significant differences in DFS, OS, SDFS, and Distant DFS from randomization in the Sequential Treatments Analyses. 14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months A double-blind, randomized, placebo-controlled trial (MA-17, NCT00003140) of Femara was performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen. The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early because of an interim analysis showing a favorable Femara effect on time without recurrence or contralateral breast cancer. At the time of unblinding, women had been followed for a median of 28 months, 30% of patients had completed 3 or more years of follow-up and less than 1% of patients had completed 5 years of follow-up. Selected baseline characteristics for the study population are shown in Table 8. Table 8: Selected Study Population Demographics (Modified ITT Population) Baseline Status Femara Placebo N = 2582 N = 2586 Hormone Receptor Status (%) ER+ and/or PgR+ 98 98 Both Unknown 2 2 Nodal Status (%) Node Negative 50 50 Reference ID: 5496852 Node Positive 46 46 Nodal Status Unknown 4 4 Chemotherapy 46 46 Table 9 shows the study results. Disease-free survival was measured as the time from randomization to the earliest event of loco-regional or distant recurrence of the primary disease or development of contralateral breast cancer or death. Disease-free survival by hormone receptor status, nodal status and adjuvant chemotherapy were similar to the overall results. Data were premature for an analysis of survival. Table 9: Extended Adjuvant Study Results Femara Placebo Hazard Ratio P-Value N = 2582 N = 2586 (95% CI) Disease Free Survival (DFS)1 Events 122 (4.7%) 193 (7.5%) 0.62 (0.49, 0.78)2 0.00003 Local Breast Recurrence 9 22 Local Chest Wall Recurrence 2 8 Regional Recurrence 7 4 Distant Recurrence 55 92 0.61 (0.44 - 0.84) 0.003 Contralateral Breast Cancer 19 29 Deaths Without Recurrence or Contralateral Breast 30 38 Cancer CI = confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of Femara (lesser risk of recurrence); hazard ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with Femara). 1First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause. 2Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P-value based on stratified log-rank test. 14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months Table 10: Update of Extended Adjuvant Study Results Femara N = 2582 (%) Placebo N = 2586 (%) Hazard Ratio1 (95% CI) P-Value2 Disease Free Survival (DFS) events3 344 (13.3) 402 (15.5) 0.89 (0.77, 1.03) 0.12 Breast cancer recurrence 209 286 0.75 (0.63, 0.89) 0.001 (Protocol definition of DFS events4) Local Breast Recurrence 15 44 Local Chest Wall Recurrence 6 14 Regional Recurrence 10 8 Distant Recurrence 140 167 Distant Recurrence (first or subsequent events) 142 169 0.88 (0.70,1.10) 0.246 Contralateral Breast Cancer 37 53 Deaths Without Recurrence or Contralateral 135 116 Breast Cancer 1Adjusted by receptor status, nodal status and prior chemotherapy. 2Stratified log-rank test, stratified by receptor status, nodal status and prior chemotherapy. 3DFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to Femara in 60% of the placebo arm. 4Protocol definition does not include deaths from any cause. Reference ID: 5496852 Updated analyses were conducted at a median follow-up of 62 months. In the Femara arm, 71% of the patients were treated for a least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at a median follow-up of 28 months, approximately 60% of the selected patients in the placebo arm opted to switch to Femara. In this updated analysis shown in Table 10 Femara significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo (HR 0.75; 95% CI 0.63, 0.89; P = 0.001). However, in the updated DFS analysis (interval between randomization and earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause) the treatment difference was heavily diluted by 60% of the patients in the placebo arm switching to Femara and accounting for 64% of the total placebo patient-years of follow-up. Ignoring these switches, the risk of DFS event was reduced by a non-significant 11% (HR 0.89; 95% CI 0.77, 1.03). There was no significant difference in distant DFS or overall survival. 14.4 First-Line Treatment of Advanced Breast Cancer A randomized, double-blind, multinational trial (P025) compared Femara 2.5 mg with tamoxifen 20 mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-regional recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer. Time to progression (TTP) was the primary endpoint of the trial. Selected baseline characteristics for this study are shown in Table 11. Table 11: Selected Study Population Demographics Baseline Status Femara Tamoxifen N = 458 N = 458 Stage of Disease IIIB 6% 7% IV 93% 92% Receptor Status ER and PgR Positive 38% 41% ER or PgR Positive 26% 26% Both Unknown 34% 33% ER- or PgR-/Other Unknown < 1% 0 Previous Antiestrogen Therapy Adjuvant 19% 18% None 81% 82% Dominant Site of Disease Soft Tissue 25% 25% Bone 32% 29% Viscera 43% 46% Femara was superior to tamoxifen in TTP and rate of objective tumor response (see Table 12). Table 12 summarizes the results of the trial, with a total median follow-up of approximately 32 months. (All analyses are unadjusted and use 2-sided P-values.) Table 12: Results of First-Line Treatment of Advanced Breast Cancer Femara Tamoxifen Hazard or Odds 2.5 mg 20 mg Ratio (95% CI) N = 453 N = 454 P-Value (2-sided) Median Time to Progression 9.4 months 6.0 months 0.72 (0.62, 0.83)1 P < 0.0001 Objective Response Rate (CR + PR) 145 (32%) 95 (21%) 1.77 (1.31, 2.39)2 Reference ID: 5496852 1.0 0.9 0.8 ' 0.7 ":" 0.6 • a I 0.5 - 0.4 E 0.3 D.2 0.1 0.0 0 ' ' ' 1 . ' -..,,._l ---~- ---------------------------------- ' .... ,!-,,, 6 ' ......... 1 ... . ,. 12 .. ,.. ............. __ ... ......... 18 24 30 36 42 48 54 M~s Femarae 2.5 mg ----- tamoxifen 20 mg 60 P = 0.0002 (CR) 42 (9%) 15 (3%) 2.99 (1.63, 5.47)2 P = 0.0004 Duration of Objective Response Median 18 months 16 months (N = 145) (N = 95) Overall Survival 35 months 32 months (N = 458) (N = 458) P = 0.51363 1Hazard ratio. 2Odds ratio. 3Overall log-rank test. Figure 2 shows the Kaplan-Meier curves for TTP. Figure 2: Kaplan-Meier Estimates of Time to Progression (Study P025) Table 13 shows results in the subgroup of women who had received prior antiestrogen adjuvant therapy, Table 14, results by disease site and Table 15, the results by receptor status. Table 13: Efficacy in Patients Who Received Prior Antiestrogen Therapy Variable Femara Tamoxifen 2.5 mg 20 mg N = 84 N = 83 Median Time to Progression (95% CI) 8.9 months (6.2, 12.5) 5.9 months (3.2, 6.2) Hazard Ratio for TTP (95% CI) 0.60 (0.43, 0.84) Objective Response Rate (CR + PR) 22 (26%) 7 (8%) Odds Ratio for Response (95% CI) 3.85 (1.50, 9.60) Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen. Reference ID: 5496852 Table 14: Efficacy by Disease Site Femara Tamoxifen 2.5 mg 20 mg Dominant Disease Site Soft Tissue: N = 113 N = 115 Median TTP 12.1 months 6.4 months Objective Response Rate 50% 34% Bone: N = 145 N = 131 Median TTP 9.5 months 6.3 months Objective Response Rate 23% 15% Viscera: N = 195 N = 208 Median TTP 8.3 months 4.6 months Objective Response Rate 28% 17% Table 15: Efficacy by Receptor Status Variable Femara Tamoxifen 2.5 mg 20 mg Receptor Positive N = 294 N = 305 Median Time to Progression (95% CI) 9.4 months (8.9, 11.8) 6.0 months (5.1, 8.5) Hazard Ratio for TTP (95% CI) 0.69 (0.58, 0.83) Objective Response Rate (CR+PR) 97 (33%) 66 (22%) Odds Ratio for Response 95% CI) 1.78 (1.20, 2.60) Receptor Unknown N = 159 N = 149 Median Time to Progression (95% CI) 9.2 months (6.1, 12.3) 6.0 months (4.1, 6.4) Hazard Ratio for TTP (95% CI) 0.77 (0.60, 0.99) Objective Response Rate (CR+PR) 48 (30%) 29 (20%) Odds Ratio for Response (95% CI) 1.79 (1.10, 3.00) Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen. Figure 3 shows the Kaplan-Meier curves for survival. Reference ID: 5496852 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 • i!!: .z: 0.5 o.s ; c 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 0 6 12 18 24 30 36 42 48 54 60 Months letrozole 1st tarnoxHen 1st Figure 3: Survival by Randomized Treatment Arm Legend: Randomized Femara: n = 458, events 57%, median overall survival 35 months (95% CI 32 to 38 months) Randomized tamoxifen: n = 458, events 57%, median overall survival 32 months (95% CI 28 to 37 months) Overall log-rank P = 0.5136 (i.e., there was no significant difference between treatment arms in overall survival). The median overall survival was 35 months for the Femara group and 32 months for the tamoxifen group, with a P-value 0.5136. Study design allowed patients to cross over upon progression to the other therapy. Approximately 50% of patients crossed over to the opposite treatment arm and almost all patients who crossed over had done so by 36 months. The median time to crossover was 17 months (Femara to tamoxifen) and 13 months (tamoxifen to Femara). In patients who did not cross over to the opposite treatment arm, median survival was 35 months with Femara (n = 219, 95% CI, 29 to 43 months) vs 20 months with tamoxifen (n = 229, 95% CI, 16 to 26 months). 14.5 Second-Line Treatment of Advanced Breast Cancer Femara was initially studied at doses of 0.1 mg to 5.0 mg daily in six noncomparative trials (AR/BC1, P01, AR/ST1, AR/PS1, AR/ES1, and NJO-03) in 181 postmenopausal estrogen/progesterone receptor positive or unknown advanced breast cancer patients previously treated with at least antiestrogen therapy. Patients had received other hormonal therapies and also may have received cytotoxic therapy. Eight (20%) of forty patients treated with Femara 2.5 mg daily in trials achieved an objective tumor response (complete or partial response). Two large randomized, controlled, multinational (predominantly European) trials (AR/BC2, AR/BC3) were conducted in patients with advanced breast cancer who had progressed despite antiestrogen therapy. Patients were randomized to Femara 0.5 mg daily, Femara 2.5 mg daily, or a comparator [megestrol acetate 160 mg daily in one study (AR/BC2); and aminoglutethimide 250 mg twice a day with corticosteroid supplementation in the other study (AR/BC3)]. In each study over 60% of the patients had received therapeutic antiestrogens, and about one-fifth of these patients had an objective response. The megestrol acetate controlled study was double-blind; the other study was open label. Selected baseline characteristics for each study are shown in Table 16. Reference ID: 5496852 Table 16: Selected Study Population Demographics Parameter Megestrol Acetate Aminoglutethimide Study Study No. of Participants 552 557 Receptor Status ER/PR Positive 57% 56% ER/PR Unknown 43% 44% Previous Therapy Adjuvant Only 33% 38% Therapeutic +/- Adj. 66% 62% Sites of Disease Soft Tissue 56% 50% Bone 50% 55% Viscera 40% 44% Confirmed objective tumor response (complete response plus partial response) was the primary endpoint of the trials. Responses were measured according to the Union Internationale Contre le Cancer (UICC) criteria and verified by independent, blinded review. All responses were confirmed by a second evaluation 4 to 12 weeks after the documentation of the initial response. Table 17 shows the results for the first trial (AR/BC2), with a minimum follow-up of 15 months that compared Femara 0.5 mg, Femara 2.5 mg, and megestrol acetate 160 mg daily (All analyses are unadjusted). Table 17: Megestrol Acetate Study Results Femara Femara Megestrol 0.5 mg 2.5 mg Acetate N = 188 N = 174 N = 190 Objective Response (CR + PR) 22 (11.7%) 41 (23.6%) 31 (16.3%) Median Duration of Response 552 days (Not reached) 561 days Median Time to Progression 154 days 170 days 168 days Median Survival 633 days 730 days 659 days Odds Ratio for Response Femara 2.5: Femara 0.5 = 2.33 Femara 2.5: megestrol = 1.58 (95% CI: 1.32, 4.17); P = 0.004* (95% CI: 0.94, 2.66); P = 0.08* Relative Risk of Progression Femara 2.5: Femara 0.5 = 0.81 Femara 2.5: megestrol = 0.77 (95% CI: 0.63, 1.03); P = 0.09* (95% CI: 0.60, 0.98); P = 0.03* *Two-sided P-value. Reference ID: 5496852 1,1! .. 7 .. , --~ ...,_""\--L.~ .. "'"' ..... ----- ~ ... "'-.,_ __ _ L..-,, -i ________ _ ---i__ ____ _ T~Gtour;: -- ~ 0..fii ll'lgl - -- -- -- Fe!ud 25 mg-- 1M The Kaplan-Meier curves for progression for the megestrol acetate study are shown in Figure 4. Figure 4: Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study) The results for the study comparing Femara to aminoglutethimide (AR/BC3), with a minimum follow-up of 9 months, are shown in Table 18 (Unadjusted analyses are used). Table 18: Aminoglutethimide Study Results Femara Femara 0.5 mg N = 193 2.5 mg N = 185 Aminoglutethimide N = 179 Objective Response (CR + PR) 34 (17.6%) 34 (18.4%) 22 (12.3%) Median Duration of Response 619 days 706 days 450 days Median Time to Progression 103 days 123 days 112 days Median Survival 636 days 792 days 592 days Odds Ratio for Response Femara 2.5: Femara 2.5: Femara 0.5 = 1.05 Aminoglutethimide = 1.61 (95% CI: 0.62, 1.79); P = 0.85* (95% CI: 0.90, 2.87); P = 0.11* Relative Risk of Progression Femara 2.5: Femara 2.5: Femara 0.5 = 0.86 Aminoglutethimide = 0.74 (95% CI: 0.68, 1.11); P = 0.25* (95% CI: 0.57, 0.94); P = 0.02* *Two-sided P-value. The Kaplan-Meier curves for progression for the aminoglutethimide study is shown in Figure 5. Reference ID: 5496852 l. ••••••••••• •.... ~-, ···-----, i L .. _ ..... ' -7 ,...,_ _ - - - - - '-~---_-_- -_--_·_--_-_··_-_ 200 300 400 500 600 700 800 900 TIME TO PROGRESSION (IN DAYS) 1000 Treatment Group: --- Femara® 0.5 mg Femara® 2.5 mg --- AG Figure 5: Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study) 16 HOW SUPPLIED/STORAGE AND HANDLING Packaged in HDPE bottles with a safety screw cap. 2.5 mg tablets Bottles of 30 tablets NDC 0078-0249-15 Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during Femara therapy and for at least 3 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Femara [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1, 8.3)]. Lactation Advise women not to breastfeed during Femara treatment and for at least 3 weeks after the last dose [see Use in Specific Populations (8.2)]. Infertility Advise females and males of reproductive potential of the potential for reduced fertility from Femara [see Use in Specific Populations (8.3)]. Fatigue and Dizziness Since fatigue and dizziness have been observed with the use of Femara and somnolence was uncommonly reported, caution is advised when driving or using machinery [see Warnings and Precautions (5.4)]. Bone Effects Consideration should be given to monitoring bone mineral density [see Warnings and Precautions (5.1)]. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey, 07936 © Novartis Reference ID: 5496852
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2025-02-12T15:47:47.692397
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ARIMIDEX safely and effectively. See full prescribing information for ARIMIDEX. ARIMIDEX® (anastrozole) tablet, for oral use Initial U.S. Approval: 1995 --------------------------- INDICATIONS AND USAGE -------------------------­ ARIMIDEX is an aromatase inhibitor indicated for: • Adjuvant treatment of postmenopausal women with hormone receptor- positive early breast cancer (1.1) • First-line treatment of postmenopausal women with hormone receptor- positive or hormone receptor unknown locally advanced or metastatic breast cancer (1.2) • Treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER- negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to ARIMIDEX (1.3) ---------------------- DOSAGE AND ADMINISTRATION ---------------------­ One 1 mg tablet taken once daily (2.1) --------------------- DOSAGE FORMS AND STRENGTHS -------------------­ 1 mg tablets (3) ------------------------------ CONTRAINDICATIONS ----------------------------­ Patients with demonstrated hypersensitivity to ARIMIDEX or any excipient (4) ----------------------- WARNINGS AND PRECAUTIONS ---------------------­ • In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events occurred with ARIMIDEX use compared to tamoxifen use. Consider risks and benefits. (5.1, 6.1) • Decreases in bone mineral density may occur. Consider bone mineral density monitoring. (5.2, 6.1) • Increases in total cholesterol may occur. Consider cholesterol monitoring. (5.3, 6.1) • Embryo-Fetal Toxicity: ARIMIDEX may cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (5.4, 8.1) ------------------------------ ADVERSE REACTIONS ----------------------------­ In the early breast cancer (ATAC) study, the most common (occurring with an incidence of ≥10%) side effects occurring in women taking ARIMIDEX included: hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema and lymphedema, regardless of causality. (6.1) In the advanced breast cancer studies, the most common (occurring with an incidence of >10%) side effects occurring in women taking ARIMIDEX included: hot flashes, nausea, asthenia, pain, headache, back pain, bone pain, increased cough, dyspnea, pharyngitis and peripheral edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS ----------------------------­ • Tamoxifen: Do not use in combination with ARIMIDEX. No additional benefit seen over tamoxifen monotherapy. (7.1, 14.1) • Estrogen-containing products: Combination use may diminish activity of ARIMIDEX. (7.2) ----------------------- USE IN SPECIFIC POPULATIONS ---------------------­ • Lactation: Do not breastfeed. (8.2) • Females and Males of Reproductive Potential: Verify pregnancy status prior to initiation of ARIMIDEX. (8.3) • Pediatric patients: Efficacy has not been demonstrated for pubertal boys of adolescent age with gynecomastia or girls with McCune-Albright Syndrome and progressive precocious puberty. (8.4) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Adjuvant Treatment 1.2 First-Line Treatment 1.3 Second-Line Treatment 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose 2.2 Patients with Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Ischemic Cardiovascular Events 5.2 Bone Effects 5.3 Cholesterol 5.4 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Post-Marketing Experience 7 DRUG INTERACTIONS 7.1 Tamoxifen 7.2 Estrogen 7.3 Warfarin 7.4 Cytochrome P450 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Adjuvant Treatment of Breast Cancer in Postmenopausal Women 14.2 First-Line Therapy in Postmenopausal Women with Advanced Breast Cancer 14.3 Second-Line Therapy in Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION Reference ID: 5496819 1 INDICATIONS AND USAGE 1.1 Adjuvant Treatment ARIMIDEX is indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. 1.2 First-Line Treatment ARIMIDEX is indicated for the first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer. 1.3 Second-Line Treatment ARIMIDEX is indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to ARIMIDEX. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The dose of ARIMIDEX is one 1 mg tablet taken once a day. For patients with advanced breast cancer, ARIMIDEX should be continued until tumor progression. ARIMIDEX can be taken with or without food. For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC trial, ARIMIDEX was administered for five years [see Clinical Studies (14.1)]. No dosage adjustment is necessary for patients with renal impairment or for elderly patients [see Use in Specific Populations (8.6)]. 2.2 Patients with Hepatic Impairment No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. ARIMIDEX has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)]. 3 DOSAGE FORMS AND STRENGTHS The tablets are white, biconvex, film-coated containing 1 mg of anastrozole. The tablets are impressed on one side with a logo consisting of a letter “A” (upper case) with an arrowhead attached to the foot of the extended right leg of the “A” and on the reverse with the tablet strength marking “Adx 1”. 4 CONTRAINDICATIONS Hypersensitivity ARIMIDEX is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients. Observed reactions include anaphylaxis, angioedema, and urticaria [see Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Ischemic Cardiovascular Events In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events was observed with ARIMIDEX in the ATAC trial (17% of patients on ARIMIDEX and 10% of patients on tamoxifen). Consider risk and benefits of ARIMIDEX therapy in patients with pre-existing ischemic heart disease [see Adverse Reactions (6.1)]. Reference ID: 5496819 5.2 Bone Effects Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving ARIMIDEX had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Consider bone mineral density monitoring in patients treated with ARIMIDEX [see Adverse Reactions (6.1)]. 5.3 Cholesterol During the ATAC trial, more patients receiving ARIMIDEX were reported to have elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively) [see Adverse Reactions (6.1)]. 5.4 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, ARIMIDEX can cause fetal harm when administered to a pregnant woman. Anastrozole caused embryo-fetal toxicities in rats at maternal exposure that were 9 times the human clinical exposure, based on area under the curve (AUC). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m2 basis. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during therapy with ARIMIDEX and for at least 3 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. 6 ADVERSE REACTIONS Serious adverse reactions with ARIMIDEX occurring in less than 1 in 10,000 patients, are: 1) skin reactions such as lesions, ulcers, or blisters; 2) allergic reactions with swelling of the face, lips, tongue, and/or throat. This may cause difficulty in swallowing and/or breathing; and 3) changes in blood tests of the liver function, including inflammation of the liver with symptoms that may include a general feeling of not being well, with or without jaundice, liver pain or liver swelling [see Adverse Reactions (6.2)]. Common adverse reactions (occurring with an incidence of ≥10%) in women taking ARIMIDEX included: hot flashes, asthenia, arthritis, pain, arthralgia, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, bone pain, peripheral edema, increased cough, dyspnea, pharyngitis and lymphedema. In the ATAC trial, the most common reported adverse reaction (>0.1%) leading to discontinuation of therapy for both treatment groups was hot flashes, although there were fewer patients who discontinued therapy as a result of hot flashes in the ARIMIDEX group. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.1 Clinical Trials Experience Adjuvant Therapy Adverse reaction data for adjuvant therapy are based on the ATAC trial [see Clinical Studies (14.1)]. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving ARIMIDEX 1 mg and tamoxifen 20 mg, respectively. Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in Table 1. Reference ID: 5496819 Table 1 - Adverse reactions occurring with an incidence of at least 5% in either treatment group during treatment, or within 14 days of the end of treatment in the ATAC trial* Body system and adverse reactions by COSTART† preferred term‡ ARIMIDEX 1 mg (N§=3092) Tamoxifen 20 mg (N§=3094) Body as a whole Asthenia 575 (19) 544 (18) Pain 533 (17) 485 (16) Back pain 321 (10) 309 (10) Headache 314 (10) 249 (8) Abdominal pain 271 (9) 276 (9) Infection 285 (9) 276 (9) Accidental injury 311 (10) 303 (10) Flu syndrome 175 (6) 195 (6) Chest pain 200 (7) 150 (5) Neoplasm 162 (5) 144 (5) Cyst 138 (5) 162 (5) Cardiovascular Vasodilatation 1104 (36) 1264 (41) Hypertension 402 (13) 349 (11) Digestive Nausea 343 (11) 335 (11) Constipation 249 (8) 252 (8) Diarrhea 265 (9) 216 (7) Dyspepsia 206 (7) 169 (6) Gastrointestinal disorder 210 (7) 158 (5) Hemic and lymphatic Lymphedema 304 (10) 341 (11) Anemia 113 (4) 159 (5) Metabolic and nutritional Peripheral edema 311 (10) 343 (11) Weight gain 285 (9) 274 (9) Hypercholesterolemia 278 (9) 108 (3.5) Musculoskeletal Arthritis 512 (17) 445 (14) Arthralgia 467 (15) 344 (11) Osteoporosis 325 (11) 226 (7) Fracture 315 (10) 209 (7) Bone pain 201 (7) 185 (6) Arthrosis 207 (7) 156 (5) Joint Disorder 184 (6) 160 (5) Myalgia 179 (6) 160 (5) Nervous system Depression 413 (13) 382 (12) Insomnia 309 (10) 281 (9) Dizziness 236 (8) 234 (8) Anxiety 195 (6) 180 (6) Paresthesia 215 (7) 145 (5) Respiratory Reference ID: 5496819 Body system and adverse reactions by COSTART† preferred term‡ ARIMIDEX 1 mg (N§=3092) Tamoxifen 20 mg (N§=3094) Pharyngitis 443 (14) 422 (14) Cough increased 261 (8) 287 (9) Dyspnea 234 (8) 237 (8) Sinusitis 184 (6) 159 (5) Bronchitis 167 (5) 153 (5) Skin and appendages Rash 333 (11) 387 (13) Sweating 145 (5) 177 (6) Special Senses Cataract Specified 182 (6) 213 (7) Urogenital Leukorrhea 86 (3) 286 (9) Urinary tract infection 244 (8) 313 (10) Breast pain 251 (8) 169 (6) Breast Neoplasm 164 (5) 139 (5) Vulvovaginitis 194 (6) 150 (5) Vaginal Hemorrhage¶ 122 (4) 180 (6) Vaginitis 125 (4) 158 (5) * The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up. † COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms. ‡ A patient may have had more than 1 adverse reaction, including more than 1 adverse reaction in the same body system. § N=Number of patients receiving the treatment. ¶ Vaginal Hemorrhage without further diagnosis. Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see Table 2). Table 2 - Number of Patients with Pre-specified Adverse Reactions in ATAC Trial* ARIMIDEX Tamoxifen Odds-ratio 95% CI N=3092 N=3094 (%) (%) Hot Flashes 1104 (36) 1264 (41) 0.80 0.73 − 0.89 Musculoskeletal Events† 1100 (36) 911 (29) 1.32 1.19 − 1.47 Fatigue/Asthenia 575 (19) 544 (18) 1.07 0.94 − 1.22 Mood Disturbances 597 (19) 554 (18) 1.10 0.97 − 1.25 Nausea and Vomiting 393 (13) 384 (12) 1.03 0.88 − 1.19 All Fractures 315 (10) 209 (7) 1.57 1.30 − 1.88 Fractures of Spine, Hip, or Wrist 133 (4) 91 (3) 1.48 1.13 − 1.95 Wrist/Colles’ fractures 67 (2) 50 (2) Spine fractures 43 (1) 22 (1) Hip fractures 28 (1) 26 (1) Cataracts 182 (6) 213 (7) 0.85 0.69 − 1.04 Vaginal Bleeding 167 (5) 317 (10) 0.50 0.41 − 0.61 Ischemic Cardiovascular Disease 127 (4) 104 (3) 1.23 0.95 − 1.60 Vaginal Discharge 109 (4) 408 (13) 0.24 0.19 − 0.30 Venous Thromboembolic Events 87 (3) 140 (5) 0.61 0.47 − 0.80 Deep Venous Thromboembolic Events 48 (2) 74 (2) 0.64 0.45 − 0.93 Ischemic Cerebrovascular Event 62 (2) 88 (3) 0.70 0.50 − 0.97 Reference ID: 5496819 ARIMIDEX Tamoxifen Odds-ratio 95% CI N=3092 N=3094 Endometrial Cancer‡ (%) 4 (0.2) (%) 13 (0.6) 0.31 0.10 − 0.94 * Patients with multiple events in the same category are counted only once in that category. † Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia. ‡ Percentages calculated based upon the numbers of patients with an intact uterus at baseline. Ischemic Cardiovascular Events Between treatment arms in the overall population of 6186 patients, there was no statistical difference in ischemic cardiovascular events (4% ARIMIDEX vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3092 (2.3%) patients in the ARIMIDEX arm and 51/3094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3092 (1.2%) patients in the ARIMIDEX arm and 34/3094 (1.1%) patients in the tamoxifen arm. In women with pre-existing ischemic heart disease 465/6186 (7.5%), the incidence of ischemic cardiovascular events was 17% in patients on ARIMIDEX and 10% in patients on tamoxifen. In this patient population, angina pectoris was reported in 25/216 (11.6%) patients receiving ARIMIDEX and 13/249 (5.2%) patients receiving tamoxifen; myocardial infarction was reported in 2/216 (0.9%) patients receiving ARIMIDEX and 8/249 (3.2%) patients receiving tamoxifen. Bone Mineral Density Findings Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving ARIMIDEX had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Because ARIMIDEX lowers circulating estrogen levels it may cause a reduction in bone mineral density. A post-marketing trial assessed the combined effects of ARIMIDEX and the bisphosphonate risedronate on changes from baseline in BMD and markers of bone resorption and formation in postmenopausal women with hormone receptor- positive early breast cancer. All patients received calcium and vitamin D supplementation. At 12 months, small reductions in lumbar spine bone mineral density were noted in patients not receiving bisphosphonates. Bisphosphonate treatment preserved bone density in most patients at risk of fracture. Postmenopausal women with early breast cancer scheduled to be treated with ARIMIDEX should have their bone status managed according to treatment guidelines already available for postmenopausal women at similar risk of fragility fracture. Cholesterol During the ATAC trial, more patients receiving ARIMIDEX were reported to have an elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively). A post-marketing trial also evaluated any potential effects of ARIMIDEX on lipid profile. In the primary analysis population for lipids (ARIMIDEX alone), there was no clinically significant change in LDL-C from baseline to 12 months and HDL-C from baseline to 12 months. In secondary population for lipids (ARIMIDEX+risedronate), there also was no clinically significant change in LDL-C and HDL-C from baseline to 12 months. In both populations for lipids, there was no clinically significant difference in total cholesterol (TC) or serum triglycerides (TG) at 12 months compared with baseline. In this trial, treatment for 12 months with ARIMIDEX alone had a neutral effect on lipid profile. Combination treatment with ARIMIDEX and risedronate also had a neutral effect on lipid profile. Reference ID: 5496819 The trial provides evidence that postmenopausal women with early breast cancer scheduled to be treated with ARIMIDEX should be managed using the current National Cholesterol Education Program guidelines for cardiovascular risk-based management of individual patients with LDL elevations. Other Adverse Reactions Patients receiving ARIMIDEX had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen. Patients receiving ARIMIDEX had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with patients receiving tamoxifen [209 (7%)]. Patients receiving ARIMIDEX had a higher incidence of carpal tunnel syndrome [78 (2.5%)] compared with patients receiving tamoxifen [22 (0.7%)]. Vaginal bleeding occurred more frequently in the tamoxifen-treated patients versus the ARIMIDEX-treated patients 317 (10%) versus 167 (5%), respectively. Patients receiving ARIMIDEX had a lower incidence of hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen. 10-year median follow-up Safety Results from the ATAC Trial Results are consistent with the previous analyses. Serious adverse reactions were similar between ARIMIDEX (50%) and tamoxifen (51%). • Cardiovascular events were consistent with the known safety profiles of ARIMIDEX and tamoxifen. • The cumulative incidences of all first fractures (both serious and non-serious, occurring either during or after treatment) was higher in the ARIMIDEX group (15%) compared to the tamoxifen group (11%). This increased first fracture rate during treatment did not continue in the post-treatment follow-up period. • The cumulative incidence of new primary cancers was similar in the ARIMIDEX group (13.7%) compared to the tamoxifen group (13.9%). Consistent with the previous analyses, endometrial cancer was higher in the tamoxifen group (0.8%) compared to the ARIMIDEX group (0.2%). • The overall number of deaths (during or off-trial treatment) was similar between the treatment groups. There were more deaths related to breast cancer in the tamoxifen than in the ARIMIDEX treatment group. First-Line Therapy Adverse reactions occurring with an incidence of at least 5% in either treatment group of trials 0030 and 0027 during or within 2 weeks of the end of treatment are shown in Table 3. Table 3 – Adverse Reactions Occurring with an Incidence of at Least 5% in Trials 0030 and 0027 Body system Adverse Reaction* Number (%) of subjects ARIMIDEX Tamoxifen (N=506) (N=511) Whole body Asthenia 83 (16) 81 (16) Pain 70 (14) 73 (14) Back pain 60 (12) 68 (13) Headache 47 (9) 40 (8) Abdominal pain 40 (8) 38 (7) Chest pain 37 (7) 37 (7) Flu syndrome 35 (7) 30 (6) Pelvic pain 23 (5) 30 (6) Reference ID: 5496819 Body system Number (%) of subjects Adverse Reaction* ARIMIDEX Tamoxifen (N=506) (N=511) Cardiovascular Vasodilation 128 (25) 106 (21) Hypertension 25 (5) 36 (7) Digestive Nausea 94 (19) 106 (21) Constipation 47 (9) 66 (13) Diarrhea 40 (8) 33 (6) Vomiting 38 (8) 36 (7) Anorexia 26 (5) 46 (9) Metabolic and Nutritional Peripheral edema 51 (10) 41 (8) Musculoskeletal Bone pain 54 (11) 52 (10) Nervous Dizziness 30 (6) 22 (4) Insomnia 30 (6) 38 (7) Depression 23 (5) 32 (6) Hypertonia 16 (3) 26 (5) Respiratory Cough increased 55 (11) 52 (10) Dyspnea 51 (10) 47 (9) Pharyngitis 49 (10) 68 (13) Skin and appendages Rash 38 (8) 34 (8) Urogenital Leukorrhea 9 (2) 31 (6) * A patient may have had more than 1 adverse event. Less frequent adverse experiences reported in patients receiving ARIMIDEX 1 mg in either Trial 0030 or Trial 0027 were similar to those reported for second-line therapy. Based on results from second-line therapy and the established safety profile of tamoxifen, the incidences of 9 pre­ specified adverse event categories potentially causally related to one or both of the therapies because of their pharmacology were statistically analyzed. No significant differences were seen between treatment groups. Table 4 – Number of Patients with Pre-specified Adverse Reactions in Trials 0030 and 0027 Adverse Reaction* Number (n) and Percentage of Patients ARIMIDEX 1 mg NOLVADEX 20 mg (N=506) (N=511) n (%) n (%) Depression 23 (5) 32 (6) Tumor Flare 15 (3) 18 (4) Thromboembolic Disease† 18 (4) 33 (6) Venous† 5 15 Coronary and Cerebral‡ 13 19 Gastrointestinal Disturbance 170 (34) 196 (38) Hot Flushes 134 (26) 118 (23) Reference ID: 5496819 Adverse Reaction* Number (n) and Percentage of Patients ARIMIDEX 1 mg NOLVADEX 20 mg (N=506) (N=511) n (%) n (%) Vaginal Dryness 9 (2) 3 (1) Lethargy 6 (1) 15 (3) Vaginal Bleeding 5 (1) 11 (2) Weight Gain 11 (2) 8 (2) * A patient may have had more than 1 adverse reaction. † Includes pulmonary embolus, thrombophlebitis, retinal vein thrombosis. ‡ Includes myocardial infarction, myocardial ischemia, angina pectoris, cerebrovascular accident, cerebral ischemia and cerebral infarct. Second-Line Therapy ARIMIDEX was tolerated in two controlled clinical trials (i.e., Trials 0004 and 0005), with less than 3.3% of the ARIMIDEX-treated patients and 4.0% of the megestrol acetate-treated patients withdrawing due to an adverse reaction. The principal adverse reaction more common with ARIMIDEX than megestrol acetate was diarrhea. Adverse reactions reported in greater than 5% of the patients in any of the treatment groups in these two controlled clinical trials, regardless of causality, are presented below: Table 5 – Number (n) and Percentage of Patients with Adverse Reactions in Trials 0004 and 0005 Adverse Reaction* ARIMIDEX ARIMIDEX Megestrol Acetate 1 mg 10 mg 160 mg (N=262) (N=246) (N=253) n % n % n % Asthenia 42 (16) 33 (13) 47 (19) Nausea 41 (16) 48 (20) 28 (11) Headache 34 (13) 44 (18) 24 (9) Hot Flashes 32 (12) 29 (11) 21 (8) Pain 28 (11) 38 (15) 29 (11) Back Pain 28 (11) 26 (11) 19 (8) Dyspnea 24 (9) 27 (11) 53 (21) Vomiting 24 (9) 26 (11) 16 (6) Cough Increased 22 (8) 18 (7) 19 (8) Diarrhea 22 (8) 18 (7) 7 (3) Constipation 18 (7) 18 (7) 21 (8) Abdominal Pain 18 (7) 14 (6) 18 (7) Anorexia 18 (7) 19 (8) 11 (4) Bone Pain 17 (6) 26 (12) 19 (8) Pharyngitis 16 (6) 23 (9) 15 (6) Dizziness 16 (6) 12 (5) 15 (6) Rash 15 (6) 15 (6) 19 (8) Dry Mouth 15 (6) 11 (4) 13 (5) Peripheral Edema 14 (5) 21 (9) 28 (11) Pelvic Pain 14 (5) 17 (7) 13 (5) Depression 14 (5) 6 (2) 5 (2) Chest Pain 13 (5) 18 (7) 13 (5) Paresthesia 12 (5) 15 (6) 9 (4) Vaginal Hemorrhage 6 (2) 4 (2) 13 (5) Reference ID: 5496819 Adverse Reaction* ARIMIDEX ARIMIDEX Megestrol Acetate 1 mg 10 mg 160 mg (N=262) (N=246) (N=253) n % n % n % Weight Gain 4 (2) 9 (4) 30 (12) Sweating 4 (2) 3 (1) 16 (6) Increased Appetite 0 (0) 1 (0) 13 (5) * A patient may have had more than one adverse reaction. Other less frequent (2% to 5%) adverse reactions reported in patients receiving ARIMIDEX 1 mg in either Trial 0004 or Trial 0005 are listed below. These adverse experiences are listed by body system and are in order of decreasing frequency within each body system regardless of assessed causality. Body as a Whole: Flu syndrome; fever; neck pain; malaise; accidental injury; infection Cardiovascular: Hypertension; thrombophlebitis Hepatic: Gamma GT increased; SGOT increased; SGPT increased Hematologic: Anemia; leukopenia Metabolic and Nutritional: Alkaline phosphatase increased; weight loss Mean serum total cholesterol levels increased by 0.5 mmol/L among patients receiving ARIMIDEX. Increases in LDL cholesterol have been shown to contribute to these changes. Musculoskeletal: Myalgia; arthralgia; pathological fracture Nervous: Somnolence; confusion; insomnia; anxiety; nervousness Respiratory: Sinusitis; bronchitis; rhinitis Skin and Appendages: Hair thinning (alopecia); pruritus Urogenital: Urinary tract infection; breast pain The incidences of the following adverse reaction groups potentially causally related to one or both of the therapies because of their pharmacology, were statistically analyzed: weight gain, edema, thromboembolic disease, gastrointestinal disturbance, hot flushes, and vaginal dryness. These six groups, and the adverse reactions captured in the groups, were prospectively defined. The results are shown in the table below. Table 6 - Number (n) and Percentage of Patients with Pre-specified Adverse Reactions in Trials 0004 and 0005 Adverse Reaction Group ARIMIDEX ARIMIDEX Megestrol Acetate 1 mg 10 mg 160 mg (N=262) (N=246) (N=253) n (%) n (%) n (%) Gastrointestinal Disturbance 77 (29) 81 (33) 54 (21) Hot Flushes 33 (13) 29 (12) 35 (14) Edema 19 (7) 28 (11) 35 (14) Thromboembolic Disease 9 (3) 4 (2) 12 (5) Vaginal Dryness 5 (2) 3 (1) 2 (1) Weight Gain 4 (2) 10 (4) 30 (12) Reference ID: 5496819 6.2 Post-Marketing Experience These adverse reactions are reported voluntarily from a population of uncertain size. Therefore, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. The following have been reported in post-approval use of ARIMIDEX: • Hepatobiliary events including increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-GT, and bilirubin; hepatitis • Rash including cases of mucocutaneous disorders such as erythema multiforme and Stevens-Johnson syndrome • Cases of allergic reactions including angioedema, urticaria and anaphylaxis [see Contraindications (4)] • Myalgia and hypercalcemia (with or without an increase in parathyroid hormone) • Tendon disorders including tendon rupture, tendonitis, tenosynovitis, and tenosynovitis stenosans (trigger finger) 7 DRUG INTERACTIONS 7.1 Tamoxifen Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%. However, the co-administration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or N­ desmethyltamoxifen. At a median follow-up of 33 months, the combination of ARIMIDEX and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor- positive subpopulation. This treatment arm was discontinued from the trial [see Clinical Studies (14.1)]. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole. 7.2 Estrogen Estrogen-containing therapies should not be used with ARIMIDEX as they may diminish its pharmacological action. 7.3 Warfarin In a study conducted in 16 male volunteers, anastrozole did not alter the exposure (as measured by Cmax and AUC) and anticoagulant activity (as measured by prothrombin time, activated partial thromboplastin time, and thrombin time) of both R- and S-warfarin. 7.4 Cytochrome P450 Based on in vitro and in vivo results, it is unlikely that co-administration of ARIMIDEX 1 mg will affect other drugs as a result of inhibition of cytochrome P450 [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, ARIMIDEX may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no studies of ARIMIDEX use in pregnant women. Anastrozole caused embryo-fetal toxicities in rats at maternal exposure that were 9 times the human clinical exposure, based on area under the curve (AUC). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 16 times the recommended human dose on a mg/m2 basis. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Reference ID: 5496819 Data Animal Data In animal reproduction studies, pregnant rats and rabbits received anastrozole during organogenesis at doses equal to or greater than 0.1 and 0.02 mg/kg/day, respectively, (about 1 and 1/3 the recommended human dose on a mg/m2 basis, respectively). In both species, anastrozole crossed the placenta, and there was increased pregnancy loss (increased pre- and/or post-implantation loss, increased resorption, and decreased numbers of live fetuses). In rats, these effects were dose related, and placental weights were significantly increased at doses equal to or greater than 0.1 mg/kg/day. Fetotoxicity, including delayed fetal development (i.e., incomplete ossification and depressed fetal body weights), occurred in rats at anastrozole doses of 1 mg/kg/day that produced peak plasma levels 19 times higher than serum levels in humans at the therapeutic dose (AUC0-24hr 9 times higher). In rabbits, anastrozole caused pregnancy failure at doses equal to or greater than 1.0 mg/kg/day (about 16 times the recommended human dose on a mg/m2 basis). 8.2 Lactation Risk Summary There are no data on the presence of anastrozole or its metabolites in human milk, or its effects on the breast-fed child or on milk production. Because many drugs are excreted in human milk and because of the tumorigenicity shown for anastrozole in animal studies, or the potential for serious adverse reactions in the breast-fed child from ARIMIDEX, advise lactating women not to breastfeed during treatment with ARIMIDEX and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiation of ARIMIDEX. Contraception Females Based on animal studies, ARIMIDEX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ARIMIDEX and for at least 3 weeks after the last dose. Infertility Females Based on studies in female animals, ARIMIDEX may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Clinical studies in pediatric patients included a placebo-controlled trial in pubertal boys of adolescent age with gynecomastia and a single-arm trial in girls with McCune-Albright Syndrome and progressive precocious puberty. The efficacy of ARIMIDEX in the treatment of pubertal gynecomastia in adolescent boys and in the treatment of precocious puberty in girls with McCune-Albright Syndrome has not been demonstrated. Gynecomastia Study A randomized, double-blind, placebo-controlled, multi-center study enrolled 80 boys with pubertal gynecomastia aged 11 to 18 years. Patients were randomized to a daily regimen of either ARIMIDEX 1 mg or placebo. After 6 months of treatment there was no statistically significant difference in the percentage of patients who experienced a ≥50% reduction Reference ID: 5496819 in gynecomastia (primary efficacy analysis). Secondary efficacy analyses (absolute change in breast volume, the percentage of patients who had any reduction in the calculated volume of gynecomastia, breast pain resolution) were consistent with the primary efficacy analysis. Serum estradiol concentrations at Month 6 of treatment were reduced by 15.4% in the ARIMIDEX group and 4.5% in the placebo group. Adverse reactions that were assessed as treatment-related by the investigators occurred in 16.3% of the ARIMIDEX- treated patients and 8.1% of the placebo-treated patients with the most frequent being acne (7% ARIMIDEX and 2.7% placebo) and headache (7% ARIMIDEX and 0% placebo); all other adverse reactions showed small differences between treatment groups. One patient treated with ARIMIDEX discontinued the trial because of testicular enlargement. The mean baseline-subtracted change in testicular volume after 6 months of treatment was + 6.6 ± 7.9 cm3 in the ARIMIDEX- treated patients and + 5.2 ± 8.0 cm3 in the placebo group. McCune-Albright Syndrome Study A multi-center, single-arm, open-label study was conducted in 28 girls with McCune-Albright Syndrome and progressive precocious puberty aged 2 to <10 years. All patients received a 1 mg daily dose of ARIMIDEX. The trial duration was 12 months. Patients were enrolled on the basis of a diagnosis of typical (27/28) or atypical (1/27) McCune-Albright Syndrome, precocious puberty, history of vaginal bleeding, and/or advanced bone age. Patients’ baseline characteristics included the following: a mean chronological age of 5.9 ± 2.0 years, a mean bone age of 8.6 ± 2.6 years, a mean growth rate of 7.9 ± 2.9 cm/year and a mean Tanner stage for breast of 2.7 ± 0.81. Compared to pre-treatment data there were no on-treatment statistically significant reductions in the frequency of vaginal bleeding days, or in the rate of increase of bone age (defined as a ratio between the change in bone age over the change of chronological age). There were no clinically significant changes in Tanner staging, mean ovarian volume, mean uterine volume and mean predicted adult height. A small but statistically significant reduction of growth rate from 7.9 ± 2.9 cm/year to 6.5 ± 2.8 cm/year was observed but the absence of a control group precludes attribution of this effect to treatment or to other confounding factors such as variations in endogenous estrogen levels commonly seen in McCune-Albright Syndrome patients. Five patients (18%) experienced adverse reactions that were considered possibly related to ARIMIDEX. These were nausea, acne, pain in an extremity, increased alanine transaminase and aspartate transaminase, and allergic dermatitis. Pharmacokinetics in Pediatric Patients Following 1 mg once daily multiple administration in pediatric patients, the mean time to reach the maximum anastrozole concentration was 1 hr. The mean (range) disposition parameters of anastrozole in pediatric patients were described by a CL/F of 1.54 L/h (0.77-4.53 L/h) and V/F of 98.4 L (50.7-330.0 L). The terminal elimination half-life was 46.8 h, which was similar to that observed in postmenopausal women treated with anastrozole for breast cancer. Based on a population pharmacokinetic analysis, the pharmacokinetics of anastrozole was similar in boys with pubertal gynecomastia and girls with McCune-Albright Syndrome. 8.5 Geriatric Use In studies 0030 and 0027, about 50% of patients were 65 or older. Patients ≥ 65 years of age had moderately better tumor response and time to tumor progression than patients < 65 years of age regardless of randomized treatment. In studies 0004 and 0005, 50% of patients were 65 or older. Response rates and time to progression were similar for the over 65 and younger patients. In the ATAC study, 45% of patients were 65 years of age or older. The efficacy of ARIMIDEX compared to tamoxifen in patients who were 65 years or older (N=1413 for ARIMIDEX and N=1410 for tamoxifen, the hazard ratio for disease-free survival was 0.93 [95% CI: 0.80, 1.08]) was less than efficacy observed in patients who were less than 65 years of age (N=1712 for ARIMIDEX and N=1706 for tamoxifen, the hazard ratio for disease-free survival was 0.79 [95% CI: 0.67, 0.94]). The pharmacokinetics of anastrozole are not affected by age. Reference ID: 5496819 8.6 Renal Impairment Since only about 10% of anastrozole is excreted unchanged in the urine, the renal impairment does not influence the total body clearance. Dosage adjustment in patients with renal impairment is not necessary [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment The plasma anastrozole concentrations in the subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials. Therefore, dosage adjustment is also not necessary in patients with stable hepatic cirrhosis. ARIMIDEX has not been studied in patients with severe hepatic impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Clinical trials have been conducted with ARIMIDEX, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were tolerated. A single dose of ARIMIDEX that results in life-threatening symptoms has not been established. There is no specific antidote to overdosage and treatment must be symptomatic. In the management of an overdose, consider that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because ARIMIDEX is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated. 11 DESCRIPTION ARIMIDEX (anastrozole) tablets for oral administration contain 1 mg of anastrozole, a non-steroidal aromatase inhibitor. It is chemically described as 1,3-Benzenediacetonitrile, a, a, a', a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl). Its molecular formula is C17H19N5 and its structural formula is: Anastrozole is an off-white powder with a molecular weight of 293.4. Anastrozole has moderate aqueous solubility (0.5 mg/mL at 25°C); solubility is independent of pH in the physiological range. Anastrozole is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile. Each tablet contains as inactive ingredients: lactose, magnesium stearate, hypromellose, polyethylene glycol, povidone, sodium starch glycolate, and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The growth of many cancers of the breast is stimulated or maintained by estrogens. In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen Reference ID: 5496819 biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme. Anastrozole is a selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone. 12.2 Pharmacodynamics Effect on Estradiol Mean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, and 10 mg of ARIMIDEX in postmenopausal women with advanced breast cancer. Clinically significant suppression of serum estradiol was seen with all doses. Doses of 1 mg and higher resulted in suppression of mean serum concentrations of estradiol to the lower limit of detection (3.7 pmol/L). The recommended daily dose, ARIMIDEX 1 mg, reduced estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with ARIMIDEX 1 mg. The effect of ARIMIDEX in premenopausal women with early or advanced breast cancer has not been studied. Because aromatization of adrenal androgens is not a significant source of estradiol in premenopausal women, ARIMIDEX would not be expected to lower estradiol levels in premenopausal women. Effect on Corticosteroids In multiple daily dosing trials with 3, 5, and 10 mg, the selectivity of anastrozole was assessed by examining effects on corticosteroid synthesis. For all doses, anastrozole did not affect cortisol or aldosterone secretion at baseline or in response to ACTH. No glucocorticoid or mineralocorticoid replacement therapy is necessary with anastrozole. Other Endocrine Effects In multiple daily dosing trials with 5 and 10 mg, thyroid stimulating hormone (TSH) was measured; there was no increase in TSH during the administration of ARIMIDEX. ARIMIDEX does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens. 12.3 Pharmacokinetics Absorption Inhibition of aromatase activity is primarily due to anastrozole, the parent drug. Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within 2 hours of dosing under fasted conditions. Studies with radiolabeled drug have demonstrated that orally administered anastrozole is well absorbed into the systemic circulation. Food reduces the rate but not the overall extent of anastrozole absorption. The mean Cmax of anastrozole decreased by 16% and the median Tmax was delayed from 2 to 5 hours when anastrozole was administered 30 minutes after food. The pharmacokinetics of anastrozole are linear over the dose range of 1 to 20 mg, and do not change with repeated dosing. The pharmacokinetics of anastrozole were similar in patients and healthy volunteers. Distribution Steady-state plasma levels are approximately 3- to 4-fold higher than levels observed after a single dose of ARIMIDEX. Plasma concentrations approach steady-state levels at about 7 days of once daily dosing. Anastrozole is 40% bound to plasma proteins in the therapeutic range. Metabolism Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. Three metabolites of anastrozole (triazole, a glucuronide conjugate of hydroxy-anastrozole, and a glucuronide conjugate of anastrozole itself) have been Reference ID: 5496819 identified in human plasma and urine. The major circulating metabolite of anastrozole, triazole, lacks pharmacologic activity. Anastrozole inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of anastrozole to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites. Excretion Eighty-five percent of radiolabeled anastrozole was recovered in feces and urine. Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Renal elimination accounts for approximately 10% of total clearance. The mean elimination half-life of anastrozole is 50 hours. Effect of Gender and Age Anastrozole pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. No age-related effects were seen over the range <50 to >80 years. Effect of Race Estradiol and estrone sulfate serum levels were similar between Japanese and Caucasian postmenopausal women who received 1 mg of anastrozole daily for 16 days. Anastrozole mean steady-state minimum plasma concentrations in Caucasian and Japanese postmenopausal women were 25.7 and 30.4 ng/mL, respectively. Effect of Renal Impairment Anastrozole pharmacokinetics have been investigated in subjects with renal impairment. Anastrozole renal clearance decreased proportionally with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment (creatinine clearance < 30 mL/min/1.73m2) compared to controls. Total clearance was only reduced 10%. No dosage adjustment is needed for renal impairment [see Dosage and Administration (2.1) and Use in Specific Populations (8.6)]. Effect of Hepatic Impairment Anastrozole pharmacokinetics have been investigated in subjects with hepatic cirrhosis related to alcohol abuse. The apparent oral clearance (CL/F) of anastrozole was approximately 30% lower in subjects with stable hepatic cirrhosis than in control subjects with normal liver function. However, these plasma concentrations were still with the range of values observed in normal subjects. The effect of severe hepatic impairment was not studied. No dose adjustment is necessary for stable hepatic cirrhosis [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A conventional carcinogenesis study in rats at doses of 1.0 to 25 mg/kg/day (about 10 to 243 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed an increase in the incidence of hepatocellular adenoma and carcinoma and uterine stromal polyps in females and thyroid adenoma in males at the high dose. A dose-related increase was observed in the incidence of ovarian and uterine hyperplasia in females. At 25 mg/kg/day, plasma AUC0-24 hr levels in rats were 110 to 125 times higher than the level exhibited in postmenopausal volunteers at the recommended dose. A separate carcinogenicity study in mice at oral doses of 5 to 50 mg/kg/day (about 24 to 243 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years produced an increase in the incidence of benign ovarian stromal, epithelial and granulosa cell tumors at all dose levels. A dose-related increase in the incidence of ovarian hyperplasia was also observed in female mice. These ovarian changes are considered to be Reference ID: 5496819 rodent-specific effects of aromatase inhibition and are of questionable significance to humans. The incidence of lymphosarcoma was increased in males and females at the high dose. At 50 mg/kg/day, plasma AUC levels in mice were 35 to 40 times higher than the level exhibited in postmenopausal volunteers at the recommended dose. ARIMIDEX has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests, CHO-K1 gene mutation assay) or clastogenic either in vitro (chromosome aberrations in human lymphocytes) or in vivo (micronucleus test in rats). Oral administration of anastrozole to female rats (from 2 weeks before mating to pregnancy day 7) produced significant incidence of infertility and reduced numbers of viable pregnancies at 1 mg/kg/day (about 10 times the recommended human dose on a mg/m2 basis and 9 times higher than the AUC0-24 hr found in postmenopausal volunteers at the recommended dose). Pre-implantation loss of ova or fetus was increased at doses equal to or greater than 0.02 mg/kg/day (about one-fifth the recommended human dose on a mg/m2 basis). Recovery of fertility was observed following a 5-week non-dosing period which followed 3 weeks of dosing. It is not known whether these effects observed in female rats are indicative of impaired fertility in humans. Multiple-dose studies in rats administered anastrozole for 6 months at doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 19 and 9 times higher than the respective values found in postmenopausal volunteers at the recommended dose) resulted in hypertrophy of the ovaries and the presence of follicular cysts. In addition, hyperplastic uteri were observed in 6-month studies in female dogs administered doses equal to or greater than 1 mg/kg/day (which produced plasma anastrozole Cssmax and AUC0-24 hr that were 22 times and 16 times higher than the respective values found in postmenopausal women at the recommended dose). It is not known whether these effects on the reproductive organs of animals are associated with impaired fertility in premenopausal women. 14 CLINICAL STUDIES 14.1 Adjuvant Treatment of Breast Cancer in Postmenopausal Women A multicenter, double-blind trial (ATAC) randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with ARIMIDEX 1 mg daily, tamoxifen 20 mg daily, or a combination of the two treatments for five years or until recurrence of the disease. The primary endpoint of the trial was disease-free survival (i.e., time to occurrence of a distant or local recurrence, or contralateral breast cancer or death from any cause). Secondary endpoints of the trial included distant disease-free survival, the incidence of contralateral breast cancer and overall survival. At a median follow-up of 33 months, the combination of ARIMIDEX and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole [see Drug Interactions (7.1)]. Demographic and other baseline characteristics were similar among the three treatment groups (see Table 7). Table 7 - Demographic and Baseline Characteristics for ATAC Trial Demographic Characteristic ARIMIDEX Tamoxifen ARIMIDEX 1 mg 1 mg 20 mg plus Tamoxifen† 20 mg (N*=3125) (N*=3116) (N*=3125) Mean age (yrs.) 64.1 64.1 64.3 Age Range (yrs.) 38.1 - 92.8 32.8 - 94.9 37.0 - 92.2 Age Distribution (%) <45 yrs. 0.7 0.4 0.5 45-60 yrs. 34.6 35.0 34.5 >60 <70 yrs. 38.0 37.1 37.7 Reference ID: 5496819 Demographic Characteristic ARIMIDEX Tamoxifen ARIMIDEX 1 mg 1 mg 20 mg plus Tamoxifen† 20 mg (N*=3125) (N*=3116) (N*=3125) >70 yrs. 26.7 27.4 27.3 Mean Weight (kg) 70.8 71.1 71.3 Receptor Status (%) Positive‡ 83.5 83.1 84.0 Negative§ 7.4 8.0 7.0 Other¶ 8.8 8.6 9.0 Other Treatment (%) prior to Randomization Mastectomy 47.8 47.3 48.1 Breast conservation# 52.3 52.8 51.9 Axillary surgery 95.5 95.7 95.2 Radiotherapy 63.3 62.5 61.9 Chemotherapy 22.3 20.8 20.8 Neoadjuvant Tamoxifen 1.6 1.6 1.7 Primary Tumor Size (%) T1 (≤2 cm) 63.9 62.9 64.1 T2 (>2 cm and ≤5 cm) 32.6 34.2 32.9 T3 (>5 cm) 2.7 2.2 2.3 Nodal Status (%) Node positive 34.9 33.6 33.5 1-3 (# of nodes) 24.4 24.4 24.3 4-9 7.5 6.4 6.8 >9 2.9 2.7 2.3 Tumor Grade (%) Well-differentiated 20.8 20.5 21.2 Moderately differentiated 46.8 47.8 46.5 Poorly/undifferentiated 23.7 23.3 23.7 Not assessed/recorded 8.7 8.4 8.5 * N=Number of patients randomized to the treatment † The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up ‡ Includes patients who were estrogen receptor (ER) positive or progesterone receptor (PgR) positive, or both positive § Includes patients with both ER negative and PgR negative receptor status ¶ Includes all other combinations of ER and PgR receptor status unknown # Among the patients who had breast conservation, radiotherapy was administered to 95.0% of patients in the ARIMIDEX arm, 94.1% in the tamoxifen arm and 94.5% in the ARIMIDEX plus tamoxifen arm. Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127] in the ARIMIDEX arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 84% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.83, 95% CI: 0.73, 0.94, p=0.0049) in the ARIMIDEX arm compared to the tamoxifen arm. Figure 1 - Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to ARIMIDEX or Tamoxifen Monotherapy in the ATAC Trial (Intent-to-Treat) Reference ID: 5496819 1.0 0.9 u.., u.., ff: 0.8 UJ U) ;','j 0.7 ~ D 0.6 D z < u.., > 0.5 ::::; < 0.4 z "2 I- 0.3 a: 0 0.. 0 0.2 a: 0.. 0.1 0.0 1.0 0.9 u.., u.., ~ 0.8 U) < 0.7 u.., U) 0 0.6 D z < w 0.5 > ::::; < 0.4 z "2 I- 0.3 a: 0 0.. 0 0.2 a: 0.. 0.1 0.0 0 -----:-:_:--.. RANDOMIZED TREATMENT ANASTROZOLE --- TAMOXIFEN 30 36 42 48 54 60 DISEASE-FREE SURVIVAL IN MONTHS NUMBER OF PATIENTS AT RISK: 12 18 24 ANASTROZOLE 3125 TAMOXIFEN 3116 3004 2992 2874 2835 2767 2709 2645 2575 66 2350 2273 72 984 933 78 RANDOMIZED TREATMENT - - - - - - • ANASTROZOLE --- TAMOXIFEN ~ ~ ~ ~ ~ 00 DISEASE-FREE SURVIVAL IN MONTHS NUMBER OF PATIENTS AT RISK: 12 18 24 ANASTROZOLE 2618 TAMOXIFEN 2598 2540 2516 2448 2398 2355 2304 2268 2189 66 2014 1932 72 830 774 78 51 47 42 36 84 84 90 90 Figure 2 - Disease-Free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to ARIMIDEX or Tamoxifen Monotherapy in the ATAC Trial The survival data with 68 months follow-up is presented in Table 9. In the group of patients who had previous adjuvant chemotherapy (N=698 for ARIMIDEX and N=647 for tamoxifen), the hazard ratio for disease-free survival was 0.91 (95% CI: 0.73 to 1.13) in the ARIMIDEX arm compared to the tamoxifen arm. The frequency of individual events in the intent-to-treat population and the hormone receptor-positive subpopulation are described in Table 8. Reference ID: 5496819 Table 8 - All Recurrence and Death Events* Intent-To-Treat Population‡ Hormone Receptor-Positive Subpopulation‡ ARIMIDEX Tamoxifen ARIMIDEX Tamoxifen 1 mg (N†=3125) 20 mg (N†=3116) 1 mg (N†=2618) 20 mg (N†=2598) Median Duration of Therapy (mo) 60 60 60 60 Median Efficacy Follow-up (mo) 68 68 68 68 Loco-regional recurrence 119 (3.8) 149 (4.8) 76 (2.9) 101 (3.9) Contralateral breast cancer 35 (1.1) 59 (1.9) 26 (1.0) 54 (2.1) Invasive 27 (0.9) 52 (1.7) 21 (0.8) 48 (1.8) Ductal carcinoma in situ 8 (0.3) 6 (0.2) 5 (0.2) 5 (0.2) Unknown 0 1 (<0.1) 0 1 (<0.1) Distant recurrence 324 (10.4) 375 (12.0) 226 (8.6) 265 (10.2) Death from Any Cause 411 (13.2) 420 (13.5) 296 (11.3) 301 (11.6) Death breast cancer 218 (7.0) 248 (8.0) 138 (5.3) 160 (6.2) Death other reason (including 193 (6.2) 172 (5.5) 158 (6.0) 141 (5.4) unknown) * The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up. † N=Number of patients randomized. ‡ Patients may fall into more than one category. A summary of the study efficacy results is provided in Table 9. Table 9 - ATAC Efficacy Summary* Intent-To-Treat Population Hormone Receptor-Positive Subpopulation ARIMIDEX 1 mg Tamoxifen 20 mg ARIMIDEX 1 mg Tamoxifen 20 mg (N=3125) (N=3116) (N=2618) (N=2598) Number of Events Number of Events Disease-free Survival 575 651 424 497 Hazard ratio 0.87 0.83 2-sided 95% CI 0.78 to 0.97 0.73 to 0.94 p-value 0.0127 0.0049 Distant Disease-free Survival 500 530 370 394 Hazard ratio 0.94 0.93 2-sided 95% CI 0.83 to 1.06 0.80 to 1.07 Overall Survival 411 420 296 301 Hazard ratio 0.97 0.97 2-sided 95% CI 0.85 to 1.12 0.83 to 1.14 * The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up. 10-year median follow-up Efficacy Results from the ATAC Trial In a subsequent analysis of the ATAC trial, patients in the two monotherapy arms were followed for a median of 120 months (10 years). Patients received study treatment for a median of 60 months (5 years) (see Table 10). Table 10 - Efficacy Summary Intent-To-Treat Population Hormone Receptor-Positive Subpopulation ARIMIDEX 1 mg Tamoxifen 20 mg ARIMIDEX 1 mg Tamoxifen 20 mg Reference ID: 5496819 1.00 0.95 LU 0.90 LU EE o.85 I- r5 0.80 > LU z 0.75 0 •• ·--••• ·---•••• , __ • '· ··-·--.. ·--........ --.. , __ _ ~ 0.70 0 ~ 0.65 er: (l_ 0.60 0.55 0.50 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 TIME TO EVENT (MONTHS) RANDOMIZED TREATMENT --- ANASTROZOLE - - - - - - TAM OX I FEN NUMBER OF PATIENTS AT RISK: MONTHS 0 12 24 36 48 60 72 84 96 108 120 A 3125 3005 2878 2765 2658 2519 2356 2194 1991 1773 934 T 3116 2992 2836 271 1 2584 2439 2261 2107 1940 1709 898 NB THE VERTICAL AXIS HAS BEEN TRUNCATED TO IMPROVE THE CLARITY OF THE KAPLAN-MEI ER CURVES (N=3125) (N=3116) (N=2618) (N=2598) Number of Events Number of Events Disease-free Survival 953 1022 735 924 Hazard ratio 0.91 0.86 2-sided 95% CI 0.83 to 0.99 0.78 to 0.95 p-value 0.0365 0.0027 Overall Survival 734 747 563 586 Hazard ratio 0.97 0.95 2-sided 95% CI 0.88 to 1.08 0.84 to 1.06 Figure 3 - Disease-Free Survival Kaplan Meier Survival Curve for all Patients Randomized to ARIMIDEX or Tamoxifen Monotherapy in the ATAC Trial (Intent-to-Treat)(a) a The proportion of patients with 120 months’ follow-up was 29.4%. Figure 4 - Disease-Free Survival for Hormone Receptor-Positive Subpopulation of Patients Randomized to ARIMIDEX or Tamoxifen Monotherapy in the ATAC Trial(b) Reference ID: 5496819 1.00 0.95 LU 0.90 LU ff: 0.85 I- ilS 0.80 > LU z 0.75 0 ~ 0.70 0 t 0.65 cc o... 0.60 0.55 0.50 0 ······-···--•••.. ____ ._. ··--... --- •• ······-·-••• ·····-... ·-·--... 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 TIME TO EVENT (MONTHS) RANDOMIZED TREATMENT --- ANASTROZOLE - - - - - - TAMOXIFEN NUMBER OF PATIENTS AT RISK: MONTHS 0 12 2541 2516 24 2452 2398 36 2362 2304 48 2279 2195 60 2163 2086 72 2028 1934 84 1896 1796 96 1728 1650 108 1542 1453 120 800 753 A T 2618 2598 NB: THE VERTICAL AXIS HAS BEEN TRUNCATED TO IMPROVE THE CLARITY OF THE KAPLAN-MEIER CURVES b The proportion of patients with 120 months’ follow-up was 29.8%. 14.2 First-Line Therapy in Postmenopausal Women with Advanced Breast Cancer Two double-blind, controlled clinical studies of similar design (0030, a North American study and 0027, a predominately European study) were conducted to assess the efficacy of ARIMIDEX compared with tamoxifen as first-line therapy for hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer in postmenopausal women. A total of 1021 patients between the ages of 30 and 92 years old were randomized to receive trial treatment. Patients were randomized to receive 1 mg of ARIMIDEX once daily or 20 mg of tamoxifen once daily. The primary endpoints for both trials were time to tumor progression, objective tumor response rate, and safety. Demographics and other baseline characteristics, including patients who had measurable and no measurable disease, patients who were given previous adjuvant therapy, the site of metastatic disease and ethnic origin were similar for the two treatment groups for both trials. The following table summarizes the hormone receptor status at entry for all randomized patients in trials 0030 and 0027. Table 11 - Demographic and Other Baseline Characteristics Number (%) of subjects Trial 0030 Trial 0027 Receptor status ARIMIDEX 1 mg Tamoxifen 20 mg ARIMIDEX 1 mg Tamoxifen 20 mg (N=171) (N=182) (N=340) (N=328) ER* and/or PgR† 151 (88.3) 162 (89.0) 154 (45.3) 144 (43.9) ER* unknown, PgR† unknown 19 (11.1) 20 (11.0) 185 (54.4) 183 (55.8) * ER=Estrogen receptor † PgR=Progesterone receptor For the primary endpoints, trial 0030 showed that ARIMIDEX had a statistically significant advantage over tamoxifen (p=0.006) for time to tumor progression; objective tumor response rates were similar for ARIMIDEX and tamoxifen. Trial 0027 showed that ARIMIDEX and tamoxifen had similar objective tumor response rates and time to tumor progression (see Table 12 and Figures 5 and 6). Table 12 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints. Reference ID: 5496819 1.0 0.9 <.!J z 0.8 u5 (f) w 0.7 0:: <.!J 0 0.6 0:: a... f- 0.5 0 z \ -- z 0.4 0 i== 0:: 0.3 0 a... 0 0:: a... 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 TIME TO PROGRESSION (MONTHS) RANDOMIZED TREATMENT --- ANASTROZOLE - - - - - - TAMOXIFEN MONTHS: 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 AT RISK: 353 317 231 176 151 128 93 74 63 43 25 19 15 6 4 3 Table 12 - Efficacy Results of First-line Treatment Endpoint Trial 0030 Trial 0027 ARIMIDEX Tamoxifen ARIMIDEX Tamoxifen 1 mg 20 mg 1 mg 20 mg (N=171) (N=182) (N=340) (N=328) Time to progression (TTP) Median TTP (months) 11.1 5.6 8.2 8.3 Number (%) of subjects who 114 (67%) 138 (76%) 249 (73%) 247 (75%) progressed Hazard ratio (LCL*)† 1.42 (1.15) 1.01 (0.87) 2-sided 95% CI‡ (1.11, 1.82) (0.85, 1.20) p-value§ 0.006 0.920 Best objective response rate Number (%) of subjects with CR¶ + PR# 36 (21.1%) 31 (17.0%) 112 (32.9%) 107 (32.6%) Odds Ratio (LCL*)♠ 1.30 (0.83) 1.01 (0.77) * LCL=Lower Confidence Limit † Tamoxifen:ARIMIDEX ‡ CI=Confidence Interval § Two-sided Log Rank ¶ CR=Complete Response # PR=Partial Response ♠ ARIMIDEX:Tamoxifen Figure 5 - Kaplan-Meier probability of time to disease progression for all randomized patients (intent-to-treat) in Trial 0030 Reference ID: 5496819 1.0 0.9 (!) 0.8 z u5 (/) 0.7 LU a: (!) 0 0.6 a: a.. t- 0 0.5 z z 0 0.4 ;:: a: 0 a.. 0.3 0 a: a.. 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 TIME TO PROGRESSION (MONTHS) RANDOMIZED TREATMENT --- ANASTROZOLE - - - - - - TAMOXIFEN MONTHS: 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 ATRISK: 668 582 440 359 322 249 188 158 117 86 65 56 45 35 24 18 9 5 3 2 Figure 6 - Kaplan-Meier probability of time to progression for all randomized patients (intent-to-treat) in Trial 0027 Results from the secondary endpoints were supportive of the results of the primary efficacy endpoints. There were too few deaths occurring across treatment groups of both trials to draw conclusions on overall survival differences. 14.3 Second-Line Therapy in Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy Anastrozole was studied in two controlled clinical trials (0004, a North American study; 0005, a predominately European study) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. Some of the patients had also received previous cytotoxic treatment. Most patients were ER-positive; a smaller fraction were ER-unknown or ER-negative; the ER-negative patients were eligible only if they had a positive response to tamoxifen. Eligible patients with measurable and non-measurable disease were randomized to receive either a single daily dose of 1 mg or 10 mg of ARIMIDEX or megestrol acetate 40 mg four times a day. The studies were double-blinded with respect to ARIMIDEX. Time to progression and objective response (only patients with measurable disease could be considered partial responders) rates were the primary efficacy variables. Objective response rates were calculated based on the Union Internationale Contre le Cancer (UICC) criteria. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated. Both trials included over 375 patients; demographics and other baseline characteristics were similar for the three treatment groups in each trial. Patients in the 0005 trial had responded better to prior tamoxifen treatment. Of the patients entered who had prior tamoxifen therapy for advanced disease (58% in Trial 0004; 57% in Trial 0005), 18% of these patients in Trial 0004 and 42% in Trial 0005 were reported by the primary investigator to have responded. In Trial 0004, 81% of patients were ER-positive, 13% were ER-unknown, and 6% were ER-negative. In Trial 0005, 58% of patients were ER- positive, 37% were ER-unknown, and 5% were ER-negative. In Trial 0004, 62% of patients had measurable disease compared to 79% in Trial 0005. The sites of metastatic disease were similar among treatment groups for each trial. On average, 40% of the patients had soft tissue metastases; 60% had bone metastases; and 40% had visceral (15% liver) metastases. Reference ID: 5496819 Efficacy results from the two studies were similar as presented in Table 13. In both studies there were no significant differences between treatment arms with respect to any of the efficacy parameters listed in the table below. Table 13 – Efficacy Results of Second-line Treatment ARIMIDEX ARIMIDEX Megestrol Acetate 1 mg 10 mg 160 mg Trial 0004 (N. America) (N=128) (N=130) (N=128) Median Follow-up (months)* 31.3 30.9 32.9 Median Time to Death (months) 29.6 25.7 26.7 2 Year Survival Probability (%) 62.0 58.0 53.1 Median Time to Progression (months) 5.7 5.3 5.1 Objective Response (all patients) (%) 12.5 10.0 10.2 Stable Disease for >24 weeks (%) 35.2 29.2 32.8 Progression (%) 86.7 85.4 90.6 Trial 0005 (Europe, Australia, S. Africa) (N=135) (N=118) (N=125) Median Follow-up (months)* 31.0 30.9 31.5 Median Time to Death (months) 24.3 24.8 19.8 2 Year Survival Probability (%) 50.5 50.9 39.1 Median Time to Progression (months) 4.4 5.3 3.9 Objective Response (all patients) (%) 12.6 15.3 14.4 Stable Disease for >24 weeks (%) 24.4 25.4 23.2 Progression (%) 91.9 89.8 92.0 * Surviving Patients When data from the two controlled trials are pooled, the objective response rates and median times to progression and death were similar for patients randomized to ARIMIDEX 1 mg and megestrol acetate. There is, in this data, no indication that ARIMIDEX 10 mg is superior to ARIMIDEX 1 mg. Table 14 – Pooled Efficacy Results of Second-line Treatment Trials 0004 & 0005 ARIMIDEX ARIMIDEX Megestrol Acetate (Pooled Data) 1 mg 10 mg 160 mg N=263 N=248 N=253 Median Time to Death (months) 26.7 25.5 22.5 2 Year Survival Probability (%) 56.1 54.6 46.3 Median Time to Progression 4.8 5.3 4.6 Objective Response (all patients) (%) 12.5 12.5 12.3 16 HOW SUPPLIED/STORAGE AND HANDLING ARIMIDEX (anastrozole) Tablets, 1 mg are supplied in bottles of 30 tablets (NDC 62559-670-30). Storage Store at controlled room temperature, 20 to 25°C (68 to 77°F) [see USP]. Reference ID: 5496819 17 PATIENT COUNSELING INFORMATION See FDA approved patient labeling (Patient Information). Hypersensitivity Reactions Inform patients of the possibility of serious allergic reactions with swelling of the face, lips, tongue and/or throat (angioedema) which may cause difficulty in swallowing and/or breathing and to seek medical attention immediately [see Contraindications (4)]. Ischemic Cardiovascular Events Patients with pre-existing ischemic heart disease should be informed that an increased incidence of cardiovascular events has been observed with ARIMIDEX use compared to tamoxifen use. Advise patients if new or worsening chest pain or shortness of breath occurs to seek medical attention immediately [see Warnings and Precautions (5.1)]. Bone Effects Inform patients that ARIMIDEX lowers the level of estrogen. This may lead to a loss of the mineral content of bones, which might decrease bone strength. A possible consequence of decreased mineral content of bones is an increase in the risk of fractures [see Warnings and Precautions (5.2)]. Cholesterol Inform patients that an increased level of cholesterol might be seen while receiving ARIMIDEX [see Warnings and Precautions (5.3)]. Carpal Tunnel Patients should be informed that if they experience tickling, tingling, or numbness they should notify their health care provider [see Adverse Reactions (6.1)]. Tamoxifen Patients should be advised not to take ARIMIDEX with Tamoxifen [see Clinical Studies (14.1)]. Missed Doses Inform patients that if they miss a dose, take it as soon as they remember. If it is almost time for their next dose, skip the missed dose and take the next regularly scheduled dose. Patients should not take two doses at the same time. Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during ARIMIDEX therapy and for at least 3 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with ARMIDEX [see Warning and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)]. Lactation Advise women not to breastfeed during ARIMIDEX treatment and for at least 2 weeks after the last dose [see Use in Specific Population (8.2)]. Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623 Reference ID: 5496819 anl Pharmaceuticals, Inc. ARIMIDEX is a registered trademark of the AstraZeneca group of companies and is licensed to ANI Pharmaceuticals, Inc. Reference ID: 5496819 Patient Information ARIMIDEX® A-rim-eh-dex (anastrozole) tablets What is the most important information I should know about ARIMIDEX? ARIMIDEX may cause serious side effects including: • heart disease. Women with early breast cancer, who have a history of blockage in their heart arteries (ischemic heart disease) and who take ARIMIDEX, may have an increase in symptoms of decreased blood flow to their heart compared to similar women who take tamoxifen. Get medical help right away if you have new or worsening chest pain or shortness of breath during treatment with ARIMIDEX. What is ARIMIDEX? ARIMIDEX is a prescription medicine used in women after menopause (“the change of life”) for: • treatment of early breast cancer ∘ after surgery ∘ in women whose breast cancer is hormone receptor-positive • the first treatment of breast cancer that has spread to nearby tissue or lymph nodes (locally advanced) or has spread to other parts of the body (metastatic), in women whose breast cancer is hormone receptor-positive or the hormone receptors are not known • treatment of advanced breast cancer, if the cancer has grown, or the disease has spread after tamoxifen therapy ARIMIDEX does not work in women with breast cancer who have not gone through menopause (premenopausal women). Who should not take ARIMIDEX? Do not take ARIMIDEX if you: • have had a severe allergic reaction to anastrozole or any of the ingredients in ARIMIDEX. See the end of this leaflet for a complete list of ingredients in ARIMIDEX. Symptoms of a severe allergic reaction to ARIMIDEX include: swelling of the face, lips, tongue, or throat, trouble breathing or swallowing, hives and itching. What should I tell my healthcare provider before taking ARIMIDEX? Before you take ARIMIDEX, tell your healthcare provider if you: • are still having menstrual periods (are not past menopause). Talk to your healthcare provider if you are not sure. • have or had a heart problem • have been told you have bone thinning or weakness (osteoporosis) • have high cholesterol • have any other medical conditions • are pregnant or plan to become pregnant. Taking ARIMIDEX during pregnancy or within 3 weeks of becoming pregnant may harm your unborn baby. ∘ Females who are able to become pregnant should have a pregnancy test before starting treatment with ARIMIDEX. ∘ Females who are able to become pregnant should use effective birth control (contraceptive) during treatment with ARIMIDEX and for 3 weeks after your last dose of ARIMIDEX. Tell your healthcare provider right away if you become pregnant or think you may be pregnant. • are breastfeeding or plan to breastfeed. It is not known if ARIMIDEX passes into breast milk. Do not breastfeed during treatment with ARIMIDEX and for 2 weeks after your last dose of ARIMIDEX. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you take: Reference ID: 5496819 • tamoxifen. You should not take ARIMIDEX if you take tamoxifen. Taking ARIMIDEX with tamoxifen may lower the amount of ARIMIDEX in your blood and may cause ARIMIDEX not to work as well. • Medicines that contain estrogen. ARIMIDEX may not work if taken with any of these medicines: ∘ hormone replacement therapy ∘ birth control pills ∘ estrogen creams ∘ vaginal rings ∘ vaginal suppositories Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take ARIMIDEX? • Take ARIMIDEX exactly as your healthcare provider tells you to take it. • Continue taking ARIMIDEX until your healthcare provider tells you to stop. • ARIMIDEX can be taken with or without food. • If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take your next regularly scheduled dose. Do not take two doses at the same time. If you take too much ARIMIDEX, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of ARIMIDEX? ARIMIDEX may cause serious side effects including: • See “What is the most important information I should know about ARIMIDEX?” • bone thinning or weakness (osteoporosis). ARIMIDEX lowers estrogen in your body, which may cause your bones to become thinner and weaker. This may increase your risk of fractures, especially of your spine, hip and wrist. Your healthcare provider may order a bone mineral density test before you start and during treatment with ARIMIDEX to check you for bone changes. • increased blood cholesterol (fat in the blood). Your healthcare provider may do blood tests to check your cholesterol while you are taking ARIMIDEX. • skin reactions. Stop taking ARIMIDEX and call your healthcare provider right away if you get any skin lesions, ulcers, or blisters. • severe allergic reactions. Get medical help right away if you get: ∘ swelling of your face, lips, tongue, or throat ∘ trouble swallowing or breathing • liver problems. ARIMIDEX can cause inflammation of your liver and changes in liver function blood tests. Your healthcare provider may check you for this. Stop taking ARIMIDEX and call your healthcare provider right away if you have any of these signs or symptoms of a liver problem: ∘ a general feeling of not being well ∘ yellowing of your skin or whites of your eyes ∘ pain on the right side of your stomach-area (abdomen) Common side effects in women taking ARIMIDEX include: • hot flashes • weakness • joint aches • joint pain, stiffness or swelling (arthritis) • pain Reference ID: 5496819 anl Pharmaceuticals, Inc. • sore throat • high blood pressure • depression • nausea and vomiting • rash • back pain • sleep problems • bone pain • headache • swelling of your legs, ankles, or feet • increased cough • shortness of breath • build up of lymph fluid in the tissues of your affected arm (lymphedema) ARIMIDEX may also cause you to have tickling, tingling or numbness of your skin. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of ARIMIDEX. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA­ 1088. How should I store ARIMIDEX? • Store ARIMIDEX at room temperature between 68°F to 77°F (20°C to 25°C). Keep ARIMIDEX and all medicines out of the reach of children. General information about the safe and effective use of ARIMIDEX. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not take ARIMIDEX for a condition for which it was not prescribed. Do not give ARIMIDEX to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ARIMIDEX that is written for health professionals. For more information call 1-800-308­ 6755 or go to www.ARIMIDEX.com. What are the ingredients in ARIMIDEX? Active ingredient: anastrozole Inactive ingredients: lactose, magnesium stearate, hypromellose, polyethylene glycol, povidone, sodium starch glycolate, and titanium dioxide. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: December 2018 Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623 Reference ID: 5496819 ARIMIDEX is a registered trademark of the AstraZeneca group of companies and is licensed to ANI Pharmaceuticals, Inc. Reference ID: 5496819
custom-source
2025-02-12T15:47:48.200690
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CEFOBID® (sterile cefoperazone) For Intravenous or Intramuscular Use To reduce the development of drug-resistant bacteria and maintain the effectiveness of CEFOBID and other antibacterial drugs, CEFOBID should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION CEFOBID® (sterile cefoperazone), formerly known as sterile cefoperazone sodium, contains cefoperazone as cefoperazone sodium. It is a semisynthetic, broad-spectrum cephalosporin antibacterial drug. Chemically, cefoperazone sodium is sodium (6R,7R)-7-[(R)-2-(4-ethyl-2,3­ dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)- acetamido-3-[[(1-methyl-1H-tetrazol-5­ yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. Its molecular formula is C25H26N9NaO8S2 with a molecular weight of 667.65. The structural formula is given below: OH H5C2 O O s s CH3 COONa H O H C CONH N S CH2S N N N N H CONH N N CEFOBID (sterile cefoperazone) contains 34 mg sodium (1.5 mEq) per gram (g). CEFOBID is a white powder which is freely soluble in water. The pH of a 25% (w/v) freshly reconstituted solution varies between 4.5–6.5 and the solution ranges from colorless to straw yellow depending on the concentration. CEFOBID (sterile cefoperazone) in crystalline form is supplied in vials containing 1 g or 2 g cefoperazone as cefoperazone sodium for intravenous or intramuscular administration. CLINICAL PHARMACOLOGY High serum and bile levels of CEFOBID are attained after a single dose of the drug. Table 1 demonstrates the serum concentrations of CEFOBID in normal volunteers following either a single 15-minute constant rate intravenous infusion of 1, 2, 3 or 4 g of the drug, or a single intramuscular injection of 1 or 2 g of the drug. 1 Reference ID: 5497444 Table 1. Cefoperazone Serum Concentrations Mean Serum Concentrations (mcg/mL) Dose/Route 0* 0.5 hr 1 hr 2 hr 4 hr 8 hr 12 hr 1 g IV 153 114 73 38 16 4 0.5 2 g IV 252 153 114 70 32 8 2 3 g IV 340 210 142 89 41 9 2 4 g IV 506 325 251 161 71 19 6 1 g IM 32** 52 65 57 33 7 1 2 g IM 40** 69 93 97 58 14 4 * Hours post-administration, with 0 time being the end of the infusion. ** Values obtained 15 minutes post-injection. The mean serum half-life of CEFOBID is approximately 2.0 hours, independent of the route of administration. In a pharmacokinetic study, a total daily dose of 16 g was administered to severely immunocompromised patients by constant infusion without complications. Steady state serum concentrations were approximately 150 mcg/mL in these patients. In vitro studies with human serum indicate that the degree of CEFOBID reversible protein binding varies with the serum concentration from 93% at 25 mcg/mL of CEFOBID to 90% at 250 mcg/mL and 82% at 500 mcg/mL. CEFOBID achieves therapeutic concentrations in the following body tissues and fluids: Table 2. Tissue or Fluid Dose Concentration Ascitic Fluid 2 g 64 mcg/mL Cerebrospinal Fluid (in patients with 50 mg/kg 1.8 mcg/mL to 8.0 mcg/mL inflamed meninges) Urine 2 g 3,286 mcg/mL Sputum 3 g 6.0 mcg/mL Endometrium 2 g 74 mcg/g Myometrium 2 g 54 mcg/g Palatine Tonsil 1 g 8 mcg/g Sinus Mucous Membrane 1 g 8 mcg/g Umbilical Cord Blood 1 g 25 mcg/mL Amniotic Fluid 1 g 4.8 mcg/mL Lung 1 g 28 mcg/g Bone 2 g 40 mcg/g CEFOBID is excreted mainly in the bile. Maximum bile concentrations are generally obtained between one and three hours following drug administration and exceed concurrent serum concentrations by up to 100 times. Reported biliary concentrations of CEFOBID range from 66 mcg/mL at 30 minutes to as high as 6000 mcg/mL at 3 hours after an intravenous bolus injection of 2 g. 2 Reference ID: 5497444 Following a single intramuscular or intravenous dose, the urinary recovery of CEFOBID over a 12-hour period averages 20–30%. No significant quantity of metabolites has been found in the urine. Urinary concentrations greater than 2200 mcg/mL have been obtained following a 15-minute infusion of a 2 g dose. After an IM injection of 2 g, peak urine concentrations of almost 1000 mcg/mL have been obtained, and therapeutic levels are maintained for 12 hours. Repeated administration of CEFOBID at 12-hour intervals does not result in accumulation of the drug in normal subjects. Peak serum concentrations, areas under the curve (AUC’s), and serum half-lives in patients with severe renal insufficiency are not significantly different from those in normal volunteers. In patients with hepatic dysfunction, the serum half-life is prolonged and urinary excretion is increased. In patients with combined renal and hepatic insufficiencies, CEFOBID may accumulate in the serum. CEFOBID has been used in pediatrics, but the safety and effectiveness in children have not been established. The half-life of CEFOBID in serum is 6–10 hours in low birth-weight neonates. Microbiology Mechanism of Action Cefoperazone, a third-generation cephalosporin, interferes with cell wall synthesis by binding to the penicillin-binding proteins (PBPs), thus preventing cross-linking of nascent peptidoglycan. Resistance There are 3 principal mechanisms of resistance to cefoperazone: mutations in the target PBPs, which occur primarily in gram-positive bacteria; production of extended spectrum beta-lactamases or over-expression of chromosomally determined beta-lactamases in gram-negative bacteria; reduced uptake or active efflux in certain gram-negative bacteria. Interactions with Other Antimicrobials When tested in vitro, cefoperazone has demonstrated synergistic interactions with aminoglycosides against gram-negative bacilli. The clinical significance of these in vitro findings is unknown. Antimicrobial Activity Cefoperazone has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections (see INDICATIONS AND USAGE). Aerobic bacteria: Gram-positive bacteria • Staphylococcus aureus (methicillin-susceptible isolates only) • Staphylococcus epidermidis (methicillin-susceptible isolates only) • Streptococcus agalactiae (Group B beta-hemolytic streptococci) • Streptococcus pneumoniae • Streptococcus pyogenes (Group A beta-hemolytic streptococci) 3 Reference ID: 5497444 Gram-negative bacteria • Citrobacter species • Enterobacter species • Escherichia coli • Haemophilus influenzae • Klebsiella species • Morganella morganii • Neisseria gonorrhoeae • Proteus mirabilis • Proteus vulgaris • Providencia rettgeri • Providencia stuartii • Pseudomonas species • Serratia marcescens Anaerobic bacteria: • Gram-positive cocci (including Peptococcus and Peptostreptococcus spp.) • Clostridioides species • Bacteroides species The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefoperazone against isolates of similar genus or organism group. However, the efficacy of cefoperazone in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials. Aerobic bacteria: Gram-negative bacteria • Bordetella pertussis • Neisseria meningitidis • Salmonella spp. • Serratia liquefaciens • Shigella spp. • Yersinia enterocolytica Anaerobic bacteria: • Eubacterium spp. • Fusobacterium spp. Susceptibility Test Methods For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see https://www.fda.gov/STIC. 4 Reference ID: 5497444 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of CEFOBID and other antibacterial drugs. CEFOBID should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CEFOBID is indicated for the treatment of the following infections when caused by susceptible organisms: Respiratory Tract Infections caused by S. pneumoniae, H. influenzae, S. aureus (penicillinase and non-penicillinase producing strains), S. pyogenes* (Group A beta-hemolytic streptococci), P. aeruginosa, Klebsiella pneumoniae, E. coli, Proteus mirabilis, and Enterobacter species. Peritonitis and Other Intra-abdominal Infections caused by E. coli, P. aeruginosa,* and anaerobic gram-negative bacilli (including Bacteroides fragilis). Bacterial Septicemia caused by S. pneumoniae, S. agalactiae,* S. aureus, Pseudomonas aeruginosa,* E. coli, Klebsiella spp.,* Klebsiella pneumoniae,* Proteus species* (indole-positive and indole-negative), Clostridioides spp.* and anaerobic gram-positive cocci.* Infections of the Skin and Skin Structures caused by S. aureus (penicillinase and non-penicillinase producing strains), S. pyogenes,* and P. aeruginosa. Pelvic Inflammatory Disease, Endometritis, and Other Infections of the Female Genital Tract caused by N. gonorrhoeae, S. epidermidis,* S. agalactiae, E. coli, Clostridioides spp.,* Bacteroides species (including Bacteroides fragilis), and anaerobic gram-positive cocci. Cefobid® has no activity against Chlamydia trachomatis. Therefore, when Cefobid is used in the treatment of patients with pelvic inflammatory disease and C. trachomatis is one of the suspected pathogens, appropriate anti-chlamydial coverage should be added. Urinary Tract Infections caused by Escherichia coli and Pseudomonas aeruginosa. Enterococcal Infections: Although cefoperazone has been shown to be clinically effective in the treatment of infections caused by enterococci in cases of peritonitis and other intra-abdominal infections, infections of the skin and skin structures, pelvic inflammatory disease, endometritis and other infections of the female genital tract, and urinary tract infections,* the majority of clinical isolates of enterococci tested are not susceptible to cefoperazone but fall just at or in the intermediate zone of susceptibility, and are moderately resistant to cefoperazone. However, in vitro susceptibility testing may not correlate directly with in vivo results. Despite this, cefoperazone therapy has resulted in clinical cures of enterococcal infections, chiefly in polymicrobial infections. Cefoperazone should be used in enterococcal infections with care and at doses that achieve satisfactory serum levels of cefoperazone. 5 Reference ID: 5497444 * Efficacy against this organism in this organ system was studied in fewer than 10 infections. Combination Therapy Synergy between CEFOBID and aminoglycosides has been demonstrated with many gram-negative bacilli. However, such enhanced activity of these combinations is not predictable. If such therapy is considered, in vitro susceptibility tests should be performed to determine the activity of the drugs in combination, and renal function should be monitored carefully. (See PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections.) CONTRAINDICATIONS CEFOBID is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated severe hypersensitivity to beta-lactams (see WARNINGS). WARNINGS Hypersensitivity Reactions SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING BETA-LACTAM ANTIBACTERIALS, INCLUDING CEFOPERAZONE. THESE REACTIONS ARE MORE APT TO OCCUR IN INDIVIDUALS WITH A HISTORY OF HYPERSENSITIVITY REACTIONS TO MULTIPLE ALLERGENS. BEFORE THERAPY WITH CEFOBID IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS, PENICILLINS, CARBAPENEMS OR OTHER DRUGS. IF AN ALLERGIC REACTION OCCURS, CEFOPERAZONE SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED. Severe and occasionally fatal skin reactions such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and exfoliative dermatitis have been reported in patients on CEFOBID therapy. If a severe skin reaction occurs CEFOBID should be discontinued and appropriate therapy should be initiated (see ADVERSE REACTIONS). Clostridioides difficile-Associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CEFOBID, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. 6 Reference ID: 5497444 If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Hemorrhage Serious hemorrhage cases, including fatalities, have been reported with cefoperazone. Monitor for signs of bleeding, thrombocytopenia, and coagulopathy. Discontinue CEFOBID if there is persistent bleeding and no alternative explanations are identified. PRECAUTIONS General Prescribing CEFOBID in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Although transient elevations of the BUN and serum creatinine have been observed, CEFOBID alone does not appear to cause significant nephrotoxicity. However, concomitant administration of aminoglycosides and other cephalosporins has caused nephrotoxicity. CEFOBID is extensively excreted in bile. The serum half-life of CEFOBID is increased 2–4 fold in patients with hepatic disease and/or biliary obstruction. In general, total daily dosage above 4 g should not be necessary in such patients. If higher dosages are used, serum concentrations should be monitored. Because renal excretion is not the main route of elimination of CEFOBID (see CLINICAL PHARMACOLOGY), patients with renal failure require no adjustment in dosage when usual doses are administered. When high doses of CEFOBID are used, concentrations of drug in the serum should be monitored periodically. If evidence of accumulation exists, dosage should be decreased accordingly. The half-life of CEFOBID is reduced slightly during hemodialysis. Thus, dosing should be scheduled to follow a dialysis period. In patients with both hepatic dysfunction and significant renal disease, CEFOBID dosage should not exceed 1–2 g daily without close monitoring of serum concentrations. As with other antibacterial drugs, vitamin K deficiency resulting in coagulopathy has occurred in patients treated with CEFOBID. The mechanism is probably related to the suppression of gut flora which normally synthesize this vitamin. Those at risk include patients with a poor nutritional status, malabsorption states (e.g., cystic fibrosis), alcoholism, and patients on prolonged hyper-alimentation regimens (administered either intravenously or via a naso-gastric tube). Hypoprothrombinemia with or without bleeding has been reported. Prothrombin time should be monitored in these patients, and patients receiving anticoagulant therapy, and exogenous vitamin K administered as indicated. 7 Reference ID: 5497444 A disulfiram-like reaction characterized by flushing, sweating, headache, and tachycardia has been reported when alcohol (beer, wine) was ingested within 72 hours after CEFOBID administration. Patients should be cautioned about the ingestion of alcoholic beverages following the administration of CEFOBID. Prolonged use of CEFOBID may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken. CEFOBID should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Information for Patients Patients should be counseled that antibacterial drugs including CEFOBID should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CEFOBID is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treated by CEFOBID or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibacterial drugs which usually ends when the drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible. Drug/Laboratory Test Interactions A false-positive reaction for glucose in the urine may occur with Benedict’s or Fehling’s solution. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. The maximum duration of CEFOBID animal toxicity studies is six months. In none of the in vivo or in vitro genetic toxicology studies did CEFOBID show any mutagenic potential at either the chromosomal or subchromosomal level. CEFOBID produced no impairment of fertility and had no effects on general reproductive performance or fetal development when administered subcutaneously at daily doses up to 500 to 1000 mg/kg prior to and during mating, and to pregnant female rats during gestation. These doses are 10 to 20 times the estimated usual single clinical dose. CEFOBID had adverse effects on the testes of prepubertal rats at all doses tested. Subcutaneous administration of 1000 mg/kg per day (approximately 16 times the average adult human dose) resulted in reduced testicular weight, arrested spermatogenesis, reduced germinal cell population and vacuolation of Sertoli cell cytoplasm. The severity of lesions was dose dependent in the 100 to 1000 mg/kg per day range; the low dose caused a minor decrease in spermatocytes. This effect has not been observed in adult rats. Histologically the lesions were 8 Reference ID: 5497444 reversible at all but the highest dosage levels. However, these studies did not evaluate subsequent development of reproductive function in the rats. The relationship of these findings to humans is unknown. Usage in Pregnancy Reproduction studies have been performed in mice, rats, and monkeys at doses up to 10 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to CEFOBID. Cefoperazone crosses the placental barrier. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Usage in Nursing Mothers Only low concentrations of CEFOBID are excreted in human milk. Although CEFOBID passes poorly into breast milk of nursing mothers, caution should be exercised when CEFOBID is administered to a nursing woman. Pediatric Use Safety and effectiveness in children have not been established. For information concerning testicular changes in prepubertal rats (see Carcinogenesis, Mutagenesis, Impairment of Fertility). Geriatric Use Clinical studies of CEFOBID® (sterile cefoperazone sodium) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Clinical Trials Experience In clinical studies the following adverse effects were observed and were considered to be related to CEFOBID therapy or of uncertain etiology: Hypersensitivity: As with all cephalosporins, hypersensitivity manifested by skin reactions (1 patient in 45), drug fever (1 in 260), or a change in Coombs’ test (1 in 60) has been reported. These reactions are more likely to occur in patients with a history of allergies, particularly to penicillin. Hematology: As with other beta-lactam antibacterial drugs, reversible neutropenia may occur with prolonged administration. Slight decreases in neutrophil count (1 patient in 50) have been reported. Decreased hemoglobins (1 in 20) or hematocrits (1 in 20) have been reported, which is consistent with published literature on other cephalosporins. Transient eosinophilia has occurred in 1 patient in 10. 9 Reference ID: 5497444 Hepatic: Of 1285 patients treated with cefoperazone in clinical trials, one patient with a history of liver disease developed significantly elevated liver function enzymes during CEFOBID therapy. Clinical signs and symptoms of nonspecific hepatitis accompanied these increases. After CEFOBID therapy was discontinued, the patient’s enzymes returned to pre-treatment levels and the symptomatology resolved. As with other antibacterial drugs that achieve high bile levels, mild transient elevations of liver function enzymes have been observed in 5–10% of the patients receiving CEFOBID therapy. The relevance of these findings, which were not accompanied by overt signs or symptoms of hepatic dysfunction, has not been established. Gastrointestinal: Diarrhea or loose stools has been reported in 1 in 30 patients. Most of these experiences have been mild or moderate in severity and self-limiting in nature. In all cases, these symptoms responded to symptomatic therapy or ceased when cefoperazone therapy was stopped. Nausea and vomiting have been reported rarely. Symptoms of pseudomembranous colitis can appear during or for several weeks subsequent to antibacterial therapy (see WARNINGS). Renal Function Tests: Transient elevations of the BUN (1 in 16) and serum creatinine (1 in 48) have been noted. Local Reactions: CEFOBID is well tolerated following intramuscular administration. Occasionally, transient pain (1 in 140) may follow administration by this route. When CEFOBID is administered by intravenous infusion some patients may develop phlebitis (1 in 120) at the infusion site. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of CEFOBID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Coagulopathy, thrombocytopenia, hypoprothrombinaemia (see PRECAUTIONS) Immune System disorders: Anaphylactic reaction including shock and fatal cases (see WARNINGS), acute myocardial ischemia with or without myocardial infarction may occur as part of an allergic reaction. Hepatobiliary Disorders: Jaundice, hepatic dysfunction Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, pruritus Vascular Disorders: Hemorrhage (see WARNINGS) 10 Reference ID: 5497444 DOSAGE AND ADMINISTRATION The usual adult daily dose of CEFOBID (sterile cefoperazone) is 2 to 4 g per day administered in equally divided doses every 12 hours. In severe infections or infections caused by less sensitive organisms, the total daily dose and/or frequency may be increased. Patients have been successfully treated with a total daily dosage of 6–12 g divided into 2, 3 or 4 administrations ranging from 1.5 to 4 g per dose. When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days. If C. trachomatis is a suspected pathogen, appropriate anti-chlamydial coverage should be added, because cefoperazone has no activity against this organism. Solutions of CEFOBID and aminoglycoside should not be directly mixed, since there is a physical incompatibility between them. If combination therapy with CEFOBID and an aminoglycoside is contemplated (see INDICATIONS AND USAGE) this can be accomplished by sequential intermittent intravenous infusion provided that separate secondary intravenous tubing is used, and that the primary intravenous tubing is adequately irrigated with an approved diluent between doses. It is also suggested that CEFOBID be administered prior to the aminoglycoside. In vitro testing of the effectiveness of drug combination(s) is recommended. RECONSTITUTION The following solutions may be used for the initial reconstitution of CEFOBID (sterile cefoperazone). Table 3. Solutions for Initial Reconstitution 5% Dextrose Injection (USP) 5% Dextrose and 0.9% Sodium Chloride Injection (USP) 5% Dextrose and 0.2% Sodium Chloride Injection (USP) 10% Dextrose Injection (USP) Bacteriostatic Water for Injection [Benzyl Alcohol or Parabens] (USP)*† * Not to be used as a vehicle for intravenous infusion. 0.9% Sodium Chloride Injection (USP) Normosol® M and 5% Dextrose Injection Normosol® R Sterile Water for Injection* † Preparations containing Benzyl Alcohol should not be used in neonates. General Reconstitution Procedures CEFOBID (sterile cefoperazone) for intravenous or intramuscular use may be initially reconstituted with any compatible solution mentioned above in Table 3. Solutions should be allowed to stand after reconstitution to allow any foaming to dissipate to permit visual inspection for complete solubilization. Vigorous and prolonged agitation may be necessary to solubilize CEFOBID in higher concentrations (above 333 mg cefoperazone/mL). 11 Reference ID: 5497444 The maximum solubility of CEFOBID (sterile cefoperazone) is approximately 475 mg cefoperazone/mL of compatible diluent. Preparation for Intravenous Use General: CEFOBID (sterile cefoperazone) concentrations between 2 mg/mL and 50 mg/mL are recommended for intravenous administration. Preparation of Vials: Vials of CEFOBID (sterile cefoperazone) may be initially reconstituted with a minimum of 2.8 mL per g of cefoperazone of any compatible reconstituting solution appropriate for intravenous administration listed above in Table 3. For ease of reconstitution the use of 5 mL of compatible solution per g of CEFOBID is recommended. The entire quantity of the resulting solution should then be withdrawn for further dilution and administration using any of the following vehicles for intravenous infusion: Table 4. Vehicles for Intravenous Infusion 5% Dextrose Injection (USP) 5% Dextrose and Lactated Ringer’s Injection 5% Dextrose and 0.9% Sodium Chloride Injection (USP) 5% Dextrose and 0.2% Sodium Chloride Injection (USP) 10% Dextrose Injection (USP) Lactated Ringer’s Injection (USP) 0.9% Sodium Chloride Injection (USP) Normosol® M and 5% Dextrose Injection Normosol® R The resulting intravenous solution should be administered in one of the following manners: Intermittent Infusion: Solutions of CEFOBID should be administered over a 15–30 minute time period. Continuous Infusion: CEFOBID can be used for continuous infusion after dilution to a final concentration of between 2 and 25 mg cefoperazone per mL. Preparation for Intramuscular Injection Any suitable solution listed above may be used to prepare CEFOBID (sterile cefoperazone) for intramuscular injection. When concentrations of 250 mg/mL or more are to be administered, a lidocaine solution should be used. These solutions should be prepared using a combination of Sterile Water for Injection and 2% Lidocaine Hydrochloride Injection (USP) that approximates a 0.5% Lidocaine Hydrochloride Solution. A two-step dilution process as follows is recommended: First, add the required amount of Sterile Water for Injection and agitate until CEFOBID powder is completely dissolved. Second, add the required amount of 2% lidocaine and mix. Final Step 1 Step 2 Cefoperazone Concentration Volume of Sterile Water Volume of 2% Lidocaine Withdrawable Volume*† 1 g vial 333 mg/mL 2.0 mL 0.6 mL 3 mL 250 mg/mL 2.8 mL 1.0 mL 4 mL 2 g vial 333 mg/mL 3.8 mL 1.2 mL 6 mL 250 mg/mL 5.4 mL 1.8 mL 8 mL 12 Reference ID: 5497444 When a diluent other than Lidocaine HCl Injection (USP) is used reconstitute as follows: Cefoperazone Volume of Diluent Withdrawable Concentration to be Added Volume* 1 g vial 333 mg/mL 2.6 mL 3 mL 250 mg/mL 3.8 mL 4 mL 2 g vial 333 mg/mL 5.0 mL 6 mL 250 mg/mL 7.2 mL 8 mL * There is sufficient excess present to allow for withdrawal of the stated volume. † Final lidocaine concentration will approximate that obtained if a 0.5% Lidocaine Hydrochloride Solution is used as diluent. STORAGE AND STABILITY CEFOBID (sterile cefoperazone) is to be stored at or below 25°C (77°F) and protected from light prior to reconstitution. After reconstitution, protection from light is not necessary. The following parenteral diluents and approximate concentrations of CEFOBID provide stable solutions under the following conditions for the indicated time periods. (After the indicated time periods, unused portions of solutions should be discarded.) Room Temperature (15°–25°C/59°–77°F) Approximate 24 Hours Concentrations Bacteriostatic Water for Injection [Benzyl Alcohol or Parabens] (USP)…………… 300 mg/mL 5% Dextrose Injection (USP)……………………………………………………. 2 mg to 50 mg/mL 5% Dextrose and Lactated Ringer’s Injection………………………………… 2 mg to 50 mg/mL 5% Dextrose and 0.9% Sodium Chloride Injection (USP)…………………. 2 mg to 50 mg/mL 5% Dextrose and 0.2% Sodium Chloride Injection (USP)…………………. 2 mg to 50 mg/mL 10% Dextrose Injection (USP)………………………………………………….. 2 mg to 50 mg/mL Lactated Ringer’s Injection (USP)………………………………………………………….. 2 mg/mL 0.5% Lidocaine Hydrochloride Injection (USP)………………………………………. 300 mg/mL 0.9% Sodium Chloride Injection (USP)……………………………………… 2 mg to 300 mg/mL Normosol® M and 5% Dextrose Injection…………………………………….. 2 mg to 50 mg/mL Normosol® R……………………………………………………………………….. 2 mg to 50 mg/mL Sterile Water for Injection………………………………………………………………… 300 mg/mL Reconstituted CEFOBID solutions may be stored in glass or plastic syringes, or in glass or flexible plastic parenteral solution containers. 13 Reference ID: 5497444 Refrigerator Temperature (2°–8°C/36°–46°F) Approximate 5 Days Concentrations Bacteriostatic Water for Injection [Benzyl Alcohol or Parabens] (USP)…………… 300 mg/mL 5% Dextrose Injection (USP)……………………………………………………. 2 mg to 50 mg/mL 5% Dextrose and 0.9% Sodium Chloride Injection (USP)…………………. 2 mg to 50 mg/mL 5% Dextrose and 0.2% Sodium Chloride Injection (USP)…………………. 2 mg to 50 mg/mL Lactated Ringer’s Injection (USP)………………………………………………………….. 2 mg/mL 0.5% Lidocaine Hydrochloride Injection (USP)………………………………………. 300 mg/mL 0.9% Sodium Chloride Injection (USP)……………………………………… 2 mg to 300 mg/mL Normosol® M and 5% Dextrose Injection…………………………………….. 2 mg to 50 mg/mL Normosol® R……………………………………………………………………….. 2 mg to 50 mg/mL Sterile Water for Injection………………………………………………………………… 300 mg/mL Reconstituted CEFOBID solutions may be stored in glass or plastic syringes, or in glass or flexible plastic parenteral solution containers. Freezer Temperature (–20° to –10°C/–4° to 14°F) Approximate 3 Weeks Concentrations 5% Dextrose Injection (USP)……………………………………………………………… 50 mg/mL 5% Dextrose and 0.9% Sodium Chloride Injection (USP)…………………………….. 2 mg/mL 5% Dextrose and 0.2% Sodium Chloride Injection (USP)…………………………….. 2 mg/mL 5 Weeks 0.9% Sodium Chloride Injection (USP)………………………………………………… 300 mg/mL Sterile Water for Injection………………………………………………………………… 300 mg/mL Reconstituted CEFOBID solutions may be stored in plastic syringes, or in flexible plastic parenteral solution containers. Frozen samples should be thawed at room temperature before use. After thawing, unused portions should be discarded. Do not refreeze. HOW SUPPLIED CEFOBID® (sterile cefoperazone) is available in vials containing cefoperazone sodium equivalent to 1 g cefoperazone × 10 (NDC 0049-1201-83) and 2 g cefoperazone × 10 (NDC 0049-1202-83) for intramuscular and intravenous administration. CEFOBID® (sterile cefoperazone) is available in 10 g (NDC 0049-1219-28) Pharmacy Bulk Package for intravenous administration. Rx only 14 Reference ID: 5497444 Distributed by Roerig Division of Pfizer Inc, NY, NY 10017 This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. LAB-0033-11.1 Revised December 2024 15 Reference ID: 5497444
custom-source
2025-02-12T15:47:48.603713
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DYMISTA® safely and effectively. See full prescribing information for DYMISTA. DYMISTA (azelastine hydrochloride and fluticasone propionate) nasal spray Initial U.S. Approval: 2012 ----------------------------RECENT MAJOR CHANGES-------------------------­ Contraindications (4) 12/2024 -------------------------INDICATIONS AND USAGE----------------------------­ DYMISTA contains an H1-receptor antagonist and a corticosteroid, and is indicated for the relief of symptoms of seasonal allergic rhinitis in adult and pediatric patients 6 years of age and older. (1) ------------------DOSAGE AND ADMINISTRATION---------------------------­ • Recommended dosage: 1 spray per nostril twice daily (2.1) • For nasal use only. (2.2) • Prime before initial use and when it has not been used for 14 or more days. (2.2) -----------------DOSAGE FORMS AND STRENGTHS-------------------------­ Nasal spray: 137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate in each spray. (3) ----------------------------CONTRAINDICATIONS--------------------------------­ Hypersensitivity to azelastine hydrochloride, fluticasone propionate, or to any ingredients of DYMISTA. Reactions have included anaphylaxis. (4) -------------------------WARNINGS AND PRECAUTIONS---------------------­ • Somnolence: Avoid engaging in hazardous occupations requiring complete mental alertness such as driving or operating machinery when taking DYMISTA. (5.1) • Avoid concurrent use of alcohol or other central nervous system (CNS) depressants with DYMISTA because further decreased alertness and impairment of CNS performance may occur. (5.1) • Epistaxis, nasal ulcerations, nasal septal perforation, impaired wound healing, Candida albicans infection: Monitor patients periodically for signs of adverse effects on the nasal mucosa. Avoid use in patients with recent nasal ulcers, nasal surgery, or nasal trauma. (5.2) • Glaucoma or posterior subcapsular cataracts: Monitor patients closely with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. (5.3) • Potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. More serious or even fatal course of chickenpox or measles in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections. (5.4) • Hypercorticism and adrenal suppression with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue DYMISTA slowly. (5.5) • Potential reduction in growth velocity in children. Monitor growth routinely in pediatric patients receiving DYMISTA. (5.7, 8.4) -----------------------------ADVERSE REACTIONS-------------------------------­ The most common adverse reactions (≥2% incidence) are: dysgeusia, epistaxis, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-888-939-6478 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------------------DRUG INTERACTIONS----------------------------­ • Potent inhibitors of cytochrome P450 (CYP) 3A4: May increase blood levels of fluticasone propionate. • Ritonavir: Coadministration is not recommended. (5.6, 7.2) • Other potent CYP3A4 inhibitors, such as ketoconazole: use caution with coadministration. (5.6, 7.2) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Important Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Somnolence 5.2 Local Nasal Effects 5.3 Glaucoma and Cataracts 5.4 Immunosuppression and Risk of Infections 5.5 Hypercorticism and Adrenal Suppression 5.6 Use of Cytochrome P450 3A4 Inhibitors 5.7 Effect on Growth 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Central Nervous System Depressants 7.2 Cytochrome P450 3A4 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5497208 1 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE DYMISTA is indicated for the relief of symptoms of seasonal allergic rhinitis in adult and pediatric patients 6 years of age and older. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage of DYMISTA is 1 spray (137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate) in each nostril twice daily. 2.2 Important Administration Instructions • Administer DYMISTA by the nasal route only. • Shake the bottle gently before each use. • Avoid spraying DYMISTA into the eyes. If sprayed in the eyes, flush eyes with water for at least 10 minutes. Priming Prime DYMISTA before initial use by releasing 6 sprays or until a fine mist appears. Repriming (as needed) When DYMISTA has not been used for 14 or more days, reprime with 1 spray or until a fine mist appears. 3 DOSAGE FORMS AND STRENGTHS Nasal spray: 137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate per spray. 4 CONTRAINDICATIONS DYMISTA is contraindicated in patients with hypersensitivity to azelastine hydrochloride, fluticasone propionate, or to any other ingredients of DYMISTA. Reactions have included anaphylaxis [see Adverse Reactions (6.2)]. WARNINGS AND PRECAUTIONS 5.1 Somnolence In clinical trials, the occurrence of somnolence has been reported in some patients (6 of 853 adult and adolescent patients and 2 of 416 children) taking DYMISTA in placebo controlled trials [see Reference ID: 5497208 5 2 Adverse Reactions (6.1)]. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as operating machinery or driving a motor vehicle after administration of DYMISTA. Concurrent use of DYMISTA with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur [see Drug Interactions (7.1)]. 5.2 Local Nasal Effects In clinical trials of 2 to 52 weeks’ duration, epistaxis was observed more frequently in patients treated with DYMISTA than those who received placebo [see Adverse Reactions (6)]. Instances of nasal ulceration and nasal septal perforation have been reported in patients following the nasal application of corticosteroids. There were no instances of nasal ulceration or nasal septal perforation observed in clinical trials with DYMISTA. Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should avoid use of DYMISTA until healing has occurred. In clinical trials with fluticasone propionate administered nasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of treatment with DYMISTA. Patients using DYMISTA over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. 5.3 Glaucoma and Cataracts Nasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. Glaucoma and cataract formation were evaluated with intraocular pressure measurements and slit lamp examinations in a controlled 12-month study in 612 adolescent and adult patients aged 12 years and older with perennial allergic or vasomotor rhinitis (VMR). Of the 612 patients enrolled in the study, 405 were randomized to receive DYMISTA (1 spray per nostril twice daily) and 207 were randomized to receive fluticasone propionate nasal spray (2 sprays per nostril once daily). In the DYMISTA group, one patient had increased intraocular pressure at month 6. In addition, three patients had evidence of posterior subcapsular cataract at month 6 and one at month 12 (end of treatment). In the fluticasone propionate group, three patients had evidence of posterior subcapsular cataract at month 12 (end of treatment). 5.4 Immunosuppression and Risk of Infections Reference ID: 5497208 3 Persons who are using drugs, such as corticosteroids, that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective Prescribing Information for VZIG and IG.) If chickenpox develops, treatment with antiviral agents may be considered. Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract; untreated local or systemic fungal or bacterial infections; systemic viral or parasitic infections; or ocular herpes simplex because of the potential for worsening of these infections. 5.5 Hypercorticism and Adrenal Suppression When nasal steroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of DYMISTA should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy. The concomitant use of nasal corticosteroids with other inhaled corticosteroids could increase the risk of signs or symptoms of hypercorticism and/or suppression of the HPA axis. The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms. 5.6 Use of Cytochrome P450 3A4 Inhibitors Ritonavir and other strong cytochrome P450 3A4 (CYP3A4) inhibitors can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of DYMISTA and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. Reference ID: 5497208 4 Use caution with the coadministration of DYMISTA and other potent CYP3A4 inhibitors, such as ketoconazole [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. 5.7 Effect on Growth Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving DYMISTA [see Use in Specific Populations (8.4)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Somnolence [see Warnings and Precautions (5.1)] • Local nasal effects, including epistaxis, nasal ulceration, nasal septal perforation, impaired wound healing, and Candida albicans infection [see Warnings and Precautions (5.2)] • Glaucoma and Cataracts [see Warnings and Precautions (5.3)] • Immunosuppression and Risk of Infections [see Warnings and Precautions (5.4)] • Hypercorticism and Adrenal Suppression, including growth reduction [see Warnings and Precautions (5.5 and 5.7), Use in Specific Populations (8.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice. Adults and Adolescents 12 Years of Age and Older The safety data described below in adults and adolescents 12 years of age and older reflect exposure to DYMISTA in 853 patients (12 years of age and older; 36% male and 64% female) with seasonal allergic rhinitis in 3 double-blind, placebo-controlled clinical trials of 2-week duration. The racial distribution for the 3 clinical trials was 80% white, 16% black, 2% Asian, and 1% other. In the 3 placebo controlled clinical trials of 2-week duration, 3411 patients with seasonal allergic rhinitis were treated with 1 spray per nostril of DYMISTA, azelastine hydrochloride nasal spray, fluticasone propionate nasal spray, or placebo, twice daily. The azelastine hydrochloride and fluticasone propionate comparators use the same vehicle and device as DYMISTA and are not commercially marketed. Overall, adverse reactions were 16% in the DYMISTA treatment groups, 15% in the azelastine hydrochloride nasal spray groups, 13% in the fluticasone propionate nasal spray groups, and 12% in the placebo groups. Overall, 1% of patients in both the DYMISTA and placebo groups discontinued due to adverse reactions. Reference ID: 5497208 5 Table 1 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with DYMISTA in the seasonal allergic rhinitis controlled clinical trials. Table 1. Adverse Reactions with ≥ 2% Incidence and More Frequently than Placebo in Placebo-Controlled Trials of 2 Weeks Duration with DYMISTA in Adult and Adolescent Patients with Seasonal Allergic Rhinitis 1 spray per nostril twice daily DYMISTA (N = 853)* Azelastine Hydrochloride Nasal Spray† (N = 851) Fluticasone Propionate Nasal Spray† (N = 846) Vehicle Placebo (N = 861) Dysgeusia 30 (4%) 44 (5%) 4 (1%) 2 (< 1%) Headache 18 (2%) 20 (2%) 20 (2%) 10 (1%) Epistaxis 16 (2%) 14 (2%) 14 (2%) 15 (2%) * Safety population N = 853, intent-to-treat population N = 848 † Not commercially marketed In the above trials, somnolence was reported in < 1% of patients treated with DYMISTA (6 of 853) or vehicle placebo (1 of 861) [see Warnings and Precautions (5.1)]. Pediatric Patients 6-11 Years of Age The safety data described below in children 6-11 years of age reflect exposure to DYMISTA in 152 patients (6-11 years of age; 57% male and 43% female) with seasonal allergic rhinitis in one double-blind, placebo-controlled clinical trial of 2-week duration. The racial distribution for the clinical trial was 69% white, 31% black, 2% Asian and 2% other. In the placebo-controlled clinical trial of 2-week duration, patients with seasonal allergic rhinitis were treated with 1 spray per nostril of DYMISTA or placebo, twice daily. Overall, adverse reactions were 16% in the DYMISTA treatment group, and 12% in the placebo group. Overall, 1% of patients in both the DYMISTA and placebo groups discontinued due to adverse reactions. Table 2 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with DYMISTA in the seasonal allergic rhinitis controlled clinical trial. Table 2. Adverse Reactions with ≥ 2% Incidence and More Frequently than Placebo in Placebo-Controlled Trials of 2 Weeks Duration with DYMISTA in Children 6 to 11 Years of Age with Seasonal Allergic Rhinitis 1 spray per nostril twice daily DYMISTA (N = 152)* Vehicle Placebo (N = 152) Dysgeusia 6 (4%) 0 (0%) Epistaxis 6 (4%) 4 (3%) * Safety population N = 152, intent-to-treat population N = 152 Reference ID: 5497208 6 In the above trial, somnolence was not reported [see Warnings and Precautions (5.1)]. Long-Term (12-Month) Safety Trial in Adults and Adolescents 12 Years of Age and Older In the 12-month open-label, active-controlled clinical trial, 404 Asian patients (240 males and 164 females) with perennial allergic rhinitis or vasomotor rhinitis were treated with DYMISTA, 1 spray per nostril twice daily. In the 12-month, open-label, active-controlled, long-term safety trial in adults and adolescents 12 years of age and older, 404 patients with perennial allergic rhinitis or vasomotor rhinitis were treated with DYMISTA 1 spray per nostril twice daily and 207 patients were treated with fluticasone propionate nasal spray, 2 sprays per nostril once daily. Overall, adverse reactions were 47% in the DYMISTA treatment group and 44% in the fluticasone propionate nasal spray group. The most frequently reported adverse reactions (≥ 2%) with DYMISTA were headache, pyrexia, cough, nasal congestion, rhinitis, dysgeusia, viral infection, upper respiratory tract infection, pharyngitis, pain, diarrhea, and epistaxis. In the DYMISTA treatment group, 7 patients (2%) had mild epistaxis and 1 patient (< 1%) had moderate epistaxis. In the fluticasone propionate nasal spray treatment group 1 patient (< 1%) had mild epistaxis. No patients had reports of severe epistaxis. Focused nasal examinations were performed and no nasal ulcerations or septal perforations were observed. Eleven of 404 patients (3%) treated with DYMISTA and 6 of 207 patients (3%) treated with fluticasone propionate nasal spray discontinued from the trial due to adverse reactions. Long-Term (3-Month) Safety Trial in Pediatric Patients 6-11 Years of Age In the 3-month open label active-controlled clinical trial, 264 patients (60% male, 40% female) (80% white, 19% black, 4% Asian and 2% other) with allergic rhinitis were treated with DYMISTA, 1 spray per nostril twice daily. In the 3-month, open label, active-controlled, safety trial in pediatric patients 6-11 years of age 264 patients (128 patients ≥ 6 to < 9 years of age, and 136 patients ≥ 9 to < 12 years of age) with allergic rhinitis (based on the Investigator’s assessment) were treated with DYMISTA, 1 spray per nostril twice daily and 89 patients (44 patients ≥ 6 to < 9 years of age, and 45 patients ≥ 9 to < 12 years of age) were treated with fluticasone propionate nasal spray, 1 spray per nostril twice daily. Overall, adverse reactions were 40% in the DYMISTA treatment group and 36% in the fluticasone propionate nasal spray group. The most frequently reported adverse reactions (≥ 2%) with DYMISTA were epistaxis, headache, oropharyngeal pain, vomiting, upper abdominal pain, cough, pyrexia, otitis media, upper respiratory tract infection, diarrhea, nausea, otitis externa, and urticaria. In the DYMISTA treatment group 23 patients (9%) had mild epistaxis and 3 patients (1%) had moderate epistaxis. In the fluticasone propionate nasal spray treatment group 8 patients (9%) had mild epistaxis. No patients had reports of severe epistaxis. Focused nasal examinations were performed and no ulcerations or septal perforations were observed. Four of 264 patients (2%) treated with DYMISTA and 3 of 89 (3%) treated with fluticasone propionate nasal spray discontinued from the trial due to adverse reactions. There were two reports of somnolence, one severe, among children taking DYMISTA [see Warnings and Precautions (5.1)]. Reference ID: 5497208 7 6.2 Postmarketing Experience The following spontaneous adverse reactions have been reported with DYMISTA or one of the components (azelastine and fluticasone). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: atrial fibrillation, increased heart rate, palpitations Eye Disorder: blurred vision, cataracts, conjunctivitis, dryness and irritation, eye swelling, glaucoma, increased intraocular pressure, vision abnormal, xerophthalmia Gastrointestinal Disorders: nausea, vomiting General Disorders and Administration Site Condition: aches and pain, application site irritation, chest pain, edema of face and tongue, fatigue, tolerance Immune System Disorders: anaphylaxis Musculoskeletal and Connective Tissue Disorders: growth suppression [see Use in Specific Populations (8.4)] Nervous System Disorders: disturbance or loss of smell and/or taste, dizziness, involuntary muscle contractions, paresthesia, parosmia Psychiatric Disorders: anxiety, confusion, nervousness Renal and Urinary Disorders: urinary retention Respiratory, Thoracic and Mediastinal Disorders: bronchospasm, cough, dysphonia, dyspnea, hoarseness, nasal septal perforation, nasal discomfort, nasal dryness, nasal sores, nasal ulcer, sore throat, throat dryness and irritation, voice changes, wheezing Skin and Subcutaneous Tissue Disorder: angioedema, erythema, face swelling, pruritus, rash, urticaria Vascular Disorder: hypertension 7 DRUG INTERACTIONS No formal drug interaction studies have been performed with DYMISTA. The drug interactions of the combination are expected to reflect those of the individual components. 7.1 Central Nervous System Depressants Reference ID: 5497208 8 Concurrent use of DYMISTA with alcohol or other central nervous system depressants should be avoided because somnolence and impairment of central nervous system performance may occur [see Warnings and Precautions (5.1)]. 7.2 Cytochrome P450 3A4 Ritonavir (a strong CYP3A4 inhibitor) significantly increased plasma fluticasone propionate exposure following administration of fluticasone propionate aqueous nasal spray, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)]. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. Ketoconazole (also a strong CYP3A4 inhibitor), administered in multiple 200 mg doses to steady-state, increased plasma exposure of fluticasone propionate, reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol, following administration of a single 1000 mcg dose of fluticasone propionate by oral inhalation route. Caution should be exercised when DYMISTA is coadministered with ketoconazole and other known strong CYP3A4 inhibitors. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited data from postmarketing experience with DYMISTA in pregnant women have not identified any drug associated risks of miscarriage, birth defects, or other adverse maternal or fetal outcomes. The individual components of DYMISTA have been marketed for decades. While the data regarding the use of nasal preparations of fluticasone propionate in pregnancy are limited, data from clinical studies of inhaled fluticasone propionate do not indicate an increased risk of adverse maternal or fetal outcomes. Animal reproduction studies with DYMISTA are not available; however, studies are available with its individual components, azelastine hydrochloride and fluticasone propionate. In animal reproduction studies, there was no evidence of fetal harm in animals at oral doses of azelastine hydrochloride approximately 10 times the clinical daily dose. Oral administration of azelastine hydrochloride to pregnant mice, rats, and rabbits, during the period of organogenesis, produced developmental toxicity that included structural abnormalities, decreased embryo-fetal survival, and decreased fetal body weights at doses 530 times and higher than the maximum recommended human daily nasal dose (MRHDID) of 0.548 mg. However, the relevance of these findings in animals to pregnant women was considered questionable based upon the high animal to human dose multiple. Reference ID: 5497208 9 --- In animal reproduction studies, fluticasone propionate administered via nose-only inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m2 basis. Teratogenicity, characteristic of corticosteroids, decreased fetal body weight and/or skeletal variations, in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the MRHDID of 200 mcg on a mcg/m2 basis (see Data). Experience with corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data: Azelastine Hydrochloride: In an embryo-fetal development study in mice dosed during the period of organogenesis, azelastine hydrochloride caused embryo-fetal death, structural abnormalities (cleft palate; short or absent tail; fused, absent or branched ribs), delayed ossification, and decreased fetal weight at approximately 610 times the MRHDID in adults (on a mg/m2 basis at a maternal oral dose of 68.6 mg/kg/day), which also caused maternal toxicity as evidenced by decreased maternal body weight. Neither fetal nor maternal effects occurred in mice at approximately 25 times the MRHDID in adults (on a mg/m2 basis at a maternal oral dose of 3 mg/kg/day). In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 7 to 17, azelastine hydrochloride caused structural abnormalities (oligo- and brachydactylia), delayed ossification, and skeletal variations, in the absence of maternal toxicity, at approximately 530 times the MRHDID in adults (on a mg/m2 basis at a maternal oral dose of 30 mg/kg/day). Azelastine hydrochloride caused embryo-fetal death and decreased fetal weight and severe maternal toxicity at approximately 1200 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 68.6 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 55 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 3 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6 to 18, azelastine hydrochloride caused abortion, delayed ossification and decreased fetal weight and severe maternal toxicity at approximately 1100 times the MRHDID in adults (on a mg/m2 basis at a maternal oral dose of 30 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 10 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 0.3 mg/kg/day). In a prenatal and postnatal development study in pregnant rats dosed from late in the gestation period and through the lactation period from gestation day 17 through lactation day 21, azelastine hydrochloride produced no adverse developmental effects on pups at maternal doses up to approximately 530 times the MRHDID (on mg/m2 basis at a maternal dose of 30 mg/kg/day). Reference ID: 5497208 10 Fluticasone Propionate: In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 5 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). Neither fetal nor maternal effects occurred in rats at approximately 1 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 30 mcg/kg/day). Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 1 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). Neither fetal nor maternal effects occurred in mice with a dose approximately 0.4 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 15 mcg/kg/day). In an embryofetal development study with pregnant rats dosed by the nose-only inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 1 times the MRHDID (on a mg/m2 basis with a maternal nose-only inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity. Neither fetal nor maternal effects occurred in rats with a dose approximately 0.25 times the MRHDID (on a mg/m2 basis with a maternal nose-only inhalation dose of 5.5 mcg/kg/day). In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.06 times the MRHDID and higher (on a mg/m2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at dose approximately 0.4 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). Neither fetal nor maternal effects occurred in rabbits with a dose approximately 0.01 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day). Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 2 times the MRHDID (on a mg/m2 basis with maternal subcutaneous doses up to 50 mcg/kg/day). 8.2 Lactation Risk Summary There are no available data on the presence of azelastine hydrochloride or fluticasone propionate in human milk, the effects on the breastfed infant, or the effects on milk production. Breastfed infants should be monitored for signs of milk rejection during DYMISTA use by lactating Reference ID: 5497208 11 women (see Clinical Considerations). Fluticasone propionate is present in rat milk (see Data). Other corticosteroids have been detected in human milk. However, fluticasone propionate concentrations in plasma after nasal therapeutic doses are low and therefore concentrations in human breast milk are likely to be correspondingly low [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DYMISTA and any potential adverse effects on the breastfed infant from DYMISTA or from the underlying maternal condition. Clinical Considerations Monitoring for Adverse Reactions: Breastfed infants of lactating women treated with DYMISTA should be monitored for possible signs of milk rejection related to the bitter taste of azelastine hydrochloride. Data Subcutaneous administration of 10 mcg/kg of tritiated fluticasone propionate to lactating rats resulted in measurable radioactivity in the milk. 8.4 Pediatric Use The safety and effectiveness of DYMISTA for seasonal allergic rhinitis have been established in pediatric patients aged 6 years and older. Use of DYMISTA for this indication in pediatric patients 6 to 11 years of age is supported by evidence from controlled clinical trials (416 patients 6 to 11 years of age with allergic rhinitis were treated with DYMISTA) [see Adverse Reactions (6.1) and Clinical Studies (14)]. Sixty-one patients ages 4-5 years of age were treated with DYMISTA in the pediatric studies described above. Safety findings in children 4-5 years of age were similar to those in children 6­ 11 years of age, but effectiveness has not been established. Safety and effectiveness of DYMISTA have not been established in pediatric patients below the age of 4 years. Controlled clinical studies have shown that nasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with nasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch­ up” growth following discontinuation of treatment with nasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving nasal corticosteroids, including DYMISTA, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives. Reference ID: 5497208 12 8.5 Geriatric Use Clinical trials of DYMISTA did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 10 OVERDOSAGE DYMISTA: DYMISTA contains both azelastine hydrochloride and fluticasone propionate; therefore, the risks associated with overdosage for the individual components described below apply to DYMISTA. Azelastine Hydrochloride: There have been no reported overdosages with azelastine hydrochloride. Acute azelastine hydrochloride overdosage by adults with this dosage form is unlikely to result in clinically significant adverse reactions, other than increased somnolence, since one (1) 23 g bottle of DYMISTA contains approximately 23 mg of azelastine hydrochloride. General supportive measures should be employed if overdosage occurs. There is no known antidote to DYMISTA. Oral ingestion of antihistamines has the potential to cause serious adverse effects in children. Accordingly, DYMISTA should be kept out of the reach of children. Fluticasone Propionate: Chronic fluticasone propionate overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)]. 11 DESCRIPTION DYMISTA (azelastine hydrochloride and fluticasone propionate) nasal spray is formulated as a white, uniform metered-spray suspension for nasal administration. It is a fixed dose combination product containing an antihistamine (H1 receptor antagonist) and a corticosteroid as active ingredients. Azelastine hydrochloride active ingredient occurs as a white, odorless, crystalline powder with a bitter taste. It has a molecular weight of 418.37. It is sparingly soluble in water, methanol, and propylene glycol and slightly soluble in ethanol, octanol, and glycerin. It has a melting point of 225°C and the pH of 5.2. Its chemical name is (±)-1-(2H)-phthalazinone,4-[(4-chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride. Its molecular formula is C22H24ClN3O•HCl with the following chemical structure: Reference ID: 5497208 13 -F Fluticasone propionate active ingredient is a white powder with a melting point of 273°C, a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. Fluticasone propionate is a synthetic corticosteroid having the chemical name S-(fluoromethyl)-6α,9α-difluoro-11β-17-dihydroxy-16α-methyl-3-oxoandrosta­ 1,4-diene-17β-carbothioate, 17-propionate, and the following chemical structure: DYMISTA (azelastine hydrochloride and fluticasone propionate) nasal spray, 137 mcg/50 mcg contains 0.1% solution of azelastine hydrochloride and 0.037% suspension of micronized fluticasone propionate in an isotonic aqueous suspension containing benzalkonium chloride (0.1 mg/g), carboxymethylcellulose sodium, edetate disodium, glycerin, microcrystalline cellulose, phenylethyl alcohol (2.5 mg/g), polysorbate 80, and purified water. It has a pH of approximately 6.0. After priming [see Dosage and Administration (2.2)], each metered spray delivers a 0.137 mL mean volume of suspension containing 137 mcg of azelastine hydrochloride (equivalent to 125 mcg of azelastine base) and 50 mcg of fluticasone propionate. The 23 g bottle provides 120 metered sprays, after priming. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Reference ID: 5497208 14 DYMISTA: DYMISTA contains both azelastine hydrochloride and fluticasone propionate; therefore, the mechanisms of actions described below for the individual components apply to DYMISTA. These drugs represent two different classes of medications (histamine H1-receptor antagonist and synthetic corticosteroid). Azelastine Hydrochloride: Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine hydrochloride in DYMISTA is administered as a racemic mixture with no difference in pharmacologic activity noted between the enantiomers in in vitro studies. The major metabolite, desmethylazelastine, also possesses H1-receptor antagonist activity. Fluticasone Propionate: Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. In vitro dose response studies on a cloned human glucocorticoid receptor system involving binding and gene expression afforded 50% responses at 1.25 and 0.17 nM concentrations, respectively. Fluticasone propionate was 3-fold to 5-fold more potent than dexamethasone in these assays. Data from the McKenzie vasoconstrictor assay in man also support its potent glucocorticoid activity. The clinical relevance of these findings is unknown. The precise mechanism through which fluticasone propionate affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. 12.2 Pharmacodynamics Cardiac Electrophysiology: In a placebo-controlled trial (95 patients with allergic rhinitis), there was no evidence of an effect of azelastine hydrochloride nasal spray (2 sprays per nostril twice daily for 56 days) on cardiac repolarization as represented by the corrected QT interval (QTc) of the electrocardiogram. Following multiple dose oral administration of azelastine 4 mg or 8 mg twice daily, the mean change in QTc was 7.2 msec and 3.6 msec, respectively. Interaction studies investigating the cardiac repolarization effects of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. These drugs had no effect on QTc based on analysis of serial electrocardiograms. 12.3 Pharmacokinetics Absorption: After nasal administration of two sprays per nostril (548 mcg of azelastine hydrochloride and 200 mcg of fluticasone) of DYMISTA, the mean (± standard deviation) peak plasma exposure (Cmax) was 194.5 ± 74.4 pg/mL for azelastine and 10.3 ± 3.9 pg/mL for fluticasone propionate and the mean total exposure (AUC) was 4217 ± 2618 pg/mL*hr for azelastine and 97.7 ± 43.1 pg/mL*hr for fluticasone. The median time to peak exposure (tmax) from a single dose was 0.5 hours for azelastine and 1.0 hours for fluticasone. Systemic bioavailability of azelastine from DYMISTA following nasal administration was comparable with monotherapy azelastine hydrochloride (Astelin®) nasal spray (i.e., Reference ID: 5497208 15 approximately 40%). Systemic bioavailability of fluticasone from DYMISTA following nasal administration was 44-61% higher than monotherapy fluticasone propionate (bioavailability for monotherapy fluticasone nasal spray was less than 2%). Due to the low nasal bioavailability, pharmacokinetic data for fluticasone propionate were obtained via other routes of administration. Studies using oral dosing of radiolabeled fluticasone propionate showed negligible oral bioavailability and high extraction from plasma. The majority of the circulating radioactivity was due to an inactive metabolite. Distribution: Based on intravenous and oral administration, the steady-state volume of distribution of azelastine hydrochloride is 14.5 L/kg. In vitro studies with human plasma indicate that the plasma protein binding of azelastine hydrochloride and its metabolite, desmethylazelastine, are approximately 88% and 97%, respectively. Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins averaged 91% with no obvious concentration relationship. Fluticasone propionate is weakly and reversibly bound to erythrocytes and freely equilibrates between erythrocytes and plasma. Fluticasone propionate is not significantly bound to human transcortin. Elimination: Following nasal administration of DYMISTA, the elimination half-life of azelastine hydrochloride is approximately 25 hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine. Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites. Metabolism: Azelastine hydrochloride is oxidatively metabolized to the principal active metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified. The total clearance of azelastine is approximately 0.50 L/kg/hr. For fluticasone propionate, the only circulating metabolite detected in man is the 17β-carboxylic acid derivative, which is formed through the CYP3A4 pathway. This inactive metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. The average total clearance of fluticasone propionate is relatively high (approximately 66 L/hr). Specific Populations: DYMISTA was not studied in any specific populations, and no gender- specific pharmacokinetic data have been obtained. Reference ID: 5497208 16 Following oral administration of azelastine hydrochloride, pharmacokinetic parameters were not influenced by hepatic impairment, age, or gender. The effect of race has not been evaluated. Patients with Renal Impairment: Based on oral, single-dose studies of azelastine hydrochloride, renal impairment (creatinine clearance < 50 mL/min) resulted in a 70-75% higher Cmax and AUC compared to healthy subjects. Time to maximum concentration was unchanged. Drug Interaction Studies: No formal drug interaction studies have been performed with DYMISTA. The drug interactions of the combination are expected to reflect those of the individual components. Erythromycin: Coadministration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days) resulted in Cmax of 5.36 ± 2.6 ng/mL and AUC of 49.7 ± 24 ng•h/mL for azelastine, whereas, administration of azelastine alone resulted in Cmax of 5.57 ± 2.7 ng/mL and AUC of 48.4 ± 24 ng•h/mL for azelastine. In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg three times daily) did not affect fluticasone propionate pharmacokinetics. Cimetidine and Ranitidine: In a multiple-dose, steady-state drug interaction trial in healthy subjects, cimetidine (400 mg twice daily) increased orally administered mean azelastine hydrochloride (4 mg twice daily) concentrations by approximately 65%. Coadministration of orally administered azelastine hydrochloride (4 mg twice daily) with ranitidine hydrochloride (150 mg twice daily) resulted in Cmax of 8.89 ± 3.28 ng/mL and AUC of 88.22 ± 40.43 ng•h/mL for azelastine hydrochloride, whereas, administration of azelastine hydrochloride alone resulted in Cmax of 7.83 ± 4.06 ng/mL and AUC of 80.09 ± 43.55 ng•h/mL for azelastine hydrochloride. Theophylline: No significant pharmacokinetic interaction was observed with the coadministration of an oral 4 mg dose of azelastine hydrochloride twice daily and theophylline 300 mg or 400 mg twice daily. Ritonavir: Coadministration of fluticasone propionate and the strong CYP3A4 inhibitor, ritonavir, is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (< 10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (Cmax) averaged 11.9 pg/mL (range, 10.8 to 14.1 pg/mL) and AUC(0-τ) averaged 8.43 pg•hr/mL (range, 4.2 to 18.8 pg•hr/mL). Fluticasone propionate Cmax and AUC(0-τ) increased to 318 pg/mL (range, 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range, 1,207.1 to 5,662.0 pg•hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC). Reference ID: 5497208 17 Caution should be exercised when other strong CYP3A4 inhibitors are coadministered with fluticasone propionate. In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased fluticasone propionate exposure and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol [see Drug Interactions (7.2)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility DYMISTA: No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with DYMISTA; however, studies are available for the individual active components, azelastine hydrochloride and fluticasone propionate, as described below. Azelastine Hydrochloride: Two-year carcinogenicity studies in Crl:CD(SD)BR rats and NMRI mice were conducted to assess the carcinogenic potential of azelastine hydrochloride. No evidence of tumorigenicity was observed in rats at doses up to 30 mg/kg/day (approximately 530 and 240 times the MRHDID for adults and children, respectively, on a mg/m2 basis). No evidence for tumorigenicity was observed in mice at doses up to 25 mg/kg (approximately 220 and 100 times the MRHDID for adults and children, respectively, on a mg/m2 basis). Azelastine hydrochloride showed no genotoxic effects in the Ames test, DNA repair test, mouse lymphoma forward mutation assay, mouse micronucleus test, or chromosomal aberration test in rat bone marrow. There were no effects on male or female fertility and reproductive performance in male and female rats at oral doses up to 30 mg/kg (approximately 530 times the MRHDID in adults on a mg/m2 basis). At 68.6 mg/kg (approximately 1200 times the MRHDID on a mg/m2 basis), the duration of estrous cycles was prolonged and copulatory activity and the number of pregnancies were decreased. The numbers of corpora lutea and implantations were decreased; however, pre­ implantation loss was not increased. Fluticasone Propionate: Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 25 and 10 times the MRHDID in adults and children, respectively, on a mcg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 3 and 1 times the MRHDID in adults and children, respectively, on a mcg/m2 basis) for 104 weeks. Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test. Fertility and reproductive performance were unaffected in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 2 times the MRHDID for adults on a mcg/m2 basis). Reference ID: 5497208 18 14 CLINICAL STUDIES Adults and Adolescents 12 Years of Age and Older: The efficacy and safety of DYMISTA in adults and adolescents 12 years of age and older with seasonal allergic rhinitis was evaluated in 3 randomized, multicenter, double-blind, placebo-controlled clinical trials in 853 patients. The population of the trials was 12 to 78 years of age (64% female, 36% male; 80% white, 16% black, 2% Asian, 1% other). Patients were randomized to one of four treatment groups: one spray per nostril twice daily of DYMISTA, azelastine hydrochloride nasal spray, fluticasone propionate nasal spray, and vehicle placebo. The azelastine hydrochloride and fluticasone propionate comparators use the same device and vehicle as DYMISTA and are not commercially marketed. Assessment of efficacy was based on the reflective total nasal symptom score (rTNSS), in addition to the instantaneous total nasal symptom score (iTNSS) and other supportive secondary efficacy variables. TNSS is calculated as the sum of the patients’ scoring of the 4 individual nasal symptoms (rhinorrhea, nasal congestion, sneezing, and nasal itching) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). Patients were required to record symptom severity daily reflecting over the previous 12 hours (morning, AM, and evening, PM). For the primary efficacy endpoint, the combined AM+PM rTNSS (maximum score of 24) was assessed as a change from baseline for each day and then averaged over a 2-week treatment period. The primary efficacy endpoint was the mean change from baseline in combined AM+PM rTNSS over 2 weeks. The iTNSS was recorded immediately prior to the next dose. In these trials, DYMISTA demonstrated statistically significant greater decreases in rTNSS as compared to azelastine hydrochloride and to fluticasone propionate, as well as to placebo. The differences between the monotherapies and placebo also were statistically significant. Representative results from one of the trials are shown below (Table 3). Table 3. Mean Change from Baseline in Reflective Total Nasal Symptom Scores Over 2 Weeks* in Adults and Children ≥ 12 Years with Seasonal Allergic Rhinitis Baseline Change from Baseline Difference from DYMISTA Nasal Spray Treatment (one spray/nostril twice daily) N LS Mean LS Mean LS Mean 95% Cl P-value DYMISTA 207 18.3 -5.6 -­ -­ -- Azelastine HCl Nasal Spray† 208 18.3 -4.3 -1.4 (-2.2, -0.5) 0.002 Fluticasone Propionate Nasal Spray† 207 18.2 -4.7 -1.0 (-1.8, -0.2) 0.022 Placebo 209 18.6 -2.9 -2.7 (-3.5, -1.9) < 0.001 * Sum of AM and PM rTNSS for each day (Maximum Score = 24) and averaged over the 14 day treatment period † Not commercially marketed LS Mean, 95% CI, and p-value are obtained from the repeated-measures analysis of covariance model using observed data. Reference ID: 5497208 19 In these trials, DYMISTA also demonstrated statistically significant, greater decreases in iTNSS as compared to placebo, as did the azelastine hydrochloride and fluticasone propionate comparators. Representative results from one of the trials are shown below (Table 4). Table 4. Mean Change from Baseline in Instantaneous Total Nasal Symptom Scores Over 2 Weeks* in Adults and Children ≥ 12 Years with Seasonal Allergic Rhinitis Baseline Change from Baseline Difference from Placebo Treatment (one spray/nostril twice daily) N LS Mean LS Mean LS Mean 95% Cl P-value DYMISTA 207 17.2 -5.6 -­ -­ -- Azelastine HCl Nasal Spray† 208 16.8 -4.3 -1.4 (-2.2, -0.5) 0.002 Fluticasone Propionate Nasal Spray† 207 16.8 -4.7 -1.0 (-1.8, -0.2) 0.022 Placebo 209 17.3 -2.9 -2.7 (-3.5, -1.9) < 0.001 * Sum of AM and PM rTNSS for each day (Maximum Score = 24) and averaged over the 14 day treatment period † Not commercially marketed LS Mean, 95% CI, and p-value are obtained from the repeated-measures analysis of covariance model using observed data. Onset of action, defined as the first timepoint at which DYMISTA was statistically superior to placebo in the mean change from baseline in iTNSS and which was sustained thereafter, was assessed in each of the three trials. Onset of action was observed as early as 30 minutes following the initial dose of DYMISTA. The subjective impact of seasonal allergic rhinitis on patient’s health-related quality of life was evaluated by the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) (28 items in 7 domains (activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) evaluated on a 7-point scale where 0 = no impairment and 6 = maximum impairment), which was administered to patients 18 years of age and older. An overall RQLQ score is calculated from the mean of all items in the instrument. A change from baseline of at least 0.5 points is considered a clinically meaningful improvement. In each of these trials, DYMISTA demonstrated a statistically significant greater decrease from baseline in the overall RQLQ than placebo, which ranged from -0.55 (95% CI -0.72, -0.39) to -0.80 (95% CI -1.05, ­ 0.55). In these trials, the treatment differences between DYMISTA and the monotherapies were less than the minimum important difference of 0.5 points. Pediatric Patients 6-11 Years of Age: The efficacy and safety of DYMISTA was evaluated in one randomized, multi-center, double-blind, placebo-controlled trial in 304 children 6 to 11 years of age with seasonal allergic rhinitis. Patients were randomized 1:1 to receive either one spray per nostril twice daily of DYMISTA or placebo (vehicle control) for 14 days. The design of this trial was similar to that of the adult trials. Reference ID: 5497208 20 The primary efficacy endpoint was the mean change from baseline in combined AM+PM reflective total nasal symptom score (rTNSS) over 2 weeks. DYMISTA was not statistically significantly different than placebo, but the results were numerically supportive (Table 5). Table 5: Mean Change from Baseline in Reflective Total Nasal Symptom Scores Over 2 Weeks in Children Age 6 to 11 Years Treatment Baseline LS Mean Change from baseline LS Mean Difference (95% CI) P-value DYMISTA N = 152 18.4 -3.7 -0.8 (-1.8, 0.2) 0.099 Placebo N = 152 18.0 -2.9 CI = confidence interval LS Mean, 95% CI, and p-value are obtained from the repeated-measures analysis of covariance model using observed data 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied: DYMISTA nasal spray (NDC 0037-0245-23) is supplied as an amber glass bottle fitted with a metered-dose spray pump unit. The spray pump unit consists of a nasal spray pump with a white nasal adapter and clear plastic dust cap. Each bottle contains a net fill weight of 23 g and will deliver 120 metered sprays after priming [see Dosage and Administration (2.2)]. After priming [see Dosage and Administration (2.2)], each spray delivers a suspension volume of 0.137 mL as a fine mist, containing 137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate (137 mcg/50 mcg). The correct amount of medication in each spray cannot be assured before the initial priming and after 120 sprays have been used, even though the bottle is not completely empty. The bottle should be discarded after 120 sprays have been used. DYMISTA should not be used after the expiration date “EXP” printed on the bottle label and carton. Storage: Store upright with the dust cap in place at controlled room temperature 20°C to 25°C (68°F to 77°F). [See USP Controlled Temperature] Protect from light. Do not store in the freezer or refrigerator. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use) Somnolence: Somnolence has been reported in some patients (8 of 1,269 patients) taking DYMISTA in controlled clinical trials. Caution patients against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of DYMISTA [see Warnings and Precautions (5.1)]. Reference ID: 5497208 21 PIEDa Concurrent Use of Alcohol and other Central Nervous System Depressants: Advise patients to avoid concurrent use of DYMISTA with alcohol or other central nervous system depressants because additional reductions in alertness and additional impairment of central nervous system performance may occur [see Warnings and Precautions (5.1)]. Local Nasal Effects: Nasal corticosteroids are associated with epistaxis, nasal ulceration, nasal septal perforation, Candida albicans infection and impaired wound healing. Patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use DYMISTA until healing has occurred [see Warnings and Precautions (5.2)]. Glaucoma and Cataracts: Inform patients that glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. Advise patients to inform his/her health care provider if a change in vision is noted while using DYMISTA [see Warnings and Precautions (5.3)]. Immunosuppression and Risk of Infections: Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Inform patients of potential worsening of existing tuberculosis, fungal, bacterial, viral or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.4)]. Effect on Growth: Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving DYMISTA [see Use in Specific Populations (8.4)]. Priming: Instruct patients to shake the bottle gently before each use and prime the pump before initial use and when DYMISTA has not been used for 14 or more days [see Dosage and Administration (2.2)]. Keep Spray Out of Eyes: Instruct patients to avoid spraying DYMISTA into their eyes. Potential Drug Interactions: Advise patients that coadministration of DYMISTA and ritonavir is not recommended and to be cautious if DYMISTA is coadministered with ketoconazole [see Drug Interactions (7.2)]. U.S. Patent 8,168,620 Manufactured by: Cipla Ltd. Indore SEZ, Pithampur, India M.L. No. 28/2/2010 Manufactured for: Meda Pharmaceuticals Inc. Canonsburg, PA 15317 U.S.A. Reference ID: 5497208 22 © 2024 Viatris Inc. DYMISTA and ASTELIN are registered trademarks of Meda Pharmaceuticals Inc., a Viatris Company. Revised: 12/2024 IN-023A6-05N Reference ID: 5497208 23 PATIENT INFORMATION DYMISTA (Dy-Mist-A) (azelastine hydrochloride and fluticasone propionate) nasal spray Important: For use in your nose only What is DYMISTA? • DYMISTA is a prescription medicine used to treat symptoms of seasonal allergic rhinitis in people 6 years of age and older. • DYMISTA may help to reduce your nasal symptoms including stuffy nose, runny nose, itching, and sneezing. It is not known if DYMISTA is safe or effective in children under 4 years of age. Do not use DYMISTA if you: • are allergic to azelastine hydrochloride, or fluticasone propionate, or any of the ingredients in DYMISTA. Stop using DYMISTA and get medical help right away if you have symptoms of a serious allergic reaction. • See the end of the leaflet for a complete list of ingredients in DYMISTA. Before using DYMISTA tell your healthcare provider about all of your medical conditions, including if you: • have had recent nasal sores, nasal surgery, or nasal injury. • have eye or vision problems, such as cataracts or glaucoma (increased pressure in your eye). • have tuberculosis or any untreated fungal, bacterial, viral infections or eye infections caused by herpes. • have been near someone who has chickenpox or measles. • are not feeling well or have any other symptoms that you do not understand. • are pregnant or plan to become pregnant. • are breastfeeding or plan to breastfeed. It is not known if DYMISTA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while using DYMISTA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. DYMISTA and other medicines may affect each other, causing side effects. Especially tell your healthcare provider if you take: • antifungal or anti-HIV medicines Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I use DYMISTA? Reference ID: 5497208 • Read the Instructions for Use at the end of this leaflet for information about the right way to use DYMISTA. • An adult should help a young child use DYMISTA. • DYMISTA is for use in your nose only. Do not spray it into your eyes or mouth. If you spray DYMISTA into your eyes, flush your eyes with large amounts of water for 10 minutes and then call your healthcare provider. • Use DYMISTA exactly as your healthcare provider tells you to use it. Your healthcare provider will tell you how much DYMISTA to use and when to use it. • If a child accidentally swallows DYMISTA or you use too much DYMISTA, call your healthcare provider or go to the nearest hospital emergency room right away. What should I avoid while using DYMISTA? • DYMISTA can cause sleepiness or drowsiness. Do not drive, operate machinery, or do anything that needs you to be alert until you know how DYMISTA affects you. • Do not drink alcohol or take any other medicines that may cause you to feel sleepy while using DYMISTA. It can increase your chances of having serious side effects. What are the possible side effects of DYMISTA? DYMISTA may cause serious side effects including: • sleepiness or drowsiness. • nasal problems. Symptoms of nasal problems may include: o crusting in the nose o nosebleeds o runny nose o hole in the cartilage between your nose (nasal septal perforation). A whistling sound when you breathe may be a symptom of nasal septal perforation. • slow wound healing. You should not use DYMISTA until your nose has healed if you have a sore in your nose, if you have had surgery on your nose, or if your nose has been injured. • thrush (candida), a fungal infection in your nose and throat. Tell your healthcare provider if you have any redness or white colored patches in your nose or mouth. • eye problems, such as glaucoma or cataracts. Some people may have eye problems, including glaucoma and cataracts. You should have regular eye exams when using DYMISTA. • immune system problems and increased risk of infections. DYMISTA may cause problems with the way your immune system protects your body against infection and increase your risk of infection. Avoid contact with people who have contagious diseases such as chickenpox or measles while you use DYMISTA. Symptoms of infection may include: o fever o aches or pains o chills o feeling tired • adrenal insufficiency. Adrenal insufficiency is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal insufficiency may include: o tiredness o weakness Reference ID: 5497208 o nausea o vomiting o low blood pressure • slowed or delayed growth in children. A child's growth should be checked regularly while using DYMISTA. Call your healthcare provider or get medical help right away if you have symptoms of any of the serious side effects listed above. The most common side effects of DYMISTA Nasal Spray include: • changes in taste • nosebleeds • headache Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of DYMISTA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store DYMISTA? • Store DYMISTA upright with the dust cap in place at room temperature between 68°F to 77°F (20°C to 25°C). • Do not freeze or refrigerate DYMISTA. • Protect DYMISTA from light. • Do not use DYMISTA after the expiration date “EXP” printed on the bottle label and carton. • Throw away your DYMISTA bottle after using 120 sprays after initial priming. Even though the bottle may not be completely empty, you may not get the correct dose of medicine if you continue to use it. Keep DYMISTA and all medicines out of reach of children. General information about the safe and effective use of DYMISTA Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use DYMISTA for a condition for which it was not prescribed. Do not give DYMISTA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about DYMISTA that is written for health professionals. What are the ingredients in DYMISTA? Active ingredients: azelastine hydrochloride and fluticasone propionate Inactive ingredients: benzalkonium chloride, carboxymethylcellulose sodium, edetate disodium, glycerin, microcrystalline cellulose, phenylethyl alcohol, polysorbate 80, and purified water. For more information, go to www.DYMISTA.com or call Meda Pharmaceuticals Inc. at 1­ 888-939-6478. Reference ID: 5497208 G-ousteap Spray Pump Tip Shoulders of---,"'--" the Spray Pump Spray Pump Unit Bottle Instructions for Use DYMISTA (Dy-Mist-A) (azelastine hydrochloride and fluticasone propionate) nasal spray For use in your nose only. Do not spray in your eyes. Read the Instructions for Use before you start to use DYMISTA and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment. Before you use DYMISTA, make sure your healthcare provider shows you the right way to use it. Shake the bottle gently before each use. Your DYMISTA pump. (See Figure A) Figure A Instructions for Using Your DYMISTA Pump. Before you use DYMISTA for the first time, you will need to shake the bottle gently and prime the pump. For use in young children: An adult should help a young child use DYMISTA. (See Steps 1 through 12). Priming your DYMISTA pump Before you prime the bottle, shake it gently. Step 1. Remove the clear plastic dust cap from the spray pump tip of the bottle. (See Figure B) Figure B Reference ID: 5497208 ----- Step 2. Hold the bottle upright with two fingers on the shoulders of the spray pump unit and put your thumb on the bottom of the bottle. Press upward with your thumb and release for the pumping action. • Repeat the pumping action until you see a fine mist. You should see a fine mist of the medicine after 6 pumps or less. (See Figure C) • To get a fine mist of medicine, you must repeat the pumping action fast and use firm pressure against the bottom of the bottle. • If you see a stream of liquid, the spray will not work right and may cause nasal discomfort. • If you do not use DYMISTA for 14 or more days, you will need to shake the bottle gently, and prime the pump with 1 spray or until you see a fine mist. If you do not see a fine mist, clean the tip of the spray nozzle. See the cleaning section below. • Once you see the fine mist of medicine, your DYMISTA pump is ready for use. Figure C Using your DYMISTA: For use in young children: An adult should help a young child use DYMISTA. Step 3. Gently blow your nose to clear nostrils. (See Figure D) Figure D Reference ID: 5497208 Step 4. Shake the bottle gently. Close 1 nostril with a finger. Tilt your head forward slightly. Keep the bottle upright and carefully place the spray pump tip ¼ to ½ inch into your other nostril. (See Figure E) Figure E Step 5. For each spray firmly press the pump 1 time. Keep your head tilted down and at the same time, gently breathe in through your nostril. (See Figure F) Do not spray directly onto the nasal septum (the wall between your 2 nostrils). • Repeat Step 5 in your other nostril. • Do not tilt your head back. This will help to keep the medicine from going into your throat. • If the medicine goes into your throat you may get a bitter taste in your mouth. This is normal. Figure F Step 6. When you finish using DYMISTA, wipe the spray tip with a clean tissue or cloth. Put the dust cap back on the spray pump tip of the bottle. (See Figure G) Figure G Reference ID: 5497208 Each bottle of DYMISTA contains enough medicine for you to spray medicine from the bottle 120 times. After initial priming, do not use your bottle of DYMISTA after 120 sprays. You may not receive the right amount of medicine. Keep track of the number of sprays you use from your bottle of DYMISTA and throw away the bottle even if it has medicine left in it. Do not count any sprays used for initially priming the bottle. Cleaning the Spray Pump Tip: Your DYMISTA should be cleaned at least 1 time each week. To do this: Step 7. Remove the dust cap and then gently pull upward on the spray pump unit to remove it from the bottle. (See Figure H) Figure H Step 8. Wash the spray pump unit and dust cap in warm tap water. (See Figure I) Figure I Step 9. Allow to dry completely. When dry, place the spray pump unit and dust cap back on the bottle. (See Figure J) Figure J Reference ID: 5497208 PIEDa Step 10. If the spray pump unit becomes blocked, it can be removed as instructed above in Step 7 and placed in warm water to soak. Do not try to unblock the spray pump unit by inserting a pin or other sharp object. This will damage the spray pump unit and cause you not to get the right dose of medicine. Step 11. After the spray pump unit is unblocked, rinse the applicator and cap with cold water, and allow them to dry as in Step 10 above. When dry, place the spray pump unit back on the bottle and put the dust cap on the spray pump tip. Step 12. Reprime the bottle as in Steps 1 and 2 above. Replace the dust cap and your DYMISTA is ready for use. This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration. U.S. Patent 8,168,620 Manufactured by: Cipla Ltd. Indore SEZ, Pithampur, India M.L. No. 28/2/2010 Manufactured for: Meda Pharmaceuticals Inc. Canonsburg, PA 15317 U.S.A. © 2024 Viatris Inc. DYMISTA is a registered trademark of Meda Pharmaceuticals Inc., a Viatris Company. Revised: 12/2024 IN-023A6-05N Reference ID: 5497208
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use STEQEYMA safely and effectively. See full prescribing information for STEQEYMA. STEQEYMA (ustekinumab-stba) injection, for subcutaneous or intravenous use Initial U.S. Approval: 2024 STEQEYMA (ustekinumab-stba) is biosimilar* to STELARA® (ustekinumab) -----------------------------INDICATIONS AND USAGE--------------------------­ STEQEYMA is a human interleukin-12 and -23 antagonist indicated for the treatment of: Adult patients with: • moderate to severe plaque psoriasis (PsO) who are candidates for phototherapy or systemic therapy. (1.1) • active psoriatic arthritis (PsA). (1.2) • moderately to severely active Crohn’s disease (CD). (1.3) • moderately to severely active ulcerative colitis. (1.4) Pediatric patients 6 years and older with: • moderate to severe plaque psoriasis, who are candidates for phototherapy or systemic therapy. (1.1) • active psoriatic arthritis (PsA). (1.2) ------------------------DOSAGE AND ADMINISTRATION----------------------­ Psoriasis Adult Subcutaneous Recommended Dosage (2.1): Weight Range (kilograms) Recommended Dosage less than or equal to 100 kg 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks greater than 100 kg 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks Psoriasis Pediatric Patients (6 to 17 years old) Subcutaneous Recommended Dosage (2.1): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter. Weight Range (kilograms) Dose 60 kg to 100 kg 45 mg greater than 100 kg 90 mg Psoriatic Arthritis Adult Subcutaneous Recommended Dosage (2.2): • The recommended dosage is 45 mg administered subcutaneously initially and 4 weeks later, followed by 45 mg administered subcutaneously every 12 weeks. • For patients with co-existent moderate-to-severe plaque psoriasis weighing greater than 100 kg, the recommended dosage is 90 mg administered subcutaneously initially and 4 weeks later, followed by 90 mg administered subcutaneously every 12 weeks. Psoriatic Arthritis Pediatric (6 to 17 years old) Subcutaneous Recommended Dosage (2.2): Weight-based dosing is recommended at the initial dose, 4 weeks later, then every 12 weeks thereafter. Weight Range (kilograms) Dose 60 kg or more 45 mg greater than 100 kg with co­ existent moderate-to-severe plaque psoriasis 90 mg Crohn’s Disease and Ulcerative Colitis Initial Adult Intravenous Recommended Dosage (2.3): A single intravenous infusion using weight- based dosing: Weight Range (kilograms) Dose up to 55 kg 260 mg (2 vials) greater than 55 kg to 85 kg 390 mg (3 vials) greater than 85 kg 520 mg (4 vials) Crohn’s Disease and Ulcerative Colitis Maintenance Adult Subcutaneous Recommended Dosage (2.3): A subcutaneous 90 mg dose 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. ----------------------DOSAGE FORMS AND STRENGTHS--------------------­ Subcutaneous Injection (3) • Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe Intravenous Infusion (3) • Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial (3) -----------------------------CONTRAINDICATIONS--------------------------------­ Clinically significant hypersensitivity to ustekinumab products or to any of the excipients in STEQEYMA. (4) -------------------------WARNINGS AND PRECAUTIONS---------------------­ • Infections: Serious infections have occurred. Avoid starting STEQEYMA during any clinically important active infection. If a serious infection or clinically significant infection develops, discontinue STEQEYMA until the infection resolves. (5.1) • Theoretical Risk for Particular Infections: Serious infections from mycobacteria, salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations have been reported in patients genetically deficient in IL­ 12/IL-23. Consider diagnostic tests for these infections as dictated by clinical circumstances. (5.2) • Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with STEQEYMA. Initiate treatment of latent TB before administering STEQEYMA. (5.3) • Malignancies: Ustekinumab products may increase risk of malignancy. The safety of ustekinumab products in patients with a history of or a known malignancy has not been evaluated. (5.4) • Hypersensitivity Reactions: If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue STEQEYMA. (5.5) • Posterior Reversible Encephalopathy Syndrome (PRES): If PRES is suspected, treat promptly, and discontinue STEQEYMA. (5.6) • Immunizations: Avoid use of live vaccines in patients during treatment with STEQEYMA. (5.7) • Noninfectious Pneumonia: Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. If diagnosis is confirmed, discontinue STEQEYMA and institute appropriate treatment. (5.8) ------------------------------ADVERSE REACTIONS------------------------------­ Most common adverse reactions are: • Psoriasis (≥3%): nasopharyngitis, upper respiratory tract infection, headache, and fatigue. (6.1) • Crohn’s Disease, induction (≥3%): vomiting. (6.1) • Crohn’s Disease, maintenance (≥3%): nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis. (6.1) • Ulcerative colitis, induction (≥3%): nasopharyngitis (6.1) • Ulcerative colitis, maintenance (≥3%): nasopharyngitis, headache, abdominal pain, influenza, fever, diarrhea, sinusitis, fatigue, and nausea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact CELLTRION USA, Inc. at 1-800-560-9414 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. *Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of STEQEYMA has been demonstrated for the condition(s) of use (e.g. indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. Revised: 12/2024 Reference ID: 5498000 1 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Plaque Psoriasis (PsO) 1.2 Psoriatic Arthritis (PsA) 1.3 Crohn’s Disease (CD) 1.4 Ulcerative Colitis 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage in Plaque Psoriasis 2.2 Recommended Dosage in Psoriatic Arthritis 2.3 Recommended Dosage in Crohn’s Disease and Ulcerative Colitis 2.4 General Considerations for Administration 2.5 Instructions for Administration of STEQEYMA Prefilled Syringes Equipped with Needle Safety Guard 2.6 Preparation and Administration of STEQEYMA 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion (Crohn’s Disease and Ulcerative Colitis) 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Infections 5.2 Theoretical Risk for Vulnerability to Particular Infections 5.3 Pre-treatment Evaluation for Tuberculosis 5.4 Malignancies 5.5 Hypersensitivity Reactions 5.6 Posterior Reversible Encephalopathy Syndrome (PRES) 5.7 Immunizations 5.8 Noninfectious Pneumonia 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Therapies 7.2 CYP450 Substrates 7.3 Allergen Immunotherapy 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Adult Plaque Psoriasis 14.2 Pediatric Plaque Psoriasis 14.3 Psoriatic Arthritis 14.4 Crohn’s Disease 14.5 Ulcerative Colitis 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5498000 2 FULL PRESCRIBING INFORMATION 1. INDICATIONS AND USAGE 1.1. Plaque Psoriasis (PsO) STEQEYMA is indicated for the treatment of adults and pediatric patients 6 years of age and older with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. 1.2. Psoriatic Arthritis (PsA) STEQEYMA is indicated for the treatment of adults and pediatric patients 6 years of age and older with active psoriatic arthritis. 1.3. Crohn’s Disease (CD) STEQEYMA is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease. 1.4. Ulcerative Colitis STEQEYMA is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis. 2. DOSAGE AND ADMINISTRATION 2.1. Recommended Dosage in Plaque Psoriasis Subcutaneous Adult Dosage Regimen • For patients weighing 100 kg or less, the recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. • For patients weighing more than 100 kg, the recommended dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. In subjects weighing more than 100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these subjects [see Clinical Studies (14)]. Subcutaneous Pediatric Dosage Regimen Administer STEQEYMA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter. The recommended dose of STEQEYMA for pediatric patients (6-17 years old) with plaque psoriasis based on body weight is shown below (Table 1). 3 Reference ID: 5498000 Table 1: Recommended Dose of STEQEYMA for Subcutaneous Injection in Pediatric Patients (6- 17 years old) with Plaque Psoriasis Body Weight of Patient at the Time of Dosing Recommended Dose 60 kg to 100 kg 45 mg more than 100 kg 90 mg There is no dosage form for STEQEYMA that allows weight-based dosing for pediatric patients below 60 kg. 2.2. Recommended Dosage in Psoriatic Arthritis Subcutaneous Adult Dosage Regimen • The recommended dosage is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. • For patients with co-existent moderate-to-severe plaque psoriasis weighing more than 100 kg, the recommended dosage is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. Subcutaneous Pediatric Dosage Regimen Administer STEQEYMA subcutaneously at Weeks 0 and 4, then every 12 weeks thereafter. The recommended dose of STEQEYMA for pediatric patients (6 to 17 years old) with psoriatic arthritis, based on body weight, is shown below (Table 2). Table 2: Recommended Dose of STEQEYMA for Subcutaneous Injection in Pediatric Patients (6 to 17 years old) with Psoriatic Arthritis Body Weight of Patient at the Time of Dosing Recommended Dose 60 kg or more* 45 mg greater than 100 kg with co-existent moderate-to-severe 90 mg plaque psoriasis *There is no dosage form for STEQEYMA that allows weight-based dosing for pediatric patients below 60 kg. 2.3. Recommended Dosage in Crohn’s Disease and Ulcerative Colitis Intravenous Induction Adult Dosage Regimen A single intravenous infusion dose of STEQEYMA using the weight-based dosage regimen specified in Table 3 [see Instructions for dilution of STEQEYMA 130 mg vial for intravenous infusion (2.6)]. Table 3: Initial Intravenous Dosage of STEQEYMA Body Weight of Patient at the time of Number of 130 mg/26 mL dosing Dose (5 mg/mL) STEQEYMA vials 55 kg or less 260 mg 2 more than 55 kg to 85 kg 390 mg 3 more than 85 kg 520 mg 4 Reference ID: 5498000 4 Subcutaneous Maintenance Adult Dosage Regimen The recommended maintenance dosage is a subcutaneous 90 mg dose administered 8 weeks after the initial intravenous dose, then every 8 weeks thereafter. 2.4. General Considerations for Administration • STEQEYMA is intended for use under the guidance and supervision of a healthcare provider. STEQEYMA should only be administered to patients who will be closely monitored and have regular follow-up visits with a healthcare provider. The appropriate dose should be determined by a healthcare provider using the patient’s current weight at the time of dosing. In pediatric patients, it is recommended that STEQEYMA be administered by a healthcare provider. If a healthcare provider determines that it is appropriate, a patient may self-inject or a caregiver may inject STEQEYMA after proper training in subcutaneous injection technique. Instruct patients to follow the directions provided in the Medication Guide [see Medication Guide]. • It is recommended that each injection be administered at a different anatomic location (such as upper arms, gluteal regions, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, or indurated. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Prior to administration, visually inspect STEQEYMA for particulate matter and discoloration. STEQEYMA is a colorless to pale yellow solution and may contain a few small translucent or white particles. Do not use STEQEYMA if it is discolored or cloudy, or if other particulate matter is present. STEQEYMA does not contain preservatives; therefore, discard any unused product remaining in the vial and/or syringe. 2.5. Instructions for Administration of STEQEYMA Prefilled Syringes Equipped with Needle Safety Guard Refer to the diagram below for the provided instructions. Reference ID: 5498000 5 Before Use After Use Medicine Finger Flange Viewingi Window 11.H""nr--Needle Needle Guard >----Needle I -Cap-I • Remove the needle cap when you are ready to inject STEQEYMA by holding the body of the prefilled syringe in one hand between the thumb and index fingers. Do not hold the plunger while removing the cap. Do not use the prefilled syringe if it has been dropped without the needle cover in place. • Inject STEQEYMA subcutaneously as recommended [see Dosage and Administration (2.1, 2.2, 2.3)]. • Inject all of the liquid by using your thumb to push the plunger all the way down. If the plunger is not fully pressed, the needle guard will not extend to cover the needle when it is removed. • After the prefilled syringe is empty, slowly lift your thumb from the plunger rod until the needle is completely covered by the needle guard, as shown by the illustration below: 6 Reference ID: 5498000 • Used syringes should be placed in a puncture-resistant container. 2.6. Preparation and Administration of STEQEYMA 130 mg/26 mL (5 mg/mL) Vial for Intravenous Infusion (Crohn’s Disease and Ulcerative Colitis) STEQEYMA solution for intravenous infusion must be diluted, prepared, and infused by a healthcare professional using aseptic technique. 1. Calculate the dose and the number of STEQEYMA vials needed based on patient weight (Table 3). Each 26 mL vial of STEQEYMA contains 130 mg of ustekinumab-stba. 2. Withdraw, and then discard a volume of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal to the volume of STEQEYMA to be added (discard 26 mL sodium chloride for each vial of STEQEYMA needed, for 2 vials- discard 52 mL, for 3 vials- discard 78 mL, 4 vials- discard 104 mL). Alternatively, a 250 mL infusion bag containing 0.45% Sodium Chloride Injection, USP may be used. 3. Withdraw 26 mL of STEQEYMA from each vial needed and add it to the 250 mL infusion bag. The final volume in the infusion bag should be 250 mL. Gently mix. 4. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if visibly opaque particles, discoloration or foreign particles are observed. 5. Infuse the diluted solution over a period of at least one hour. Once diluted, the infusion should be completely administered within four hours of the dilution in the infusion bag. 6. Use only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 0.2 micrometer). 7. Do not infuse STEQEYMA concomitantly in the same intravenous line with other agents. 8. STEQEYMA does not contain preservatives. Each vial is for one-time use in only one patient. Discard any remaining solution. Dispose any unused medicinal product in accordance with local requirements. Reference ID: 5498000 7 Storage If necessary, the diluted infusion solution may be kept at room temperature up to 30°C (86°F) for up to 3 hours. Storage time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within 4 hours after the dilution in the infusion bag (cumulative time after preparation including the storage and the infusion period). Do not freeze. Discard any unused portion of the infusion solution. 3. DOSAGE FORMS AND STRENGTHS STEQEYMA (ustekinumab-stba) is a colorless to pale yellow solution and may contain a few small translucent or white particles. Subcutaneous Injection • Injection: 45 mg/0.5 mL or 90 mg/mL solution in a single-dose prefilled syringe Intravenous Infusion • Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial 4. CONTRAINDICATIONS STEQEYMA is contraindicated in patients with clinically significant hypersensitivity to ustekinumab products or to any of the excipients in STEQEYMA [see Warnings and Precautions (5.5)]. 5. WARNINGS AND PRECAUTIONS 5.1. Infections Ustekinumab products may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab products [see Adverse Reactions (6.1, 6.3)]. Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in clinical trials included the following: • Plaque Psoriasis: diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis, and urinary tract infections. • Psoriatic arthritis: cholecystitis. • Crohn’s disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis. • Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis. Avoid initiating treatment with STEQEYMA in patients with any clinically important active infection until the infection resolves or is adequately treated. Consider the risks and benefits of treatment prior to initiating use of STEQEYMA in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur while Reference ID: 5498000 8 on treatment with STEQEYMA and discontinue STEQEYMA for serious or clinically significant infections until the infection resolves or is adequately treated. 5.2. Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with ustekinumab products may be susceptible to these types of infections. Consider appropriate diagnostic testing (e.g., tissue culture, stool culture, as dictated by clinical circumstances). 5.3. Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis infection prior to initiating treatment with STEQEYMA. Avoid administering STEQEYMA to patients with active tuberculosis infection. Initiate treatment of latent tuberculosis prior to administering STEQEYMA. Consider anti-tuberculosis therapy prior to initiation of STEQEYMA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Closely monitor patients receiving STEQEYMA for signs and symptoms of active tuberculosis during and after treatment. 5.4. Malignancies Ustekinumab products are immunosuppressants and may increase the risk of malignancy. Malignancies were reported among subjects who received ustekinumab in clinical trials [see Adverse Reactions (6.1)]. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy [see Nonclinical Toxicology (13)]. The safety of ustekinumab products has not been evaluated in patients who have a history of malignancy or who have a known malignancy. There have been post-marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving ustekinumab products who had pre-existing risk factors for developing non-melanoma skin cancer. Monitor all patients receiving STEQEYMA for the appearance of non-melanoma skin cancer. Closely follow patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment [see Adverse Reactions (6.1)]. 5.5. Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with ustekinumab products [see Adverse Reactions (6.1, 6.3)]. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue STEQEYMA. Reference ID: 5498000 9 5.6. Posterior Reversible Encephalopathy Syndrome (PRES) Two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported in clinical trials. Cases have also been reported in postmarketing experience in patients with psoriasis, psoriatic arthritis, and Crohn’s disease. Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab product initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab products. Monitor all patients treated with STEQEYMA for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue STEQEYMA. 5.7. Immunizations Prior to initiating therapy with STEQEYMA, patients should receive all age-appropriate immunizations as recommended by current immunization guidelines. Patients being treated with STEQEYMA should avoid receiving live vaccines. Avoid administering BCG vaccines during treatment with STEQEYMA or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving STEQEYMA because of the potential risk for shedding from the household contact and transmission to patient. Non-live vaccinations received during a course of STEQEYMA may not elicit an immune response sufficient to prevent disease. 5.8. Noninfectious Pneumonia Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during post-approval use of ustekinumab products. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Serious outcomes have included respiratory failure and prolonged hospitalization. Patients improved with discontinuation of therapy and in certain cases administration of corticosteroids. If diagnosis is confirmed, discontinue STEQEYMA and institute appropriate treatment [see Postmarketing Experience (6.3)]. 6. ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the label: • Infections [see Warnings and Precautions (5.1)] • Malignancies [see Warnings and Precautions (5.4)] Reference ID: 5498000 10 • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.6)] • Noninfectious Pneumonia [see Warnings and Precautions (5.8)] 6.1. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Subjects with Plaque Psoriasis The safety data reflect exposure to ustekinumab in 3117 adult subjects with plaque psoriasis, including 2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at least five years. Table 4 summarizes the adverse reactions that occurred at a rate of at least 1% with higher rates in the ustekinumab groups during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2 [see Clinical Studies (14)]. Table 4: Adverse Reactions, Reported by ≥1% of Subjects with Plaque Psoriasis at Higher Rates in the ustekinumab groups through Week 12 in Ps STUDY 1 and Ps STUDY 2 Ustekinumab Placebo 45 mg 90 mg Subjects treated 665 664 666 Nasopharyngitis 51 (8%) 56 (8%) 49 (7%) Upper respiratory tract infection 30 (5%) 36 (5%) 28 (4%) Headache 23 (3%) 33 (5%) 32 (5%) Fatigue 14 (2%) 18 (3%) 17 (3%) Back pain 8 (1%) 9 (1%) 14 (2%) Dizziness 8 (1%) 8 (1%) 14 (2%) Pharyngolaryngeal pain 7 (1%) 9 (1%) 12 (2%) Pruritus 9 (1%) 10 (2%) 9 (1%) Injection site erythema 3 (<1%) 6 (1%) 13 (2%) Myalgia 4 (1%) 7 (1%) 8 (1%) Depression 3 (<1%) 8 (1%) 4 (1%) Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 through week 12 included: cellulitis, herpes zoster, diverticulitis, and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation). One case of PRES occurred during adult plaque psoriasis clinical trials [see Warnings and Precautions (5.6)]. Infections In the placebo-controlled period of clinical trials of subjects with plaque psoriasis (average follow­ up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for ustekinumab-treated subjects), 27% of ustekinumab-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up). Serious Reference ID: 5498000 11 infections occurred in 0.3% of ustekinumab-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) [see Warnings and Precautions (5.1)]. In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of ustekinumab-treated subjects reported infections (0.87 per subject-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up). Malignancies In the controlled and non-controlled portions of plaque psoriasis clinical trials (median follow-up of 3.2 years, representing 8998 subject-years of exposure), 1.7% of ustekinumab-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of ustekinumab-treated subjects (0.52 per hundred subject-years of follow-up) [see Warnings and Precautions (5.4)]. The most frequently observed malignancies other than non-melanoma skin cancer during the clinical trials were: prostate, melanoma, colorectal and breast. Malignancies other than non-melanoma skin cancer in ustekinumab-treated subjects during the controlled and uncontrolled portions of trials were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).1 Pediatric Subjects with Plaque Psoriasis The safety of ustekinumab was assessed in two trials of pediatric subjects with moderate to severe plaque psoriasis. Ps STUDY 3 evaluated safety for up to 60 weeks in 110 pediatric subjects 12 to 17 years old. Ps STUDY 4 evaluated safety for up to 56 weeks in 44 pediatric subjects 6 to 11 years old. The safety profile in pediatric subjects was similar to the safety profile from trials in adults with plaque psoriasis. Psoriatic Arthritis The safety of ustekinumab was assessed in 927 subjects in two randomized, double-blind, placebo- controlled trials in adults with active psoriatic arthritis (PsA). The overall safety profile of ustekinumab in subjects with PsA was consistent with the safety profile seen in adult psoriasis clinical trials. A higher incidence of arthralgia, nausea, and dental infections was observed in ustekinumab-treated subjects when compared with placebo-treated subjects (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical trials. Crohn’s Disease The safety of ustekinumab was assessed in 1407 subjects with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] greater than or equal to 220 and less than or equal to 450) in three randomized, double-blind, placebo-controlled, parallel-group, multicenter trials. These 1407 subjects included 40 subjects who received a prior investigational intravenous ustekinumab formulation but were not included in the efficacy analyses. In trials CD-1 and CD-2 there were 470 subjects who received ustekinumab 6 mg/kg as a weight-based single intravenous induction dose and 466 who received placebo [see Dosage and Administration (2.3)]. Subjects who were responders in either trial CD-1 or CD-2 were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, or placebo for 44 weeks in trial Reference ID: 5498000 12 CD-3. Subjects in these 3 trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents [azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX)], oral corticosteroids (prednisone or budesonide), and/or antibiotics for their Crohn’s disease [see Clinical Studies (14.4)]. The overall safety profile of ustekinumab was consistent with the safety profile seen in the adult psoriasis and psoriatic arthritis clinical trials. Common adverse reactions in trials CD-1 and CD-2 and in trial CD-3 are listed in Tables 5 and 6, respectively. Table 5: Common adverse reactions through Week 8 in Trials CD-1 and CD-2 occurring in ≥3% of Ustekinumab-treated subjects and higher than placebo Ustekinumab Placebo 6 mg/kg single intravenous induction dose N=466 N=470 Vomiting 3% 4% Other less common adverse reactions reported in subjects in trials CD-1 and CD-2 included asthenia (1% vs 0.4%), acne (1% vs 0.4%), and pruritus (2% vs 0.4%). Table 6: Common adverse reactions through Week 44 in Trial CD-3 occurring in ≥3% of Ustekinumab-treated subjects and higher than placebo Ustekinumab 90 mg subcutaneous Placebo maintenance dose every 8 weeks N=133 N=131 Nasopharyngitis 8% 11% Injection site erythema 0 5% Vulvovaginal candidiasis/mycotic infection 1% 5% Bronchitis 3% 5% Pruritus 2% 4% Urinary tract infection 2% 4% Sinusitis 2% 3% Infections In subjects with Crohn’s disease, serious or other clinically significant infections included anal abscess, gastroenteritis, and pneumonia. In addition, listeria meningitis and ophthalmic herpes zoster were reported in one patient each [see Warnings and Precautions (5.1)]. Malignancies With up to one year of treatment in the Crohn’s disease clinical trials, 0.2% of ustekinumab­ treated subjects (0.36 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.58 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.2% of ustekinumab-treated subjects (0.27 events per hundred patient-years) and in none of the placebo-treated subjects. Hypersensitivity Reactions Including Anaphylaxis In CD trials, two subjects reported hypersensitivity reactions following ustekinumab administration. One patient experienced signs and symptoms consistent with anaphylaxis Reference ID: 5498000 13 (tightness of the throat, shortness of breath, and flushing) after a single subcutaneous administration (0.1% of subjects receiving subcutaneous ustekinumab). In addition, one subject experienced signs and symptoms consistent with or related to a hypersensitivity reaction (chest discomfort, flushing, urticaria, and increased body temperature) after the initial intravenous ustekinumab dose (0.08% of subjects receiving intravenous ustekinumab). These subjects were treated with oral antihistamines or corticosteroids and in both cases symptoms resolved within an hour. Ulcerative Colitis The safety of ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials (UC-1 [IV induction] and UC-2 [SC maintenance]) in 960 adult subjects with moderately to severely active ulcerative colitis [see Clinical Studies (14.5)]. The overall safety profile of ustekinumab in subjects with ulcerative colitis was consistent with the safety profile seen across all approved indications. Adverse reactions reported in at least 3% of ustekinumab-treated subjects and at a higher rate than placebo were: • Induction (UC-1): nasopharyngitis (7% vs 4%). • Maintenance (UC-2): nasopharyngitis (24% vs 20%), headache (10% vs 4%), abdominal pain (7% vs 3%), influenza (6% vs 5%), fever (5% vs. 4%), diarrhea (4% vs 1%), sinusitis (4% vs 1%), fatigue (4% vs 2%), and nausea (3% vs 2%). Infections In subjects with ulcerative colitis, serious or other clinically significant infections included gastroenteritis and pneumonia. In addition, listeriosis and ophthalmic herpes zoster were reported in one subject each [see Warnings and Precautions (5.1)]. Malignancies With up to one year of treatment in the ulcerative colitis clinical trials, 0.4% of ustekinumab­ treated subjects (0.48 events per hundred patient-years) and 0.0% of placebo-treated subjects (0.00 events per hundred patient-years) developed non-melanoma skin cancer. Malignancies other than non-melanoma skin cancers occurred in 0.5% of ustekinumab-treated subjects (0.64 events per hundred patient-years) and 0.2% of placebo-treated subjects (0.40 events per hundred patient- years). 6.2. Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ustekinumab or of other ustekinumab products. Approximately 6 to 12.4% of subjects treated with ustekinumab in plaque psoriasis and psoriatic arthritis clinical trials developed antibodies to ustekinumab, which were generally low-titer. In plaque psoriasis clinical trials, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. In plaque psoriasis trials, the majority of subjects who were positive for antibodies to ustekinumab had neutralizing antibodies. In Crohn’s disease and ulcerative colitis clinical trials, 2.9% and 4.6% of subjects, respectively, Reference ID: 5498000 14 developed antibodies to ustekinumab when treated with ustekinumab for approximately one year. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen. 6.3. Postmarketing Experience The following adverse reactions have been reported during post-approval use of ustekinumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ustekinumab product exposure. Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria). Infections and infestations: Lower respiratory tract infection (including opportunistic fungal infections and tuberculosis). Neurological disorders: Posterior Reversible Encephalopathy Syndrome (PRES). Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia. Skin reactions: Pustular psoriasis, erythrodermic psoriasis, hypersensitivity vasculitis. 7. DRUG INTERACTIONS 7.1. Concomitant Therapies In plaque psoriasis trials the safety of ustekinumab products in combination with immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis trials, concomitant MTX use did not appear to influence the safety or efficacy of ustekinumab. In Crohn’s disease and ulcerative colitis induction trials, immunomodulators (6-MP, AZA, MTX) were used concomitantly in approximately 30% of subjects and corticosteroids were used concomitantly in approximately 40% and 50% of Crohn’s disease and ulcerative colitis subjects, respectively. Use of these concomitant therapies did not appear to influence the overall safety or efficacy of ustekinumab. 7.2. CYP450 Substrates The formation of CYP450 enzymes can be suppressed by increased levels of certain cytokines (e.g., IL-1, IL-6, TNFα, IFN) during chronic inflammation. Thus, use of ustekinumab products, antagonists of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of STEQEYMA in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and adjust the individual dosage of the CYP substrate as needed. See the prescribing information of specific CYP substrates. A CYP-mediated drug interaction effect was not observed in subjects with Crohn’s disease [see Clinical Pharmacology (12.3)]. 7.3. Allergen Immunotherapy Reference ID: 5498000 15 Ustekinumab products have not been evaluated in patients who have undergone allergy immunotherapy. Ustekinumab products may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis. 8. USE IN SPECIFIC POPULATIONS 8.1. Pregnancy Risk Summary Limited data from observational studies, published case reports, and postmarketing surveillance on the use of ustekinumab products during pregnancy are insufficient to inform a drug associated risk of major birth defects, miscarriage, and other adverse maternal or fetal outcomes. Transport of human IgG antibody across the placenta increases as pregnancy progresses and peaks during the third trimester; therefore, ustekinumab products may be transferred to the developing fetus [see Clinical Considerations]. In animal reproductive and developmental toxicity studies, no adverse developmental effects were observed in offspring after administration of ustekinumab to pregnant monkeys at exposures greater than 100 times the maximum recommended human dose (MRHD). The background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Because ustekinumab products may theoretically interfere with immune response to infections, consider risks and benefits prior to administering live vaccines to infants exposed to STEQEYMA in utero. There are insufficient data regarding exposed infant serum levels of ustekinumab products at birth and the duration of persistence of ustekinumab products in infant serum after birth. Although a specific timeframe to delay administration of live attenuated vaccines in infants exposed in utero is unknown, consider the risks and benefits of delaying a minimum of 6 months after birth because of the clearance of the product. Data Animal Data Ustekinumab was tested in two embryo-fetal development toxicity studies in cynomolgus monkeys. No teratogenic or other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab subcutaneously twice weekly or intravenously weekly during the period of organogenesis. Serum concentrations of ustekinumab in pregnant monkeys were greater than 100 times the serum concentration in patients treated subcutaneously with 90 mg of ustekinumab weekly for 4 weeks. Reference ID: 5498000 16 In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly at exposures greater than 100 times the MRHD from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related-effects on functional, morphological, or immunological development were observed in the neonates from birth through six months of age. 8.2. Lactation Risk Summary Limited data from published literature suggests that ustekinumab is present in human breast milk. There are no available data on the effects of ustekinumab products on milk production. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to ustekinumab products are unknown. No adverse effects on the breastfed infant causally related to ustekinumab products have been identified in the published literature or postmarketing experience. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for STEQEYMA and any potential adverse effects on the breastfed child from STEQEYMA or from the underlying maternal condition. 8.4. Pediatric Use Plaque Psoriasis The safety and effectiveness of STEQEYMA have been established for the treatment of moderate to severe plaque psoriasis in pediatric patients 6 to 17 years of age who are candidates for phototherapy or systemic therapy. Use of STEQEYMA in pediatric patients 12 to less than 17 years of age is supported by evidence from a multicenter, randomized, 60week trial (Ps STUDY 3) of ustekinumab that included a 12­ week, double-blind, placebo-controlled, parallel group portion, in 110 pediatric subjects 12 years of age and older [see Adverse Reactions (6.1), Clinical Studies (14.2)]. Use of STEQEYMA in pediatric patients 6 to 11 years of age is supported by evidence from an open-label, single-arm, efficacy, safety, and pharmacokinetics trial (Ps STUDY 4) of ustekinumab in 44 subjects [see Adverse Reactions (6.1), Pharmacokinetics (12.3)]. The safety and effectiveness of STEQEYMA have not been established in pediatric patients less than 6 years of age with plaque psoriasis. Psoriatic Arthritis The safety and effectiveness of STEQEYMA have been established for treatment of psoriatic arthritis in pediatric patients 6 to 17 years old. Use of STEQEYMA in these age groups is supported by evidence from adequate and well controlled trials of ustekinumab in adults with psoriasis and PsA, pharmacokinetic data from adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and safety data of ustekinumab from two clinical trials in 44 pediatric subjects 6 to 11 years old with psoriasis and 110 pediatric subjects 12 to 17 years old with psoriasis. The observed pre-dose (trough) Reference ID: 5498000 17 concentrations are generally comparable between adult subjects with psoriasis, adult subjects with PsA and pediatric subjects with psoriasis, and the PK exposure is expected to be comparable between adult and pediatric subjects with PsA [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1, 14.2, 14.3)]. The safety and effectiveness of STEQEYMA have not been established in pediatric patients less than 6 years old with psoriatic arthritis. Crohn’s Disease and Ulcerative Colitis The safety and effectiveness of STEQEYMA have not been established in pediatric patients with Crohn’s disease or ulcerative colitis. 8.5. Geriatric Use Of the 6709 subjects exposed to ustekinumab, a total of 340 were 65 years of age or older (183 subjects with plaque psoriasis, 65 subjects with psoriatic arthritis, 58 subjects with Crohn’s disease, and 34 subjects with ulcerative colitis), and 40 subjects were 75 years of age or older. Clinical trials of ustekinumab did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects. 10. OVERDOSAGE Single doses up to 6 mg/kg intravenously have been administered in clinical trials without dose- limiting toxicity. In case of overdosage, monitor the patient for any signs or symptoms of adverse reactions or effects and institute appropriate symptomatic treatment immediately. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations. 11. DESCRIPTION Ustekinumab-stba, a human IgG1κ monoclonal antibody, is a human interleukin-12 and -23 antagonist. Using DNA recombinant technology, ustekinumab-stba is produced in a Chinese Hamster Ovary (CHO) cell line. The manufacturing process contains steps for the clearance of viruses. Ustekinumab-stba is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons. STEQEYMA (ustekinumab-stba) injection is a sterile, preservative-free, colorless to pale yellow solution and may contain a few small translucent or white particles with pH of 5.7. STEQEYMA for Subcutaneous Use Available as 45 mg of ustekinumab-stba in 0.5 mL and 90 mg of ustekinumab-stba in 1 mL, supplied as a sterile solution in a single-dose prefilled syringe with a 27 gauge fixed ½ inch needle. The syringe is fitted with a passive needle guard and a needle cover. Reference ID: 5498000 18 Each 0.5 mL prefilled syringe delivers 45 mg ustekinumab-stba, histidine (0.18 mg), L-histidine monohydrochloride monohydrate (0.46 mg), polysorbate 80 (0.02 mg), sucrose (38 mg), and Water for Injection. Each 1 mL prefilled syringe delivers 90 mg ustekinumab-stba, histidine (0.36 mg), L-histidine monohydrochloride monohydrate (0.91 mg), polysorbate 80 (0.04 mg), sucrose (76 mg), and Water for Injection. STEQEYMA for Intravenous Infusion Available as 130 mg of ustekinumab-stba in 26 mL, supplied as a single-dose 30 mL Type I glass vial with a coated stopper. Each 26 mL vial delivers 130 mg ustekinumab-stba, edetate disodium (0.47 mg), histidine (9.36 mg), L-histidine monohydrochloride monohydrate (23.66 mg), methionine (10.56 mg), polysorbate 80 (10.37 mg), sucrose (1,976 mg), and Water for Injection. 12. CLINICAL PHARMACOLOGY 12.1. Mechanism of Action Ustekinumab products are human IgG1қ monoclonal antibodies that bind with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab products were shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1. The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn’s disease and ulcerative colitis. In animal models of colitis, genetic absence or antibody blockade of the p40 subunit of IL-12 and IL-23, the target of ustekinumab products, was shown to be protective. 12.2. Pharmacodynamics Plaque Psoriasis In a small exploratory trial, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in lesional skin biopsies measured at baseline and up to two weeks post-treatment in subjects with plaque psoriasis. Ulcerative Colitis In both trial UC-1 (induction) and trial UC-2 (maintenance), a positive relationship was observed between exposure and rates of clinical remission, clinical response, and endoscopic improvement. The response rate approached a plateau at the ustekinumab exposures associated with the recommended dosing regimen for maintenance treatment [see Clinical Studies (14.5)]. 12.3. Pharmacokinetics Absorption In adult subjects with plaque psoriasis, the median time to reach the maximum serum concentration (Tmax) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of Reference ID: 5498000 19 45 mg (N=22) and 90 mg (N=24) of ustekinumab. In healthy subjects (N=30), the median Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in subjects with plaque psoriasis. Following multiple subcutaneous doses of ustekinumab in adult subjects with plaque psoriasis, steady- state serum concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady- state trough serum ustekinumab concentrations were 0.69 ± 0.69 mcg/mL for subjects less than or equal to 100 kg receiving a 45 mg dose and 0.74 ± 0.78 mcg/mL for subjects greater than 100 kg receiving a 90 mg dose. There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks. Following the recommended intravenous induction dose, mean ±SD peak serum ustekinumab concentration was 125.2 ± 33.6 mcg/mL in subjects with Crohn’s disease, and 129.1 ± 27.6 mcg/mL in subjects with ulcerative colitis. Starting at Week 8, the recommended subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 weeks. Steady state ustekinumab concentration was achieved by the start of the second maintenance dose. There was no apparent accumulation in ustekinumab concentration over time when given subcutaneously every 8 weeks. Mean ±SD steady-state trough concentration was 2.5 ± 2.1 mcg/mL in subjects with Crohn’s disease, and 3.3 ± 2.3 mcg/mL in subjects with ulcerative colitis for 90 mg ustekinumab administered every 8 weeks. Distribution Population pharmacokinetic analyses showed that the volume of distribution of ustekinumab in the central compartment was 2.7 L (95% CI: 2.69, 2.78) in subjects with Crohn’s disease and 3.0 L (95% CI: 2.96, 3.07) in subjects with ulcerative colitis. The total volume of distribution at steady- state was 4.6 L in subjects with Crohn’s disease and 4.4 L in subjects with ulcerative colitis. Elimination The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all plaque psoriasis trials following subcutaneous administration. Population pharmacokinetic analyses showed that the clearance of ustekinumab was 0.19 L/day (95% CI: 0.185, 0.197) in subjects with Crohn’s disease and 0.19 L/day (95% CI: 0.179, 0.192) in subjects with ulcerative colitis with an estimated median terminal half-life of approximately 19 days for both IBD (Crohn’s disease and ulcerative colitis) populations. These results indicate the pharmacokinetics of ustekinumab were similar between subjects with Crohn’s disease and ulcerative colitis. Metabolism The metabolic pathway of ustekinumab products has not been characterized. As a human IgG1κ monoclonal antibody, ustekinumab products are expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Reference ID: 5498000 20 Specific Populations Weight When given the same dose, subjects with plaque psoriasis or psoriatic arthritis weighing more than 100 kg had lower median serum ustekinumab concentrations compared with those subjects weighing 100 kg or less. The median trough serum concentrations of ustekinumab in subjects of higher weight (greater than 100 kg) in the 90 mg group were comparable to those in subjects of lower weight (100 kg or less) in the 45 mg group. Age: Geriatric Population A population pharmacokinetic analysis (N=106/1937 subjects with plaque psoriasis greater than or equal to 65 years old) was performed to evaluate the effect of age on the pharmacokinetics of ustekinumab. There were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution) in subjects older than 65 years old. Age: Pediatric Population Following multiple recommended doses of ustekinumab in pediatric subjects 6 to 17 years of age with plaque psoriasis, steady-state serum concentrations of ustekinumab were achieved by Week 28. At Week 28, the mean ±SD steady-state trough serum ustekinumab concentrations were 0.36 ± 0.26 mcg/mL and 0.54 ± 0.43 mcg/mL, respectively, in pediatric subjects 6 to 11 years of age and pediatric subjects 12 to 17 years of age. Overall, the observed steady-state ustekinumab trough concentrations in pediatric subjects with plaque psoriasis were within the range of those observed for adult subjects with plaque psoriasis and adult subjects with PsA after administration of ustekinumab. Drug Interaction Studies The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4). No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly with ustekinumab at the approved recommended dosage in subjects with Crohn’s disease [see Drug Interactions (7.2)]. Population pharmacokinetic analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to a TNF blocker in subjects with psoriatic arthritis. In subjects with Crohn’s disease and ulcerative colitis, population pharmacokinetic analyses did not indicate changes in ustekinumab clearance with concomitant use of corticosteroids or immunomodulators (AZA, 6-MP, or MTX); and serum ustekinumab concentrations were not impacted by concomitant use of these medications. Reference ID: 5498000 21 13. NONCLINICAL TOXICOLOGY 13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of ustekinumab products. Published literature showed that administration of murine IL-12 caused an anti- tumor effect in mice that contained transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed UV- induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in mouse models for malignancy risk in humans is unknown. No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab at subcutaneous doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and during the mating period. However, fertility and pregnancy outcomes were not evaluated in mated females. No effects on fertility were observed in female mice that were administered an analogous IL-12/IL­ 23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and during early pregnancy. 13.2. Animal Toxicology and/or Pharmacology In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly for 26 weeks had a bacterial infection. 14. CLINICAL STUDIES 14.1. Adult Plaque Psoriasis Two multicenter, randomized, double-blind, placebo-controlled trials (Ps STUDY 1 and Ps STUDY 2) enrolled a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded from the trials. Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The trials had the same design through Week 28. In both trials, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of ustekinumab. Subjects randomized to ustekinumab received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo at Weeks 0 and 4 crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16. In both trials, subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline PGA score was marked or severe in 44% of subjects in Ps STUDY 1 and 40% of subjects in Ps STUDY 2. Approximately two-thirds of all subjects had received prior phototherapy, 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis, with 56% receiving prior conventional systemic therapy and 43% receiving prior biologic therapy. A total of 28% of subjects had a history of psoriatic arthritis. In both trials, the endpoints were the proportion of subjects who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on Reference ID: 5498000 22 the Physician’s Global Assessment (PGA). The PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician’s overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling. Clinical Response The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 7 below. Table 7: Clinical Outcomes at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2 Ps STUDY 1 Ps STUDY 2 Ustekinumab Ustekinumab Placebo 45 mg 90 mg Placebo 45 mg 90 mg Subjects randomized 255 255 256 410 409 411 PASI 75 response 8 (3%) 171 (67%) 170 (66%) 15 (4%) 273 (67%) 311 (76%) PGA of Cleared or Minimal 10 (4%) 151 (59%) 156 (61%) 18 (4%) 277 (68%) 300 (73%) Examination of age, gender, and race subgroups did not identify differences in response to ustekinumab among these subgroups. In subjects who weighed 100 kg or less, response rates were comparable with both the 45 mg and 90 mg doses; however, in subjects who weighed greater than 100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg dosing (Table 8 below). Table 8: Clinical Outcomes by Weight at Week 12 in Adults with Plaque Psoriasis in Ps STUDY 1 and Ps STUDY 2 Ps STUDY 1 Ps STUDY 2 Ustekinumab Ustekinumab Placebo 45 mg 90 mg Placebo 45 mg 90 mg Subjects randomized 255 255 256 410 409 411 PASI 75 response * <100 kg 4% 74% 65% 4% 73% 78% 6/166 124/168 107/164 12/290 218/297 225/289 >100 kg 2% 54% 68% 3% 49% 71% 2/89 47/87 63/92 3/120 55/112 86/121 PGA of Cleared or Minimal* <100 kg 4% 64% 63% 5% 74% 75% 7/166 108/168 103/164 14/290 220/297 216/289 >100 kg 3% 49% 58% 3% 51% 69% 3/89 43/87 53/92 4/120 57/112 84/121 * Subjects were dosed with trial medication at Weeks 0 and 4. Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re- randomized at Week 40 to either continued dosing of ustekinumab (ustekinumab at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re- randomized to ustekinumab treatment were PASI 75 responders compared with 63% (100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks. Reference ID: 5498000 23 14.2. Pediatric Plaque Psoriasis A multicenter, randomized, double blind, placebo-controlled trial (Ps STUDY 3) enrolled 110 pediatric subjects 12 to 17 years of age with a minimum BSA involvement of 10%, a PASI score greater than or equal to 12, and a PGA score greater than or equal to 3, who were candidates for phototherapy or systemic therapy and whose disease was inadequately controlled by topical therapy. Subjects were randomized to receive placebo (n = 37), the recommended dose of ustekinumab (n = 36), or one-half the recommended dose of ustekinumab (n = 37) by subcutaneous injection at Weeks 0 and 4 followed by dosing every 12 weeks (q12w). The recommended dose of ustekinumab was 0.75 mg/kg for subjects weighing less than 60 kg, 45 mg for subjects weighing 60 kg to 100 kg, and 90 mg for subjects weighing greater than 100 kg. At Week 12, subjects who received placebo were crossed over to receive ustekinumab at the recommended dose or one-half the recommended dose. Of the pediatric subjects, approximately 63% had prior exposure to phototherapy or conventional systemic therapy and approximately 11% had prior exposure to biologics. The endpoints were the proportion of subjects who achieved a PGA score of cleared (0) or minimal (1), PASI 75, and PASI 90 at Week 12. Subjects were followed for up to 60 weeks following first administration of trial agent. Clinical Response The efficacy results at Week 12 for Ps STUDY 3 are presented in Table 9. Table 9: Efficacy Results at Week 12 in Pediatric Subjects 12 to 17 years with Plaque Psoriasis in Ps STUDY 3 Ps STUDY 3 Placebo Ustekinumab* n (%) n (%) N 37 36 PGA PGA of cleared (0) or minimal (1) 2 (5.4%) 25 (69.4%) PASI PASI 75 responders 4 (10.8%) 29 (80.6%) PASI 90 responders 2 (5.4%) 22 (61.1%) * Using the weight-based dosage regimen specified in Table 1. 14.3. Psoriatic Arthritis The safety and efficacy of ustekinumab was assessed in 927 subjects (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled trials in adult subjects 18 years of age and older with active PsA (≥5 swollen joints and ≥5 tender joints) despite nonsteroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Subjects in these trials had a diagnosis of PsA for at least 6 months. Subjects with each subtype of PsA were enrolled, including polyarticular arthritis with the absence of rheumatoid nodules (39%), spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%) and arthritis mutilans (0.5%). Over 70% and 40% of the subjects, respectively, had enthesitis and dactylitis at baseline. Subjects were randomized to receive treatment with ustekinumab 45 mg, 90 mg, or placebo Reference ID: 5498000 24 subcutaneously at Weeks 0 and 4 followed by every 12 weeks (q12w) dosing. Approximately 50% of subjects continued on stable doses of MTX (≤25 mg/week). The primary endpoint was the percentage of subjects achieving ACR 20 response at Week 24. In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the subjects, respectively, had been previously treated with DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-α agent was not allowed. In PsA STUDY 2, 58% (n=180) of the subjects had been previously treated with TNF blocker, of whom over 70% had discontinued their TNF blocker treatment for lack of efficacy or intolerance at any time. Clinical Response In both trials, a greater proportion of subjects achieved ACR 20, ACR 50 and PASI 75 response in the ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 10). ACR 70 responses were also higher in the ustekinumab 45 mg and 90 mg groups, although the difference was only numerical (p=NS) in STUDY 2. Responses were consistent in subjects treated with ustekinumab alone or in combination with methotrexate. Responses were similar in subjects regardless of prior TNFα exposure. Table 10: ACR 20, ACR 50, ACR 70 and PASI 75 responses in PsA STUDY 1 and PsA STUDY 2 at Week 24 PsA STUDY 1 PsA STUDY 2 Ustekinumab Ustekinumab Placebo 45 mg 90 mg Placebo 45 mg 90 mg Number of subjects randomized 206 205 204 104 103 105 ACR 20 response, N (%) 47 (23%) 87 (42%) 101 (50%) 21 (20%) 45 (44%) 46 (44%) ACR 50 response, N (%) 18 (9%) 51 (25%) 57 (28%) 7 (7%) 18 (17%) 24 (23%) ACR 70 response, N (%) 5 (2%) 25 (12%) 29 (14%) 3 (3%) 7 (7%) 9 (9%) Number of subjects with ≥ 3% BSAa 146 145 149 80 80 81 PASI 75 response, N (%) 16 (11%) 83 (57%) 93 (62%) 4 (5%) 41 (51%) 45 (56%) a Number of subjects with ≥ 3% BSA psoriasis skin involvement at baseline Reference ID: 5498000 25 60 ii= ,.-., 40 ;:?_ ~ "' ...... C: Q) ·;::; 20 ro P-. 4 8 12 16 20 24 Weeks1 -0- Placebo (n=206)~ Ustekinumab 45 mg (n=205)~ - TJstekinumah 90 mg (11=204)~ The percent of subjects achieving ACR 20 responses by visit is shown in Figure 1. Figure 1: Percent of subjects achieving ACR 20 response through Week 24 PsA STUDY 1 The results of the components of the ACR response criteria are shown in Table 11. Table 11: Mean change from baseline in ACR components at Week 24 PsA STUDY 1 Ustekinumab Placebo 45 mg 90 mg (N = 206) (N = 205) (N = 204) Number of swollen jointsa Baseline 15 12 13 Mean Change at Week 24 -3 -5 -6 Number of tender jointsb Baseline 25 22 23 Mean Change at Week 24 -4 -8 -9 Subject’s assessment of painc Baseline 6.1 6.2 6.6 Mean Change at Week 24 -0.5 -2.0 -2.6 Subject global assessmentc Baseline 6.1 6.3 6.4 Mean Change at Week 24 -0.5 -2.0 -2.5 Physician global assessmentc Baseline 5.8 5.7 6.1 Mean Change at Week 24 -1.4 -2.6 -3.1 Disability index (HAQ)d Baseline 1.2 1.2 1.2 26 Reference ID: 5498000 Mean Change at Week 24 -0.1 -0.3 -0.4 CRP (mg/dL)e Baseline 1.6 1.7 1.8 Mean Change at Week 24 0.01 -0.5 -0.8 a Number of swollen joints counted (0-66) b Number of tender joints counted (0-68) c Visual analogue scale; 0= best, 10=worst. d Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient’s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity. e CRP: (Normal Range 0.0-1.0 mg/dL) An improvement in enthesitis and dactylitis scores was observed in each ustekinumab group compared with placebo at Week 24. Physical Function Ustekinumab-treated subjects showed improvement in physical function compared to subjects treated with placebo as assessed by HAQ-DI at Week 24. In both trials, the proportion of HAQ- DI responders (≥0.3 improvement in HAQ-DI score) was greater in the ustekinumab 45 mg and 90 mg groups compared to placebo at Week 24. 14.4. Crohn’s Disease Ustekinumab was evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult subjects with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] score of 220 to 450). There were two 8-week intravenous induction trials (CD-1 and CD-2) followed by a 44-week subcutaneous randomized withdrawal maintenance trial (CD- 3) representing 52 weeks of therapy. Subjects in CD-1 had failed or were intolerant to treatment with one or more TNF blockers, while subjects in CD-2 had failed or were intolerant to treatment with immunomodulators or corticosteroids, but never failed treatment with a TNF blocker. Trials CD-1 and CD-2 In trials CD-1 and CD-2, 1409 subjects were randomized, of whom 1368 (CD-1, n=741; CD-2, n=627) were included in the final efficacy analysis. Induction of clinical response (defined as a reduction in CDAI score of greater than or equal to 100 points or CDAI score of less than 150) at Week 6 and clinical remission (defined as a CDAI score of less than 150) at Week 8 were evaluated. In both trials, subjects were randomized to receive a single intravenous administration of ustekinumab at either approximately 6 mg/kg, placebo (see Table 3), or 130 mg (a lower dose than recommended). In trial CD-1, subjects had failed or were intolerant to prior treatment with a TNF blocker: 29% subjects had an inadequate initial response (primary non-responders), 69% responded but subsequently lost response (secondary non-responders) and 36% were intolerant to a TNF blocker. Of these subjects, 48% failed or were intolerant to one TNF blocker and 52% had failed 2 or 3 prior TNF blockers. At baseline and throughout the trial, approximately 46% of the subjects were receiving corticosteroids and 31% of the subjects were receiving immunomodulators (AZA, 6-MP, Reference ID: 5498000 27 MTX). The median baseline CDAI score was 319 in the ustekinumab approximately 6 mg/kg group and 313 in the placebo group. In trial CD-2, subjects had failed or were intolerant to prior treatment with corticosteroids (81% of subjects), at least one immunomodulator (6-MP, AZA, MTX; 68% of subjects), or both (49% of subjects). Additionally, 69% never received a TNF blocker and 31% previously received but had not failed a TNF blocker. At baseline, and throughout the trial, approximately 39% of the subjects were receiving corticosteroids and 35% of the subjects were receiving immunomodulators (AZA, 6-MP, MTX). The median baseline CDAI score was 286 in the ustekinumab and 290 in the placebo group. In these induction trials, a greater proportion of subjects treated with ustekinumab (at the recommended dose of approximately 6 mg/kg dose) achieved clinical response at Week 6 and clinical remission at Week 8 compared to placebo (see Table 12 for clinical response and remission rates). Clinical response and remission were significant as early as Week 3 in ustekinumab-treated subjects and continued to improve through Week 8. Table 12: Induction of Clinical Response and Remission in CD-1* and CD-2** CD-1 CD-2 n = 741 n = 627 Treatment Treatment Placebo Ustekinumab difference Placebo Ustekinumab difference N = 247 † and 95% CI N = 209 † and 95% CI N = 249 N = 209 Clinical Response 53 (21%) 84 (34%)a 12% 60 (29%) 116 (56%)b 27% (100 point), Week 6 Clinical Remission, 18 (7%) 52 (21%)b (4%, 20%) 14% 41 (20%) 84 (40%)b (18%, 36%) 21% Week 8 Clinical Response 50 (20%) 94 (38%)b (8%, 20%) 18% 67 (32%) 121 (58%)b (12%, 29%) 26% (100 point), Week 8 70 Point Response, 75 (30%) 109 (44%)a (10%, 25%) 13% 81 (39%) 135 (65%)b (17%, 35%) 26% Week 6 70 Point Response, 67 (27%) 101 (41%)a (5%, 22%) 13% 66 (32%) 106 (51%)b (17%, 35%) 19% Week 3 (5%, 22%) (10%, 28%) Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI score by at least 100 points or being in clinical remission: 70 point response is defined as reduction in CDAI score by at least 70 points * Patient population consisted of subjects who failed or were intolerant to TNF blocker therapy ** Patient population consisted of subjects who failed or were intolerant to corticosteroids or immunomodulators (e.g., 6-MP, AZA, MTX) and previously received but not failed a TNF blocker or were never treated with a TNF blocker. † Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 3. a 0.001≤ p < 0.01 b p < 0.001 Trial CD-3 The maintenance trial (CD-3), evaluated 388 subjects who achieved clinical response (≥100 point reduction in CDAI score) at Week 8 with either induction dose of ustekinumab in trials CD-1 or CD-2. Subjects were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks or placebo for 44 weeks (see Table 13). Reference ID: 5498000 28 Table 13: Clinical Response and Remission in CD-3 (Week 44; 52 weeks from initiation of the induction dose) 90 mg Treatment Placebo* Ustekinumab difference and N = 131† every 8 weeks 95% CI N = 128† Clinical Remission 47 (36%) 68 (53%)a 17% (5%, 29%) Clinical Response 58 (44%) 76 (59%)b 15% (3%, 27%) Clinical Remission in subjects in remission 36/79 (46%) 52/78 (67%)a 21% (6%, 36%) at the start of maintenance therapy** Clinical remission is defined as CDAI score < 150; Clinical response is defined as reduction in CDAI of at least 100 points or being in clinical remission * The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the start of maintenance therapy. ** Subjects in remission at the end of maintenance therapy who were in remission at the start of maintenance therapy. This does not account for any other time point during maintenance therapy. † Subjects who achieved clinical response to ustekinumab at the end of the induction trial. a p < 0.01 b 0.01≤ p < 0.05 At Week 44, 47% of subjects who received ustekinumab were corticosteroid-free and in clinical remission, compared to 30% of subjects in the placebo group. At Week 0 of trial CD-3, 34/56 (61%) ustekinumab-treated subjects who previously failed or were intolerant to TNF blocker therapies were in clinical remission and 23/56 (41%) of these subjects were in clinical remission at Week 44. In the placebo arm, 27/61 (44%) subjects were in clinical remission at Week 0 while 16/61 (26%) of these subjects were in remission at Week 44. At Week 0 of trial CD-3, 46/72 (64%) ustekinumab-treated subjects who had previously failed immunomodulator therapy or corticosteroids (but not TNF blockers) were in clinical remission and 45/72 (63%) of these subjects were in clinical remission at Week 44. In the placebo arm, 50/70 (71%) of these subjects were in clinical remission at Week 0 while 31/70 (44%) were in remission at Week 44. In the subset of these subjects who were also naïve to TNF blockers, 34/52 (65%) of ustekinumab-treated subjects were in clinical remission at Week 44 as compared to 25/51 (49%) in the placebo arm. Subjects who were not in clinical response 8 weeks after ustekinumab induction were not included in the primary efficacy analyses for trial CD-3; however, these subjects were eligible to receive a 90 mg subcutaneous injection of ustekinumab upon entry into trial CD-3. Of these subjects, 102/219 (47%) achieved clinical response eight weeks later and were followed for the duration of the trial. 14.5. Ulcerative Colitis Ustekinumab was evaluated in two randomized, double-blind, placebo-controlled clinical trials [UC-1 and UC-2 (NCT02407236)] in adult subjects with moderately to severely active ulcerative colitis who had an inadequate response to or failed to tolerate a biologic (i.e., TNF blocker and/or vedolizumab), corticosteroids, and/or 6-MP or AZA therapy. The 8-week intravenous induction trial (UC-1) was followed by the 44-week subcutaneous randomized withdrawal maintenance trial (UC-2) for a total of 52 weeks of therapy. Reference ID: 5498000 29 Disease assessment was based on the Mayo score, which ranged from 0 to 12 and has four subscores that were each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on centrally-reviewed endoscopy, and physician global assessment. Moderately to severely active ulcerative colitis was defined at baseline (Week 0) as Mayo score of 6 to 12, including a Mayo endoscopy subscore ≥2. An endoscopy score of 2 was defined by marked erythema, absent vascular pattern, friability, erosions; and a score of 3 was defined by spontaneous bleeding, ulceration. At baseline, subjects had a median Mayo score of 9, with 84% of subjects having moderate disease (Mayo score 6-10) and 15% having severe disease (Mayo score 11-12). Subjects in these trials may have received other concomitant therapies including aminosalicylates, immunomodulatory agents (AZA, 6-MP, or MTX), and oral corticosteroids (prednisone). Trial UC-1 In UC-1, 961 subjects were randomized at Week 0 to a single intravenous administration of ustekinumab of approximately 6 mg/kg, 130 mg (a lower dose than recommended), or placebo. Subjects enrolled in UC-1 had to have failed therapy with corticosteroids, immunomodulators or at least one biologic. A total of 51% had failed at least one biologic and 17% had failed both a TNF blocker and an integrin receptor blocker. Of the total population, 46% had failed corticosteroids or immunomodulators but were biologic-naïve and an additional 3% had previously received but had not failed a biologic. At induction baseline and throughout the trial, approximately 52% subjects were receiving oral corticosteroids, 28% subjects were receiving immunomodulators (AZA, 6-MP, or MTX) and 69% subjects were receiving aminosalicylates. The primary endpoint was clinical remission at Week 8. Clinical remission with a definition of: Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0 (no rectal bleeding), and Mayo endoscopy subscore of 0 or 1 (Mayo endoscopy subscore of 0 defined as normal or inactive disease and Mayo subscore of 1 defined as presence of erythema, decreased vascular pattern and no friability) is provided in Table 14. The secondary endpoints were clinical response, endoscopic improvement, and histologic­ endoscopic mucosal improvement. Clinical response with a definition of (≥ 2 points and ≥ 30% decrease in modified Mayo score, defined as 3-component Mayo score without the Physician’s Global Assessment, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1), endoscopic improvement with a definition of Mayo endoscopy subscore of 0 or 1, and histologic-endoscopic mucosal improvement with a definition of combined endoscopic improvement and histologic improvement of the colon tissue [neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue]) are provided in Table 14. In UC-1, a significantly greater proportion of subjects treated with ustekinumab (at the recommended dose of approximately 6 mg/kg dose) were in clinical remission and response and achieved endoscopic improvement and histologic-endoscopic mucosal improvement compared to placebo (see Table 14). Reference ID: 5498000 30 Table 14: Proportion of Subjects Meeting Efficacy Endpoints at Week 8 in UC-1 Endpoint Placebo N = 319 Ustekinumab† N = 322 Treatment difference and 97.5% CI a N % N % Clinical Remission* 22 7% 62 19% 12% (7%, 18%) b Bio-naïve⸸ 14/151 9% 36/147 24% Prior biologic failure 7/161 4% 24/166 14% Endoscopic Improvement§ 40 13% 80 25% 12% (6%, 19%) b Bio-naïve⸸ 28/151 19% 43/147 29% Prior biologic failure 11/161 7% 34/166 20% Clinical Response† 99 31% 186 58% 27% (18%, 35%) b Bio-naïve⸸ 55/151 36% 94/147 64% Prior biologic failure 42/161 26% 86/166 52% Histologic-Endoscopic Mucosal Improvement‡ 26 8% 54 17% 9% (3%, 14%) b Bio-naïve⸸ 19/151 13% 30/147 20% Prior biologic failure 6/161 4% 21/166 13% † Infusion dose of ustekinumab using the weight-based dosage regimen specified in Table 3. ⸸ An additional 7 subjects on placebo and 9 subjects on ustekinumab (6 mg/kg) had been exposed to, but had not failed, biologics. * Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). § Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). † Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥30% and ≥2 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. ‡ Histologic-endoscopic mucosal improvement was defined as combined endoscopic improvement (Mayo endoscopy subscore of 0 or 1) and histologic improvement of the colon tissue (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue). a Adjusted treatment difference (97.5% CI) b p < 0.001 The relationship of histologic-endoscopic mucosal improvement, as defined in UC-1, at Week 8 to disease progression and long-term outcomes was not evaluated during UC-1. Rectal Bleeding and Stool Frequency Subscores Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in ustekinumab-treated subjects. Trial UC-2 The maintenance trial (UC-2) evaluated 523 subjects who achieved clinical response 8 weeks following the intravenous administration of either induction dose of ustekinumab in UC-1. These subjects were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, or every 12 weeks (a lower dose than recommended), or placebo for 44 weeks. The primary endpoint was the proportion of subjects in clinical remission at Week 44. The secondary endpoints included the proportion of subjects maintaining clinical response at Week 44, the proportion of subjects with endoscopic improvement at Week 44, the proportion of subjects Reference ID: 5498000 31 with corticosteroid-free clinical remission at Week 44, and the proportion of subjects maintaining clinical remission at Week 44 among subjects who achieved clinical remission 8 weeks after induction. Results of the primary and secondary endpoints at Week 44 in subjects treated with ustekinumab at the recommended dosage (90 mg every 8 weeks) compared to the placebo are shown in Table 15. Table 15: Efficacy Endpoints of Maintenance at Week 44 in UC-2 (52 Weeks from Initiation of the Induction Dose) Endpoint Placebo* N = 175† 90 mg Ustekinumab every 8 weeks N = 176 Treatment difference and 95% CI N % N % Clinical Remission** 46 26% 79 45% 19% (9%, 28%) a Bio-naïve⸸ 30/84 36% 39/79 49% Prior biologic failure 16/88 18% 37/91 41% Maintenance of Clinical Response at Week 44† 84 48% 130 74% 26% (16%, 36%) a Bio-naïve⸸ 49/84 58% 62/79 78% Prior biologic failure 35/88 40% 64/91 70% Endoscopic Improvement§ 47 27% 83 47% 20% (11%, 30%) a Bio-naïve⸸ 29/84 35% 42/79 53% Prior biologic failure 18/88 20% 38/91 42% Corticosteroid-free Clinical Remission‡ 45 26% 76 43% 17% (8%, 27%) a Bio-naïve⸸ 30/84 36% 38/79 48% Prior biologic failure 15/88 17% 35/91 38% Maintenance of Clinical Remission at Week 44 in subjects who achieved clinical remission 8 weeks after induction 18/50 36% 27/41 66% 31% (12%, 50%) b Bio-naïve⸸ 12/27 44% 14/20 70% Prior biologic failure 6/23 26% 12/18 67% ⸸ An additional 3 subjects on placebo and 6 subjects on ustekinumab had been exposed to, but had not failed, biologics. * The placebo group consisted of subjects who were in response to ustekinumab and were randomized to receive placebo at the start of maintenance therapy. ** Clinical remission was defined as Mayo stool frequency subscore of 0 or 1, Mayo rectal bleeding subscore of 0, and Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). † Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥30% and ≥2 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. § Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 (modified so that 1 does not include friability). ‡ Corticosteroid-free clinical remission was defined as subjects in clinical remission and not receiving corticosteroids at Week 44. a p =<0.001 b p=0.004 Reference ID: 5498000 32 Other Endpoints Week 16 Responders to Ustekinumab Induction Subjects who were not in clinical response 8 weeks after induction with ustekinumab in UC-1 were not included in the primary efficacy analyses for trial UC-2; however, these subjects were eligible to receive a 90 mg subcutaneous injection of ustekinumab at Week 8. Of these subjects, 55/101 (54%) achieved clinical response eight weeks later (Week 16) and received ustekinumab 90 mg subcutaneously every 8 weeks during the UC-2 trial. At Week 44, there were 97/157 (62%) subjects who maintained clinical response and there were 51/157 (32%) who achieved clinical remission. Histologic-Endoscopic Mucosal Improvement at Week 44 The proportion of subjects achieving histologic-endoscopic mucosal improvement during maintenance treatment in UC-2 was 75/172 (44%) among subjects on ustekinumab and 40/172 (23%) in subjects on placebo at Week 44. The relationship of histologic-endoscopic mucosal improvement, as defined in UC-2, at Week 44 to progression of disease or long-term outcomes was not evaluated in UC-2. Endoscopic Normalization Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0. At Week 8 in UC-1, endoscopic normalization was achieved in 25/322 (8%) of subjects treated with ustekinumab and 12/319 (4%) of subjects in the placebo group. At Week 44 of UC-2, endoscopic normalization was achieved in 51/176 (29%) of subjects treated with ustekinumab and in 32/175 (18%) of subjects in placebo group. 15. REFERENCES 1 Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 6.6.2 Regs Research Data, Nov 2009 Sub (1973­ 2007) - Linked To County Attributes - Total U.S., 1969-2007 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2010, based on the November 2009 submission. 16. HOW SUPPLIED/STORAGE AND HANDLING STEQEYMA (ustekinumab-stba) injection is a sterile, preservative-free, colorless to pale yellow solution and may contain a few small translucent or white particles. It is supplied as individually packaged, single-dose prefilled syringes or single-dose vials. For Subcutaneous Use Prefilled Syringes • 45 mg/0.5 mL (NDC 72606-027-01) • 90 mg/mL (NDC 72606-028-01) Reference ID: 5498000 33 Each prefilled syringe is equipped with a 27-gauge fixed ½ inch needle, a needle safety guard, and a needle cover. For Intravenous Infusion Single-dose Vial • 130 mg/26 mL (5 mg/mL) (NDC 72606-029-01) Storage and Stability Store STEQEYMA vials and prefilled syringes refrigerated between 2ºC to 8ºC (36ºF to 46ºF). Store STEQEYMA vials upright. Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. If needed, individual vials and prefilled syringes may be stored at room temperature up to 30°C (86°F) for a maximum single period of up to 15 days in the original carton to protect from light. Record the date when the vial or the prefilled syringe is first removed from the refrigerator on the carton in the space provided. Once a vial or a syringe has been stored at room temperature, do not return to the refrigerator. Discard the vial or syringe if not used within 15 days at room temperature storage. Do not use STEQEYMA after the expiration date on the carton or on the vial or the prefilled syringe. 17. PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Infections Inform patients that STEQEYMA may lower the ability of their immune system to fight infections and to contact their healthcare provider immediately if they develop any signs or symptoms of infection [see Warnings and Precautions (5.1)]. Malignancies Inform patients of the risk of developing malignancies while receiving STEQEYMA [see Warnings and Precautions (5.4)]. Hypersensitivity Reactions • Advise patients to seek immediate medical attention if they experience any signs or symptoms of serious hypersensitivity reactions and discontinue STEQEYMA [see Warnings and Precautions (5.5)]. Reference ID: 5498000 34 Posterior Reversible Encephalopathy Syndrome (PRES) Inform patients to immediately contact their healthcare provider if they experience signs and symptoms of PRES (which may include headache, seizures, confusion, or visual disturbances) [see Warnings and Precautions (5.6)]. Immunizations Inform patients that STEQEYMA can interfere with the usual response to immunizations and that they should avoid live vaccines [see Warnings and Precautions (5.7)]. Administration Instruct patients to follow sharps disposal recommendations, as described in the Instructions for Use. STEQEYMA® (ustekinumab-stba) Manufactured by: CELLTRION, Inc. 23, Academy-ro, Yeonsu-gu, Incheon, 22014, Republic of Korea US License No.: 1996 Distributed by: CELLTRION USA, Inc. One Evertrust Plaza Suite 1207, Jersey City, New Jersey, 07302, USA Reference ID: 5498000 35 MEDICATION GUIDE STEQEYMA (ste-qey-ma) (ustekinumab-stba) injection, for subcutaneous or intravenous use What is the most important information I should know about STEQEYMA? STEQEYMA is a medicine that affects your immune system. STEQEYMA can increase your risk of having serious side effects, including: Serious infections. STEQEYMA may lower the ability of your immune system to fight infections and may increase your risk of infections. Some people have serious infections while taking ustekinumab products, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses. Some people have to be hospitalized for treatment of their infection. • Your doctor should check you for TB before starting STEQEYMA. • If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with STEQEYMA and during treatment with STEQEYMA. • Your doctor should watch you closely for signs and symptoms of TB while you are being treated with STEQEYMA. You should not start taking STEQEYMA if you have any kind of infection unless your doctor says it is okay. Before starting STEQEYMA, tell your doctor if you: • think you have an infection or have symptoms of an infection such as: o fever, sweat, or chills o weight loss o muscle aches o warm, red, or painful skin or sores on your body o cough o diarrhea or stomach pain o shortness of breath o burning when you urinate or urinate more often than normal o blood in phlegm o feel very tired • are being treated for an infection or have any open cuts. • get a lot of infections or have infections that keep coming back. • have TB, or have been in close contact with someone with TB. After starting STEQEYMA, call your doctor right away if you have any symptoms of an infection (see above). These may be signs of infections such as chest infections, or skin infections or shingles that could have serious complications. STEQEYMA can make you more likely to get infections or make an infection that you have worse. People who have a genetic problem where the body does not make any of the proteins interleukin 12 (IL-12) and interleukin 23 (IL-23) are at a higher risk for certain serious infections. These infections can spread throughout the body and cause death. People who take STEQEYMA may also be more likely to get these infections. Cancers. STEQEYMA may decrease the activity of your immune system and increase your risk for certain types of cancers. Tell your doctor if you have ever had any type of cancer. Some people who are receiving ustekinumab products and have risk factors for skin cancer have developed certain types of skin cancers. During your treatment with STEQEYMA, tell your doctor if you develop any new skin growths. Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a rare condition that affects the brain and can cause death. The cause of PRES is not known. If PRES is found early and treated, most people recover. Tell your doctor right away if you have any new or worsening medical problems including: o headache o confusion o seizures o vision problems What is STEQEYMA? STEQEYMA is a prescription medicine used to treat: • adults and children 6 years and older with moderate or severe psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills). • adults and children 6 years and older with active psoriatic arthritis. • adults 18 years and older with moderately to severely active Crohn’s disease. • adults 18 years and older with moderately to severely active ulcerative colitis. It is not known if STEQEYMA is safe and effective in children less than 6 years of age. Do not take STEQEYMA if you are allergic to ustekinumab products or any of the ingredients in STEQEYMA. See the end of this Medication Guide for a complete list of ingredients in STEQEYMA. Reference ID: 5498000 Before you receive STEQEYMA, tell your doctor about all of your medical conditions, including if you: • have any of the conditions or symptoms listed in the section “What is the most important information I should know about STEQEYMA?” • ever had an allergic reaction to ustekinumab products. Ask your doctor if you are not sure. • have recently received or are scheduled to receive an immunization (vaccine). People who take STEQEYMA should not receive live vaccines. Tell your doctor if anyone in your house needs a live vaccine. The viruses used in some types of live vaccines can spread to people with a weakened immune system, and can cause serious problems. You should not receive the BCG vaccine during the one year before receiving STEQEYMA or one year after you stop receiving STEQEYMA. • have any new or changing lesions within psoriasis areas or on normal skin. • are receiving or have received allergy shots, especially for serious allergic reactions. Allergy shots may not work as well for you during treatment with STEQEYMA. STEQEYMA may also increase your risk of having an allergic reaction to an allergy shot. • receive or have received phototherapy for your psoriasis. • are pregnant or plan to become pregnant. It is not known if STEQEYMA can harm your unborn baby. You and your doctor should decide if you will receive STEQEYMA. See “What should I avoid while using STEQEYMA?” • received STEQEYMA while you were pregnant. It is important that you tell your baby’s healthcare provider before any vaccinations are given to your baby. • are breastfeeding or plan to breastfeed. STEQEYMA can pass into your breast milk. • Talk to your doctor about the best way to feed your baby if you receive STEQEYMA. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I use STEQEYMA? • Use STEQEYMA exactly as your doctor tells you to. • Adults with Crohn’s disease and ulcerative colitis will receive the first dose of STEQEYMA through a vein in the arm (intravenous infusion) in a healthcare facility by a healthcare provider. It takes at least 1 hour to receive the full dose of medicine. You will then receive STEQEYMA as an injection under the skin (subcutaneous injection) 8 weeks after the first dose of STEQEYMA, as described below. • Adults with psoriasis or psoriatic arthritis, and children 6 years and older with psoriasis or psoriatic arthritis will receive STEQEYMA as an injection under the skin (subcutaneous injection) as described below. • Injecting STEQEYMA under your skin o STEQEYMA is intended for use under the guidance and supervision of your doctor. In children 6 years and older, it is recommended that STEQEYMA be administered by a healthcare provider. If your doctor decides that you or a caregiver may give your injections of STEQEYMA at home, you should receive training on the right way to prepare and inject STEQEYMA. Your doctor will determine the right dose of STEQEYMA for you, the amount for each injection, and how often you should receive it. Do not try to inject STEQEYMA yourself until you or your caregiver have been shown how to inject STEQEYMA by your doctor or nurse. o Inject STEQEYMA under the skin (subcutaneous injection) in your upper arms, buttocks, upper legs (thighs) or stomach area (abdomen). o Do not give an injection in an area of the skin that is tender, bruised, red or hard. o Use a different injection site each time you use STEQEYMA. o If you inject more STEQEYMA than prescribed, call your doctor right away. o Be sure to keep all of your scheduled follow-up appointments. Read the detailed Instructions for Use at the end of this Medication Guide for instructions about how to prepare and inject a dose of STEQEYMA, and how to properly throw away (dispose of) used needles and syringes. The syringe, needle and vial must never be re-used. After the rubber stopper is punctured, STEQEYMA can become contaminated by harmful bacteria which could cause an infection if re-used. Therefore, throw away any unused portion of STEQEYMA. What should I avoid while using STEQEYMA? You should not receive a live vaccine while taking STEQEYMA. See “Before you receive STEQEYMA, tell your doctor about all of your medical conditions, including if you:” Reference ID: 5498000 What are the possible side effects of STEQEYMA? STEQEYMA may cause serious side effects, including: • See “What is the most important information I should know about STEQEYMA?” • Serious allergic reactions. Serious allergic reactions can occur with STEQEYMA. Stop using STEQEYMA and get medical help right away if you have any of the following symptoms of a serious allergic reaction: o feeling faint o chest tightness o swelling of your face, eyelids, tongue, or throat o skin rash • Lung inflammation. Cases of lung inflammation have happened in some people who receive ustekinumab products, and may be serious. These lung problems may need to be treated in a hospital. Tell your doctor right away if you develop shortness of breath or a cough that doesn’t go away during treatment with STEQEYMA. Common side effects of STEQEYMA include: • nasal congestion, sore throat, and runny nose • redness at the injection site • upper respiratory infections • vaginal yeast infections • fever • urinary tract infections • headache • sinus infection • tiredness • bronchitis • itching • diarrhea • nausea and vomiting • stomach pain These are not all of the possible side effects of STEQEYMA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to CELLTRION USA, Inc. at 1-800-560-9414. How should I store STEQEYMA? • Store STEQEYMA vials and prefilled syringes in a refrigerator between 36°F to 46°F (2°C to 8°C). • Store STEQEYMA vials standing up straight. • Store STEQEYMA in the original carton to protect it from light until time to use it. • Do not freeze STEQEYMA. • Do not shake STEQEYMA. If needed, individual STEQEYMA vials and prefilled syringes may also be stored at room temperature up to 86ºF (30°C) for a maximum single period of up to 15 days in the original carton to protect from light. Record the date when the vial or the prefilled syringe is first removed from the refrigerator on the carton in the space provided. Once a vial or a syringe has been stored at room temperature, it should not be returned to the refrigerator. Discard the vial or syringe if not used within 15 days at room temperature storage. Do not use STEQEYMA after the expiration date on the carton or on the vial or the prefilled syringe. Keep STEQEYMA and all medicines out of the reach of children. General information about the safe and effective use of STEQEYMA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use STEQEYMA for a condition for which it was not prescribed. Do not give STEQEYMA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about STEQEYMA that was written for health professionals. What are the ingredients in STEQEYMA? Active ingredient: ustekinumab-stba Inactive ingredients: Single-dose prefilled syringe for subcutaneous use contains histidine, L-histidine monohydrochloride monohydrate, polysorbate 80, sucrose, and Water for Injection. Single-dose vial for intravenous infusion contains edetate disodium, histidine, L-histidine monohydrochloride monohydrate, methionine, polysorbate 80, sucrose, and Water for Injection. Manufactured by: CELLTRION, Inc. 23, Academy-ro, Yeonsu-gu, Incheon, 22014, Republic of Korea, US License No. 1996 Distributed by: CELLTRION USA, Inc. One Evertrust Plaza Suite 1207, Jersey City, New Jersey, 07302, USA For more information go to www.steqeyma.com or call 1-888-804-3433. This Medication Guide has been approved by the U.S. Food and Drug Administration. Approved: 12/2024 Reference ID: 5498000 INSTRUCTIONS FOR USE STEQEYMA (ste-qey-ma) (ustekinumab-stba) injection, for subcutaneous use Instructions for injecting STEQEYMA using a prefilled syringe. This Instructions for Use contains information on how to inject STEQEYMA. Read and follow this Instructions for Use before you start using STEQEYMA. Your doctor or nurse should show you how to prepare and give your injection of STEQEYMA the right way. If you cannot give yourself the injection: • ask your doctor or nurse to help you, or • ask someone who has been trained by a doctor or nurse to give your injections. Do not try to inject STEQEYMA yourself until you have been shown how to inject STEQEYMA by your doctor, nurse or health professional. STEQEYMA prefilled syringes are available in 2 dose strengths (see Figure A). These instructions can be used for both dose strengths. 45 mg/0.5 mL Prefilled Syringe 90 mg/mL Prefilled Syringe Figure A Important Information • Before you start, check the carton to make sure that it is the right dose. You will have either 45 mg or 90 mg as prescribed by your doctor. o If your dose is 45 mg, you will receive one 45 mg prefilled syringe. o If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself two injections, one right after the other. • Children 12 years of age and older with psoriasis who weigh 132 pounds or more may use a prefilled syringe. • Do not use the prefilled syringe if the liquid is discolored, cloudy, or has large particles. Get a new prefilled syringe. • Do not shake the prefilled syringe at any time. Shaking your prefilled syringe may damage your STEQEYMA medicine. If your prefilled syringe has been shaken, do not use it. Get a new prefilled syringe. • To reduce the risk of accidental needle sticks, each prefilled syringe has a needle guard that is automatically activated to cover the needle after you have given your injection. Do not pull back on the plunger rod at any time. Storing STEQEYMA • Store the STEQEYMA prefilled syringe in a refrigerator between 36°F to 46°F (2°C to 8ºC). • Store STEQEYMA in the original carton to protect it from light until time to use it. • Do not freeze STEQEYMA. • Do not shake STEQEYMA. • If needed, individual STEQEYMA prefilled syringes may be stored at room temperature up to 86℉ (30℃) for a maximum single period of up to 15 days in the original carton to protect from light. Record the date when the prefilled syringe is first removed from the refrigerator on the carton in the space provided. When a syringe has been stored at room temperature, it should not be returned to the refrigerator. Throw away (discard) the syringe if Reference ID: 5498000 Before Use After Use Finger Flange Viewingi Window l!J:1=1'11---- Needle Needle Guard f----Needle -Cap-----0 not used within 15 days at room temperature storage. Do not use STEQEYMA after the expiration date on the carton or the prefilled syringe. • Keep STEQEYMA and all medicines out of the reach of children. Parts of the Prefilled Syringe (see Figure B) Figure B Preparing to Inject STEQEYMA Carton containing Cotton ball prefilled syringe or gauze and alcohol swab Adhesive Sharps disposal bandage container Figure C 1. Gather the supplies for the injection 1.a. Prepare a clean, flat surface, such as a table or counter top, in a well-lit area. 1.b. Take the carton(s) containing the prefilled syringe(s) needed to administer your prescribed dose out of the refrigerator. Each STEQEYMA carton contains 1 prefilled syringe. Note: Depending on the dose prescribed to you by your healthcare provider you may need to prepare 1 or more prefilled syringes and inject the contents of them all. 1.c. Make sure you have the following supplies (see Figure C) - Carton containing prefilled syringe Not included in the carton: - Cotton ball or gauze - Adhesive bandage - FDA-cleared sharps disposal container - Alcohol swab Figure D 2. Check the expiration date on the carton (see Figure D). • Do not use it if the expiration date has passed. If the expiration date has passed, safely throw away (dispose of) the carton in an FDA-cleared sharps disposal container (see step 13. Throw away (dispose of) STEQEYMA). Reference ID: 5498000 Figure E 30 minutes 3. Wait 30 minutes. 3.a. Open the carton. Gripping from the syringe body, lift the prefilled syringe from the carton. 3.b. Leave the prefilled syringe outside of the carton at room temperature 68°F to 77°F (20°C to 25°C) for 30 minutes to allow it to warm up (see Figure E). • Do not warm the prefilled syringe using heat sources such as hot water or a microwave. • If the prefilled syringe does not reach room temperature, this could cause the injection to feel uncomfortable and make it hard to push the plunger. Figure F 4. Wash your hands. 4.a. Wash your hands with soap and water and dry them thoroughly (see Figure F). Figure G 5. Inspect the prefilled syringe. 5.a. Look at the prefilled syringe and make sure you have the correct medicine (STEQEYMA) and dosage. 5.b. Look at the prefilled syringe and make sure it is not cracked or damaged. 5.c. Check the expiration date on the label of the prefilled syringe (see Figure G). • Do not use if the expiration date has passed. Figure H 6. Inspect the medicine. 6.a. Look at the medicine and make sure that the liquid is clear to slightly opalescent and colorless to pale yellow. (see Figure H). • Do not use the prefilled syringe if the liquid is discolored, cloudy, or has large particles. Get a new prefilled syringe. • You may see air bubbles in the liquid. This is normal. Reference ID: 5498000 D = Caregiver ONLY D = Self-injection and Caregiver Figure I 7. Choose an injection site (see Figure I). 7.a. Choose an injection site around your stomach area (abdomen), buttocks, upper legs (thighs). If a caregiver is giving you the injection, the outer area of the upper arms may also be used (see Figure I). • Use a different injection site for each injection. • Do not give an injection in an area of the skin that is tender, bruised, red or hard. Figure J 8. Clean the injection site. 8.a. Clean the skin with an alcohol swab where you plan to give your injection (see Figure J). • Do not touch this area again before giving the injection. Let your skin dry before injecting. • Do not fan or blow on the clean area. Reference ID: 5498000 r Injecting STEQEYMA Figure K 9. Remove the cap. 9.a. Remove the needle cap when you are ready to inject your STEQEYMA by holding the body of the prefilled syringe in one hand between the thumb and index fingers (see Figure K). • Do not hold the plunger while removing the cap. • You may see a drop of liquid at the tip of the needle. This is normal. 9.b. Throw away (dispose of) the cap right away in an FDA-cleared sharps disposal container (see step 13. Throw away (dispose of) STEQEYMA). • Do not re-cap the prefilled syringe. • Do not touch the needle. Doing so may result in a needle stick injury. • Do not use the prefilled syringe if it has been dropped without the needle cover in place. Call your doctor, nurse or health professional for further instructions. Figure L 10.Insert the prefilled syringe into the injection site. 10.a. Hold the body of the prefilled syringe in one hand between the thumb and index fingers (see Figure L). 10.b. Gently pinch a fold of skin at the injection site with one hand. Note: Pinching the skin is important to make sure that you inject under the skin (into the fatty area) but not any deeper (into muscle). 10.c. With a quick and dart-like motion, insert the needle completely into the fold of skin at a 45-degree angle (see Figure L). • Do not pull back on the plunger rod at any time. Figure M 11.Give the injection. 11.a. After the needle is inserted, release the pinch. 11.b. Inject all of the liquid by using your thumb to push the plunger all the way down (see Figure M). • If the plunger is not fully pressed, the needle guard will not extend to cover the needle when it is removed. Figure N 12.Remove the prefilled syringe from the injection site. 12.a. After the prefilled syringe is empty, slowly lift your thumb from the plunger rod until the needle is completely covered by the needle guard (see Figure N). • If the needle is not covered, proceed carefully to throw away (dispose of) the syringe (see step 13. Throw away (dispose of) STEQEYMA). • Some bleeding may occur. This is normal (see step 14. Care for the injection site). • Do not rub the injection site. If your dose is 90 mg, you will receive either one 90 mg prefilled syringe or two 45 mg prefilled syringes. If you receive two 45 mg prefilled syringes for a 90 mg dose, you will need to give yourself a second injection right after Reference ID: 5498000 the first. Repeat Steps 1 to 12 for the second injection using a new syringe. Choose a different site for the second injection. After the Injection 13. Throw away (dispose of) STEQEYMA. 13.a. Put the used prefilled syringe in an FDA-cleared sharps disposal container right away after use (see Figure O). • STEQEYMA prefilled syringe is a single-dose syringe and should not be used again. • Do not throw away (dispose of) the prefilled syringe in your household trash. • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: - made of a heavy-duty plastic, - can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, Figure O - upright and stable during use, - leak-resistant, and - properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of it. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. • Do not recycle your used sharps disposal container. 14. Care for the injection site. 14.a. If some bleeding occurs, treat the injection site by gently pressing, not rubbing, a cotton ball or gauze to the site and apply an adhesive bandage if needed. If you have any questions about using your STEQEYMA prefilled syringe, please call your healthcare provider or Company at 1-888-804-3433. Manufactured by: CELLTRION, Inc. 23, Academy-ro, Yeonsu-gu, Incheon, 22014, Republic of Korea, US License No. 1996 Distributed by: CELLTRION USA, Inc. One Evertrust Plaza Suite 1207, Jersey City, New Jersey, 07302, USA This Instructions for Use has been approved by the U.S. Food and Drug Administration. Approved: 12/2024 Reference ID: 5498000
custom-source
2025-02-12T15:47:51.034266
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ENSACOVE safely and effectively. See full prescribing information for ENSACOVE. ENSACOVETM (ensartinib) capsules, for oral use Initial U.S. Approval: 2024 -----------------------------INDICATIONS AND USAGE-------------------------­ ENSACOVE is a kinase inhibitor indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) who have not previously received an ALK-inhibitor. (1, 2.1) ------------------------DOSAGE AND ADMINISTRATION---------------------­ • Select patients with ALK-positive locally advanced or metastatic NSCLC for treatment with ENSACOVE. (2.1) • Prior to initiating ENSACOVE, evaluate liver function tests and fasting blood glucose. (2.2) • Recommended dosage: 225 mg orally once daily with or without food until disease progression or unacceptable toxicity. (2.3) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ Capsules: 25 mg and 100 mg of ensartinib (3) -------------------------------CONTRAINDICATIONS-----------------------------­ Hypersensitivity reaction to ENSACOVE, FD&C Yellow No. 5 (tartrazine), or to any of its components. (4) ------------------------WARNINGS AND PRECAUTIONS----------------------­ • Interstitial Lung Disease (ILD)/Pneumonitis: Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis. Permanently discontinue in patients with ILD/pneumonitis. (5.1) • Hepatotoxicity: Monitor liver function tests during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity. (5.2) • Dermatologic Adverse Reaction: Monitor for dermatologic adverse reactions during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity. (5.3) • Bradycardia: Monitor heart rate regularly during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity. (5.4) • Hyperglycemia: Monitor serum glucose periodically during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity. (5.5) • Visual Disturbances: Advise patients to report visual symptoms during treatment with ENSACOVE. Withhold ENSACOVE and obtain ophthalmologic evaluation, then reduce the dose or permanently discontinue ENSACOVE. (5.6) • Increased Creatine Phosphokinase (CPK): Monitor CPK periodically during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity. (5.7) • Hyperuricemia: Monitor uric acid periodically during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity. (5.8) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (5.9) -------------------------------ADVERSE REACTIONS-----------------------------­ • Most common adverse reactions (incidence ≥20%) were rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, and pyrexia. (6.1) • Most common Grade 3-4 laboratory abnormality (incidence ≥2%) were increased uric acid, decreased lymphocytes, increased alanine aminotransferase, decreased phosphate, increased gamma glutamyl transferase, increased magnesium, increased amylase, decreased sodium, increased glucose, decreased hemoglobin, increased bilirubin, decreased potassium, and increased creatine phosphokinase. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Xcovery Holdings, Inc. at (866) 367-2268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------­ • Moderate or Strong CYP3A Inhibitors: Avoid concomitant use with ENSACOVE. (7.1) • Moderate or Strong CYP3A Inducers: Avoid concomitant use with ENSACOVE. (7.1) • P-gp Inhibitor: Avoid concomitant use with ENSACOVE. (7.1) --------------------------USE IN SPECIFIC POPULATIONS--------------------­ • Lactation: Advise not to breastfeed. (8.2) • Severe Hepatic Impairment: Avoid use of ENSACOVE in patients with severe hepatic impairment. (8.6) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Recommended Testing and Advice Prior to Initiating ENSACOVE 2.3 Recommended Dosage 2.4 Dosage Modifications for Adverse Reactions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Interstitial Lung Disease (ILD)/Pneumonitis 5.2 Hepatotoxicity 5.3 Dermatologic Adverse Reactions 5.4 Bradycardia 5.5 Hyperglycemia 5.6 Visual Disturbances 5.7 Increased Creatine Phosphokinase 5.8 Hyperuricemia 5.9 Embryo-Fetal Toxicity 5.10 FD&C Yellow No. 5 (Tartrazine) 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on ENSACOVE 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 TKI-naive ALK-Positive Locally Advanced or Metastatic NSCLC 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed Reference ID: 5498877 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE ENSACOVE is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) who have not previously received an ALK-inhibitor. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients for the treatment of locally advanced or metastatic NSCLC with ENSACOVE based on the presence of ALK rearrangement(s) in tumor specimens [see Clinical Studies (14.1)]. An FDA-approved test to detect ALK rearrangements for selecting patients for treatment with ENSACOVE is not currently available. 2.2 Recommended Testing and Advice Prior to Initiating ENSACOVE Prior to initiating ENSACOVE, evaluate liver function tests [see Warnings and Precautions (5.2)] and fasting blood glucose [see Warnings and Precautions (5.5)]. 2.3 Recommended Dosage The recommended dosage of ENSACOVE is 225 mg orally once daily, with or without food [see Clinical Pharmacology (12.3)], until disease progression or unacceptable toxicity. Swallow capsules whole, do not crush or chew. Do not open or dissolve the contents of the capsule. Take ENSACOVE at the same time each day. Missed dose If a dose is missed, then take the missed dose as soon as possible unless the next dose is due within 12 hours. Do not take 2 doses on the same day. Vomiting If vomiting occurs after taking a dose, do not take an additional dose and take the next dose at its scheduled time. 2.4 Dosage Modification for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 1. Reference ID: 5498877 2 Table 1: Recommended Dose Reductions for Adverse Reactions Dosage Reduction Recommended Dose and Schedule First 200 mg orally once daily Second 150 mg orally once daily Permanently discontinue ENSACOVE if patients are unable to tolerate 150 mg orally once daily. Once the dose has been reduced for adverse reactions, do not subsequently increase the dose of ENSACOVE. The recommended dosage modifications for the management of adverse reactions are provided in Table 2. Table 2: Recommended ENSACOVE Dosage Modifications and Management for Adverse Reactions Adverse Reaction Severity* ENSACOVE Dose Modification and Management for Adverse Reactions Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.1)] Any Grade Permanently discontinue ENSACOVE. Hepatotoxicity [see Warnings and Grade 3 or 4 elevation (greater than 5 times ULN) of either ALT or AST with concurrent total bilirubin elevation less than or equal to 2 times ULN • Withhold ENSACOVE until recovery to Grade ≤1 (≤3 times ULN) or to baseline. • Resume ENSACOVE at reduced dose as per Table 1. Precautions (5.2)] Grade 2 to 4 elevation (greater than 3 times ULN) of either ALT or AST with concurrent total bilirubin Permanently discontinue ENSACOVE. elevation greater than 2 times ULN in the absence of cholestasis or hemolysis Grade 1 Consider topical corticosteroids. Dermatologic Adverse Reactions [see Warnings and Precautions (5.3)] Grade 2 • Administer topical corticosteroids. • If not improved in ≤7 days after initiation of topical corticosteroids, administer oral corticosteroids. • If not improved in ≤7 days after initiation of oral corticosteroids, withhold ENSACOVE until recovery to Grade ≤1. Reference ID: 5498877 3 Adverse Reaction Severity* ENSACOVE Dose Modification and Management for Adverse Reactions • Resume ENSACOVE at reduced dose as per Table 1. Grade 3 • Withhold ENSACOVE. Administer topical corticosteroids. • If not improved after 7 days of initiation of topical corticosteroids, administer oral corticosteroids. • Resume ENSACOVE at reduced dose as per Table 1 upon improvement to Grade ≤1. Grade 4 • Permanently discontinue ENSACOVE. • Administer systemic corticosteroids and consider antibiotic use. Bradycardia (HR less than 60 bpm) [see Warnings and Precautions (5.4)] Symptomatic bradycardia • Withhold ENSACOVE until recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above. • If a concomitant medication known to cause bradycardia is identified and discontinued or dose-adjusted, resume ENSACOVE at same dose upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above. • If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume ENSACOVE at reduced dose as per Table 1 upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above. Bradycardia with life- threatening consequences, urgent intervention indicated • Permanently discontinue ENSACOVE if no contributing concomitant medication is identified. • If contributing concomitant medication is identified and discontinued or dose- adjusted, resume ENSACOVE at reduced dose as per Table 1 upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. Reference ID: 5498877 4 Adverse Reaction Severity* ENSACOVE Dose Modification and Management for Adverse Reactions • For recurrence, permanently discontinue ENSACOVE. Hyperglycemia [see Warnings and Precautions (5.5)] Grade 3 (greater than 250 mg/dL) despite optimal anti­ hyperglycemic therapy OR Grade 4 • Withhold ENSACOVE until hyperglycemia is adequately controlled, then resume ENSACOVE at reduced dose as per Table 1. • If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue ENSACOVE. Visual Disturbance [see Warnings and Grade 2 or 3 Withhold ENSACOVE until recovery to Grade 1 or baseline, then consider resuming at reduced dose as per Table 1. Precautions (5.6)] Grade 4 Permanently discontinue ENSACOVE. Increased Creatine Phosphokinase [see Warnings and Precautions (5.7)] CPK elevation greater than 5 times ULN • Temporarily withhold ENSACOVE until recovery to baseline or to less than or equal to 2.5 times ULN, then resume at same dose. CPK elevation greater than • Temporarily withhold ENSACOVE 10 times ULN or second until recovery to baseline or to less than occurrence of CPK elevation or equal to 2.5 times ULN, then resume of greater than 5 times ULN at reduced dose as per Table 1. Hyperuricemia • Initiate urate-lowering medication. [see Warnings and • Withhold ENSACOVE until Precautions (5.8)] Symptomatic or Grade 4 improvement of signs or symptoms. • Resume ENSACOVE at same or reduced dose. Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 3 or 4 • Withhold ENSACOVE until recovery to Grade 1 or baseline. • Resume ENSACOVE at reduced dose as per Table 1. Recurrent Grade 4 Permanently discontinue ENSACOVE. ALT = alanine aminotransferase; AST = aspartate aminotransferase; bpm = beats per minute; HR = heart rate; ULN = upper limit of normal *Graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.03. 3 DOSAGE FORMS AND STRENGTHS ENSACOVE capsules are available as: • 25 mg: size 2 capsule, white opaque cap and body, with “X-396” on the cap and “25 mg” on the body printed in blue ink. Each capsule contains the equivalent of 25 mg of ensartinib. Reference ID: 5498877 5 • 100 mg: size 0 capsule, blue opaque cap and yellow opaque body, with “X-396” on the cap and “100 mg” on the body printed in white ink. Each capsule contains the equivalent of 100 mg of ensartinib. 4 CONTRAINDICATIONS ENSACOVE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ENSACOVE, FD&C Yellow No. 5 (tartrazine), or to any of its components [see Warnings and Precautions (5.10)]. 5 WARNINGS AND PRECAUTIONS 5.1 Interstitial Lung Disease/Pneumonitis ENSACOVE can cause severe interstitial lung disease (ILD)/pneumonitis. In the pooled safety population [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 5% of patients treated with ENSACOVE, including Grade 3 in 1.3% and Grade 4 in 0.4%. ILD/pneumonitis leading to dose interruption occurred in 0.4% and permanent discontinuation of ENSACOVE in 1.5% of patients. Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever) during treatment with ENSACOVE. Immediately withhold ENSACOVE in patients with suspected ILD/pneumonitis. Permanently discontinue ENSACOVE if ILD/pneumonitis is confirmed [see Dosage and Administration (2.4)]. 5.2 Hepatotoxicity ENSACOVE can cause hepatotoxicity including drug-induced liver injury. In the pooled safety population [see Adverse Reactions (6.1)], 59% of patients treated with ENSACOVE had increased alanine aminotransferase (ALT), including 5% Grade 3. Increased aspartate aminotransferase (AST) occurred in 58% of patients treated with ENSACOVE, including 1.8% Grade 3. Increased bilirubin occurred in 12% of patients treated with ENSACOVE, including 2.3% Grade 3 and 0.2% Grade 4. There was one case of drug-induced liver injury in ENSACOVE-treated patients. The median time to first onset of increased ALT or AST was 5.3 weeks (range: 0.4 to 152 weeks). The dose of ENSACOVE was interrupted in 4.6% of patients for increased ALT or AST. Increased ALT or AST leading to dose reduction occurred in 2.6% and permanent discontinuation of ENSACOVE in 1.1% of patients. The dose of ENSACOVE was interrupted in 1.3% of patients for increased bilirubin. Increased bilirubin leading to dose reduction occurred in 0.7% and permanent discontinuation of ENSACOVE in 1.3% of patients. Monitor liver function tests including ALT, AST, and total bilirubin at baseline and every 2 weeks during the first cycle of treatment with ENSACOVE, and then monthly and as clinically indicated. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on the severity of the adverse reaction [see Dosage and Administration (2.4)]. Reference ID: 5498877 6 5.3 Dermatologic Adverse Reactions ENSACOVE can cause dermatologic adverse reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), rash, pruritus, and photosensitivity. In the pooled safety population [see Adverse Reactions (6.1)], dermatologic adverse reactions occurred in 80% of patients receiving ENSACOVE, including Grade 3 in 14% of patients. Rash occurred in 72% of patients receiving ENSACOVE, including Grade 3 in 12% of patients. The median time to onset of rash was 9 days (range: 1 day to 17.3 months). Pruritus occurred in 32% of patients receiving ENSACOVE, with Grade 3 in 2.4%. There was one Grade 3 case (0.2%) of drug reaction with eosinophilia and systemic symptoms (DRESS). The dose of ENSACOVE was interrupted in 12% of patients for dermatologic adverse reactions. Dermatologic adverse reactions leading to dose reduction occurred in 11% and permanent discontinuation of ENSACOVE in 1.5% of patients. In the pooled safety population [see Adverse Reactions (6.1)], photosensitivity occurred in 0.9% of patients receiving ENSACOVE; all were Grade 1. Monitor patients for dermatologic adverse reactions during treatment with ENSACOVE. If dermatologic adverse reactions occur, treat with antihistamine, topical or systemic steroids based on the severity. Advise patients to limit direct sun exposure while taking ENSACOVE and for at least 1 week after discontinuation. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on the severity of the adverse reaction [see Dosage and Administration (2.4)]. 5.4 Bradycardia ENSACOVE can cause symptomatic bradycardia. In the pooled safety population [see Adverse Reactions (6.1)], bradycardia (heart rate less than 60 beats per minute) occurred in 6% of patients treated with ENSACOVE. All bradycardia events were Grade 1 or 2. Bradycardia requiring dose reduction occurred in 0.2% and led to dose interruption in 0.4% of ENSACOVE-treated patients. Monitor heart rate regularly during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity [see Dosage and Administration (2.4)]. 5.5 Hyperglycemia ENSACOVE can cause hyperglycemia. In the pooled safety population [see Adverse Reactions (6.1)], based on laboratory data, 44% of patients receiving ENSACOVE experienced increased blood glucose, including Grade 3 in 2.5%. The median time to onset of increased blood glucose was 5.9 weeks (0.4 weeks to 3.4 years). Assess fasting serum glucose at baseline and monitor serum glucose periodically during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity [see Dosage and Administration (2.4)]. 5.6 Visual Disturbances ENSACOVE can cause visual disturbances including blurred vision, diplopia, photopsia, vitreous floaters, visual impairment, visual field defect, and reduced visual acuity. Reference ID: 5498877 7 In the pooled safety population [see Adverse Reactions (6.1)], 8% of patients receiving ENSACOVE experienced visual disturbance, including 0.2% Grade 3. Visual disturbances led to dose interruption in 0.4% of patients. Obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity [see Dosage and Administration (2.4)]. 5.7 Increased Creatine Phosphokinase In the pooled safety population [see Adverse Reactions (6.1)], of the 203 patients with creatine phosphokinase (CPK) laboratory data available, increased CPK occurred in 43% of patients who received ENSACOVE. The incidence of Grade 3 increased CPK was 1.5% and 0.5% were Grade 4. The median time to onset of increased CPK was 123 days (range: 13 days to 22 months). Increased CPK leading to dose interruption occurred in 0.2% and dose reduction in 0.4%. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during treatment with ENSACOVE. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity [see Dosage and Administration (2.4), Adverse Reactions (6.1)]. 5.8 Hyperuricemia ENSACOVE can cause hyperuricemia. In the pooled safety population [see Adverse Reactions (6.1)], based on adverse reactions, 6% of patients experienced hyperuricemia, with 0.4% Grade 3 and 0.7% Grade 4. Nine patients (1.9%) required hydration and two patients (0.4%) required urate-lowering medication. Monitor serum uric acid levels prior to initiating ENSACOVE and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold, reduce the dose, or permanently discontinue ENSACOVE based on severity [see Dosage and Administration (2.4)]. 5.9 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, ENSACOVE can cause fetal harm when administered to a pregnant woman. In embryo-fetal developmental studies, oral administration of ensartinib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural abnormalities. Adverse embryo-fetal findings were seen at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on area under the curve (AUC). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ENSACOVE and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ENSACOVE and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. 5.10 FD&C Yellow No. 5 (Tartrazine) This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of Reference ID: 5498877 8 FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)] • Hepatoxicity [see Warnings and Precautions (5.2)] • Dermatologic Adverse Reactions [see Warnings and Precautions (5.3)] • Bradycardia [see Warnings and Precautions (5.4)] • Hyperglycemia [see Warnings and Precautions (5.5)] • Visual Disturbances [see Warnings and Precautions (5.6)] • Increased Creatine Phosphokinase [see Warnings and Precautions (5.7)] • Hyperuricemia [see Warnings and Precautions (5.8)] • FD&C Yellow No. 5 (Tartrazine) [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to ENSACOVE as a single agent in 458 patients with locally advanced or metastatic ALK-positive NSCLC in the following trials: eXALT3 Study (N=143) [see Clinical Studies (14.1)], Study 101 (NCT01625234, N=98), Study BTP-28311 (NCT02959619, N=35), and Study BTP-42322 (NCT03215693, N=182). Patients received ENSACOVE 225 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Among 458 patients who received ENSACOVE, 63% were exposed for 6 months or longer and 47% were exposed for greater than one year. In this pooled safety population, the most common adverse reactions (≥20%) were rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, and pyrexia. The most frequent Grade 3 or 4 laboratory abnormalities (≥2%) were increased uric acid, decreased lymphocytes, increased alanine aminotransferase, decreased phosphate, increased gamma glutamyl transferase, increased magnesium, increased amylase, decreased sodium, increased glucose, decreased hemoglobin, increased bilirubin, decreased potassium, and increased creatine phosphokinase. TKI-naive ALK-Positive Locally Advanced or Metastatic NSCLC The safety of ENSACOVE was evaluated in the eXALT3 study [see Clinical Studies (14.1)]. Patients received ENSACOVE 225 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Among patients who received ENSACOVE, 78% were exposed for 6 months or longer and 66% were exposed for greater than one year. The median age of patients who received ENSACOVE was 54 years (range: 25-86); 50% male; 54% Asian, 43% White; 0.7% Black or African American; and 11% Hispanic or Latino. Reference ID: 5498877 9 Serious adverse reactions occurred in 23% of patients treated with ENSACOVE. Serious adverse reactions that occurred in ≥1% were pneumonia (4.9%), hemorrhage (2.1%), rash (2.1%) and cellulitis (1.4%). One fatal adverse reaction (0.7%) occurred due to bronchopneumonia. Permanent discontinuation of ENSACOVE due to an adverse reaction occurred in 12% of patients. Adverse reactions which resulted in permanent discontinuation of ENSACOVE (≥1%) included increased ALT (2.1%), increased AST (2.1%), pneumonitis/ILD (2.1%). increased blood bilirubin (1.4%), and increased conjugated bilirubin (1.4%). Dose interruptions of ENSACOVE due to an adverse reaction occurred in 41% of patients. Adverse reactions which required dose interruptions (≥2%) included rash (13%), increased ALT (6%), pneumonia (3.5%), edema (2.8%), pruritus (2.8%), pyrexia (2.8%), increased AST (2.1%), hemorrhage (2.1%), and decreased appetite (2.1%). Dose reductions of ENSACOVE due to an adverse reaction occurred in 24% of patients. Adverse reactions which required dose reductions (≥2%) included rash (11%), increased ALT (4.2%), pruritus (2.8%), and edema (2.1%). Tables 3 and 4 summarize the most frequent adverse reactions and laboratory abnormalities, respectively. Table 3: Adverse Reactions ( ≥10%) in Patients with ALK-Positive Locally Advanced or Metastatic NSCLC Who Received ENSACOVE in eXALT3 Study ENSACOVE N = 143 Crizotinib N = 146 Adverse Reaction All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Skin and Subcutaneous Tissue Disorders Rasha 66 12 10 0 Pruritusb 30 2.1 4.1 0 Alopecia 11 0 4.8 0 Dry skin 10 0.7 0.7 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Painc 36 1.4 20 0 Respiratory, Thoracic and Mediastinal Disorders Coughd 31 0.7 16 0 Gastrointestinal Disorders Constipation 31 0 26 0 Nausea 28 1.4 30 2.1 Vomitinge 16 0.7 32 0 General Disorders and Administration Site Conditions Edemaf 27 2.1 28 2.1 Pyrexiag 22 0.7 10 0.7 Fatigueh 21 0.7 14 1.4 Metabolism and Nutrition Disorders Decreased appetite 15 0 12 1.4 Infection and Infestation Respiratory Tract Infection 13 0.7 10 0 Reference ID: 5498877 10 ENSACOVE N = 143 Crizotinib N = 146 Adverse Reaction All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Nervous System Disorders Dizzinessi 12 0.7 14 0.7 Dysgeusia 10 0 11 0 Vascular Disorders Hemorrhagej 10 1.4 4.8 0 Adverse reactions were graded using NCI CTCAE version 4.03. a Includes dermatitis, dermatitis acneiform, dermatitis bullous, drug eruption, eczema, exfoliative rash, palmar-plantar erythrodysaesthesia, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular, skin exfoliation, and vulvovaginal rash b Includes ear pruritus, eye pruritus, eyelids pruritus, lip pruritus, pruritus, and pruritus generalized c Includes arthritis, spinal pain, myalgia, musculoskeletal pain, back pain, pain in extremity, neck pain, arthralgia, non-cardiac check pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort d Includes cough, productive cough, upper-airway cough syndrome e Includes vomiting and retching f Includes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, gravitational edema, skin edema, eye edema, and periorbital edema. g Includes pyrexia and hyperthermia h Includes fatigue and asthenia. i Includes dizziness, vertigo, postural dizziness j Includes hemoptysis, intracranial hemorrhage, gastrointestinal hemorrhage, hematuria, upper gastrointestinal hemorrhage, vaginal hemorrhage, gingival bleeding, vitreous hemorrhage, epistaxis, rectal hemorrhage, anal hemorrhage Table 4: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ALK-Positive Locally Advanced or Metastatic NSCLC Who Received ENSACOVE in eXALT3 Study ENSACOVE N = 143 Crizotinib N = 146 Lab Abnormality All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Chemistry Alanine aminotransferase increased 73 5 74 8 Alkaline phosphatase increased 64 2.2 50 0.7 Aspartate aminotransferase increased 64 1.4 62 3.5 Glucose increased 49 5 35 0.7 Albumin decreased 46 0.7 56 1.4 Phosphate decreased 39 7 42 4.9 Urate increased 39 39 27 27 Creatinine increased 37 0 27 0 Calcium decreased 36 1.4 64 4.9 Sodium decreased 27 4.3 27 4.2 Hematology Lymphocytes decreased 57 7 47 5 Hemoglobin decreased 43 0.7 31 1.4 Adverse reactions were graded using NCI CTCAE version 4.03. ALT = Alanine aminotransferase; AST = Aspartate aminotransferase Reference ID: 5498877 11 Clinically relevant adverse reactions in <10% of patients who received ENSACOVE included interstitial lung disease, photosensitivity, increased creatinine phosphokinase, bradycardia, and visual disturbances. 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on ENSACOVE Table 5 describes drug interactions where concomitant use of another drug affects ENSACOVE. Table 5: Effect of Other Drugs on ENSACOVE Strong or Moderate CYP3A Inhibitors Prevention or Management Avoid concomitant use of strong or moderate CYP3A inhibitors with ENSACOVE. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a CYP3A4 substrate in vitro [see Clinical Pharmacology (12.3)]. Concomitant use with strong or moderate CYP3A inhibitors may increase ensartinib exposure; however, this has not been studied clinically. Strong or Moderate CYP3A Inducers Prevention or Management Avoid concomitant use of strong or moderate CYP3A inducers with ENSACOVE. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a CYP3A4 substrate in vitro [see Clinical Pharmacology (12.3)]. Concomitant use with strong or moderate CYP3A inducers may decrease ensartinib exposure; however, this has not been studied clinically. P-gp Inhibitors Prevention or Management Avoid concomitant use of P-gp inhibitors with ENSACOVE. Mechanism and Clinical Effect(s) This recommendation is based upon a mechanistic understanding of ensartinib pharmacokinetics and it being a P-gp substrate in vitro [see Clinical Pharmacology (12.3)]. Concomitant use with P-gp inhibitors may increase ensartinib exposure; however, this has not been studied clinically. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], ENSACOVE can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ENSACOVE in pregnant women to inform a drug-associated risk. Reference ID: 5498877 8 12 Oral administration of ensartinib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural abnormalities. Adverse embryo-fetal findings were seen at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study, pregnant rats received 20, 40, or 80 mg/kg/day of ensartinib during the period of organogenesis (gestation day 6 to 17). Ensartinib doses ≥40 mg/kg/day (approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC) resulted in an increase in the incidence of fetal malformations (aortic dislocation, ventricular septal defect, separated vertebrae) and dose-dependent delayed skeletal development, including decreased or delayed ossification of the vertebrae. Ensartinib at 80 mg/kg (approximately 6.4 times the human exposure at the recommended dose of 225 mg/day based on AUC) resulted in maternal toxicity (reduced body weight and food consumption), decreased fetal body weight, increased pre- and post-implantation loss, decreases in the number of live fetuses, and visceral variations (missing renal papillae, pyelectasis). 8.2 Lactation Risk Summary There are no data on the presence of ensartinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with ENSACOVE and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential ENSACOVE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating ENSACOVE. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with ENSACOVE and for at 1 week after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENSACOVE and for 1 week after the last. Reference ID: 5498877 13 (_r q b , -0 8.4 Pediatric Use The safety and effectiveness of ENSACOVE in pediatric patients have not been established. 8.5 Geriatric Use Of the 458 patients enrolled in clinical studies and received ENSACOVE 225 mg once daily, 16% of the participants were aged 65 years or older. Clinical studies of ENSACOVE did not include sufficient numbers of patients ages 65 and over to determine whether they respond differently from younger patients. Exploratory analysis suggests a higher incidence of serious adverse events (43% vs 27%), more frequent adverse events leading to treatment discontinuations (18% vs 10%) and dose modifications (34% vs 16%) in patients 65 years or older as compared to those younger than 65 years. 8.6 Hepatic Impairment Ensartinib is primarily metabolized by the liver and patients with hepatic impairment may have increased exposures [see Clinical Pharmacology (12.3)]. Avoid use of ENSACOVE for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST) since it has not been studied in this population. Monitor patients with moderate hepatic impairment (total bilirubin >1.5 to ≤ 3 ULN and any AST) for increased adverse reactions and adjust ENSACOVE dosage as clinically indicated [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]. No dosage modification is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin 1 to 1.5 x ULN and any AST). 11 DESCRIPTION ENSACOVE capsules contain ensartinib, a kinase inhibitor, present as ensartinib hydrochloride with the chemical name 6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-{4-[(3R,5S)­ 3,5-dimethylpiperazine-1-carbonyl]phenyl}pyridazine-3-carboxamide, dihydrochloride. The molecular formula is C26H27Cl2FN6O3·2HCl and its molecular weight is 634.4 g/mol with the following structure: F O N N Cl Cl (R) O N H O H 2 N N (S) NH (R) CH3 CH3 2HCl ENSACOVE capsules are intended for oral administration and are available in two dosage strengths: 25 mg ensartinib (equivalent to 28.25 mg ensartinib hydrochloride) and 100 mg ensartinib (equivalent to 113.02 mg ensartinib hydrochloride). The inactive ingredients of ENSACOVE capsules are microcrystalline cellulose and stearic acid. The inactive ingredients of the 25 mg empty capsule shells are hypromellose and titanium dioxide. The inactive ingredients of the 100 mg empty capsules shells are black iron oxide, FD&C Blue No. 1, FD&C Yellow No. 5, hypromellose, red iron oxide, and titanium dioxide. Reference ID: 5498877 14 The imprinting ink for the 25 mg capsules contains butyl alcohol, dehydrated alcohol, FD&C Blue No. 2, isopropyl alcohol, propylene glycol, shellac, and strong ammonia solution. The imprinting ink for the 100 mg capsules contains butyl alcohol, dehydrated alcohol, isopropyl alcohol, povidone, propylene glycol, shellac, sodium hydroxide, and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ensartinib is a kinase inhibitor of anaplastic lymphoma kinase (ALK) and inhibits other kinases including MET and ROS1. In vitro, ensartinib inhibited phosphorylation of ALK and its downstream signaling proteins AKT, ERK, and S6, thereby blocking ALK-mediated signaling pathways and inhibiting proliferation in cell lines harboring ALK fusions and mutations. In vivo, ensartinib showed anti-tumor activity in a mouse xenograft model of human NSCLC harboring an ALK fusion. 12.2 Pharmacodynamics Exposure-response relationship Ensartinib exposure-response relationships and the time course of the pharmacodynamic response have not been fully characterized. Cardiac Electrophysiology At the approved recommended dosage, a mean increase in the QTc interval > 20 ms was not observed. 12.3 Pharmacokinetics Ensartinib mean (coefficient of variation [CV%]) maximum concentration (Cmax) is 292 ng/mL (60%), and the area under the concentration-time curve (AUC0–24h) is 4,920 ng·h /ml (62%) at the approved recommended dosage. Ensartinib steady state is reached within 15 days with a mean accumulation ratio of 2.7. Absorption Ensartinib median (minimum, maximum) time to reach Cmax (Tmax) at steady state is 3 hours (2, 8 hours). Effect of Food No clinically significant differences in ensartinib pharmacokinetics were observed following administration of ENSACOVE with a high-fat meal (total 800-1000 calories, > 50% fat) compared to fasted conditions. Distribution Ensartinib mean (CV%) apparent volume of distribution is 1,720 L (42%). Ensartinib is 91.6% bound to human plasma protein. Elimination Ensartinib mean (standard deviation [SD]) steady-state half-life (t1/2) is 30 (20) hours. Reference ID: 5498877 15 Metabolism Ensartinib is predominantly metabolized by CYP3A. Excretion Following a single oral 200 mg dose of radiolabeled ensartinib, 91% of the radioactivity was recovered in feces (38% as unchanged) and 10% in urine (4.4% as unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of ensartinib were observed based on age (20 to 86 years), sex, race (Asian vs White), body weight (38 to 148 kg), mild to moderate renal impairment (eGFR 30 to 89 mL/min) and mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin 1 to 1.5 x ULN and any AST). The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR <15 mL/min) with or without hemodialysis, and moderate (total bilirubin >1.5 to ≤ 3 ULN and any AST) or severe (total bilirubin >3 times ULN and any AST) hepatic impairment on ensartinib pharmacokinetics is unknown. Drug Interaction Studies In Vitro Studies Cytochrome P450 (CYP) Enzymes: Ensartinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and does not induce CYP1A2, CYP2B6, or CYP3A. Transporter Systems: Ensartinib is a P-gp substrate but is not a substrate of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. Ensartinib does not inhibit BCRP, P-gp, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2 or OCT3. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with ensartinib. Ensartinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human lymphocyte chromosome aberration assay or an in vivo rat bone marrow micronucleus assay. Dedicated fertility studies were not conducted with ensartinib. No adverse effects on male or female reproductive organs were observed in up to 3-month repeat-dose toxicology studies conducted in rats and dogs. 14 CLINICAL STUDIES 14.1 TKI-naive ALK-Positive Locally Advanced or Metastatic NSCLC (eXALT3 Study) The efficacy of ENSACOVE was evaluated in the eXALT3 study (NCT02767804), an open- label, randomized, active-controlled, multicenter study in adult patients with locally advanced (stage IIIB following prior chemotherapy or chemoradiation or not amenable to curative intent Reference ID: 5498877 16 therapy) or metastatic ALK-positive NSCLC. Patients were required to have ALK-positive NSCLC and an ECOG performance status of 0, 1, or 2. Patients could have received one prior regimen of chemotherapy but could not have previously received an ALK-targeted therapy. Patients with asymptomatic, untreated brain metastases who were not on corticosteroids and patients with asymptomatic, treated brain metastases who were on stable or decreasing dose of corticosteroids were eligible. Patients were required to have completed radiation therapy at least 2 weeks, or chemotherapy at least 4 weeks, prior to enrollment. Patients with leptomeningeal disease were ineligible. Patients were randomized 1:1 to receive ENSACOVE 225 mg orally once daily or crizotinib 250 mg orally twice daily in 28-day cycles until disease progression or unacceptable toxicity. Randomization was stratified by prior chemotherapy (0 vs. 1), ECOG performance status (0 or 1 vs. 2), presence of central nervous system (CNS) metastases (yes or no), and geographic region (Asia vs. the rest of the world). Tumor assessments were performed every 8 weeks. The main efficacy outcome measure was progression-free survival (PFS) as evaluated by Blinded Independent Central Review (BICR) according to RECIST version 1.1. The key secondary efficacy outcome measure was overall survival (OS); other secondary outcome measures included CNS response rate, time to CNS progression, and overall response rate (ORR). A total of 290 patients were randomized to ENSACOVE (n=143) or crizotinib (n=147). The baseline demographic characteristics of the overall study population were median age 54 years (range: 25-90); 16% age > 65 years; 51% male; 56% Asian; 41% White and 1.4% Black; 8% Hispanic or Latino; ECOG PS 0 or 1 (95%); and 62% never smokers. Patients had Stage IIIB (8%) or Stage IV NSCLC (92%); 26% had received prior chemotherapy for advanced disease and 17% had received prior radiation. Baseline CNS metastases were present in 36% of the patients. The eXALT3 study demonstrated a statistically significant improvement in PFS for patients randomized to ENSACOVE compared to patients randomized to crizotinib. The efficacy results as assessed by BICR are summarized in Table 6 and Figure 1. Table 6: Efficacy Results for eXALT3 Study According to BICR Assessment Efficacy Parameter ENSACOVE N=143 Crizotinib N=147 Progression-free survival Number of events, n (%) 59 (41%) 80 (54%) Progressive disease, n (%) 51 (36%) 77 (52%) Death, n (%) 8 (6%) 3 (2%) Median, months (95% Cl) 25.8 (21.8, NE) 12.7 (9.2, 16.6) Hazard ratio (95% Cl) 0.56 (0.40, 0.79) p-valuea 0.0007 Overall response rate Overall response rate % (95% Cl) 74% (66, 81) 67% (58, 74) Complete response % 12% 5% Partial response % 62% 61% Reference ID: 5498877 17 100 90 80 t 70 C ~ 60 ·;: ~ g 50 + Censored ~ 0 . !ji'j 40 ~ e c.. 30 20 10 I I I + -+-\ _+\ ___ ' ½+- - ~ - -\ ·-~ I I I - - ... - - -ti-It +++ +-+ +- + - - ; 'l, ~- - -+--- - -- ----- - --+ ENSACOVE Crizotinib o._~--~--~--~--~--~---~--~--~--~--~--~---~--~--~--~-' 0 Nwnbcr al Risk ENSACOVE 143 Crizotinib 147 125 124 106 94 98 75 12 86 56 I 5 78 43 18 72 32 21 24 T imc (Monl hs) 54 23 30 10 27 21 6 30 10 2 33 36 39 42 0 45 0 0 Efficacy Parameter ENSACOVE N=143 Crizotinib N=147 Duration of response Number of responders, n 106 98 Median, months (95% Cl) NE (22.0, NE) 27.3 (12.9, NE) CI = Confidence Interval; NE=not estimable; BICR = Blinded Independent Central Review a p-value based on unstratified log-rank test Figure 1: Kaplan-Meier Curves of Progression-Free Survival by BICR in eXALT3 Study At the time of the primary PFS analysis, OS results were immature. At the time of final analysis of OS, there was no statistically significant difference (p-value = 0.4570) between ENSACOVE and crizotinib. Median OS was 63.2 months in the ENSACOVE arm and 55.7 months in the crizotinib arm, with the hazard ratio of 0.88 (95% CI: 0.63, 1.23). The results of the pre-specified analyses of CNS response rate by BICR in patients with baseline measurable CNS disease are summarized in Table 7. Table 7: CNS ORR and DOR by BICR in Patients with Baseline Measurable CNS Disease in eXALT3 Study Efficacy Parameter ENSACOVE N=17 crizotinib N=24 CNS overall response rate % (95% Cl) 59% (33, 82) 21% (7, 42) Complete response % 24% 8% Partial response % 35% 13% Duration of Response Number of responders, n 10 5 Patients with DOR ≥ 12 months 30% 40% BICR = Blinded Independent Central Review; CI = Confidence Interval Reference ID: 5498877 18 16 HOW SUPPLIED/STORAGE AND HANDLING ENSACOVE (ensartinib) capsules are supplied as follows: Capsule Strength Description Package Configuration NDC Code 25 mg Size 2 capsule, white opaque cap and body, with “X-396” on the cap and “25 mg” on the body printed in blue ink. Bottles of 30 83076-1025-3 100 mg Size 0 capsule, blue opaque cap and yellow opaque body, with “X­ 396” on the cap and “100 mg” on the body printed in white ink. Bottles of 60 83076-1100-6 Store at controlled room temperature 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Store and dispense in the original bottle with desiccant to protect from moisture. Do not remove desiccant from bottle. Keep out of reach of children. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Interstitial Lung Disease (ILD)/Pneumonitis Inform patients of the risk of severe ILD/pneumonitis during treatment with ENSACOVE. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.1)]. Hepatoxicity Inform patients of the potential risk of hepatoxicity during treatment with ENSACOVE and of the need to monitor for aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin elevations during treatment with ENSACOVE. Advise patients to inform their healthcare provider of any new or worsening symptoms [see Warnings and Precautions (5.2)]. Dermatologic Adverse Reactions Inform patients of the potential risk of dermatologic adverse reactions, including rash, pruritus, and photosensitivity during treatment with ENSACOVE. If dermatologic reactions occur, advise patients to limit sun exposure while taking ENSACOVE and for at least 1 week after the final dose [see Warnings and Precautions (5.3)]. Bradycardia Advise patients of the risk of bradycardia during treatment with ENSACOVE and to report any symptoms of bradycardia. Advise patients to inform their healthcare provider about the use of Reference ID: 5498877 19 any heart or blood pressure medications during treatment with ENSACOVE [see Warnings and Precautions (5.4)]. Hyperglycemia Inform patients of the risks of new or worsening hyperglycemia during treatment with ENSACOVE and the need to periodically monitor glucose levels. Advise patients with diabetes mellitus or glucose intolerance that antihyperglycemic medications may need to be adjusted during treatment with ENSACOVE [see Warnings and Precautions (5.5)]. Visual Disturbances Advise patients to inform their healthcare provider of any new or worsening vision symptoms during treatment with ENSACOVE [see Warnings and Precautions (5.6)]. Creatine Phosphokinase (CPK) Elevation Inform patients of the signs and symptoms of creatine phosphokinase (CPK) elevation and the need for monitoring during treatment with ENSACOVE. Advise patients to inform their healthcare provider of any new or worsening symptoms [see Warnings and Precautions (5.7)]. Hyperuricemia Inform patients of the signs and symptoms of hyperuricemia. Advise patients to inform their healthcare provider if they experience signs or symptoms associated with hyperuricemia during treatment with ENSACOVE [see Warnings and Precautions (5.8)]. Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with ENSACOVE and for 1 week after the last dose [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1, 8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with ENSACOVE and for 1 week after the last dose [See Warnings and Precautions (5.9) and Use in Specific Populations (8.3)]. FD&C Yellow No. 5 (tartrazine) Advise patients that this product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type or asthma-type reactions in certain susceptible persons (e.g., patients who also have aspirin hypersensitivity) [see Warnings and Precautions (5.10). Advise patients to contact their healthcare provider and seek medical help right away if they develop symptoms of an allergic reaction to FD&C Yellow No. 5 (tartrazine). Lactation Advise women not to breastfeed during treatment with ENSACOVE and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Administration Instruct patients to take ENSACOVE once a day with or without food and to swallow ENSACOVE capsules whole [see Dosage and Administration (2.2)]. Reference ID: 5498877 20 Missed Dose Advise patients to take ENSACOVE at the same time each day. If a dose is missed, then they should take the missed dose as soon as possible unless the next dose is due within 12 hours. Patients should be instructed not to take 2 doses at the same time to make up for a missed dose. In addition, instruct patients not to take an extra dose if they vomit after taking ENSACOVE [see Dosage and Administration (2.2)]. Manufactured for: Xcovery Holdings, Inc. Miami, FL 33131 ENSACOVE is a trademark of Xcovery Holdings, Inc. ©2024, Xcovery Holdings, Inc. All rights reserved. Reference ID: 5498877 21 PATIENT INFORMATION ENSACOVETM (En-sa-kowv) (ensartinib) capsules, for oral use What is ENSACOVE? ENSACOVE is a prescription medicine used to treat adults with non-small cell lung cancer (NSCLC): • that is caused by an abnormal anaplastic lymphoma kinase (ALK) gene, • that has spread to other parts of your body, and • who have not received medicines called ALK-inhibitors. Your healthcare provider will perform a test to make sure that ENSACOVE is right for you. It is not known if ENSACOVE is safe and effective in children. Do not use ENSACOVE if you are allergic to ENSACOVE, FD&C No. 5 (tartrazine), or to any of the ingredients in ENSACOVE. See the end of this leaflet for a complete list of ingredients in ENSACOVE. Before using ENSACOVE, tell your healthcare provider about all of your medical conditions, including if you: • have lung or breathing problems • have liver problems • have problems with your heartbeat • have diabetes mellitus or glucose intolerance • have problems with your vision • are pregnant or plan to become pregnant. ENSACOVE can harm your unborn baby. o Your healthcare provider will do a pregnancy test before you start treatment with ENSACOVE. o Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ENSACOVE. • Females who are able to become pregnant should use effective birth control (contraception) during treatment with ENSACOVE and for 1 week after the last dose of ENSACOVE. Talk to your healthcare provider about birth control choices that are right for you during treatment with ENSACOVE. • Males who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ENSACOVE and for 1 week after the last dose of ENSACOVE. • are breastfeeding or plan to breastfeed. It is not known if ENSACOVE passes into your breast milk. Do not breastfeed during treatment with ENSACOVE and for 1 week after the last dose. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the other medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Certain other medicines may affect the way that ENSACOVE works and may increase your risk of certain side effects. Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. How should I take ENSACOVE? • Take ENSACOVE exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking ENSACOVE unless your healthcare provider tells you to. • Swallow ENSACOVE capsules whole. Do not crush or chew capsules. Do not open or dissolve the contents of the capsule. • Take ENSACOVE 1 time a day, at the same time each day. • You may take ENSACOVE with or without food. • If you miss a dose, take it as soon as you remember. If your next dose is due within 12 hours, skip the missed dose and take your next dose at your regular time. Do not take 2 doses of ENSACOVE on the same day to make up for the missed dose. • If you vomit after taking a dose of ENSACOVE, do not take an extra dose. Take your next dose at your regular time. What should I avoid while taking ENSACOVE? • Limit your time in the sun during treatment with ENSACOVE and for at least 1 week after your last dose. ENSACOVE may make your skin sensitive to sunlight. You may burn more easily and get severe sunburns. When you are in the sun, wear a hat and protective clothing, and use a broad-spectrum sunscreen and lip balm with a Sun Protection Factor (SPF) of 30 or greater to protect against sunburn. Reference ID: 5498877 What are the possible side effects of ENSACOVE? ENSACOVE can cause serious side effects, including: • Lung problems. ENSACOVE can cause severe or life-threatening swelling (inflammation) of the lungs. Symptoms may be similar to those from lung cancer. Tell your healthcare provider right away if you get any new or worsening symptoms of lung problems during treatment with ENSACOVE, including: o trouble breathing or shortness of breath o cough with or without mucus o chest pain o fever • Liver problems. ENSACOVE can increase enzymes called aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and levels of bilirubin in your blood. Tell your healthcare provider if you get new or worsening signs or symptoms of liver problems, including: o yellowing of your skin or the white part of o bleed or bruise more easily than normal your eyes o itchy skin o dark or brown (tea color) urine o decreased appetite o nausea or vomiting o feeling tired o pain on the right side of your stomach area • Skin reactions. ENSACOVE may cause skin reactions that require treatment. Tell your healthcare provider if you get symptoms of skin reactions, such as rash, itching, or skin swelling. • Slow heart rate (bradycardia). ENSACOVE can cause very slow heartbeats that can be severe. Your healthcare provider will check your heart rate during treatment with ENSACOVE. Tell your healthcare provider right away if you feel dizzy, lightheaded, or faint during treatment with ENSACOVE. Tell your healthcare provider if you take any heart or blood pressure medicines. • High blood sugar (hyperglycemia). ENSACOVE can increase your blood sugar levels. Hyperglycemia is common with ENSACOVE treatment but can be serious. If you take medicine for diabetes or glucose intolerance your healthcare provider may change your medicine during treatment with ENSACOVE. Tell your healthcare provider if you get new or worsening signs and symptoms of hyperglycemia, including: o feeling very thirsty o feeling sick to your stomach o needing to urinate more than usual o feeling weak or tired o feeling very hungry o feeling confused • Vision problems. ENSACOVE can cause vision problems. Your healthcare provider may refer you to an eye specialist if you develop new or worsening vision problems during treatment with ENSACOVE. Tell your healthcare provider if you have any loss of vision or any change in vision, including: o blurry vision o light hurting eyes o double vision o new or increased floaters o seeing flashes of light • Muscle pain, tenderness, and weakness (myalgia). ENSACOVE can increase the level of an enzyme in your blood called creatine phosphokinase (CPK), which may be a sign of muscle damage. Myalgia is common with ENSACOVE treatment but can be serious. Tell your healthcare provider if you get new or worsening signs and symptoms of muscle problems, including unexplained muscle pain or muscle pain that does not go away, tenderness, or weakness. • Increased uric acid level in your blood (hyperuricemia). ENSACOVE can cause too much uric acid in your blood. Hyperuricemia is common with ENSACOVE treatment but can be serious. Your healthcare provider may prescribe medicines if you have high blood uric acid levels. Tell your healthcare provider if you develop any of the following symptoms of hyperuricemia: o red, hot, tender, or swollen joints, especially your big toe o nausea or vomiting o pain in your stomach-area or sides o pink or brown urine • Allergic reactions to FD&C Yellow No. 5 (tartrazine). ENSACOVE 100 mg capsules contain FD&C Yellow No. 5. FD&C Yellow No. 5 (tartrazine) that can cause allergic reactions in certain people, especially people who also have Reference ID: 5498877 an allergy to aspirin. Tell your healthcare provider if you get hives, rash, or trouble breathing during treatment with ENSACOVE. Your healthcare provider will do certain blood tests before and during treatment with ENSACOVE to check you for side effects. If you have serious side effects during treatment with ENSACOVE, your healthcare provider may change your dose, stop your treatment for a period of time (temporary), or completely stop treatment with ENSACOVE. The most common side effects of ENSACOVE are: • rash • tiredness • muscle or bone pain • fever • constipation • increased levels of liver and pancreatic enzymes • itching • decreased white blood cell counts • coughing • changes in blood levels of phosphate, magnesium, sodium, and potassium • nausea • decreased protein (hemoglobin) in red blood cells • skin swelling (edema) • increased bilirubin blood levels • vomiting These are not all the possible side effects with ENSACOVE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ENSACOVE? • Store ENSACOVE at room temperature between 68ºF to 77ºF (20ºC to 25ºC). • Keep ENSACOVE capsules in the original bottle. • The bottle of ENSACOVE capsules contains a drying agent (desiccant) to help keep your medicine dry. Do not remove the desiccant from the bottle after opening. Do not open or eat the desiccant. Keep ENSACOVE and all medicines out of the reach of children. General information about the safe and effective use of ENSACOVE. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ENSACOVE for a condition for which it was not prescribed. Do not give ENSACOVE to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist of healthcare provider for information about ENSACOVE that is written for health professionals. What are the ingredients in ENSACOVE? Active ingredient: ensartinib hydrochloride Inactive ingredients: butyl alcohol, dehydrated alcohol, hypromellose, isopropyl alcohol, microcrystalline cellulose, propylene glycol, shellac, stearic acid, and titanium dioxide. The 25 mg capsules also contain the following inactive ingredients: FD&C Blue No. 2 and strong ammonia solution. The 100 mg capsules also contain the following inactive ingredients: black iron oxide, FD&C Blue No. 1, FD&C Yellow No. 5, povidone, red iron oxide, and sodium hydroxide. Manufactured for: Xcovery Holdings, Inc., Miami, FL, 33131 ENSACOVE is a trademark of Xcovery Holdings, Inc. ©2024, Xcovery Holdings, Inc. All rights reserved. For more information, call Xcovery Holdings, Inc. at (866) 367-2268. This Patient Information has been approved by the U.S. Food and Drug Administration Issued: 12/2024 Reference ID: 5498877
custom-source
2025-02-12T15:47:51.198905
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BLINCYTO® safely and effectively. See full prescribing information for BLINCYTO. BLINCYTO® (blinatumomab) for injection, for intravenous use Initial U.S. Approval: 2014 WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME See full prescribing information for complete boxed warning. • Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO and treat with corticosteroids as recommended. (2.4, 5.1) • Neurological toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS), which may be severe, life-threatening, or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. (2.4, 5.2) -----------------------RECENT MAJOR CHANGES------------------------------­ Boxed Warning 2/2024 Indications and Usage (1.1, 1.2, 1.3) 6/2024 Dosage and Administration (2.1, 2.2, 2.3) 12/2024 Dosage and Administration (2.4, 2.5, 2.6, 2.7, 2.8) 12/2024 Warnings and Precautions, Cytokine Release Syndrome (5.1) 6/2024 Warnings and Precautions, Neurological Toxicities including Immune Effector Cell-Associated Neurotoxicity (5.2) 6/2024 Warnings and Precautions, Effects on Ability to Drive and Use Machines (5.6) 2/2024 Warnings and Precautions, Benzyl Alcohol Toxicity in Neonates (5.12) 12/2024 ---------------------------INDICATIONS AND USAGE---------------------------­ BLINCYTO is a bispecific CD19-directed CD3 T-cell engager indicated for the treatment of adult and pediatric patients one month and older with: • CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. (1.1) • Relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL). (1.2) • CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (ALL) in the consolidation phase of multiphase chemotherapy. (1.3) -----------------------DOSAGE AND ADMINISTRATION----------------------­ • For the treatment of MRD-positive B-cell Precursor ALL - See Full Prescribing Information for recommended dose by patient weight and schedule. (2.1) - Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. (2.1) - Premedicate with prednisone or equivalent dexamethasone. (2.1) • For the treatment of Relapsed or Refractory B-cell Precursor ALL - See Full Prescribing Information for recommended dose by patient weight and schedule. (2.2) - Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. (2.2) - Premedicate with dexamethasone. (2.2) • For the treatment of B-cell Precursor ALL in the Consolidation Phase - See Full Prescribing Information for recommended dose by patient weight and schedule. (2.3) - Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. (2.3) - Premedicate with dexamethasone. (2.3) • Refer to Full Prescribing Information for important preparation and administration information. (2.5) • Administer as a continuous intravenous infusion at a constant flow rate using an infusion pump. - See Instructions for Use for infusion over 24 hours or 48 hours. - See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). This option is not recommended for patients weighing less than 5.4 kg. ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ For injection: 35 mcg of lyophilized powder in a single-dose vial for reconstitution. (3) -------------------------------CONTRAINDICATIONS-----------------------------­ Known hypersensitivity to blinatumomab or to any component of the product formulation. (4) ---------------------------WARNINGS AND PRECAUTIONS-------------------­ • Infections: Monitor patients for signs or symptoms; treat appropriately. (5.3) • Effects on Ability to Drive and Use Machines: Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. (5.6) • Pancreatitis: Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO. (5.8) • Preparation and Administration Errors: Strictly follow instructions for preparation (including admixing) and administration. (5.10) • Benzyl Alcohol Toxicity in Neonates: Use BLINCYTO prepared with preservative-free saline for neonates. BLINCYTO solution containing benzyl alcohol is not recommended for patients weighing less than 5.4 kg. (5.12, 8.4) • Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (5.13, 8.1, 8.3) ------------------------------ADVERSE REACTIONS------------------------------­ The most common adverse reactions (≥ 20%) are pyrexia, infusion-related reactions, headache, infection, musculoskeletal pain, neutropenia, nausea, anemia, thrombocytopenia, and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 12/2024 1 of 42 Reference ID: 5497479 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME 1 INDICATIONS AND USAGE 1.1 MRD-positive B-cell Precursor ALL 1.2 Relapsed or Refractory B-cell Precursor ALL 1.3 B-cell Precursor ALL in the Consolidation Phase 2 DOSAGE AND ADMINISTRATION 2.1 Treatment of MRD-positive B-cell Precursor ALL 2.2 Treatment of Relapsed or Refractory B-cell Precursor ALL 2.3 Treatment of B-cell Precursor ALL in the Consolidation Phase 2.4 Dosage Modifications for Adverse Reactions 2.5 Preparation and Administration of BLINCYTO 2.6 Storage of Reconstituted BLINCYTO 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cytokine Release Syndrome 5.2 Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity 5.3 Infections 5.4 Tumor Lysis Syndrome 5.5 Neutropenia and Febrile Neutropenia 5.6 Effects on Ability to Drive and Use Machines 5.7 Elevated Liver Enzymes 5.8 Pancreatitis 5.9 Leukoencephalopathy 5.10 Preparation and Administration Errors 5.11 Immunization 5.12 Benzyl Alcohol Toxicity in Neonates 5.13 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 MRD-positive B-cell Precursor ALL 14.2 Relapsed/Refractory B-cell Precursor ALL 14.3 Philadelphia Chromosome-Negative B-cell Precursor ALL in the Consolidation Phase 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. 2 of 42 Reference ID: 5497479 FULL PRESCRIBING INFORMATION WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME • Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO and treat with corticosteroids as recommended [see Dosage and Administration (2.4), Warnings and Precautions (5.1)]. • Neurological toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS) which may be severe, life-threatening, or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE 1.1 MRD-positive B-cell Precursor ALL BLINCYTO is indicated for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adult and pediatric patients one month and older. 1.2 Relapsed or Refractory B-cell Precursor ALL BLINCYTO is indicated for the treatment of relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients one month and older. 1.3 B-cell Precursor ALL in the Consolidation Phase BLINCYTO is indicated for the treatment of CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (ALL) in the consolidation phase of multiphase chemotherapy in adult and pediatric patients one month and older. 2 DOSAGE AND ADMINISTRATION 2.1 Treatment of MRD-positive B-cell Precursor ALL • A treatment course consists of 1 cycle of BLINCYTO for induction followed by up to 3 additional cycles for consolidation. • A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days). • See Table 1 for the recommended dose by patient weight and schedule. Patients weighing 45 kg or more receive a fixed-dose. For patients weighing less than 45 kg, the dose is calculated using the patient’s body surface area (BSA). 3 of 42 Reference ID: 5497479 Table 1. Recommended BLINCYTO Dose and Schedule for the Treatment of MRD-positive B-cell Precursor ALL Cycle Patients Weighing 45 kg or More (Fixed-dose) Patients Weighing Less Than 45 kg (BSA-based dose) Induction Cycle 1 Days 1-28 Days 29-42 28 mcg/day 14-day treatment-free interval 15 mcg/m2/day (not to exceed 28 mcg/day) 14-day treatment-free interval Consolidation Cycles 2-4 Days 1-28 Days 29-42 28 mcg/day 14-day treatment-free interval 15 mcg/m2/day (not to exceed 28 mcg/day) 14-day treatment-free interval • Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended. • Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse. • Premedicate with prednisone or equivalent for MRD-positive B-cell Precursor ALL: • For adult patients, premedicate with prednisone 100 mg intravenously or equivalent (e.g., dexamethasone 16 mg) 1 hour prior to the first dose of BLINCYTO in each cycle. • For pediatric patients, premedicate with 5 mg/m2 of dexamethasone intravenously or orally, to a maximum dose of 20 mg, prior to the first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle. • For administration of BLINCYTO: • See Instructions for Use for infusion over 24 hours or 48 hours. • See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg. 2.2 Treatment of Relapsed or Refractory B-cell Precursor ALL • A treatment course consists of up to 2 cycles of BLINCYTO for induction followed by 3 additional cycles for consolidation and up to 4 additional cycles of continued therapy. • A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days). • A single cycle of treatment of BLINCYTO continued therapy consists of 28 days of continuous intravenous infusion followed by a 56-day treatment-free interval (total 84 days). 4 of 42 Reference ID: 5497479 • See Table 2 for the recommended dose by patient weight and schedule. Patients weighing 45 kg or more receive a fixed-dose and for patients weighing less than 45 kg, the dose is calculated using the patient’s BSA. Table 2. Recommended BLINCYTO Dose and Schedule for the Treatment of Relapsed or Refractory B-cell Precursor ALL Cycle Patients Weighing 45 kg or More (Fixed-dose) Patients Weighing Less Than 45 kg (BSA-based dose) Induction Cycle 1 Days 1-7 Days 8-28 Days 29-42 9 mcg/day 28 mcg/day 14-day treatment-free interval 5 mcg/m2/day (not to exceed 9 mcg/day) 15 mcg/m2/day (not to exceed 28 mcg/day) 14-day treatment-free interval Induction Cycle 2 Days 1-28 Days 29-42 28 mcg/day 14-day treatment-free interval 15 mcg/m2/day (not to exceed 28 mcg/day) 14-day treatment-free interval Consolidation Cycles 3-5 Days 1-28 Days 29-42 28 mcg/day 14-day treatment-free interval 15 mcg/m2/day (not to exceed 28 mcg/day) 14-day treatment-free interval Continued Therapy Cycles 6-9 Days 1-28 Days 29-84 28 mcg/day 56-day treatment-free interval 15 mcg/m2/day (not to exceed 28 mcg/day) 56-day treatment-free interval • Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended. • Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse. 5 of 42 Reference ID: 5497479 • Premedicate with dexamethasone: • For adult patients, premedicate with 20 mg of dexamethasone intravenously or orally 1 hour prior to the first dose of BLINCYTO of each cycle, prior to a step dose (such as Cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours. • For pediatric patients, premedicate with 5 mg/m2 of dexamethasone intravenously or orally, to a maximum dose of 20 mg, prior to the first dose of BLINCYTO in the first cycle, prior to a step dose (such as Cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours in the first cycle. • For administration of BLINCYTO: • See Instructions for Use for infusion over 24 hours or 48 hours. • See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg. 2.3 Treatment of B-cell Precursor ALL in the Consolidation Phase • A single cycle of BLINCYTO monotherapy in consolidation is 28 days of continuous infusion followed by a 14-day treatment-free interval (total 42 days) [see Table 3 and Clinical Studies (14.3)]. • Patients weighing 45 kg or more receive a fixed-dose, and for patients weighing less than 45 kg, the dose is calculated using the patient’s BSA (see Table 3). Table 3. Recommended BLINCYTO Dose and Schedule in the Consolidation Phase of Treatment of B-cell Precursor ALL BLINCYTO Consolidation Cycle Patients Weighing 45 kg or More (Fixed-dose) Patients Weighing Less Than 45 kg (BSA-based dose) Days 1-28 Days 29-42 28 mcg/day 14-day treatment-free interval 15 mcg/m2/day (not to exceed 28 mcg/day) 14-day treatment-free interval • Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended. • Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse. • Premedicate with dexamethasone: • For adult patients, premedicate with dexamethasone 20 mg intravenously within 1 hour prior to the first dose of BLINCYTO of each cycle. • For pediatric patients, premedicate with 5 mg/m2 of dexamethasone intravenously or orally, to a maximum dose of 20 mg prior to the first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle. • For administration of BLINCYTO: 6 of 42 Reference ID: 5497479 • See Instructions for Use for infusion over 24 hours or 48 hours. • See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg. 2.4 Dosage Modifications for Adverse Reactions If the interruption after an adverse reaction is no longer than 7 days, continue the same cycle to a total of 28 days of infusion inclusive of days before and after the interruption in that cycle. If an interruption due to an adverse reaction is longer than 7 days, start a new cycle. Table 4. Dosage Modifications for Adverse Reactions Adverse Patients Weighing Patients Weighing Grade* Reaction 45 kg or More Less Than 45 kg Cytokine Release Grade 3 • Interrupt BLINCYTO. • Interrupt BLINCYTO. Syndrome (CRS) • Administer dexamethasone • Administer dexamethasone 8 mg every 8 hours 5 mg/m2 (maximum 8 mg) every intravenously or orally for up to 8 hours intravenously or orally for 3 days and taper thereafter over up to 3 days and taper thereafter 4 days. over 4 days. • When CRS is resolved, restart • When CRS is resolved, restart BLINCYTO at 9 mcg/day, and BLINCYTO at 5 mcg/m2/day, and escalate to 28 mcg/day after escalate to 15 mcg/m2/day after 7 days if the adverse reaction 7 days if the adverse reaction does does not recur. not recur. Discontinue BLINCYTO permanently. Administer dexamethasone as Grade 4 instructed for Grade 3 CRS. Neurological Seizure Discontinue BLINCYTO permanently if more than one seizure occurs. Toxicity Grade 2 Interrupt BLINCYTO until ICANS Interrupt BLINCYTO until ICANS ICANS resolves. resolves. Administer corticosteroids and Administer corticosteroids and manage according to current manage according to current practice guidelines. practice guidelines. When ICANS is resolved, restart When ICANS is resolved, restart BLINCYTO at 9 mcg/day. BLINCYTO at 5 mcg/m2/day. Escalate to 28 mcg/day after 7 days Escalate to 15 mcg/m2/day after if the adverse reaction does not 7 days if the adverse reaction does recur. not recur. 7 of 42 Reference ID: 5497479 Adverse Grade* Reaction Patients Weighing 45 kg or More Patients Weighing Less Than 45 kg Grade 3 Neurologic Events including ICANS Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 9 mcg/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently. Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 5 mcg/m2/day. Escalate to 15 mcg/m2/day after 7 days if the adverse reaction does not recur. If the adverse reaction occurred at 5 mcg/m2/day, or if the adverse reaction takes more than 7 days to resolve, discontinue BLINCYTO permanently. If ICANS, administer corticosteroids and manage according to current practice guidelines. Grade 4 Discontinue BLINCYTO permanently. Neurologic Events If ICANS, administer corticosteroids and manage according to current including practice guidelines. ICANS Other Clinically Relevant Adverse Reactions Grade 3 Withhold BLINCYTO until no Withhold BLINCYTO until no more more than Grade 1 (mild), then than Grade 1 (mild), then restart restart BLINCYTO at 9 mcg/day. BLINCYTO at 5 mcg/m2/day. Escalate to 28 mcg/day after Escalate to 15 mcg/m2/day after 7 days if the adverse reaction 7 days if the adverse reaction does does not recur. If the adverse not recur. If the adverse reaction reaction takes more than 14 days takes more than 14 days to resolve, to resolve, discontinue discontinue BLINCYTO BLINCYTO permanently. permanently. Grade 4 Consider discontinuing BLINCYTO permanently. * Based on the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is severe, and Grade 4 is life-threatening. 2.5 Preparation and Administration of BLINCYTO It is very important that the instructions for preparation (including admixing) and administration provided in this section are strictly followed to minimize medication errors (including underdose and overdose) [see Warnings and Precautions (5.10)]. 8 of 42 Reference ID: 5497479 BLINCYTO can be infused over 24 hours (preservative-free), 48 hours (preservative-free), 72 hours (with preservative), 96 hours (with preservative), or 7 days (with preservative). The choice between these options for the infusion duration should be made by the treating healthcare provider considering the frequency of the infusion bag changes and the weight of the patient. The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg. For preparation, reconstitution, and administration of BLINCYTO: The BLINCYTO Instructions for Use contains more detailed instructions on the preparation of infusion [see Instructions for Use]. The preparation steps differ based on the infusion duration. Follow the steps specific to the infusion duration you are preparing. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Call 1-800-77-AMGEN (1-800-772-6436) if you have questions about the reconstitution and preparation of BLINCYTO. 2.6 Storage of Reconstituted BLINCYTO The information in Table 5 indicates the storage time for the reconstituted BLINCYTO vial and prepared infusion bag. Table 5. Storage Time for Reconstituted BLINCYTO Vial and Prepared BLINCYTO Infusion Bag Maximum Storage Time Room Temperature 23°C to 27°C (73°F to 81°F) Refrigerated 2°C to 8°C (36°F to 46°F) Reconstituted BLINCYTO Vial 4 hours 24 hours Prepared BLINCYTO 24-Hour and 48-Hour Infusion Bag (Preservative-free) 48 hours* 8 days Prepared BLINCYTO 72-Hour and 96-Hour Infusion Bag (with Preservative) 4 days* 14 days Prepared BLINCYTO 7-Day Infusion Bag (with Preservative) 7 days* 14 days * Storage time includes infusion time. If the prepared BLINCYTO infusion bag is not administered within the time frames and temperatures indicated, it must be discarded; it should not be refrigerated again. 3 DOSAGE FORMS AND STRENGTHS For injection: 35 mcg of white to off-white lyophilized powder in a single-dose vial for reconstitution. 9 of 42 Reference ID: 5497479 4 CONTRAINDICATIONS BLINCYTO is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation. 5 WARNINGS AND PRECAUTIONS 5.1 Cytokine Release Syndrome Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. The median time to onset of CRS was 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved. Manifestations of CRS include fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin, and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS). Using all of these terms to define CRS in clinical trials of BLINCYTO, CRS was reported in 15% of patients with relapsed or refractory ALL, in 7% of patients with MRD-positive ALL, and in 16% of patients receiving BLINCYTO cycles in the consolidation phase of therapy [see Adverse Reactions (6.1)]. Monitor patients for signs or symptoms of these events. Advise outpatients on BLINCYTO to contact their healthcare professional for signs and symptoms associated with CRS. If severe CRS occurs, interrupt BLINCYTO until CRS resolves. Discontinue BLINCYTO permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS [see Dosage and Administration (2.4)]. 5.2 Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome BLINCYTO can cause serious or life-threatening neurologic toxicity, including ICANS [see Adverse Reactions 6.1]. The incidence of neurologic toxicities in clinical trials was approximately 65% [see Adverse Reactions (6.1)]. Among patients that experienced a neurologic toxicity, the median time to the first event was within the first 2 weeks of BLINCYTO treatment. The most common (≥ 10%) manifestations of neurological toxicity were headache, and tremor; the neurological toxicity profile varied by age group [see Use in Specific Populations (8.4, 8.5)]. Grade 3 or higher neurological toxicities following initiation of BLINCYTO administration occurred in approximately 13% of patients and included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. The majority of neurologic toxicities resolved following interruption of BLINCYTO, but some resulted in treatment discontinuation. The incidence of signs and symptoms consistent with ICANS in clinical trials was 7.5%. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. There is limited experience with BLINCYTO in patients with active ALL in the central nervous system (CNS) or a history of neurologic events. Patients with a history or presence of clinically relevant CNS pathology were excluded from clinical studies. Patients with Down Syndrome may have a higher risk of seizures with BLINCYTO therapy. 10 of 42 Reference ID: 5497479 Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities, including ICANS. Advise outpatients on BLINCYTO to contact their healthcare professional if they develop signs or symptoms of neurological toxicities. Management of neurologic toxicity may require interruption or discontinuation of BLINCYTO as recommended and/or treatment with corticosteroids [see Dosage and Administration (2.4)]. 5.3 Infections In patients with ALL receiving BLINCYTO in clinical studies, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of patients, some of which were life-threatening or fatal [see Adverse Reactions (6.1)]. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with BLINCYTO. Monitor patients for signs and symptoms of infection and treat appropriately. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving BLINCYTO [see Adverse Reactions (6.1)]. Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used for the prevention of TLS during BLINCYTO treatment. Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of BLINCYTO [see Dosage and Administration (2.4)]. 5.5 Neutropenia and Febrile Neutropenia Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO [see Adverse Reactions (6.1)]. Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion. Interrupt BLINCYTO if prolonged neutropenia occurs. 5.6 Effects on Ability to Drive and Use Machines Due to the potential for neurologic events, including seizures and ICANS, patients receiving BLINCYTO are at risk for loss of consciousness [see Warnings and Precautions (5.2)]. Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. 5.7 Elevated Liver Enzymes Treatment with BLINCYTO was associated with transient elevations in liver enzymes [see Adverse Reactions (6.1)]. In patients with ALL receiving BLINCYTO in clinical studies, the median time to onset of elevated liver enzymes was 3 days. The majority of these transient elevations in liver enzymes were observed in the setting of CRS. For the events that were observed outside the setting of CRS, the median time to onset was 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. 11 of 42 Reference ID: 5497479 Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatment. Interrupt BLINCYTO if the transaminases rise to greater than 5 times the upper limit of normal or if total bilirubin rises to more than 3 times the upper limit of normal. 5.8 Pancreatitis Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical studies and the postmarketing setting [see Adverse Reactions (6.2)]. Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO and dexamethasone [see Dosage and Administration (2.4)]. 5.9 Leukoencephalopathy Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown. 5.10 Preparation and Administration Errors Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration strictly to minimize medication errors (including underdose and overdose) [see Dosage and Administration (2.5) and Instructions for Use]. 5.11 Immunization The safety of immunization with live viral vaccines during or following BLINCYTO therapy has not been studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO. 5.12 Benzyl Alcohol Toxicity in Neonates Serious adverse reactions, including fatal reactions and the “gasping syndrome,” have been reported in very low birth weight (VLBW) neonates born weighing less than 1500 g, and early preterm neonates (infants born less than 34 weeks gestational age) who received intravenous drugs containing benzyl alcohol as a preservative. Early preterm VLBW neonates may be more likely to develop these reactions, because they may be less able to metabolize benzyl alcohol [see Use in Specific Populations (8.4)]. Use the preservative-free preparations of BLINCYTO where possible in neonates. When prescribing BLINCYTO (with preservative) for neonatal patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative), other products containing benzyl alcohol or other excipients (e.g., ethanol, propylene glycol) which compete with benzyl alcohol for the same metabolic pathway. Monitor neonatal patients receiving BLINCYTO (with preservative) for new or worsening metabolic acidosis. The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known. The BLINCYTO 72-Hour bag (with preservative) and 96-Hour bag (with preservative) contain 2.5 mg of benzyl alcohol per mL, and the 7-Day bag (with preservative) contains 12 of 42 Reference ID: 5497479 7.4 mg of benzyl alcohol per mL. The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg [see Use in Specific Populations (8.4)]. 5.13 Embryo-Fetal Toxicity Based on its mechanism of action, BLINCYTO may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with BLINCYTO and for 48 hours after the last dose [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Cytokine Release Syndrome [see Warnings and Precautions (5.1)] • Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome [see Warnings and Precautions (5.2)] • Infections [see Warnings and Precautions (5.3)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] • Neutropenia and Febrile Neutropenia [see Warnings and Precautions (5.5)] • Effects on Ability to Drive and Use Machines [see Warnings and Precautions (5.6)] • Elevated Liver Enzymes [see Warnings and Precautions (5.7)] • Pancreatitis [see Warnings and Precautions (5.8)] • Leukoencephalopathy [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of BLINCYTO in adult and pediatric patients one month and older with MRD-positive B-cell precursor ALL (n = 137), relapsed or refractory B-cell precursor ALL (n = 267), and Philadelphia chromosome-negative B-cell precursor ALL in consolidation (n = 165) was evaluated in clinical studies. The most common adverse reactions (≥ 20%) to BLINCYTO in this pooled population were pyrexia, infusion-related reactions, headache, infection, musculoskeletal pain, neutropenia, nausea, anemia, thrombocytopenia, and diarrhea. MRD-positive B-cell Precursor ALL The safety of BLINCYTO in patients with MRD-positive B-cell precursor ALL was evaluated in two single-arm clinical studies in which 137 adult patients were treated with BLINCYTO. The median age of the study population was 45 years (range: 18 to 77 years). The most common adverse reactions (≥ 20%) were pyrexia, infusion-related reactions, headache, infections (pathogen unspecified), tremor, and chills. Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal 13 of 42 Reference ID: 5497479 infection. Adverse reactions of Grade 3 or higher were reported in 64% of patients. Discontinuation of therapy due to adverse reactions occurred in 17% of patients; neurologic events were the most frequently reported reasons for discontinuation. There were 2 fatal adverse reactions that occurred within 30 days of the end of BLINCYTO treatment (atypical pneumonia and subdural hemorrhage). Table 6 summarizes the adverse reactions occurring at a ≥ 10% incidence for any grade or ≥ 5% incidence for Grade 3 or higher. Table 6. Adverse Reactions Occurring at ≥ 10% Incidence for Any Grade or ≥ 5% Incidence for Grade 3 or Higher in BLINCYTO-treated Adult Patients with MRD-Positive B-cell Precursor ALL Adverse Reaction BLINCYTO (N = 137) Any Grade* n (%) Grade ≥ 3* n (%) Blood and lymphatic system disorders Neutropenia1 21 (15) 21 (15) Leukopenia2 19 (14) 13 (9) Thrombocytopenia3 14 (10) 8 (6) Cardiac disorders Arrhythmia4 17 (12) 3 (2) General disorders and administration site conditions Pyrexia5 125 (91) 9 (7) Chills 39 (28) 0 (0) Infections and infestations Infections - pathogen unspecified 53 (39) 11 (8) Injury, poisoning and procedural complications Infusion-related reaction6 105 (77) 7 (5) Investigations Decreased immunoglobulins7 25 (18) 7 (5) Weight increased 14 (10) 1 (< 1) Hypertransaminasemia8 13 (9) 9 (7) Musculoskeletal and connective tissue disorders Back pain 16 (12) 1 (< 1) Nervous system disorders Headache9 54 (39) 5 (4) Tremor9,10 43 (31) 6 (4) Aphasia9 16 (12) 1 (< 1) Dizziness9 14 (10) 1 (< 1) Encephalopathy9,11 14 (10) 6 (4) Psychiatric disorders Insomnia9,12 24 (18) 1 (< 1) Respiratory, thoracic and mediastinal disorders Cough 18 (13) 0 (0) Skin and subcutaneous tissue disorders 14 of 42 Reference ID: 5497479 Adverse Reaction Rash13 Vascular disorders Hypotension BLINCYTO (N = 137) Any Grade* Grade ≥ 3* n (%) n (%) 22 (16) 1 (< 1) 19 (14) 1 (< 1) * Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 1 Neutropenia includes febrile neutropenia, neutropenia, and neutrophil count decreased. 2 Leukopenia includes leukopenia and white blood cell count decreased. 3 Thrombocytopenia includes platelet count decreased and thrombocytopenia. 4 Arrhythmia includes bradycardia, sinus arrhythmia, sinus bradycardia, sinus tachycardia, tachycardia and ventricular extrasystoles. 5 Pyrexia includes body temperature increased and pyrexia. 6 Infusion-related reaction is a composite term that includes the term infusion-related reaction and the following events occurring with the first 48 hours of infusion and the event lasted ≤ 2 days: cytokine release syndrome, eye swelling, hypertension, hypotension, myalgia, periorbital edema, pruritus generalized, pyrexia, and rash. 7 Decreased immunoglobulins includes blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, hypogammaglobulinemia, hypoglobulinemia, and immunoglobulins decreased. 8 Hypertransaminasemia includes alanine aminotransferase increased, aspartate aminotransferase increased, and hepatic enzyme increased. 9 May represent ICANS. 10 Tremor includes essential tremor, intention tremor, and tremor. 11 Encephalopathy includes cognitive disorder, depressed level of consciousness, disturbance in attention, encephalopathy, lethargy, leukoencephalopathy, memory impairment, somnolence, and toxic encephalopathy. 12 Insomnia includes initial insomnia, insomnia, and terminal insomnia. 13 Rash includes dermatitis contact, eczema, erythema, rash, and rash maculopapular. Additional adverse reactions in adult patients with MRD-positive ALL that did not meet the threshold criteria for inclusion in Table 6 were: Blood and lymphatic system disorders: anemia General disorders and administration site conditions: edema peripheral, pain, and chest pain (includes chest pain and musculoskeletal chest pain) Hepatobiliary disorders: blood bilirubin increased Immune system disorders: hypersensitivity and cytokine release syndrome Infections and infestations: viral infectious disorders, bacterial infectious disorders, and fungal infectious disorders Injury, poisoning and procedural complications: medication error and overdose (includes overdose and accidental overdose) Investigations: blood alkaline phosphatase increased Musculoskeletal and connective tissue disorders: pain in extremity and bone pain Nervous system disorders: seizure (includes seizure and generalized tonic-clonic seizure), speech disorder, and hypoesthesia Psychiatric disorders: confusional state, disorientation, and depression Respiratory, thoracic and mediastinal disorders: dyspnea and productive cough Vascular disorders: hypertension (includes blood pressure increased and hypertension) flushing (includes flushing and hot flush), and capillary leak syndrome Relapsed or Refractory B-cell Precursor ALL 15 of 42 Reference ID: 5497479 The safety of BLINCYTO was evaluated in a randomized, open-label, active-controlled clinical study (TOWER Study) in which 376 adult patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL were treated with BLINCYTO (n = 267) or standard of care (SOC) chemotherapy (n = 109). The median age of BLINCYTO-treated patients was 37 years (range: 18 to 80 years), 60% were male, 84% were White, 7% Asian, 2% were Black or African American, 2% were American Indian or Alaska Native, and 5% were Multiple/Other. The most common adverse reactions (≥ 20%) in the BLINCYTO arm were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia. Adverse reactions of Grade 3 or higher were reported in 87% of patients. Discontinuation of therapy due to adverse reactions occurred in 12% of patients treated with BLINCYTO; neurologic events and infections were the most frequently reported reasons for discontinuation of treatment due to an adverse reaction. Fatal adverse events occurred in 16% of patients. The majority of the fatal events were infections. The adverse reactions occurring at a ≥ 10% incidence for any grade or ≥ 5% incidence for Grade 3 or higher in the BLINCYTO-treated patients in first cycle of therapy are summarized in Table 7. Table 7. Adverse Reactions Occurring at ≥ 10% Incidence for Any Grade or ≥ 5% Incidence for Grade 3 or Higher in BLINCYTO-Treated Patients in First Cycle of Therapy for Adult Patients with Relapsed or Refractory B-cell Precursor ALL (TOWER Study) Adverse Reaction BLINCYTO (N = 267) Standard of Care (SOC) Chemotherapy (N = 109) Any Grade* n (%) Grade ≥ 3* n (%) Any Grade* n (%) Grade ≥ 3* n (%) Blood and lymphatic system disorders Neutropenia1 84 (31) 76 (28) 67 (61) 61 (56) Anemia2 68 (25) 52 (19) 45 (41) 37 (34) Thrombocytopenia3 57 (21) 47 (18) 42 (39) 40 (37) Leukopenia4 21 (8) 18 (7) 9 (8) 9 (8) Cardiac disorders Arrhythmia5 37 (14) 5 (2) 18 (17) 0 (0) General disorders and administration site conditions Pyrexia 147 (55) 15 (6) 43 (39) 4 (4) Edema6 48 (18) 3 (1) 20 (18) 1 (1) Immune system disorders Cytokine release syndrome7 37 (14) 8 (3) 0 (0) 0 (0) Infections and infestations Infections - pathogen unspecified 74 (28) 40 (15) 50 (46) 35 (32) Bacterial infectious disorders 38 (14) 19 (7) 35 (32) 21 (19) Viral infectious disorders 30 (11) 4 (1) 14 (13) 0 (0) Fungal infectious disorders 27 (10) 13 (5) 15 (14) 9 (8) Injury, poisoning and procedural complications Infusion-related reaction8 79 (30) 9 (3) 9 (8) 1 (1) Investigations 16 of 42 Reference ID: 5497479 Adverse Reaction BLINCYTO (N = 267) Standard of Care (SOC) Chemotherapy (N = 109) Any Grade* n (%) Grade ≥ 3* n (%) Any Grade* n (%) Grade ≥ 3* n (%) Hypertransaminasemia9 40 (15) 22 (8) 13 (12) 7 (6) Nervous system disorders Headache10 61 (23) 1 (< 1) 30 (28) 3 (3) Skin and subcutaneous tissue disorders Rash11 31 (12) 2 (1) 21 (19) 0 (0) * Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 1 Neutropenia includes agranulocytosis, febrile neutropenia, neutropenia, and neutrophil count decreased. 2 Anemia includes anemia and hemoglobin decreased. 3 Thrombocytopenia includes platelet count decreased and thrombocytopenia. 4 Leukopenia includes leukopenia and white blood cell count decreased. 5 Arrhythmia includes arrhythmia, atrial fibrillation, atrial flutter, bradycardia, sinus bradycardia, sinus tachycardia, supraventricular tachycardia, and tachycardia. 6 Edema includes face edema, fluid retention, edema, edema peripheral, peripheral swelling, and swelling face. 7 Cytokine release syndrome includes cytokine release syndrome and cytokine storm. 8 Infusion-related reaction is a composite term that includes the term infusion-related reaction and the following events occurring with the first 48 hours of infusion and the event lasted ≤ 2 days: pyrexia, cytokine release syndrome, hypotension, myalgia, acute kidney injury, hypertension, and rash erythematous. 9 Hypertransaminasemia includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, and transaminases increased. 10 May represent ICANS. 11 Rash includes erythema, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash pruritic, skin exfoliation, and toxic skin eruption. Selected laboratory abnormalities worsening from baseline Grade 0-2 to treatment-related maximal Grade 3-4 in first cycle of therapy are shown in Table 8. Table 8. Selected Laboratory Abnormalities Worsening from Baseline Grade 0-2 to Treatment-related Maximal Grade 3-4* in First Cycle of Therapy for Adult Patients with Relapsed or Refractory B-cell Precursor ALL (TOWER Study) BLINCYTO Grade 3 or 4 (%) SOC Chemotherapy Grade 3 or 4 (%) Hematology Decreased lymphocyte count Decreased white blood cell count Decreased hemoglobin Decreased neutrophil count Decreased platelet count 80 53 29 57 47 83 97 43 68 85 Chemistry Increased ALT Increased bilirubin Increased AST 11 5 8 11 4 4 * Includes only patients who had both baseline and at least one laboratory measurement during first cycle of therapy available. 17 of 42 Reference ID: 5497479 Other important adverse reactions from pooled relapsed or refractory B-cell precursor ALL studies were: Blood and lymphatic system disorders: lymphadenopathy, hematophagic histiocytosis, and leukocytosis (includes leukocytosis and white blood cell count increased) General disorders and administration site conditions: chills, chest pain (includes chest discomfort, chest pain, musculoskeletal chest pain, and non-cardiac chest pain), pain, body temperature increased, hyperthermia, and systemic inflammatory response syndrome Hepatobiliary disorders: hyperbilirubinemia (includes blood bilirubin increased and hyperbilirubinemia) Immune system disorders: hypersensitivity (includes hypersensitivity, anaphylactic reaction, angioedema, dermatitis allergic, drug eruption, drug hypersensitivity, erythema multiforme, and urticaria) Injury, poisoning and procedural complications: medication error and overdose (includes overdose, medication error, and accidental overdose) Investigations: weight increased, decreased immunoglobulins (includes immunoglobulins decreased, blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, and hypogammaglobulinemia), blood alkaline phosphatase increased, and hypertransaminasemia Metabolism and nutrition disorders: tumor lysis syndrome Musculoskeletal and connective tissue disorders: back pain, bone pain, and pain in extremity Nervous system disorders: tremor (resting tremor, intention tremor, essential tremor, and tremor), altered state of consciousness (includes altered state of consciousness, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, stupor, and somnolence), dizziness, memory impairment, seizure (includes seizure, and atonic seizure), aphasia, cognitive disorder, speech disorder, hypoesthesia, encephalopathy, paresthesia, and cranial nerve disorders (trigeminal neuralgia, trigeminal nerve disorder, sixth nerve paralysis, cranial nerve disorder, facial nerve disorder, and facial paresis) Psychiatric disorders: insomnia, disorientation, confusional state, and depression (includes depressed mood, depression, suicidal ideation, and completed suicide) Respiratory, thoracic and mediastinal disorders: dyspnea (includes acute respiratory failure, dyspnea, dyspnea exertional, respiratory failure, respiratory distress, bronchospasm, bronchial hyperreactivity, tachypnea, and wheezing), cough, and productive cough Vascular disorders: hypotension (includes blood pressure decreased, hypotension, hypovolemic shock, and circulatory collapse), hypertension (includes blood pressure increased, hypertension, and hypertensive crisis), flushing (includes flushing and hot flush), and capillary leak syndrome B-cell Precursor ALL in the Consolidation Phase Study E1910 The safety of a consolidation regimen comprised of multiple cycles of BLINCYTO monotherapy in addition to multiple cycles of chemotherapy (BLINCYTO arm) was evaluated in a randomized trial in adult patients with newly diagnosed Philadelphia chromosome-negative B-cell precursor ALL (Study E1910) [NCT02003222] [see Clinical Studies (14.3)] which included 111 patients treated in the BLINCYTO arm and 112 patients treated in the chemotherapy alone arm. In the BLINCYTO arm, the median (range) of cycles was 8 (1-8) (4 cycles of BLINCYTO and 4 cycles of chemotherapy). In the chemotherapy alone arm, the median (range) of cycles was 4 (1-4). Fatal adverse reactions occurred in 2 patients (2%) during BLINCYTO cycles and were due to infection (n = 1) and coagulopathy (n = 1). Permanent discontinuation of BLINCYTO due to an adverse reaction occurred in 2% of patients. Dosage interruptions of BLINCYTO due to an adverse reaction occurred in 5% of patients. Dose reductions of BLINCYTO due to an adverse reaction occurred in 28% of patients. 18 of 42 Reference ID: 5497479 The most common (≥ 20%) adverse reactions during consolidation cycles in the BLINCYTO arm were neutropenia, thrombocytopenia, anemia, leukopenia, headache, infection, nausea, lymphopenia, diarrhea, musculoskeletal pain, and tremor. The adverse reactions occurring at a difference between arms in incidence of ≥ 10% for All Grades or ≥ 5% for Grade 3 or higher are summarized in Table 9. Table 9. Adverse Reactions with a Difference Between Arms of ≥ 10% for Any Grade or ≥ 5% for Grade 3 or 4 during Consolidation (Study E1910) Adverse Reaction Consolidation Consisting of BLINCYTO Cycles + Chemotherapy Cycles (n = 111) Chemotherapy Cycles Alone (n = 112) All Grades (%)7 Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Blood and lymphatic system disorders Neutropenia1 82 77 89 89 Thrombocytopenia1 75 57 75 71 Anemia 59 29 50 38 Leukopenia1 43 41 57 56 Lymphopenia1 32 30 25 23 Febrile neutropenia 19 19 25 25 Gastrointestinal disorders Nausea2 32 5 22 4 Diarrhea1 29 3 15 3 Immune system disorders Cytokine release syndrome3 16 4 0 0 Infections and infestations Infection – pathogen unspecified 35 31 22 21 Musculoskeletal and connective tissue disorders Musculoskeletal pain4 23 5 5 4 Nervous system disorders Headache6 41 5 30 5 Tremor6 23 3 3 0 Aphasia5,6 10 8 0 0 Vascular disorders Hypertension 12 10 5 3 1 Other related adverse reactions included: 2Nausea: vomiting; 3Cytokine release syndrome: capillary leak syndrome; 4Musculoskeletal pain: pain in extremity, back pain, arthralgia, myalgia, neck pain, flank pain, bone pain, non-cardiac chest pain; 5Aphasia: dysarthria. 6 May represent ICANS. 7 Includes the following fatal adverse reaction: infection (n = 1). Study 20120215 The safety of BLINCYTO as the 3rd cycle of the consolidation phase was evaluated in a randomized, open-label study (Study 20120215) following induction and two cycles of consolidation chemotherapy in pediatric and young adult patients with high-risk first-relapsed B-cell precursor ALL [see Clinical Studies (14.3)]. The study included 54 patients treated with one cycle of BLINCYTO and 52 patients treated with one cycle of chemotherapy. 19 of 42 Reference ID: 5497479 Serious adverse reactions occurred in 28% of patients who received BLINCYTO. Permanent discontinuation of BLINCYTO due to an adverse reaction occurred in 4% of patients. Adverse reactions that led to discontinuation included nervous system disorder and seizure. Dosage interruptions of BLINCYTO due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dosage interruption in > 2% of patients included nervous system disorder. The most common (≥ 20%) adverse reactions in the BLINCYTO arm were pyrexia, nausea, headache, rash, hypogammaglobulinemia, and anemia. The adverse reactions occurring at a difference of ≥ 10% incidence for any grade or at a difference of ≥ 5% incidence for Grade 3 or 4 between the BLINCYTO arm and chemotherapy arm are summarized in Table 10. Table 10. Adverse Reactions with a Difference Between Arms of ≥ 10% for Any Grade or ≥ 5% for Grade 3 or 4 during Consolidation Cycle 3 (Study 20120215) Adverse Reaction BLINCYTO (n = 54) Chemotherapy (n = 52) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Blood and lymphatic system disorders Anemia1 24 15 46 42 Neutropenia1 19 17 35 31 Thrombocytopenia1 15 15 39 35 Febrile neutropenia 2 2 25 25 Gastrointestinal disorders Nausea2 43 2 31 2 Abdominal pain1 13 0 23 2 Stomatitis3 11 4 60 29 General disorders and administration site conditions Pyrexia 76 6 19 0 Hepatobiliary disorders Liver function test abnormal4 9 6 27 17 Immune system disorders Hypogammaglobulinemia1 24 2 12 2 Infections and infestations Infection – pathogen unspecified 13 6 29 10 Musculoskeletal and connective tissue disorders Musculoskeletal pain5 9 0 29 2 Nervous system disorders Headache7 37 0 15 0 Skin and subcutaneous disorders Rash1 22 2 12 0 Vascular disorders Hemorrhage6 11 2 23 6 1 Other related adverse reactions included: 2Nausea: vomiting; 3Stomatitis: mouth ulceration, mucosal inflammation; 4Liver function test abnormal: alanine aminotransferase increased, aspartate aminotransferase increased, gamma­ glutamyltransferase increased, hypertransaminasemia; 5Musculoskeletal pain: back pain, pain in extremity, bone pain; 6Hemorrhage: Epistaxis, petechiae, hemarthrosis, hematoma, hematuria. 7 May represent ICANS. 20 of 42 Reference ID: 5497479 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of BLINCYTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Fatal pancreatitis in patients receiving BLINCYTO in combination with dexamethasone. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with BLINCYTO. Initiation of BLINCYTO treatment causes transient release of cytokines that may suppress CYP450 enzymes. The highest drug-drug interaction risk is during the first 9 days of the first cycle and the first 2 days of the second cycle in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index. In these patients, monitor for toxicity (e.g., warfarin) or drug concentrations (e.g., cyclosporine). Adjust the dose of the concomitant drug as needed [see Clinical Pharmacology (12.2, 12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, BLINCYTO may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of BLINCYTO in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, a murine surrogate molecule administered to pregnant mice crossed the placental barrier (see Data). Blinatumomab causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on expression of CD19 on B-cells and the finding of B-cell depletion in non-pregnant animals, blinatumomab can cause B-cell lymphocytopenia in infants exposed to blinatumomab in-utero. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Due to the potential for B-cell lymphocytopenia in infants following exposure to BLINCYTO in utero, the infant’s B lymphocytes should be monitored before the initiation of live virus vaccination [see Warnings and Precautions (5.11)]. 21 of 42 Reference ID: 5497479 Data Animal Data Animal reproduction studies have not been conducted with blinatumomab. In embryo-fetal developmental toxicity studies, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis. The surrogate molecule crossed the placental barrier and did not cause embryo-fetal toxicity or teratogenicity. The expected depletions of B and T cells were observed in the pregnant mice, but hematological effects were not assessed in fetuses. 8.2 Lactation Risk Summary There is no information regarding the presence of blinatumomab in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breastfed infants from BLINCYTO, including B-cell lymphocytopenia, advise patients not to breastfeed during treatment with BLINCYTO and for 48 hours after the last dose. 8.3 Females and Males of Reproductive Potential BLINCYTO may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating BLINCYTO treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with BLINCYTO and for 48 hours after the last dose. 8.4 Pediatric Use The safety and efficacy of BLINCYTO in pediatric patients less than 1 month of age have not been established for any indication [see Indications and Usage (1)]. Minimal Residual Disease (MRD)-Positive B-cell Precursor ALL The safety and efficacy of BLINCYTO for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% have been established in pediatric patients one month and older. Use of BLINCYTO is supported by evidence from two randomized, controlled trials (Study AALL1331, NCT02101853 and Study 20120215, NCT02393859) [see Clinical Studies (14.3)] in pediatric patients with first relapsed B-cell precursor ALL. Both studies included pediatric patients with MRD-positive B-cell precursor ALL. The studies included pediatric patients treated with BLINCYTO in the following age groups: 6 infants (1 month up to less than 2 years), 165 children (2 years up to less than 12 years), 22 of 42 Reference ID: 5497479 and 70 adolescents (12 years to less than 17 years). In general, the adverse reactions in BLINCYTO-treated pediatric patients were similar in type to those seen in adult patients with MRD-positive ALL [see Adverse Reactions (6.1)], and no differences in safety were observed between the different pediatric age subgroups. Relapsed or Refractory B-cell Precursor ALL The safety and efficacy of BLINCYTO have been established in pediatric patients one month and older with relapsed or refractory B-cell precursor ALL. Use of BLINCYTO is supported by a single-arm trial in pediatric patients with relapsed or refractory B-cell precursor ALL. This study included pediatric patients in the following age groups: 10 infants (1 month up to less than 2 years), 40 children (2 years up to less than 12 years), and 20 adolescents (12 years to less than 18 years). No differences in efficacy were observed between the different age subgroups [see Clinical Studies (14.2)]. In general, the adverse reactions in BLINCYTO-treated pediatric patients with relapsed or refractory ALL were similar in type to those seen in adult patients with relapsed or refractory B-cell precursor ALL [see Adverse Reactions (6.1)]. Adverse reactions that were observed more frequently (≥ 10% difference) in the pediatric population compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increased (17% vs. 6%). In pediatric patients less than 2 years old (infants) with relapsed or refractory ALL, the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%). B-cell Precursor ALL in the Consolidation Phase The safety and efficacy of BLINCYTO for the treatment of Philadelphia-chromosome negative B-cell precursor ALL in the consolidation phase have been established in pediatric patients one month and older. Use of BLINCYTO for this indication is supported by extrapolation from a randomized controlled study in adults (Study E1910, NCT02003222) and evidence from two randomized, controlled studies in pediatric patients (Study 20120215 and Study AALL1331) [see Adverse Reactions (6.1), Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14.3)]. Benzyl Alcohol Toxicity in Neonates Serious and fatal adverse reactions, including “gasping syndrome,” can occur in very low birth weight (VLBW) neonates born weighing less than 1500 g, and early preterm neonates (infants born less than 34 weeks gestational age) treated with benzyl alcohol-preserved drugs intravenously. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high concentrations of benzyl alcohol and its metabolite in the blood and urine (blood concentration of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known [see Warnings and Precautions (5.12)]. Use the preservative-free formulations of BLINCYTO where possible in neonates. When prescribing BLINCYTO (with preservative) in neonatal patients, consider the combined daily metabolic load of 23 of 42 Reference ID: 5497479 benzyl alcohol from all sources including BLINCYTO (with preservative). The BLINCYTO 72-Hour bag (with preservative) and 96-Hour bag (with preservative) contain 2.5 mg of benzyl alcohol per mL, and the 7-Day bag (with preservative) contains 7.4 mg of benzyl alcohol per mL. The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg [see Warnings and Precautions (5.12)]. Benzyl alcohol administration may contribute to metabolic acidosis in pediatric patients, particularly those with immaturity of the metabolic pathway for alcohol, or those with underlying conditions or receiving concomitant medications that could predispose to acid base imbalance. Monitor these patients during use of BLINCYTO (with preservative) for new or worsening metabolic acidosis. 8.5 Geriatric Use There were 158 (7%) patients 65 years and older in clinical studies of BLINCYTO for patients with MRD positive, CD19-positive B-cell precursor ALL in first or second complete remission, relapsed or refractory CD19-positive B-cell precursor ALL, and CD19-positive, Philadelphia-chromosome negative B-cell precursor ALL in the consolidation phase. Of the total number of BLINCYTO-treated patients in these studies, 123 (8%) were 65 years of age and older and 21 (1%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, elderly patients experienced a higher rate of serious infections and neurological toxicities, including cognitive disorder, encephalopathy, and confusion [see Warnings and Precautions (5.2, 5.3)]. 10 OVERDOSAGE Overdoses have been observed, including one adult patient who received 133-fold the recommended therapeutic dose of BLINCYTO delivered over a short duration. In the dose evaluation phase of a study in pediatric and adolescent patients with relapsed or refractory B-cell precursor ALL, one patient experienced a fatal cardiac failure event in the setting of life-threatening cytokine release syndrome (CRS) at a 30 mcg/m2/day (higher than the maximum tolerated/recommended) dose [see Warnings and Precautions (5.1) and Adverse Reactions (6)]. Overdoses resulted in adverse reactions, which were consistent with the reactions observed at the recommended dosage and included fever, tremors, and headache. In the event of overdose, interrupt the infusion, monitor the patient for signs of adverse reactions, and provide supportive care [see Warnings and Precautions (5.10)]. Consider re-initiation of BLINCYTO at the recommended dosage when all adverse reactions have resolved and no earlier than 12 hours after interruption of the infusion [see Dosage and Administration (2.1, 2.2 and 2.3)]. 11 DESCRIPTION Blinatumomab is a bispecific CD19-directed CD3 T-cell engager. Blinatumomab is produced in Chinese hamster ovary cells. It consists of 504 amino acids and has a molecular weight of approximately 54 kilodaltons. Each BLINCYTO package contains one vial BLINCYTO and one vial IV Solution Stabilizer. 24 of 42 Reference ID: 5497479 BLINCYTO (blinatumomab) for injection is supplied in a single-dose vial as a sterile, preservative-free, white to off-white lyophilized powder for intravenous use. Each single-dose vial of BLINCYTO contains 35 mcg blinatumomab, citric acid monohydrate (3.35 mg), lysine hydrochloride (23.23 mg), polysorbate 80 (0.64 mg), trehalose dihydrate (95.5 mg), and sodium hydroxide to adjust pH to 7.0. After reconstitution with 3 mL of preservative-free Sterile Water for Injection, USP, the resulting concentration is 12.5 mcg/mL blinatumomab. IV Solution Stabilizer is supplied in a single-dose vial as a sterile, preservative-free, colorless to slightly yellow, clear solution. Each single-dose vial of IV Solution Stabilizer contains citric acid monohydrate (52.5 mg), lysine hydrochloride (2283.8 mg), polysorbate 80 (10 mg), sodium hydroxide to adjust pH to 7.0, and water for injection. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T-cells. It activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B-cells. Blinatumomab mediates the formation of a synapse between the T-cell and the tumor cell, upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T-cells, which result in redirected lysis of CD19+ cells. 12.2 Pharmacodynamics During the continuous intravenous infusion over 4 weeks, the pharmacodynamic response was characterized by T-cell activation and initial redistribution, reduction in peripheral B-cells, and transient cytokine elevation. Peripheral T-cell redistribution (i.e., T-cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred after start of BLINCYTO infusion or dose escalation. T-cell counts initially declined within 1 to 2 days and then returned to baseline levels within 7 to 14 days in the majority of patients. Increase of T-cell counts above baseline (T-cell expansion) was observed in few patients. Peripheral B-cell counts decreased to less than or equal to 10 cells/microliter during the first treatment cycle at doses ≥ 5 mcg/m2/day or ≥ 9 mcg/day in the majority of patients. No recovery of peripheral B-cell counts was observed during the 2-week BLINCYTO-free period between treatment cycles. Incomplete depletion of B-cells occurred at doses of 0.5 mcg/m2/day and 1.5 mcg/m2/day and in a few patients at higher doses. Cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, and IFN-γ were measured, and IL-6, IL-10, and IFN-γ were elevated. The highest elevation of cytokines was observed in the first 2 days following start of BLINCYTO infusion. The elevated cytokine levels returned to baseline within 24 to 48 hours during the infusion. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial 48 hours of the first treatment cycle. 12.3 Pharmacokinetics The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 90 mcg/m2/day (approximately equivalent to 9 to 162 mcg/day) in adult patients. Following continuous intravenous 25 of 42 Reference ID: 5497479 infusion, the steady-state serum concentration (Css) was achieved within a day and remained stable over time. The increase in mean Css values was approximately proportional to the dose in the range tested. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed or refractory ALL, the mean (SD) Css was 228 (356) pg/mL and 616 (537) pg/mL, respectively. The pharmacokinetics of blinatumomab in adult patients with MRD-positive B-cell precursor ALL and in adult patients with B-cell precursor ALL in the consolidation phase were similar to adult patients with relapsed or refractory ALL. Distribution The estimated mean (SD) volume of distribution based on terminal phase (Vz) was 5.27 (4.37) L with continuous intravenous infusion of blinatumomab. Elimination The estimated mean (SD) systemic clearance with continuous intravenous infusion in patients receiving blinatumomab in clinical studies was 3.10 (2.94) L/hour. The mean (SD) half-life was 2.20 (1.34) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses. Metabolism The metabolic pathway of blinatumomab has not been characterized. Like other protein therapeutics, blinatumomab is expected to be degraded into small peptides and amino acids via catabolic pathways. Specific Populations There were no clinically meaningful differences in the pharmacokinetics of blinatumomab based on age (0.6 to 80 years of age), sex, race (72% White, 17% Asian, 3% Black), ethnicity, Philadelphia chromosome status or mild (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST) or moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST). The effect of other races or severe hepatic impairment (total bilirubin > 3 × ULN, any AST) on the pharmacokinetics of blinatumomab is unknown. Body surface area (0.4 to 2.9 m2) influences the pharmacokinetics of blinatumomab, supporting BSA-based dosing in patients < 45 kg. Pediatric Patients The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 30 mcg/m2/day in pediatric patients. At the recommended doses of 5 and 15 mcg/m2/day for the treatment of relapsed or refractory B-cell precursor ALL, the mean (SD) steady-state concentration (Css) values were 162 (179) and 533 (392) pg/mL, respectively. The pharmacokinetics of blinatumomab in pediatric patients with MRD-positive B-cell precursor ALL and in pediatric patients with B-cell precursor ALL in the consolidation phase were similar to pediatric patients with relapsed or refractory ALL. In all pediatric patients with ALL, the estimated mean (SD) volume of distribution (Vz), clearance (CL), and terminal half-life (t1/2,z) in Cycle 1 were 4.14 (3.32) L/m2, 1.65 (1.62) L/hour/m2, and 2.14 (1.44) hours, respectively. The steady-state concentrations of blinatumomab were comparable in adult and pediatric patients at the equivalent dose levels based on BSA-based regimens. 26 of 42 Reference ID: 5497479 Patients with Renal Impairment Pharmacokinetic analyses showed an approximately 2-fold difference in mean blinatumomab clearance values between patients with moderate renal impairment (CrCL ranging from 30 to 59 mL/min, N = 49) and normal renal function (CrCL more than 90 mL/min, N = 674). However, high interpatient variability was discerned (CV% up to 98.4%), and clearance values in renal impaired patients were essentially within the range observed in patients with normal renal function. There is no information available in patients with severe renal impairment (CrCL 15-29 mL/min) or patients on hemodialysis. Drug Interaction Studies Transient elevation of cytokines may suppress CYP450 enzyme activities [see Drug Interactions (7) and Clinical Pharmacology (12.2)]. 12.6 Immunogenicity The observed incidence of anti-drug antibody is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibody in the studies described below with the incidence of anti-drug antibodies in other studies, including those of BLINCYTO. The immunogenicity of BLINCYTO has been evaluated using either an electrochemiluminescence detection technology (ECL) or an enzyme-linked immunosorbent assay (ELISA) screening immunoassay for the detection of binding anti-blinatumomab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies. In clinical studies, less than 2% of patients treated with BLINCYTO tested positive for binding anti-blinatumomab antibodies. Of patients who developed anti-blinatumomab antibodies, 7 out of 9 (78%) had in vitro neutralizing activity. Anti-blinatumomab antibody formation may affect pharmacokinetics of BLINCYTO. Overall, the totality of clinical evidence supports the finding that anti-blinatumomab antibodies are not suggestive of any clinical impact on the safety or effectiveness of BLINCYTO. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or genotoxicity studies have been conducted with blinatumomab. No studies have been conducted to evaluate the effects of blinatumomab on fertility. A murine surrogate molecule had no adverse effects on male and female reproductive organs in a 13-week repeat-dose toxicity study in mice. 27 of 42 Reference ID: 5497479 14 CLINICAL STUDIES 14.1 MRD-positive B-cell Precursor ALL BLAST Study The efficacy of BLINCYTO was evaluated in an open-label, multicenter, single-arm study (BLAST Study) [NCT01207388] that included patients who were ≥ 18 years of age, had received at least 3 chemotherapy blocks of standard ALL therapy, were in hematologic complete remission (defined as < 5% blasts in bone marrow, absolute neutrophil count > 1 Gi/L, platelets > 100 Gi/L) and had MRD at a level of ≥ 0.1% using an assay with a minimum sensitivity of 0.01%. BLINCYTO was administered at a constant dose of 15 mcg/m2/day (equivalent to the recommended dosage of 28 mcg/day) intravenously for all treatment cycles. Patients received up to 4 cycles of treatment. Dose adjustment was possible in case of adverse events. The treated population included 86 patients in first or second hematologic complete remission (CR1 or CR2). The demographics and baseline characteristics are shown in Table 11. The median number of treatment cycles was 2 (range: 1 to 4). Following treatment with BLINCYTO, 45 out of 61 (73.8%) patients in CR1 and 14 out of 25 (56.0%) patients in CR2 underwent allogeneic hematopoietic stem cell transplantation in continuous hematologic complete remission. Table 11. Demographics and Baseline Characteristics in BLAST Study Characteristics BLINCYTO (N = 86) Age Median, years (min, max) 43 (18, 76) ≥ 65 years, n (%) 10 (12) Males, n (%) 50 (58) Race, n (%) Asian 1 (1) Other (mixed) 0 (0) White 76 (88) Unknown 9 (11) Philadelphia chromosome disease status, n (%) Positive 1 (1) Negative 85 (99) Relapse history, n (%) Patients in 1st CR 61 (71) Patients in 2nd CR 25 (29) MRD level at baseline*, n (%) ≥ 10% 7 (8) 28 of 42 Reference ID: 5497479 Characteristics BLINCYTO (N = 86) ≥ 1% and < 10% 34 (40) ≥ 0.1% and < 1% 45 (52) * Assessed centrally using an assay with minimum sensitivity of 0.01%. Efficacy was based on achievement of undetectable MRD within one cycle of BLINCYTO treatment and hematological relapse-free survival (RFS). The assay used to assess MRD response had a sensitivity of 0.01% for 6 patients and ≤ 0.005% for 80 patients. Overall, undetectable MRD was achieved by 70 patients (81.4%: 95% CI: 71.6%, 89.0%). The median hematological RFS was 22.3 months. Table 12 shows the MRD response and hematological RFS by remission number. Table 12. Efficacy Results in Patients ≥ 18 Years of Age with MRD-positive B-cell Precursor ALL (BLAST Study) Patients in CR1 (n = 61) Patients in CR2 (n = 25) Complete MRD response1, n (%), [95% CI] 52 (85.2) [73.8, 93.0] 18 (72.0) [50.6, 87.9] Median hematological relapse-free survival2 in months (range) 35.2 (0.4, 53.5) 12.3 (0.7, 42.3) 1. Complete MRD response was defined as the absence of detectable MRD confirmed in an assay with minimum sensitivity of 0.01%. 2. Relapse was defined as either hematological or extramedullary relapse, secondary leukemia, or death due to any cause; Includes time after transplantation; Kaplan-Meier estimate. Undetectable MRD was achieved by 65 of 80 patients (81.3%: 95% CI: 71.0%, 89.1%) with an assay sensitivity of at least 0.005%. The estimated median hematological RFS among the 80 patients using the higher sensitivity assay was 24.2 months (95% CI: 17.9, NE). 14.2 Relapsed/Refractory B-cell Precursor ALL TOWER Study The efficacy of BLINCYTO was compared to standard of care (SOC) chemotherapy in a randomized, open-label, multicenter study (TOWER Study) [NCT02013167]. Eligible patients were ≥ 18 years of age with relapsed or refractory B-cell precursor ALL [> 5% blasts in the bone marrow and refractory to primary induction therapy or refractory to last therapy, untreated first relapse with first remission duration < 12 months, untreated second or later relapse, or relapse at any time after allogeneic hematopoietic stem cell transplantation (alloHSCT)]. BLINCYTO was administered at 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for Cycles 2-5 in 42-day cycles and for Cycles 6-9 in 84-day cycles. Dose adjustment was possible in case of adverse events. SOC chemotherapy included fludarabine, cytarabine arabinoside, and granulocyte colony-stimulating factor (FLAG); high-dose cytarabine arabinoside (HiDAC); high-dose methotrexate- (HDMTX) based combination; or clofarabine/clofarabine-based regimens. 29 of 42 Reference ID: 5497479 There were 405 patients randomized 2:1 to receive BLINCYTO or investigator-selected SOC chemotherapy. Randomization was stratified by age (< 35 years vs. ≥ 35 years of age), prior salvage therapy (yes vs. no), and prior alloHSCT (yes vs. no) as assessed at the time of consent. The demographics and baseline characteristics were well-balanced between the two arms (see Table 13). Table 13. Demographics and Baseline Characteristics in TOWER Study Characteristics BLINCYTO (N = 271) Standard of Care (SOC) Chemotherapy (N = 134) Age Median, years (min, max) 37 (18, 80) 37 (18, 78) < 35 years, n (%) 124 (46) 60 (45) ≥ 35 years, n (%) 147 (54) 74 (55) ≥ 65 years, n (%) 33 (12) 15 (11) ≥ 75 years, n (%) 10 (4) 2 (2) Males, n (%) 162 (60) 77 (58) Race, n (%) American Indian or Alaska Native 4 (2) 1 (1) Asian 19 (7) 9 (7) Black (or African American) 5 (2) 3 (2) Multiple 2 (1) 0 Native Hawaiian or Other Pacific Islander 1 (0) 1 (1) Other 12 (4) 8 (6) White 228 (84) 112 (84) Prior salvage therapy 171 (63) 70 (52) Prior alloHSCT1 94 (35) 46 (34) Eastern Cooperative Group Status - n (%) 0 96 (35) 52 (39) 1 134 (49) 61 (46) 2 41 (15) 20 (15) Unknown 0 1 (1) Refractory to salvage treatment - n (%) Yes 87 (32) 34 (25) No 182 (67) 99 (74) Unknown 2 (1) 1 (1) Maximum of central/local bone marrow blasts - n (%) ≤ 5% 0 0 > 5 to < 10% 9 (3) 7 (5) 10 to < 50% 60 (22) 23 (17) ≥ 50% 201 (74) 104 (78) Unknown 1 (0) 0 1 alloHSCT = allogeneic hematopoietic stem cell transplantation. Of the 271 patients randomized to the BLINCYTO arm, 267 patients received BLINCYTO treatment. The median number of treatment cycles was two (range: 1 to 9 cycles); 267 (99%) received Cycles 1-2 30 of 42 Reference ID: 5497479 1.0 0.9 0.8 -~ 0.7 :s 0.6 .l!l e 0.5 Q. oi > 0.4 ·~ en 0.3 0.2 0.1 0.0 0 Number of Subjects at Risk Blincyto 271 SOC Chemo 1 34 176 71 A censored subject is indicated by a Vertical Bar I. 124 41 Blincyto (N=271) Median OS, mo 7.7 (5.6, 9.6) HR (Blincyto/SOC Chemo) (95% Cl) p-value (2-sided) 9 12 15 18 Months J ------ Blincyto --- SOC Chemo I 79 27 45 17 27 7 9 4 0.71 (0 .55, 0.93) 0.012 21 I I I I I SOC Chemo (N=134) 4.0 (2.9, 5.3) 24 27 0 0 GRH03SB,1 (induction), 86 (32%) received Cycles 3-5 (consolidation), and 27 (10%) received Cycles 6-9 (continued therapy). Of the 134 patients on the SOC arm, 25 dropped out prior to start of study treatment, and 109 patients received a median of 1 treatment cycle (range: 1 to 4 cycles). The determination of efficacy was based on overall survival (OS). The study demonstrated statistically significant improvement in OS for patients treated with BLINCYTO as compared to SOC chemotherapy. See Figure 1 and Table 14 below for efficacy results from the TOWER Study. Figure 1. Kaplan-Meier Curve of Overall Survival in TOWER Study Table 14. Efficacy Results in Patients ≥ 18 Years of Age with Philadelphia Chromosome-Negative Relapsed or Refractory B-cell Precursor ALL (TOWER Study) BLINCYTO (N = 271) SOC Chemotherapy (N = 134) Overall Survival Number of deaths (%) 164 (61) 87 (65) Median, months [95% CI] 7.7 [5.6, 9.6] 4.0 [2.9, 5.3] Hazard Ratio [95% CI]1 0.71 [0.55, 0.93] p-value2 0.012 Overall Response CR4/CRh*5, n (%) [95% CI] 115 (42) [37, 49] 27 (20) [14, 28] Treatment difference [95% CI] 22 [13, 31] p-value3 < 0.001 CR, n (%) [95% CI] 91 (34) [28, 40] 21 (16) [10, 23] Treatment difference [95% CI] 18 [10, 26] p-value3 < 0.001 31 of 42 Reference ID: 5497479 I I I I BLINCYTO (N = 271) SOC Chemotherapy (N = 134) MRD Response6 for CR/CRh* n1/n2 (%)7 [95% CI] 73/115 (64) [54, 72] 14/27 (52) [32, 71] 1 Based on stratified Cox’s model. 2 The p-value was derived using stratified log rank test. 3 The p-value was derived using Cochran-Mantel-Haenszel test. 4 CR (complete remission) was defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/microliter and absolute neutrophil counts [ANC] > 1,000/microliter). 5 CRh* (complete remission with partial hematologic recovery) was defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/microliter and ANC > 500/microliter). 6 MRD (minimum residual disease) response was defined as MRD by PCR or flow cytometry < 1 × 10-4 (0.01%). 7 n1: number of patients who achieved MRD response and CR/CRh*; n2: number of patients who achieved CR/CRh* and had a postbaseline assessment. Study MT103-211 Study MT103-211 [NCT01466179] was an open-label, multicenter, single-arm study. Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (relapsed with first remission duration of ≤ 12 months in first salvage or relapsed or refractory after first salvage therapy or relapsed within 12 months of alloHSCT, and had ≥ 10% blasts in bone marrow). BLINCYTO was administered as a continuous intravenous infusion. The recommended dose for this study was determined to be 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. The treated population included 185 patients who received at least 1 infusion of BLINCYTO; the median number of treatment cycles was 2 (range: 1 to 5). Patients who responded to BLINCYTO but later relapsed had the option to be retreated with BLINCYTO. Among treated patients, the median age was 39 years (range: 18 to 79 years), 63 out of 185 (34.1%) had undergone HSCT prior to receiving BLINCYTO, and 32 out of 185 (17.3%) had received more than 2 prior salvage therapies. Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with an MRD-negative CR/CR with partial hematological recovery (CR/CRh*) within 2 cycles of treatment with BLINCYTO. Table 15 shows the efficacy results from this study. The HSCT rate among those who achieved CR/CRh* was 39% (30 out of 77). Table 15. Efficacy Results in Patients ≥ 18 Years of Age with Philadelphia Chromosome-Negative Relapsed or Refractory B-cell Precursor ALL (Study MT103-211) N = 185 CR1 CRh*2 CR/CRh* n (%) [95% CI] 60 (32.4) [25.7, 39.7] 17 (9.2) [5.4, 14.3] 77 (41.6) [34.4, 49.1] MRD response3 n1/n2 (%)4 [95% CI] 48/60 (80.0) [67.7, 89.2] 10/17 (58.8) [32.9, 81.6] 58/77 (75.3) [64.2, 84.4] 32 of 42 Reference ID: 5497479 N = 185 CR1 CRh*2 CR/CRh* DOR/RFS5 Median (months) (range) 6.7 (0.46 – 16.5) 5.0 (0.13 – 8.8) 5.9 (0.13 – 16.5) 1 CR (complete remission) was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/microliter and absolute neutrophil counts [ANC] > 1,000/microliter). 2 CRh* (complete remission with partial hematological recovery) was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/microliter and ANC > 500/microliter). 3 MRD (minimal residual disease) response was defined as MRD by PCR < 1 × 10-4 (0.01%). 4 n1: number of patients who achieved MRD response and the respective remission status; n2: number of patients who achieved the respective remission status. Six CR/CRh* responders with missing MRD data were considered as MRD-nonresponders. 5 DOR (duration of response)/RFS (relapse-free survival) was defined as time since first response of CR or CRh* to relapse or death, whichever is earlier. Relapse was defined as hematological relapse (blasts in bone marrow greater than 5% following CR) or an extramedullary relapse. ALCANTARA Study The efficacy of BLINCYTO for treatment of Philadelphia chromosome-positive B-cell precursor ALL was evaluated in an open-label, multicenter, single-arm study (ALCANTARA Study) [NCT02000427]. Eligible patients were ≥ 18 years of age with Philadelphia chromosome-positive B-cell precursor ALL, relapsed or refractory to at least 1 second generation or later tyrosine kinase inhibitor (TKI), or intolerant to second generation TKI, and intolerant or refractory to imatinib mesylate. BLINCYTO was administered at 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. The treated population included 45 patients who received at least one infusion of BLINCYTO; the median number of treatment cycles was 2 (range: 1 to 5). The demographics and baseline characteristics are shown in Table 16. Table 16. Demographics and Baseline Characteristics in ALCANTARA Study Characteristics BLINCYTO (N = 45) Age Median, years (min, max) 55 (23, 78) ≥ 65 years and < 75 years, n (%) 10 (22) ≥ 75 years, n (%) 2 (4) Males, n (%) 24 (53) Race, n (%) Asian 1 (2) Black (or African American) 3 (7) Other 2 (4) White 39 (87) Disease History Prior TKI treatment1, n (%) 1 7 (16) 2 21 (47) 33 of 42 Reference ID: 5497479 Characteristics BLINCYTO (N = 45) ≥ 3 17 (38) Prior salvage therapy 31 (62) Prior alloHSCT2 20 (44) Bone marrow blasts3 ≥ 50% to < 75% 6 (13) ≥ 75% 28 (62) 1 Number of patients that failed ponatinib = 23 (51%) 2 alloHSCT = allogeneic hematopoietic stem cell transplantation 3 centrally assessed Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with an MRD-negative CR/CR with partial hematological recovery (CR/CRh*) within 2 cycles of treatment with BLINCYTO. Table 17 shows the efficacy results from ALCANTARA Study. Five of the 16 responding (31%) patients underwent allogeneic HSCT in CR/CRh* induced with BLINCYTO. There were 10 patients with documented T315I mutation; four achieved CR within 2 cycles of treatment with BLINCYTO. Table 17. Efficacy Results in Patients ≥ 18 Years of Age with Philadelphia Chromosome-Positive Relapsed or Refractory B-cell Precursor ALL (ALCANTARA Study) N = 45 CR1 CRh*2 CR/CRh* n (%) [95% CI] 14 (31) [18, 47] 2 (4) [1, 15] 16 (36) [22, 51] MRD response3 n1/n2 (%)4 [95% CI] 12/14 (86) [57, 98] 2/2 (100) [16, 100] 14/16 (88) [62, 98] DOR/RFS5 Median (months) (range) 6.7 (3.6 – 12.0) NE6 (3.7 – 9.0) 6.7 (3.6 – 12.0) 1 CR (complete remission) was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/microliter and absolute neutrophil counts [ANC] > 1,000/microliter). 2 CRh* (complete remission with partial hematological recovery) was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/microliter and ANC > 500/microliter). 3 MRD (minimal residual disease) response was defined as MRD by PCR < 1 × 10-4 (0.01%). 4 n1: number of patients who achieved MRD response and the respective remission status; n2: number of patients who achieved the respective remission status. Six CR/CRh* responders with missing MRD data were considered as MRD-nonresponders. 5 DOR (duration of response)/RFS (relapse-free survival) was defined as time since first response of CR or CRh* to relapse or death, whichever is earlier. Relapse was defined as hematological relapse (blasts in bone marrow greater than 5% following CR) or an extramedullary relapse. 6 NE = not estimable Study MT103-205 Study MT103-205 [NCT01471782] was an open-label, multicenter, single-arm study in pediatric patients with relapsed or refractory B-cell precursor ALL (second or later bone marrow relapse, any marrow relapse after allogeneic HSCT, or refractory to other treatments, and had > 25% blasts in bone marrow). BLINCYTO was administered at 5 mcg/m2/day on Days 1-7 and 15 mcg/m2/day on Days 8-28 for Cycle 1, and 15 mcg/m2/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of 34 of 42 Reference ID: 5497479 adverse events. Patients who responded to BLINCYTO but later relapsed had the option to be retreated with BLINCYTO. Among the 70 treated patients, the median age was 8 years (range: 7 months to 17 years), 40 out of 70 (57.1%) had undergone allogeneic HSCT prior to receiving BLINCYTO, and 39 out of 70 (55.7%) had refractory disease. The median number of treatment cycles was 1 (range: 1 to 5). Twenty-three out of 70 (32.9%) patients achieved CR/CRh* within the first 2 treatment cycles with 17 out of 23 (73.9%) occurring within Cycle 1 of treatment. See Table 18 for the efficacy results from the study. The HSCT rate among those who achieved CR/CRh* was 48% (11 out of 23). Table 18. Efficacy Results in Patients < 18 Years of Age with Relapsed or Refractory B-cell Precursor ALL (Study MT103-205) N = 70 CR1 CRh*2 CR/CRh* n (%) [95% CI] 12 (17.1) [9.2, 28.0] 11 (15.7) [8.1, 26.4] 23 (32.9) [22.1, 45.1] MRD response3 n1/n2 (%)4 [95% CI] 6/12 (50.0) [21.1, 78.9] 4/11 (36.4) [10.9, 69.2] 10/23 (43.5) [23.2, 65.5] DOR/RFS5 Median (months) (range) 6.0 (0.5 – 12.1) 3.5 (0.5 – 16.4) 6.0 (0.5 – 16.4) 1 CR (complete remission) was defined as ≤ 5% of blasts in the bone marrow, no evidence of circulating blasts or extra-medullary disease, and full recovery of peripheral blood counts (platelets > 100,000/microliter and absolute neutrophil counts [ANC] > 1,000/microliter). 2 CRh* (complete remission with partial hematological recovery) was defined as ≤ 5% of blasts in the bone marrow, no evidence of circulating blasts or extramedullary disease, and partial recovery of peripheral blood counts (platelets > 50,000/microliter and ANC > 500/microliter). 3 MRD (minimal residual disease) response was defined as MRD by PCR or flow cytometry < 1 × 10-4 (0.01%). 4 n1: number of patients who achieved MRD response and the respective remission status; n2: number of patients who achieved the respective remission status. One CR/CRh* responder with missing MRD data was considered as a MRD-nonresponder. 5 DOR (duration of response)/RFS (relapse-free survival) was defined as time since first response of CR or CRh* to relapse or death, whichever is earlier. Relapse was defined as hematological relapse (blasts in bone marrow greater than 5% following CR) or an extramedullary relapse. 14.3 Philadelphia Chromosome-Negative B-cell Precursor ALL in the Consolidation Phase Study E1910 The efficacy of BLINCYTO was evaluated in a randomized, controlled study in adult patients with newly diagnosed Philadelphia chromosome-negative B-cell precursor ALL (Study E1910) [NCT02003222]. Eligible patients in hematologic complete remission (CR) or CR with incomplete peripheral blood count recovery (CRi) following induction and intensification chemotherapy were randomized 1:1 to receive a consolidation regimen comprised of multiple cycles of BLINCYTO monotherapy in addition to multiple cycles of intensive chemotherapy (BLINCYTO arm) or to intensive chemotherapy alone (chemotherapy arm). Randomization was stratified by age (< 55 years versus ≥ 55 years), CD20 status, rituximab use, and intent to undergo allogeneic stem cell transplantation (HSCT). The postremission treatment consisted of a BFM-like chemotherapy regimen adapted from the E2993/UKALLXII clinical trial. Patients randomized to the BLINCYTO arm were to receive 2 cycles of BLINCYTO followed by 3 cycles of consolidation chemotherapy, then a third cycle of BLINCYTO 35 of 42 Reference ID: 5497479 followed by the fourth cycle of chemotherapy and a fourth cycle of BLINCYTO (total 8 cycles). BLINCYTO was administered as a continuous intravenous infusion at 28 mcg/day on Days 1-28. Patients randomized to the chemotherapy arm of the study were to receive 4 cycles of chemotherapy alone (total 4 cycles). Patients on the BLINCYTO arm could go to HSCT after 1 - 2 cycles of BLINCYTO and up to 2 cycles of consolidation chemotherapy, and patients randomized to the chemotherapy arm could go to HSCT after intensification and up to 3 cycles of consolidation chemotherapy. All patients who completed consolidation but did not go to HSCT received maintenance therapy through 2 1/2 years from the start of intensification. The demographics and baseline characteristics are provided in Table 19. Table 19. Demographics and Baseline Characteristics in Study E1910 Characteristics Consolidation Consisting of BLINCYTO Cycles + Chemotherapy Cycles (n = 112) Chemotherapy Cycles Alone (n = 112) Age Median, years (min, max) 52 (31, 69) 50 (30, 70) Males, n (%) 55 (49) 56 (50) Race, n (%) American Indian or Alaska Native 2 (2) 1 (1) Asian 3 (3) 2 (2) Black (or African American) 9 (8) 4 (4) Native Hawaiian or Other Pacific Islander 1 (1) 0 White 87 (78) 89 (79) Not Reported 5 (4) 6 (5) Unknown 5 (4) 10 (9) Ethnicity, n (%) Hispanic or Latino 13 (12) 10 (9) Not Hispanic or Latino 95 (85) 95 (85) Not Reported 1 (1) 2 (2) Unknown 3 (3) 5 (4) Stratification Factors, n (%) Age < 55 years at randomization 65 (58) 65 (58) CD20 positive 45 (40) 46 (41) Rituximab use 33 (29) 36 (32) Planned allogeneic SCTa 36 (32) 35 (31) a allogeneic SCT = allogeneic stem cell transplantation. Efficacy was established on the basis of overall survival (OS). The results with a median follow-up of 3.6 years are shown in Figure 2 and Table 20. 36 of 42 Reference ID: 5497479 1.0 0.9 0.8 _ ~ Stratified Log Rank: p = 0.003 '--~ ~-- -~J1--1H Hazard ratio (95% Cl) from stratified Cox regression: 0.42 (0.24, 0.75) ll!Hf---1~+-Hf +-Hll: -f +Hl:-fl- - --f-fH!lll- - - - - -f--f H-+- -1 0.7 ~ 0.6 :0 "' .0 0.5 2 c... c,j 0.4 > -~ 0.3 :::, (/) 0.2 0.1 0.0 Number of Subjects at Risk: 1: 112 106 99 65 41 18 7 1 0 2: 112 96 85 53 28 14 4 0 0 2 3 4 5 6 7 8 9 10 Years Treatment (N): 3-year KM estimate% (95% Cl) 1: Blincyto + Chemotherapy (N = 112): 84.8 (76.3, 90.4) --- 2: Chemotherapy (N = 112): 69.0 (58.7, 77.2) Figure 2. Kaplan-Meier for Overall Survival in Study E1910 KM = Kaplan-Meier. CI = Confidence Interval. N = Number of patients in the analysis set. Censor indicated by vertical bar. Table 20. Overall Survival in Study E1910 BLINCYTO + Chemotherapy Chemotherapy Number of patients 112 112 Overall Survival 3-year Kaplan-Meier estimate (%) [95% CI] 84.8 [76.3, 90.4] 69.0 [58.7, 77.2] Hazard ratio [95% CI]a 0.42 [0.24, 0.75] p-valueb 0.003 CI = Confidence interval. Overall survival (OS) is calculated from time of randomization until death due to any cause. a The hazard ratio estimates are obtained from a stratified Cox regression model at the 3rd interim analysis. b The p-value was derived using the stratified log rank test. In a later analysis with a median follow-up of 4.5 years, the 5-year OS was 82.4% [95% CI (73.7, 88.4)] in the BLINCYTO + chemotherapy arm and 62.5% [95% CI (52.0, 71.3)] in the chemotherapy arm. The hazard ratio was 0.44 [95% CI (0.25, 0.76)]. Study 20120215 The efficacy of BLINCYTO compared to consolidation chemotherapy was evaluated in a randomized, controlled, open-label, multicenter study (Study 20120215) [NCT02393859]. Eligible patients were 28 days to 18 years old and had high-risk, first-relapsed, Philadelphia chromosome-negative B-cell precursor ALL with < 25% blasts in the bone marrow after induction and 2 cycles of consolidation chemotherapy. Patients were randomized 1:1 to receive BLINCYTO or the IntReALLHR2010 HC3 intensive combination chemotherapy as the third cycle of consolidation. Patients in the BLINCYTO arm received one cycle of BLINCYTO as a continuous intravenous infusion at 15 mcg/m2/day over 4 weeks (maximum daily dose was not to exceed 28 mcg/day). Randomization was stratified by age, minimal residual disease status determined at the end of induction based on local assessment, and bone marrow 37 of 42 Reference ID: 5497479 status determined at the end of the second block of consolidation chemotherapy. Patients were to proceed to HSCT after this cycle of consolidation. There were 54 patients randomized to the BLINCYTO arm and 57 to the chemotherapy arm. The demographics and baseline characteristics are shown in Table 21. Table 21. Demographics and Baseline Characteristics in Study 20120215 Characteristics Consolidation Cycle 3 BLINCYTO (N = 54) Chemotherapy (N = 57) Age, n (%) Median, (range) 6 (1, 17) 5 (1, 17) < 1 year 0 0 1 to 9 years 39 (72) 41 (72) ≥ 10 to 18 years 15 (28) 16 (28) Males, n (%) 30 (56) 23 (40) Race, n (%) American Indian or Alaska Native 0 0 Asian 1 (2) 3 (5) Black (or African American) 0 3 (5) Native Hawaiian or Other Pacific Islander 0 0 Other 3 (6) 5 (9) White 50 (93) 46 (81) Cytomorphology at randomization, n (%) Blasts < 5% 54 (100) 54 (95) Blasts ≥ 5% and < 25% 0 2 (4) Blasts ≥ 25% blasts 0 0 Not evaluable 0 1 (2) MRD PCR value at randomization, n (%) ≥ 10-3 11 (20) 16 (28) < 10-3 and ≥ 10-4 15 (28) 6 (11) < 10-4 20 (37) 23 (40) Unknown 8 (15) 12 (21) Time from first diagnosis to relapse (month), n (%) < 18 months 19 (35) 22 (39) ≥ 18 months and ≤ 30 months 32 (59) 31 (54) > 30 months 3 (6) 4 (7) N = number of patients in the analysis set; n = number of patients with observed data; MRD = minimal residual disease; PCR = polymerase chain reaction. Efficacy was established on the basis of overall survival (OS) and relapse-free survival (RFS). See Table 22, Figure 3, and Figure 4 for results of OS and RFS from Study 20120215. 38 of 42 Reference ID: 5497479 1.0 0.9 0.8 ~ 0.7 :c 0.6 "' .c 0.5 e "- 'iii 0.4 > ·2: 0.3 :::, C/l 0.2 0.1 0.0 1: 2: I I I I I Hazard ratio (95% Cl) from stratified Cox regression: 0.35 (0.17, 0.70) ·---, .. f--------------+----f-------------------------l----H-1-------14l __ l-+H-f------+-H----+--H---li-+--+----fl----f+---l---f Number of Subjects at Risk: 57 49 47 42 37 35 33 28 27 25 25 25 25 23 20 19 16 14 13 10 7 4 4 4 4 4 2 0 54 53 48 46 45 42 42 41 40 39 39 39 39 38 36 35 28 25 23 22 20 18 16 10 9 6 4 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 84 Months Treatment (N): 5 year KM estimate(%) (95% Cl) -- 1: Chemotherapy (N = 57): 41 .4 (26.3, 55.9) ·---------· 2: Blincyto (N = 54): 78.4 (64.2, 87.4) Table 22. Efficacy Results in Pediatric Patients with High-Risk First Relapsed B-cell Precursor ALL (Study 20120215) Consolidation Cycle 3 BLINCYTO (N = 54) Chemotherapy (N = 57) Overall Survival Number of deaths (%) 11 (20.4) 28 (49.1) 5-year KM estimate (%) [95% CI]a 78.4 [64.2, 87.4] 41.4 [26.3, 55.9] Hazard Ratio [95% CI]b 0.35 [0.17, 0.70] Relapse-free Survival Events, n (%) 20 (37.0) 37 (64.9) 5-year KM estimate (%) [95% CI]a 61.1 [46.3, 72.9] 27.6 [16.2, 40.3] Hazard Ratio [95% CI]b 0.38 [0.22, 0.66] NE = Not estimable. CI = Confidence interval. a Months were calculated as days from randomization date to event/censor date, divided by 30.5. b The hazard ratio estimates are obtained from the Cox proportional hazard model. The median follow-up time for OS was 55.2 months for the overall population. Figure 3 presents a Kaplan-Meier plot comparing OS between treatment arms for the overall population. Figure 3. Kaplan-Meier for Overall Survival (Study 20120215) KM = Kaplan-Meier. CI = Confidence Interval. N = Number of patients in the analysis set. Censor indicated by vertical bar. 39 of 42 Reference ID: 5497479 1.0 f···\ Hazard ratio (95% Cl) from stratified Cox regression: 0.38 (0.22, 0.66) 0.9 0.8 0.7 ~ 0.6 i5 ,.,,\.., ••• , .. , ....................... . 1······························++····L~1fH··fH+-····+··+···-+···H+·+···+····IH····+···H···I "' .c 0.5 e Cl. oi 0.4 > ·2: 0.3 ::, en 0.2 0.1 0.0 Number of Subjects at Risk: 1 : 57 38 29 22 20 18 17 16 15 15 14 14 14 13 11 10 8 7 7 7 6 3 3 3 3 3 2 0 2: 54 53 44 37 35 34 34 34 34 31 31 31 31 31 30 28 21 18 16 15 14 13 12 8 7 4 3 1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 84 Months Treatment (N): 5 year KM estimate(%) (95% Cl) 1: Chemotherapy (N = 57): 27.6 (16.2, 40.3) •·········· 2: Blincyto (N = 54): 61 .1 (46.3, 72.9) Figure 4. Kaplan-Meier for Relapse-free Survival (Study 20120215) KM = Kaplan-Meier. CI = Confidence Interval. N = Number of patients in the analysis set. Censor indicated by vertical bar. 16 HOW SUPPLIED/STORAGE AND HANDLING Each BLINCYTO package (NDC 55513-160-01) contains: • One BLINCYTO (blinatumomab) for injection 35 mcg single-dose vial containing a sterile, preservative-free, white to off-white lyophilized powder and • One IV Solution Stabilizer 10 mL single-dose glass vial containing a sterile, preservative-free, colorless to slightly yellow, clear solution. Store BLINCYTO and IV Solution Stabilizer vials in the original package refrigerated at 2°C to 8°C (36°F to 46°F) and protect from light until time of use. Do not freeze. BLINCYTO and IV Solution Stabilizer vials may be stored for a maximum of 8 hours at room temperature [23°C to 27°C (73°F to 81°F)] in the original carton to protect from light. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Cytokine Release Syndrome (CRS) Advise patients of the risk of CRS and infusion reactions, and to contact their healthcare professional for signs and symptoms associated with CRS or infusion reactions (pyrexia, fatigue, nausea, vomiting, chills, hypotension, rash, and wheezing) [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. 40 of 42 Reference ID: 5497479 Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome Advise patients of the risk of neurological toxicities, including ICANS, and to contact their healthcare professional for signs and symptoms associated with this event (including convulsions, speech disorders, and confusion) [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Infections Advise patients of the risk of infections, and to contact their healthcare professional for signs or symptoms of infection [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. Inform patients of the importance of keeping the skin clean around the intravenous catheter to reduce the risk of infection. Pancreatitis Advise patients of the risk of pancreatitis and to contact their healthcare provider for signs or symptoms of pancreatitis, which include severe and persistent stomach pain, with or without nausea and vomiting [see Warnings and Precautions (5.8) and Adverse Reactions (6.2)]. Driving and Engaging in Hazardous Occupations Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. Patients should be advised that they may experience neurological events, including seizures and ICANS [see Warnings and Precautions (5.6)]. Infusion Pump Errors Inform patients they should not adjust the setting on the infusion pump. Any changes to pump function may result in dosing errors. If there is a problem with the infusion pump or the pump alarms, patients should contact their doctor or nurse immediately. Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant [see Warnings and Precautions (5.13) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with BLINCYTO and for 48 hours after the last dose [see Warnings and Precautions (5.13) and Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment with BLINCYTO and for 48 hours after the last dose [see Use in Specific Populations (8.2)]. Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 41 of 42 Reference ID: 5497479 AMGEN® U.S. License No. 1080 BLINCYTO® (blinatumomab) Patent: http://pat.amgen.com/blincyto/ © 2014-20XX Amgen Inc. All rights reserved. VXX 42 of 42 Reference ID: 5497479 Medication Guide BLINCYTO® (blin sye toe) (blinatumomab) for injection What is the most important information I should know about BLINCYTO? Call your healthcare provider or get emergency medical help right away if you get any of the symptoms listed below. BLINCYTO may cause serious side effects that can be severe, life-threatening, or lead to death, including: • Cytokine Release Syndrome (CRS) and Infusion Reactions. Symptoms of CRS and infusion reactions may include: o fever o vomiting o tiredness or weakness o chills o dizziness o face swelling o headache o wheezing or trouble breathing o low blood pressure o skin rash o nausea • Neurologic problems. Symptoms of neurologic problems may include: o seizures o loss of balance o difficulty in speaking or slurred speech o headache o loss of consciousness o difficulty with facial movements, hearing, vision, o trouble sleeping or swallowing o confusion and disorientation o tremors People with Down Syndrome may have a higher risk of seizures with BLINCYTO treatment. Your healthcare provider will check for these problems during treatment with BLINCYTO. Your healthcare provider may temporarily stop or completely stop your treatment with BLINCYTO, if you have severe side effects. See “What are the possible side effects of BLINCYTO?” below for other side effects of BLINCYTO. What is BLINCYTO? BLINCYTO is a prescription medicine used to treat adults and children 1 month and older with: • B-cell precursor acute lymphoblastic leukemia (ALL) in remission when only a small number of cancer cells remain in the body (minimal residual disease) • B-cell precursor ALL that has come back or did not respond to previous treatments • Philadelphia-chromosome negative B-cell precursor ALL in the consolidation phase of chemotherapy treatment with multiple phases ALL is a cancer of the blood in which a particular kind of white blood cell is growing out of control. It is not known if BLINCYTO is safe and effective in children less than 1 month of age. Who should not receive BLINCYTO? Do not receive BLINCYTO if you are allergic to blinatumomab or to any of the ingredients of BLINCYTO. See the end of this Medication Guide for a complete list of ingredients in BLINCYTO. Before receiving BLINCYTO, tell your healthcare provider about all of your medical conditions, including if you or your child: • have a history of neurological problems, such as seizures, confusion, trouble speaking or loss of balance • have Down Syndrome • have an infection • have ever had an infusion reaction after receiving BLINCYTO or other medications • have a history of radiation treatment to the brain, or chemotherapy treatment • are scheduled to receive a vaccine. You should not receive a “live vaccine” for at least 2 weeks before you start treatment with BLINCYTO, during treatment, and until your immune system recovers after you receive your last cycle of BLINCYTO. If you are not sure about the type of vaccine, ask your healthcare provider. • are pregnant or plan to become pregnant. BLINCYTO may harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with BLINCYTO. o If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with BLINCYTO. o Females who are able to become pregnant should use an effective form of birth control (contraception) during treatment with BLINCYTO, and for 48 hours after your last dose of BLINCYTO. • are breastfeeding or plan to breastfeed. It is not known if BLINCYTO passes into your breast milk. You should not breastfeed during treatment with BLINCYTO and for 48 hours after your last dose. Reference ID: 5497479 Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will I receive BLINCYTO? • BLINCYTO will be given to you by intravenous (IV) infusion into your vein by an infusion pump. • Your healthcare provider will decide the number of treatment cycles of BLINCYTO. o You will receive BLINCYTO by continuous IV infusion for 4 weeks (28 days), followed by a 2-week (14 days) break during which you will not receive BLINCYTO. This is 1 treatment cycle (42 days). • Your healthcare provider may prescribe continued therapy. o You will receive BLINCYTO by continuous IV infusion for 4 weeks (28 days), followed by an 8-week (56 days) break during which you will not receive BLINCYTO. This is 1 treatment cycle (84 days). • Your healthcare provider may give you BLINCYTO in a hospital or clinic for the first 3 or 9 days of the first treatment cycle and for the first 2 days of the second cycle to check you for side effects. If you receive additional treatment cycles of BLINCYTO or if your treatment is stopped for a period of time and restarted, you may also be treated in a hospital or clinic. • Your healthcare provider may change your dose of BLINCYTO, delay, or completely stop treatment with BLINCYTO if you have certain side effects. • Your healthcare provider will do blood tests during treatment with BLINCYTO to check you for side effects. • Before you receive BLINCYTO, you will be given a corticosteroid medicine to help reduce infusion reactions. • Before and during treatment with BLINCYTO, you may be given chemotherapy as an injection into the space that surrounds the spinal cord and the brain (intrathecal injection) to help prevent central nervous system relapse of ALL. • It is very important to keep the area around the IV catheter clean to reduce the risk of getting an infection. Your healthcare provider will show you how to care for your catheter site. • Do not change the settings on your infusion pump, even if there is a problem with your pump or your pump alarm sounds. Any changes to your infusion pump settings may cause a dose that is too high or too low to be given. Call your healthcare provider or nurse right away if you have any problems with your pump or your pump alarm sounds. What should I avoid while receiving BLINCYTO? Do not drive, operate heavy machinery, or do other dangerous activities while you are receiving BLINCYTO because BLINCYTO can cause neurological symptoms, such as dizziness, seizures, and confusion. What are the possible side effects of BLINCYTO? BLINCYTO may cause serious side effects, including: See “What is the most important information I should know about BLINCYTO?” • Infections. BLINCYTO may cause life-threatening infections that may lead to death. Tell your healthcare provider right away if you develop any signs or symptoms of an infection. • Tumor Lysis Syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can be life-threatening and may lead to death. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with BLINCYTO, including: o nausea and vomiting o dark or cloudy urine o confusion o reduced amount of urine o shortness of breath o unusual tiredness o irregular heartbeat o muscle cramps • Low white blood cell counts (neutropenia). Neutropenia is common with BLINCYTO treatment and may sometimes be life-threatening. Low white blood cell counts can increase your risk of infection. Your healthcare provider will do blood tests to check your white blood cell count during treatment with BLINCYTO. Tell your healthcare provider right away if you get a fever. • Abnormal liver blood tests. Your healthcare provider will do blood tests to check your liver before you start BLINCYTO and during treatment with BLINCYTO. • Inflammation of the pancreas (pancreatitis). Pancreatitis may happen in people treated with BLINCYTO and corticosteroids. It may be severe and lead to death. Tell your healthcare provider right away if you have severe stomach-area pain that does not go away. The pain may happen with or without nausea and vomiting. The most common side effects of BLINCYTO include: • fever • muscle, joint and bone pain • reactions related to infusion of the medicine • low white blood cell count (neutropenia) such as face swelling, low blood pressure, and high • nausea blood pressure (infusion-related reactions) • low red blood cell count (anemia) • headache • low platelet count (thrombocytopenia) Reference ID: 5497479 AMGEN® • infection • diarrhea These are not all the possible side effects of BLINCYTO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store BLINCYTO? Intravenous (IV) bags containing BLINCYTO for infusion will arrive in a special package. • Do not open the package. • Do not freeze the package. • The package containing BLINCYTO will be opened by your healthcare provider and stored in the refrigerator at 36°F to 46°F (2°C to 8°C). • Do not throw away (dispose of) any BLINCYTO in your household trash. Talk with your healthcare provider about disposal of BLINCYTO and used supplies. Keep BLINCYTO and all medicines out of reach of children. General information about safe and effective use of BLINCYTO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BLINCYTO for a condition for which it was not prescribed. Do not give BLINCYTO to other people even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about BLINCYTO that is written for health professionals. What are the ingredients in BLINCYTO? Active ingredient: blinatumomab Inactive ingredients: citric acid monohydrate, lysine hydrochloride, polysorbate 80, trehalose dihydrate, sodium hydroxide and preservative-free sterile water for injection. Inactive ingredients of IV Solution Stabilizer: citric acid monohydrate, lysine hydrochloride, polysorbate 80, sodium hydroxide and water for injection. Manufactured by: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799 U.S. License No. 1080 © 2014-2024 Amgen Inc. All rights reserved. vxx For more information, go to www.blincyto.com or call Amgen at 1-800-772-6436. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2024 Reference ID: 5497479 24-Hour or 48-Hour Infusion INSTRUCTIONS FOR USE: 24-HOUR OR 48-HOUR INFUSION The preparation steps differ based on the infusion duration. Follow the steps specific to the infusion duration you are preparing. It is very important that the instructions for preparation (including admixing) and administration provided in this section are strictly followed to minimize medication errors (including underdose and overdose) [see Dosage and Administration (2.5), Warnings and Precautions (5.10)]. Aseptic Preparation Strictly observe aseptic technique when preparing the solution for infusion since BLINCYTO vials do not contain antimicrobial preservatives. To prevent accidental contamination, prepare BLINCYTO according to aseptic standards, including but not limited to: • Prepare BLINCYTO in a USP <797> compliant facility. • Prepare BLINCYTO in an ISO Class 5 laminar flow hood or better. • Ensure that the admixing area has appropriate environmental specifications, confirmed by periodic monitoring. • Ensure that personnel are appropriately trained in aseptic manipulations and admixing of oncology drugs. • Ensure that personnel wear appropriate protective clothing and gloves. • Ensure that gloves and surfaces are disinfected. Gather Equipment and Supplies for 24-Hour or 48-Hour Infusion • Preservative-Free Sterile Water for Injection, USP. • Preservative-Free 0.9% Sodium Chloride Injection, USP. • Sterile, non-pyrogenic, low protein-binding, 0.2 micron in-line filter. • Infusion bags/pump cassettes and intravenous tubing sets: Use either polyolefin, DEHP-free PVC, or ethyl vinyl acetate (EVA). - BLINCYTO is incompatible with diethylhexylphthalate (DEHP) due to the possibility of particle formation, leading to a cloudy solution. • BLINCYTO package(s), each BLINCYTO package contains: - One BLINCYTO for injection 35 mcg single-dose vial containing a sterile, preservative-free, white to off-white lyophilized powder. - More than one vial of BLINCYTO may be needed to prepare the recommended dose. - One IV Solution Stabilizer 10 mL single-dose glass vial containing a sterile, preservative-free, colorless to slightly yellow, clear solution. - Do not use IV Solution Stabilizer for reconstitution of BLINCYTO. - IV Solution Stabilizer is used to coat the intravenous bag prior to addition of reconstituted BLINCYTO to prevent adhesion of BLINCYTO to intravenous bags and intravenous tubing. 1 of 12 Reference ID: 5497479 + -- ~-----I 0 + Preparation of BLINCYTO: Reconstitution_ 1. Determine the number of BLINCYTO vials needed for a dose and infusion duration. • Refer to Table 1 (patients weighing 45 kg or more) or Table 2 (patients weighing less than 45 kg). a. Reconstitute each BLINCYTO vial with 3 mL of preservative-free Sterile Water for Injection, USP by directing the water along the walls of the BLINCYTO vial and not directly on the lyophilized powder. The resulting concentration per BLINCYTO vial is 12.5 mcg/mL. • Do not reconstitute BLINCYTO vials with the IV Solution Stabilizer (IVSS). sWFI 3 mL of Lyophilized Reconstituted Preservative-Free Sterile BLINCYTO BLINCYTO Water for Injection, USP Important: Do not reconstitute BLINCYTO vials with IV Solution Stabilizer (IVSS). b. Gently swirl contents to avoid excess foaming. • Do not shake. c. Visually inspect the reconstituted solution for particulate matter and discoloration during reconstitution and prior to preparing the intravenous bag. The resulting solution should be clear to slightly opalescent, colorless to slightly yellow. • Do not use if solution is cloudy or has precipitated. _Preparation of BLINCYTO: 24-Hour or 48-Hour Intravenous Bag_ 2. Aseptically add 270 mL of preservative-free 0.9% Sodium Chloride Injection, USP to the empty intravenous bag. Empty IV Bag Material, 270 mL of use either: Preservative-Free • Polyolefin, 0.9% NaCl Injection, Normal • DEHP-free PVC, or USP Saline • EVA IV Bag 2 of 12 Reference ID: 5497479 I + - I c:::::::::::::. l 3. Aseptically transfer 5.5 mL of IV Solution Stabilizer (IVSS) to the intravenous bag containing preservative-free 0.9% Sodium Chloride Injection, USP. • Gently mix the contents of the bag to avoid foaming. • For 24-hour infusion, transfer 5.5 mL IV Solution Stabilizer. IV Solution • For 48-hour infusion, transfer 5.5 mL IV Solution Stabilizer. Stabilizer • Discard the vial containing the unused IV Solution Stabilizer. 4. Aseptically transfer the required volume of reconstituted BLINCYTO solution into the intravenous bag containing preservative-free 0.9% Sodium Chloride Injection, USP and IV Solution Stabilizer. • Gently mix the contents of the bag to avoid foaming. • Refer to Table 1 for patients weighing 45 kg or more for the specific volume of reconstituted BLINCYTO. Reconstituted • Refer to Table 2 for patients weighing less than 45 kg BLINCYTO (dose based on BSA) for the specific volume of reconstituted BLINCYTO. • Discard the vial containing unused BLINCYTO. 5. Remove air from the intravenous bag. This is particularly important for use with an ambulatory infusion pump. Remove air from the IV Bag 6. Under aseptic conditions, attach the intravenous tubing to the intravenous bag with the sterile 0.2 micron in-line filter. • Ensure that the intravenous tubing is compatible with the infusion pump. • Use either polyolefin, DEHP-free PVC or EVA intravenous tubing sets. 7. Prime the intravenous tubing only with the solution in the bag containing the FINAL prepared BLINCYTO solution for infusion. Prime with FINAL prepared BLINCYTO solution 3 of 12 Reference ID: 5497479 8. Store refrigerated at 2°C to 8°C (36°F to 46°F) if not used immediately [see Dosage and Administration (2.6)]. Table 1. For 24-Hour and 48-Hour Infusion: Patients Weighing 45 kg or More Infusion Duration 24 hours 48 hours Reconstituted BLINCYTO Dose Volume Vials 9 mcg/day 0.83 mL 1 28 mcg/day 2.6 mL 1 9 mcg/day 1.7 mL 1 28 mcg/day 5.2 mL 2 Table 2. For 24-Hour and 48-Hour Infusion: Patients Weighing Less Than 45 kg Infusion Duration 24 hours 24 hours Dose 5 mcg/m2/day 15 mcg/m2/day BSA (m2) 1.5 – 1.59 1.4 – 1.49 1.3 – 1.39 1.2 – 1.29 1.1 – 1.19 1 – 1.09 0.9 – 0.99 0.8 – 0.89 0.7 – 0.79 0.6 – 0.69 0.5 – 0.59 0.4 – 0.49 0.35 – 0.39 0.3 – 0.34 0.25 – 0.29 0.2 – 0.24 1.5 – 1.59 1.4 – 1.49 1.3 – 1.39 1.2 – 1.29 1.1 – 1.19 1 – 1.09 0.9 – 0.99 0.8 – 0.89 0.7 – 0.79 0.6 – 0.69 0.5 – 0.59 0.4 – 0.49 0.35 – 0.39 Reconstituted BLINCYTO Volume 0.7 mL 0.66 mL 0.61 mL 0.56 mL 0.52 mL 0.47 mL 0.43 mL 0.38 mL 0.33 mL 0.29 mL 0.24 mL 0.2 mL 0.17 mL 0.15 mL 0.12 mL 0.1 mL 2.1 mL 2 mL 1.8 mL 1.7 mL 1.6 mL 1.4 mL 1.3 mL 1.1 mL 1 mL 0.86 mL 0.72 mL 0.59 mL 0.51 mL Vials 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4 of 12 Reference ID: 5497479 1 1 1 1 1 1 1 1 1 1 0.3 – 0.34 0.44 mL 1 0.25 – 0.29 0.37 mL 1 0.2 – 0.24 0.3 mL 1 48 hours 5 mcg/m2/day 1.5 – 1.59 1.4 mL 1 1.4 – 1.49 1.3 mL 1 1.3 – 1.39 1.2 mL 1 1.2 – 1.29 1.1 mL 1 1.1 – 1.19 1 mL 1 1 – 1.09 0.94 mL 1 0.9 – 0.99 0.85 mL 1 0.8 – 0.89 0.76 mL 1 0.7 – 0.79 0.67 mL 1 0.6 – 0.69 0.57 mL 1 0.5 – 0.59 0.48 mL 1 0.4 – 0.49 0.39 mL 1 0.35 – 0.39 0.34 mL 1 0.3 – 0.34 0.29 mL 1 0.25 – 0.29 0.25 mL 1 0.2 – 0.24 0.2 mL 1 48 hours 15 mcg/m2/day 1.5 – 1.59 4.2 mL 2 1.4 – 1.49 3.9 mL 2 1.3 – 1.39 3.7 mL 2 1.2 – 1.29 3.4 mL 2 1.1 – 1.19 3.1 mL 2 1 – 1.09 2.8 mL 1 0.9 – 0.99 2.6 mL 1 0.8 – 0.89 2.3 mL 1 0.7 – 0.79 2 mL 1 0.6 – 0.69 1.7 mL 1 0.5 – 0.59 1.4 mL 1 0.4 – 0.49 1.2 mL 1 0.35 – 0.39 1 mL 1 0.3 – 0.34 0.88 mL 1 0.25 – 0.29 0.75 mL 1 0.2 – 0.24 0.61 mL 1 _Administration of BLINCYTO: 24-Hour or 48-Hour Intravenous Bag_ • Administer BLINCYTO as a continuous intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm. • The starting volume (270 mL) is more than the volume administered to the patient (240 mL) to account for the priming of the intravenous tubing and to ensure that the patient will receive the full dose of BLINCYTO. • Ensure that the intravenous tubing is primed only with the solution in the bag containing the FINAL prepared BLINCYTO solution for infusion. 5 of 12 Reference ID: 5497479 • Administer the FINAL prepared BLINCYTO infusion solution using intravenous tubing that contains a sterile, non-pyrogenic, low protein-binding, 0.2 micron in-line filter for 24-hour or 48-hour bags. - For 72-hour, 96-hour, or 7-day bag administration information [see “Administration of BLINCYTO: 72-Hour, 96-Hour, or 7-Day Intravenous Bag”]. • Infuse the FINAL prepared BLINCYTO infusion solution according to the instructions on the pharmacy label on the prepared bag at one of the following constant infusion rates: - Infusion rate of 10 mL/hour for a duration of 24 hours, OR - Infusion rate of 5 mL/hour for a duration of 48 hours. • Important Note: Do not flush the BLINCYTO infusion line, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof. When administering via a multi-lumen venous catheter, infuse BLINCYTO through a dedicated lumen. Before flushing the catheter system, residual amounts of BLINCYTO must be aspirated from the catheter system to avoid bolus administration. • At the end of the infusion, any remaining solution in the intravenous bag and intravenous tubing should be discarded in accordance with local requirements. 72-Hour, 96-Hour, or 7-Day Infusion (Preservative) INSTRUCTIONS FOR USE: 72-HOUR OR 96-HOUR, OR 7-DAY INFUSION The preparation steps differ based on the infusion duration. Follow the steps specific to the infusion duration you are preparing. It is very important that the instructions for preparation (including admixing) and administration provided in this section are strictly followed to minimize medication errors (including underdose and overdose) [see Dosage and Administration (2.5), Warnings and Precautions (5.10)]. The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg [see Warnings and Precautions (5.12)]. Aseptic Preparation Strictly observe aseptic technique when preparing the solution for infusion since BLINCYTO vials do not contain antimicrobial preservatives. To prevent accidental contamination, prepare BLINCYTO according to aseptic standards, including but not limited to: • Prepare BLINCYTO in a USP <797> compliant facility. • Prepare BLINCYTO in an ISO Class 5 laminar flow hood or better. • Ensure that the admixing area has appropriate environmental specifications, confirmed by periodic monitoring. • Ensure that personnel are appropriately trained in aseptic manipulations and admixing of oncology drugs. • Ensure that personnel wear appropriate protective clothing and gloves. 6 of 12 Reference ID: 5497479 ~ / "' + I I - I I / - i ~ ~ ' ' ~ ' 0 • Ensure that gloves and surfaces are disinfected. Gather Equipment and Supplies for 72-Hour, 96-Hour, or 7-Day Infusion • Preservative-Free Sterile Water for Injection, USP. • Preservative-Free 0.9% Sodium Chloride Injection, USP. • Bacteriostatic 0.9% Sodium Chloride Injection, USP. • Infusion bags/pump cassettes and intravenous tubing sets: Use either polyolefin, DEHP-free PVC, or ethyl vinyl acetate (EVA). - BLINCYTO is incompatible with diethylhexylphthalate (DEHP) due to the possibility of particle formation, leading to a cloudy solution. • BLINCYTO package(s), each BLINCYTO package contains: - One BLINCYTO for injection 35 mcg single-dose vial containing a sterile, preservative-free, white to off-white lyophilized powder. - More than one vial of BLINCYTO may be needed to prepare the recommended dose. - One IV Solution Stabilizer 10 mL single-dose glass vial containing a sterile, preservative-free, colorless to slightly yellow, clear solution. - Do not use IV Solution Stabilizer for reconstitution of BLINCYTO. - IV Solution Stabilizer is used to coat the intravenous bag prior to addition of reconstituted BLINCYTO to prevent adhesion of BLINCYTO to intravenous bags and intravenous tubing. _Preparation of BLINCYTO: Reconstitution_ 1. Determine the number of BLINCYTO vials needed for a dose and infusion duration. • Refer to Table 3 (patients weighing 45 kg or more) or Table 4 (patients weighing between 5.4 kg and less than 45 kg). a. Reconstitute each BLINCYTO vial with 3 mL of preservative-free Sterile Water for Injection, USP by directing the water along the walls of the BLINCYTO vial and not directly on the lyophilized powder. The resulting concentration per BLINCYTO vial is 12.5 mcg/mL. • Do not reconstitute BLINCYTO vials with the IV Solution Stabilizer (IVSS). sWFI 3 mL of Lyophilized Reconstituted Preservative-Free Sterile BLINCYTO BLINCYTO Water for Injection, USP Important: Do not reconstitute BLINCYTO vials with IV Solution Stabilizer (IVSS). 7 of 12 Reference ID: 5497479 -------.§ ;; + . I~ ~= =d b. Gently swirl contents to avoid excess foaming. • Do not shake. c. Visually inspect the reconstituted solution for particulate matter and discoloration during reconstitution and prior to preparing the intravenous bag. The resulting solution should be clear to slightly opalescent, colorless to slightly yellow. • Do not use if solution is cloudy or has precipitated. _Preparation of BLINCYTO: 72-Hour, 96-Hour, or 7-Day Intravenous Bag_ 2. Aseptically add the required volume of Bacteriostatic 0.9% Sodium Chloride Injection, USP to the empty intravenous bag. • For 72-hour infusion, add 45 mL Bacteriostatic 0.9% Sodium Chloride Injection. • For 96-hour infusion, add 56 mL Bacteriostatic 0.9% Sodium Chloride Injection. • For 7-day infusion, add 90 mL Bacteriostatic 0.9% Sodium Chloride Injection. Empty IV Bag Material, Bacteriostatic use either: 0.9% NaCl • Polyolefin, Injection, USP • DEHP-free PVC, or • EVA IV Bag 3. Aseptically transfer the required volume of IV Solution Stabilizer (IVSS) to the intravenous bag containing Bacteriostatic 0.9% Sodium Chloride Injection, USP. • Gently mix the contents of the bag to avoid foaming. B.static Saline • For 72-hour infusion, transfer 3.2 mL IV Solution Stabilizer. IV Solution • For 96-hour infusion, transfer 4 mL IV Solution Stabilizer. Stabilizer • For 7-day infusion, transfer 2.2 mL IV Solution Stabilizer. • Discard the vial containing the unused IV Solution Stabilizer. 4. Aseptically transfer the required volume of reconstituted BLINCYTO solution into the intravenous bag containing Bacteriostatic 0.9% Sodium Chloride Injection, USP and IV Solution Stabilizer. • Gently mix the contents of the bag to avoid foaming. • Refer to Table 3 for patients weighing 45 kg or more for the specific volume of reconstituted BLINCYTO. Reconstituted • Refer to Table 4 for patients weighing between 5.4 kg BLINCYTO and less than 45 kg (dose based on BSA) for the specific volume of reconstituted BLINCYTO. • Discard the vial containing unused BLINCYTO. 8 of 12 Reference ID: 5497479 + I c-e:::::-, I 5. 6. 7. Aseptically add the needed volume of preservative-free 0.9% Sodium Chloride Injection, USP to the intravenous bag to obtain the final volumes within Table 3 and Table 4. • Gently mix the contents of the bag to avoid foaming. • Refer to Table 3 for patients weighing 45 kg or more for the specific volume of preservative-free Preservative-Free 0.9% Sodium Chloride Injection, USP. 0.9% NaCl • Refer to Table 4 for patients weighing between Normal Injection, USP 5.4 kg and less than 45 kg (dose based on BSA) for Saline the specific volume of preservative-free 0.9% Sodium Chloride Injection, USP. Remove air from the intravenous bag. This is particularly important for use with an ambulatory infusion pump. Remove air from the IV Bag Under aseptic conditions, attach the intravenous tubing to the intravenous bag. Do not use an in-line filter for 72-hour, 96-hour, or 7-day bags. • Ensure that the intravenous tubing is compatible with the infusion pump. • Use either polyolefin, DEHP-free PVC or EVA intravenous tubing sets. Important: Do not use an in-line filter for 72-hour, 96-hour, or 7-day bags. 8. 9. Prime the intravenous tubing only with the solution in the bag containing the FINAL prepared BLINCYTO solution for infusion. Prime with FINAL prepared BLINCYTO solution Store refrigerated at 2°C to 8°C (36°F to 46°F) if not used immediately [see Dosage and Administration (2.6)]. Table 3. For 72-Hour, 96-Hour, and 7-Day Infusion: Patients Weighing 45 kg or More 9 of 12 Reference ID: 5497479 Infusion Duration Dose Reconstituted BLINCYTO Volume of Preservative-Free 0.9% Sodium Chloride Injection, USP needed to q.s. to Final Volume Final Volume of IV Bag Volume Vials 72 hours 28 mcg/day 8.4 mL 3 105 mL 162 mL 96 hours 28 mcg/day 10.4 mL 4 130 mL 200 mL 7 days 28 mcg/day 16.8 mL 6 1 mL 110 mL Table 4. For 72-Hour, 96-Hour, and 7-Day Infusion: Patients Weighing Between 5.4 kg and Less Than 45 kg Infusion Duration Dose BSA (m2) Reconstituted BLINCYTO Volume of Preservative-Free 0.9% Sodium Chloride Injection, USP needed to q.s. to Final Volume Final Volume of IV Bag Volume Vials 72 hours 15 mcg/m2/day 1.5 – 1.59 6.8 mL 3 107 mL 162 mL 1.4 – 1.49 6.4 mL 3 107 mL 162 mL 1.30 – 1.39 6 mL 3 108 mL 162 mL 1.20 – 1.29 5.4 mL 2 108 mL 162 mL 1.10 – 1.19 5 mL 2 109 mL 162 mL 1 – 1.09 4.6 mL 2 109 mL 162 mL 0.9 – 0.99 4.2 mL 2 110 mL 162 mL 0.8 – 0.89 3.8 mL 2 110 mL 162 mL 0.7 – 0.79 3.2 mL 2 111 mL 162 mL 0.6 – 0.69 2.8 mL 1 111 mL 162 mL 0.5 – 0.59 2.3 mL 1 111 mL 162 mL 0.4 – 0.49 2 mL 1 112 mL 162 mL 0.35 – 0.39 1.7 mL 1 112 mL 162 mL 0.3 – 0.34 1.4 mL 1 112 mL 162 mL 0.25 – 0.29 1.2 mL 1 113 mL 162 mL 96 hours 15 mcg/m2/day 1.5 – 1.59 8.4 mL 3 132 mL 200 mL 1.4 – 1.49 7.8 mL 3 132 mL 200 mL 1.30 – 1.39 7.4 mL 3 133 mL 200 mL 1.20 – 1.29 6.8 mL 3 133 mL 200 mL 1.10 – 1.19 6.2 mL 3 134 mL 200 mL 1 – 1.09 5.6 mL 2 134 mL 200 mL 0.9 – 0.99 5.2 mL 2 135 mL 200 mL 0.8 – 0.89 4.6 mL 2 135 mL 200 mL 0.7 – 0.79 4 mL 2 136 mL 200 mL 0.6 – 0.69 3.4 mL 2 137 mL 200 mL 0.5 – 0.59 2.8 mL 1 137 mL 200 mL 0.4 – 0.49 2.4 mL 1 138 mL 200 mL 0.35 – 0.39 2.1 mL 1 138 mL 200 mL 0.3 – 0.34 1.8 mL 1 138 mL 200 mL 10 of 12 Reference ID: 5497479 0.25 – 0.29 1.5 mL 1 139 mL 200 mL 7 days 15 mcg/m2/day 1.5 – 1.59 14 mL 5 3.8 mL 110 mL 1.4 – 1.49 13.1 mL 5 4.7 mL 110 mL 1.30 – 1.39 12.2 mL 5 5.6 mL 110 mL 1.20 – 1.29 11.3 mL 5 6.5 mL 110 mL 1.10 – 1.19 10.4 mL 4 7.4 mL 110 mL 1 – 1.09 9.5 mL 4 8.3 mL 110 mL 0.9 – 0.99 8.6 mL 4 9.2 mL 110 mL 0.8 – 0.89 7.7 mL 3 10.1 mL 110 mL 0.7 – 0.79 6.8 mL 3 11 mL 110 mL 0.6 – 0.69 5.9 mL 3 11.9 mL 110 mL 0.5 – 0.59 5 mL 2 12.8 mL 110 mL 0.4 – 0.49 4.1 mL 2 13.7 mL 110 mL 0.35 – 0.39 3.4 mL 2 14.4 mL 110 mL 0.3 – 0.34 2.8 mL 1 15 mL 110 mL 0.25 – 0.29 2.5 mL 1 15.3 mL 110 mL The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg. _Administration of BLINCYTO: 72-Hour, 96-Hour, or 7-Day Intravenous Bag_ • Administer BLINCYTO as a continuous intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm. • The final volume of infusion solution will be more than the volume administered to the patient to account for the priming of the intravenous tubing and to ensure that the patient will receive the full dose of BLINCYTO. - For 72-hour infusion (162 mL) will be more than the volume administered to the patient (130 mL). - For 96-hour infusion (200 mL) will be more than the volume administered to the patient (173 mL). - For 7-day infusion (110 mL) will be more than the volume administered to the patient (100 mL). • Ensure that the intravenous tubing is primed only with the solution in the bag containing the FINAL prepared BLINCYTO solution for infusion. • Do not use an in-line filter for 72-hour, 96-hour, or 7-day bags. • Infuse the FINAL prepared BLINCYTO infusion solution according to the instructions on the pharmacy label on the prepared bag at one of the following constant infusion rates: - Infusion rate of 1.8 mL/hour for a duration of 72 hours or 96 hours, OR - Infusion rate of 0.6 mL/hour for a duration of 7 days. • Important Note: Do not flush the BLINCYTO infusion line, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof. When administering via a multi-lumen venous catheter, infuse BLINCYTO through a dedicated lumen. Before flushing the catheter system, residual amounts of BLINCYTO must be aspirated from the catheter system to avoid bolus administration. 11 of 12 Reference ID: 5497479 • At the end of the infusion, any remaining solution in the intravenous bag and intravenous tubing should be discarded in accordance with local requirements. Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 U.S. License No. 1080 BLINCYTO® (blinatumomab) Patent: http://pat.amgen.com/blincyto/ © YYYY Amgen Inc. All rights reserved. V1 Approved: 12/2024 12 of 12 Reference ID: 5497479
custom-source
2025-02-12T15:47:51.552287
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ADALIMUMAB-AACF safely and effectively. See full prescribing information for ADALIMUMAB-AACF. ADALIMUMAB-AACF injection, for subcutaneous use Initial U.S. Approval: 2022 This product is IDACIO® (adalimumab-aacf). IDACIO® (adalimumab-aacf) is biosimilar* to HUMIRA® (adalimumab). WARNING: SERIOUS INFECTIONS and MALIGNANCY See full prescribing information for complete boxed warning. SERIOUS INFECTIONS (5.1, 6.1): • Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens. • Discontinue Adalimumab-aacf if a patient develops a serious infection or sepsis during treatment. • Perform test for latent TB; if positive, start treatment for TB prior to starting Adalimumab-aacf. • Monitor all patients for active TB during treatment, even if initial latent TB test is negative. MALIGNANCY (5.2) : • Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including adalimumab products. • Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have occurred in adolescent and young adults with inflammatory bowel disease treated with TNF blockers including adalimumab products. ----------------------------RECENT MAJOR CHANGES------------------------­ Indications and Usage, Hidradenitis Suppurativa (1.8) 10/2023 Indications and Usage, Uveitis (1.9) 10/2023 Dosage and Administration, Juvenile Idiopathic Arthritis (2.2) 1/2024 Dosage and Administration, Crohn’s Disease (2.3) 1/2024 Dosage and Administration, Plaque Psoriasis or Adult Uveitis (2.5) 10/2023 Dosage and Administration, Hidradenitis Suppurativa (2.6) 10/2023 Dosage and Administration, General Considerations for Administration (2.8) 1/2024 Warnings and Precautions, Malignancies (5.2) 10/2023 Warnings and Precautions, Neurological Reactions (5.5) 10/2023 -----------------------------INDICATIONS AND USAGE------------------------­ Adalimumab-aacf is a tumor necrosis factor (TNF) blocker indicated for: • Rheumatoid Arthritis (RA) (1.1): reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA. • Juvenile Idiopathic Arthritis (JIA) (1.2): reducing signs and symptoms of moderately to severely active polyarticular JIA in patients 2 years of age and older. • Psoriatic Arthritis (PsA) (1.3): reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active PsA. • Ankylosing Spondylitis (AS) (1.4): reducing signs and symptoms in adult patients with active AS. • Crohn’s Disease (CD) (1.5): treatment of moderately to severely active Crohn’s disease in adults and pediatric patients 6 years of age and older. • Ulcerative Colitis (UC) (1.6): treatment of moderately to severely active ulcerative colitis in adult patients. Limitations of Use: Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. • Plaque Psoriasis (Ps) (1.7): treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. • Hidradenitis Suppurativa (HS) (1.8): treatment of moderate to severe hidradenitis suppurativa in adult patients. • Uveitis (UV) (1.9): treatment of non-infectious intermediate, posterior, and panuveitis in adult patients. -----------------------------DOSAGE AND ADMINISTRATION--------------­ • Administer by subcutaneous injection (2) Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis (2.1): • Adults: 40 mg every other week. • Some patients with RA not receiving methotrexate may benefit from increasing the dosage to 40 mg every week or 80 mg every other week. Juvenile Idiopathic Arthritis (2.2): Pediatric Weight 2 Years of Age and Older Recommended Dosage 10 kg (22 lbs) to less than 15 kg (33 lbs) 10 mg every other week 15 kg (33 lbs) to less than 30 kg (66 lbs) 20 mg every other week 30 kg (66 lbs) and greater 40 mg every other week Crohn's Disease (2.3): • Adults: 160 mg on Day 1 (given in one day or split over two consecutive days); 80 mg on Day 15; and 40 mg every other week starting on Day 29. • Pediatric Patients 6 Years of Age and Older: Pediatric Weight Recommended Dosage Days 1 and 15 Starting on Day 29 17 kg (37 lbs) to less than 40 kg (88 lbs) Day 1: 80 mg Day 15: 40 mg 20 mg every other week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) Day 15: 80 mg 40 mg every other week Ulcerative Colitis (2.4): • Adults: 160 mg on Day 1 (given in one day or split over two consecutive days), 80 mg on Day 15 and 40 mg every other week starting on Day 29. Discontinue in patients without evidence of clinical remission by eight weeks (Day 57). Plaque Psoriasis or Adult Uveitis (2.5): • Adults: 80 mg initial dose, followed by 40 mg every other week starting one week after initial dose. Hidradenitis Suppurativa (2.6): • Adults: o Day 1: 160 mg (given in one day or split over two consecutive days) o Day 15: 80 mg o Day 29 and subsequent doses: 40 mg every week or 80 mg every other week ------------------------DOSAGE FORMS AND STRENGTHS---------------­ Injection: • Single-dose prefilled pen (Adalimumab-aacf Pen): 40 mg/0.8 mL (3) • Single-dose prefilled glass syringe: 40 mg/0.8 mL (3) • Single dose glass vial kit for institutional use only: 40mg/0.8 mL (3) -------------------------------CONTRAINDICATIONS---------------------------­ None (4) -------------------------------WARNINGS AND PRECAUTIONS--------------­ • Serious infections: Do not start Adalimumab-aacf during an active infection. If an infection develops, monitor carefully, and stop Adalimumab-aacf if infection becomes serious. (5.1) • Invasive fungal infections: For patients who develop a systemic illness on Adalimumab-aacf, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic. (5.1) • Malignancies: Incidence of malignancies was greater in adalimumab-treated patients than in controls (5.2) • Anaphylaxis or serious hypersensitivity reactions may occur (5.3) • Hepatitis B virus reactivation: Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop Adalimumab-aacf and begin anti- viral therapy. (5.4) • Demyelinating disease: Exacerbation or new onset, may occur. (5.5) • Cytopenias, pancytopenia: Advise patients to seek immediate medical attention if symptoms develop and consider stopping Adalimumab-aacf. (5.6) • Heart failure: Worsening or new onset, may occur. (5.8) • Lupus-like syndrome: Stop Adalimumab-aacf if syndrome develops. (5.9) 1 Reference ID: 5498630 ---- -------------------------------ADVERSE REACTIONS-------------------------­ Most common adverse reactions (>10%) are infections (e.g. upper respiratory, sinusitis), injection site reactions, headache and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088- or www.fda.gov/medwatch ------------------------------DRUG INTERACTIONS-----------------------------­ • Abatacept: Increased risk of serious infection. (5.1, 5.11, 7.2) • Anakinra: Increased risk of serious infection. (5.1, 5.7, 7.2) • Live vaccines: Avoid use with Adalimumab-aacf. (5.10, 7.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. *Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of Adalimumab-aacf has been demonstrated for the condition(s) of use (e.g. indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information. Revised: 06/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SERIOUS INFECTIONS AND MALIGNANCY 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis 1.2 Juvenile Idiopathic Arthritis 1.3 Psoriatic Arthritis 1.4 Ankylosing Spondylitis 1.5 Crohn’s Disease 1.6 Ulcerative Colitis 1.7 Plaque Psoriasis 1.8 Hidradenitis Suppurativa 1.9 Uveitis 2 DOSAGE AND ADMINISTRATION 2.1 Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis 2.2 Juvenile Idiopathic Arthritis 2.3 Crohn’s Disease 2.4 Ulcerative Colitis 2.5 Plaque Psoriasis or Adult Uveitis 2.6 Hidradenitis Suppurativa 2.7 Monitoring to Assess Safety 2.8 General Considerations for Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections 5.2 Malignancies 5.3 Hypersensitivity Reactions 5.4 Hepatitis B Virus Reactivation 5.5 Neurologic Reactions 5.6 Hematological Reactions 5.7 Increased Risk of Infection When Used with Anakinra 5.8 Heart Failure 5.9 Autoimmunity 5.10 Immunizations 5.11 Increased risk of Infection When Used with Abatacept 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Methotrexate 7.2 Biological Products 7.3 Live Vaccines 7.4 Cytochrome P450 Substrates 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis 14.2 Juvenile Idiopathic Arthritis 14.3 Psoriatic Arthritis 14.4 Ankylosing Spondylitis 14.5 Adult Crohn’s Disease 14.6 Pediatric Crohn’s Disease 14.7 Adult Ulcerative Colitis 14.8 Plaque Psoriasis 14.9 Hidradenitis Suppurativa 14.10 Adult Uveitis 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 2 Reference ID: 5498630 FULL PRESCRIBING INFORMATION WARNING: SERIOUS INFECTIONS and MALIGNANCY SERIOUS INFECTIONS Patients treated with adalimumab products including Adalimumab-aacf are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue Adalimumab-aacf if a patient develops a serious infection or sepsis. Reported infections include: • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before Adalimumab-aacf use and during therapy. Initiate treatment for latent TB prior to Adalimumab-aacf use. • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti- fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness. • Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria. Carefully consider the risks and benefits of treatment with Adalimumab-aacf prior to initiating therapy in patients with chronic or recurrent infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with Adalimumab-aacf, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including adalimumab products [see Warnings and Precautions (5.2)]. Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including adalimumab products. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants [see Warnings and Precautions (5.2)]. Reference ID: 5498630 3 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis Adalimumab-aacf is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. Adalimumab-aacf can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti- rheumatic drugs (DMARDs). 1.2 Juvenile Idiopathic Arthritis Adalimumab-aacf is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. Adalimumab-aacf can be used alone or in combination with methotrexate. 1.3 Psoriatic Arthritis Adalimumab-aacf is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. Adalimumab-aacf can be used alone or in combination with non-biologic DMARDs. 1.4 Ankylosing Spondylitis Adalimumab-aacf is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis. 1.5 Crohn’s Disease Adalimumab-aacf is indicated for the treatment of moderately to severely active Crohn’s disease in adults and pediatric patients 6 years of age and older. 1.6 Ulcerative Colitis Adalimumab-aacf is indicated for the treatment of moderately to severely active ulcerative colitis in adult patients. Limitations of Use The effectiveness of adalimumab products has not been established in patients who have lost response to or were intolerant to TNF blockers [see Clinical Studies (14.7)]. 1.7 Plaque Psoriasis Adalimumab-aacf is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. Adalimumab-aacf should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Warnings and Precautions (5)]. 1.8 Hidradenitis Suppurativa Adalimumab-aacf is indicated for the treatment of moderate to severe hidradenitis suppurativa in 1 Reference ID: 5498630 adult patients. 1.9 Uveitis Adalimumab-aacf is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adult patients. 2 DOSAGE AND ADMINISTRATION 2.1 Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis The recommended subcutaneous dosage of Adalimumab-aacf for adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) is 40 mg administered every other week. Methotrexate (MTX), other non-biologic DMARDS, glucocorticoids, nonsteroidal anti- inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with Adalimumab-aacf. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosage of Adalimumab-aacf to 40 mg every week or 80 mg every other week. 2.2 Juvenile Idiopathic Arthritis The recommended subcutaneous dosage of Adalimumab-aacf for patients 2 years of age and older with polyarticular juvenile idiopathic arthritis (JIA) is based on weight as shown below. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with Adalimumab-aacf. Pediatric Weight (2 Years of Age and older) Recommended Dosage 10 kg (22 lbs) to less than 15 kg (33 lbs) 10 mg every other week 15 kg (33 lbs) to less than 30 kg (66 lbs) 20 mg every other week 30 kg (66 lbs) and greater 40 mg every other week The only dosage form for Adalimumab-aacf that allows weight-based dosing for pediatric patients below 30 kg is the single-dose glass vial kit for institutional use only. Adalimumab products have not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg. 2.3 Crohn’s Disease Adults The recommended subcutaneous dosage of Adalimumab-aacf for adult patients with Crohn’s disease (CD) is 160 mg initially on Day 1 (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) begin a dosage of 40 mg every other week. Aminosalicylates and/or corticosteroids may be continued during treatment with Adalimumab-aacf. Azathioprine, 6-mercaptopurine (6-MP) [see Warnings and Precautions (5.2)] or MTX may be continued during treatment with Adalimumab-aacf if necessary. Pediatrics The recommended subcutaneous dosage of Adalimumab-aacf for pediatric patients 6 years of age and older with Crohn’s disease (CD) is based on body weight as shown below: 2 Reference ID: 5498630 Pediatric Weight Recommended Dosage Days 1 through 15 Starting on Day 29 17 kg (37 lbs) to less than 40 kg (88 lbs) Day 1: 80 mg Day 15: 40 mg 20 mg every other week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) Day 15: 80 mg 40 mg every other week The only dosage form for Adalimumab-aacf that allows weight-based dosing for pediatric patients below 40 kg is the single-dose glass vial kit for institutional use only 2.4 Ulcerative Colitis Adults The recommended subcutaneous dosage of Adalimumab-aacf for adult patients with ulcerative colitis is 160 mg initially on Day 1 (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15). Two weeks later (Day 29) continue with a dosage of 40 mg every other week. Discontinue Adalimumab-aacf in adult patients without evidence of clinical remission by eight weeks (Day 57) of therapy. Aminosalicylates and/or corticosteroids may be continued during treatment with Adalimumab-aacf. Azathioprine and 6-mercaptopurine (6-MP) [see Warnings and Precautions (5.2)] may be continued during treatment with Adalimumab-aacf if necessary. 2.5 Plaque Psoriasis or Adult Uveitis The recommended subcutaneous dosage of Adalimumab-aacf for adult patients with plaque psoriasis (Ps) or Uveitis (UV) is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. The use of adalimumab products in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies. 2.6 Hidradenitis Suppurativa Adults The recommended subcutaneous dosage of Adalimumab-aacf for adult patients with hidradenitis suppurativa (HS) is an initial dose of 160 mg (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15). Begin 40 mg weekly or 80 mg every other week dosing two weeks later (Day 29). 2.7 Monitoring to Assess Safety Prior to initiating Adalimumab-aacf and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions (5.1)]. 3 Reference ID: 5498630 2.8 General Considerations for Administration Adalimumab-aacf Pen or prefilled syringe is intended for use under the guidance and supervision of a physician. A patient may self-inject Adalimumab-aacf or a caregiver may inject Adalimumab-aacf using either the Adalimumab-aacf Pen or prefilled syringe if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique. Adalimumab-aacf may be taken out of the refrigerator for 15 to 30 minutes before injecting to allow the liquid to come to room temperature. Do not remove the cap or cover while allowing it to reach room temperature. Carefully inspect the solution in the Adalimumab-aacf Pen, or prefilled syringe or single dose institutional use vial for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. Adalimumab-aacf does not contain preservatives. Therefore, discard unused portions of drug remaining in the syringe. Instruct patients using the Adalimumab-aacf Pen or prefilled syringe to inject the full amount in the syringe, according to the directions provided in the Instructions for Use [see Instructions for Use]. Injections should occur at separate sites in the thigh or abdomen. Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red or hard. If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time. The Adalimumab-aacf syringe plunger stopper and needle cover are not made with natural rubber latex. The Adalimumab-aacf single-dose institutional use vial kit is for administration within an institutional setting only, such as a hospital, physician’s office, or clinic. Withdraw the dose using the vial adapter, the sterile syringe and needle provided. Only administer one dose per vial. The vial does not contain preservatives; discard unused portion. The Adalimumab-aacf vial and syringe stopper are not made with natural rubber latex. Read these Administration Instructions before using the Adalimumab-aacf Vial kit. Adalimumab-aacf is supplied in a carton containing 1 sterile single-use syringe, 1 sterile needle, 1 vial adapter, 2 alcohol preps and 1 glass vial providing 40 mg/0.8 mL of Adalimumab-aacf (Figure A) The contents of the Idacio Vial Kit are for single-dose (one-time) use only. Discard unused portion. 4 Reference ID: 5498630 Vial lliCbp1~r 1\kobol p,q,s Figure A Prior to Administration • Remove the Adalimumab-aacf Vial Kit from the refrigerator and let it sit at room temperature for at least 30 minutes. • Check the expiration date. • Remove Vial Kit contents from the carton and inspect for damage. Do not use if any kit component or packaging has been damaged. • Check the vial contents to make sure that the liquid is clear, colorless, and free of particles and flakes. Note: Prepare syringe just prior to administration and inject immediately. Do not store Adalimumab-aacf in the syringe. Step 1. Prepare Vial and Vial Adapter 1.1 Remove plastic flip off cap from vial and disinfect the rubber stopper. Do not touch the top of the vial after cleaning. 1.2 Without removing the vial adapter from its packaging, peel off the top cover (Figure B). Do not touch the vial adapter. Figure B 5 Reference ID: 5498630 1.3 With the vial adapter still in its packaging, push the vial adapter onto the vial top until it snaps in place (Figure C). Figure C 1.4 Remove the vial adapter packaging (Figure D) Step 2.Connect Syringe to Vial Adapter 2.1 Remove syringe from outer packaging. Do not touch the syringe tip. 2.2 Hold the base of the vial adapter and connect the syringe to the vial adapter by turning it clockwise (Figure E). Figure E Step 3.Withdraw the Dose 3.1 Invert the vial completely with the vial adapter and syringe still connected (Figure F). Figure D Figure F 6 Reference ID: 5498630 3.2 Slowly withdraw the prescribed dose of Adalimumab­ aacf into the syringe for administration (Figure G). Remove air bubbles from the syringe. Do not pull the plunger rod out. Figure G Step 4.Disconnect the syringe 4.1 Turn over the vial and syringe. Hold the base of the vial adapter and disconnect the syringe from the vial adapter by turning it counterclockwise (Figure H). Do not touch the syringe tip. Step 5.Attach Needle Figure H Textured Pink nee~ver ..R:ir pad Yellow o---- syringe connector i Clear needle cap 1 Outer Needle Packaging Figure I 5.1 Peel open the outer needle packaging to uncover the yellow syringe connector (Figure J). Figure J 7 Reference ID: 5498630 t 5.2 Insert the syringe tip into the syringe connector. Turn the syringe connector in a clockwise direction to tighten (Figure K). Figure K 5.3 Pull the outer needle packaging off (Figure L). Do not remove the clear needle cap. Figure L 5.4 Pull back the needle safety cover toward the syringe (Figure M). Do not remove the needle cover from the connector. Step 6.Administer medication 6.1 When you are ready to inject Adalimumab-aacf remove the clear needle cap by pulling it straight off and throw it away (Figure N). Do not recap the needle. Figure M Figure N 8 Reference ID: 5498630 6.2 Administer the dose subcutaneously. 6.3 Place your thumb or index finger on the center of the textured finger pad and push the pink needle safety cover forward over the needle until you hear it click or feel it lock (Figure O). Figure O Step 7.Discard Used Syringe and Needle 7.1 Discard used syringe and needle into an appropriate sharps container. 3 DOSAGE FORMS AND STRENGTHS Adalimumab-aacf is a clear and colorless to pale yellow solution available as: • Pen (Adalimumab-aacf Pen) Injection: 40 mg/0.8 mL in a single-dose pen. • Prefilled Syringe Injection: 40 mg/0.8 mL in a single-dose prefilled glass syringe. • Single-Dose Institutional Use Vial Kit Injection: 40 mg/0.8 mL in a single-dose, glass vial kit for institutional use only. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections Patients treated with adalimumab products including Adalimumab-aacf are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease. The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of Adalimumab-aacf and these biologic products is not recommended in the treatment of patients 9 Reference ID: 5498630 with RA [see Warnings and Precautions (5.7, 5.11) and Drug Interactions (7.2)]. Treatment with Adalimumab-aacf should not be initiated in patients with an active infection, including localized infections. Patients 65 years of age and older, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating therapy in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or • with underlying conditions that may predispose them to infection. Tuberculosis Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients receiving adalimumab products, including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating Adalimumab-aacf and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating Adalimumab-aacf, assess if treatment for latent tuberculosis is needed; and consider an induration of ≥ 5 mm a positive tuberculin skin test result, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). Consider anti-tuberculosis therapy prior to initiation of Adalimumab-aacf in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with adalimumab products. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti- tuberculosis therapy is appropriate for an individual patient. Strongly consider tuberculosis in the differential diagnosis in patients who develop a new infection during Adalimumab-aacf treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. Monitoring Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Adalimumab-aacf, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with Adalimumab-aacf. Discontinue Adalimumab-aacf if a patient develops a serious infection or sepsis. For a patient who develops a new infection during treatment with Adalimumab-aacf, closely monitor them, perform a prompt and complete diagnostic workup appropriate for an immunocompromised 10 Reference ID: 5498630 patient, and initiate appropriate antimicrobial therapy. Invasive Fungal Infections If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider appropriate empiric antifungal therapy, taking into account both the risk for severe fungal infection and the risks of antifungal therapy, while a diagnostic workup is being performed. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections. 5.2 Malignancies Consider the risks and benefits of TNF-blocker treatment including Adalimumab-aacf prior to initiating therapy in patients with a known malignancy other than a successfully treated non- melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy. Malignancies in Adults In the controlled portions of clinical trials of some TNF-blockers, including adalimumab products, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared to control-treated adult patients. During the controlled portions of 39 global adalimumab clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), plaque psoriasis (Ps), hidradenitis suppurativa (HS) and uveitis (UV), malignancies, other than non- melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.7 (0.48, 1.03) per 100 patient-years among 7973 adalimumab-treated patients versus a rate of 0.7 (0.41, 1.17) per 100 patient-years among 4848 control-treated patients (median duration of treatment of 4 months for adalimumab-treated patients and 4 months for control- treated patients). In 52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, HS, and UV, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in adalimumab-treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group. Non-Melanoma Skin Cancer During the controlled portions of 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS, and UV, the rate (95% confidence interval) of NMSC was 0.8 (0.52, 1.09) per 100 patient-years among adalimumab-treated patients and 0.2 (0.10, 0.59) per 100 patient-years among control-treated patients. Examine all patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment for the presence of NMSC prior to and during treatment with Adalimumab­ aacf. Lymphoma and Leukemia 11 Reference ID: 5498630 In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF-blocker-treated patients compared to control-treated patients. In the controlled portions of 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS, and UV, 2 lymphomas occurred among 7973 adalimumab-treated patients versus 1 among 4848 control-treated patients. In 52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, HS, and UV with a median duration of approximately 0.7 years, including 24,605 patients and over 40,215 patient- years of adalimumab, the observed rate of lymphomas was approximately 0.11 per 100 patient- years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 Rates of lymphoma in clinical trials of adalimumab cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with RA and other chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Post- marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. Malignancies in Pediatric Patients and Young Adults Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy ≤ 18 years of age), of which Adalimumab-aacf is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including adalimumab products. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. The potential risk with the combination of azathioprine or 6-mercaptopurine and Adalimumab-aacf should be carefully considered. 5.3 Hypersensitivity Reactions Anaphylaxis and angioneurotic edema have been reported following administration of adalimumab products. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue administration of Adalimumab-aacf and institute appropriate therapy. In clinical trials of adalimumab, hypersensitivity reactions (e.g., rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed. 5.4 Hepatitis B Virus Reactivation 12 Reference ID: 5498630 Use of TNF blockers, including Adalimumab-aacf, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. Exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. For patients who are carriers of HBV and require treatment with TNF blockers, closely monitor such patients for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, stop Adalimumab-aacf and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of Adalimumab-aacf therapy in this situation and monitor patients closely. 5.5 Neurologic Reactions Use of TNF blocking agents, including adalimumab products, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of Adalimumab-aacf in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of Adalimumab-aacf should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders. 5.6 Hematological Reactions Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with adalimumab products. The causal relationship of these reports to adalimumab products remains unclear. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on Adalimumab-aacf. Consider discontinuation of Adalimumab-aacf therapy in patients with confirmed significant hematologic abnormalities. 5.7 Increased Risk of Infection when Used with Anakinra Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of Adalimumab-aacf and anakinra is not recommended [see Drug Interactions (7.2)]. 5.8 Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with adalimumab products. Adalimumab products have not been formally studied in patients with CHF; however, in clinical trials of another TNF blocker, a higher rate of serious CHF-related adverse reactions was 13 Reference ID: 5498630 observed. Exercise caution when using Adalimumab-aacf in patients who have heart failure and monitor them carefully. 5.9 Autoimmunity Treatment with adalimumab products may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus- like syndrome following treatment with Adalimumab-aacf, discontinue treatment [see Adverse Reactions (6.1)]. 5.10 Immunizations In a placebo-controlled clinical trial of patients with RA, no difference was detected in anti­ pneumococcal antibody response between adalimumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with adalimumab. Similar proportions of patients developed protective levels of anti-influenza antibodies between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving adalimumab. The clinical significance of this is unknown. Patients on Adalimumab-aacf may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving adalimumab products. It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Adalimumab-aacf therapy. Patients on Adalimumab-aacf may receive concurrent vaccinations, except for live vaccines. The safety of administering live or live-attenuated vaccines in infants exposed to adalimumab products in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live- attenuated) exposed infants [see Use in Specific Populations (8.1, 8.4)]. 5.11 Increased Risk of Infection When Used with Abatacept In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including Adalimumab-aacf is not recommended [see Drug Interactions (7.2)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections [see Warnings and Precautions (5.1)] • Malignancies [see Warnings and Precautions (5.2)] • Hypersensitivity Reactions [see Warnings and Precautions (5.3)] • Hepatitis B Virus Reactivation [see Warnings and Precautions (5.4)] • Neurologic Reactions [see Warnings and Precautions (5.5)] • Hematological Reactions [see Warnings and Precautions (5.6)] • Heart Failure [see Warnings and Precautions (5.8)] • Autoimmunity [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience 14 Reference ID: 5498630 Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reaction with adalimumab was injection site reactions. In placebo- controlled trials, 20% of patients treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation. The proportion of patients who discontinued treatment due to adverse reactions during the double- blind, placebo-controlled portion of studies in patients with RA (i.e., Studies RA-I, RA- II, RA-III and RA-IV) was 7% for patients taking adalimumab and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of adalimumab in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%). Infections In the controlled portions of the 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate of serious infections was 4.3 per 100 patient-years in 7973 adalimumab-treated patients versus a rate of 2.9 per 100 patient-years in 4848 control- treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post- surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions (5.1)]. Tuberculosis and Opportunistic Infections In 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, HS, and UV that included 24,605 adalimumab-treated patients, the rate of reported active tuberculosis was 0.20 per 100 patient-years and the rate of positive PPD conversion was 0.09 per 100 patient-years. In a subgroup of 10,113 U.S. and Canadian adalimumab-treated patients, the rate of reported active TB was 0.05 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.05 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see Warnings and Precautions (5.1)]. Autoantibodies In the rheumatoid arthritis controlled trials, 12% of patients treated with adalimumab and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with adalimumab developed clinical signs suggestive of new- onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with adalimumab products on the development of autoimmune diseases is unknown. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of adalimumab (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of adalimumab-treated patients and 1.5% of control- treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between adalimumab and 15 Reference ID: 5498630 the liver enzyme elevations is not clear. In a controlled Phase 3 trial of adalimumab in patients with polyarticular JIA who were 4 to 17 years, ALT elevations ≥ 3 x ULN occurred in 4.4% of adalimumab-treated patients and 1.5% of control-treated patients (ALT more common than AST); liver enzyme test elevations were more frequent among those treated with the combination of adalimumab and MTX than those treated with adalimumab alone. In general, these elevations did not lead to discontinuation of adalimumab treatment. No ALT elevations ≥ 3 x ULN occurred in the open-label study of adalimumab in patients with polyarticular JIA who were 2 to <4 years. In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in adult patients with Crohn’s Disease with a control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of adalimumab-treated patients and 0.9% of control-treated patients. In the Phase 3 trial of adalimumab in pediatric patients with Crohn’s disease which evaluated efficacy and safety of two body weight based maintenance dose regimens following body weight based induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of patients, of whom 4 were receiving concomitant immunosuppressants at baseline; none of these patients discontinued due to abnormalities in ALT tests. In controlled Phase 3 trials of adalimumab (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in adult patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥3 x ULN occurred in 1.5% of adalimumab-treated patients and 1.0% of control-treated patients. In controlled Phase 3 trials of adalimumab (initial dose of 80 mg then 40 mg every other week) in patients with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of adalimumab-treated patients and 1.8% of control-treated patients. In controlled trials of adalimumab (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in subjects with HS with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of adalimumab-treated subjects and 0.6% of control-treated subjects. In controlled trials of adalimumab (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult patients with uveitis with an exposure of 165.4 PYs and 119.8 PYs in adalimumab-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of adalimumab-treated patients and 2.4% of control-treated patients. Other Adverse Reactions Rheumatoid Arthritis Clinical Studies The data described below reflect exposure to adalimumab in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well- controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). Adalimumab was studied primarily in placebo- controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg adalimumab every other week [see Clinical Studies (14.1)]. Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with adalimumab 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion. 16 Reference ID: 5498630 Table 1. Adverse Reactions Reported by ≥5% of Patients Treated with Adalimumab during Placebo-Controlled Period of Pooled RA Studies (Studies RA-I, RA-II, RA-III, and RA-IV) Adalimumab 40 mg subcutaneous Every Other Week Placebo (N=705) (N=690) Adverse Reaction (Preferred Term) Respiratory Upper respiratory infection 17% 13% Sinusitis 11% 9% Flu syndrome 7% 6% Gastrointestinal Nausea 9% 8% Abdominal pain 7% 4% Laboratory Tests* Laboratory test abnormal 8% 7% Hypercholesterolemia 6% 4% Hyperlipidemia 7% 5% Hematuria 5% 4% Alkaline phosphatase increased 5% 3% Other Headache 12% 8% Rash 12% 6% Accidental injury 10% 8% Injection site reaction ** 8% 1% Back pain 6% 4% Urinary tract infection 8% 5% Hypertension 5% 3% * Laboratory test abnormalities were reported as adverse reactions in European trials ** Does not include injection site erythema, itching, hemorrhage, pain or swelling Less Common Adverse Reactions in Rheumatoid Arthritis Clinical Studies Other infrequent serious adverse reactions that do not appear in the Warnings and Precautions or Adverse Reaction sections that occurred at an incidence of less than 5% in adalimumab-treated patients in RA studies were: Body As A Whole: Pain in extremity, pelvic pain, surgery, thorax pain Cardiovascular System: Arrhythmia, atrial fibrillation, chest pain, coronary artery disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, 17 Reference ID: 5498630 pericarditis, syncope, tachycardia Digestive System: Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, hepatic necrosis, vomiting Endocrine System: Parathyroid disorder Hemic And Lymphatic System: Agranulocytosis, polycythemia Metabolic And Nutritional Disorders: Dehydration, healing abnormal, ketosis, paraproteinemia, peripheral edema Musculo-Skeletal System: Arthritis, bone disorder, bone fracture (not spontaneous), bone necrosis, joint disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, tendon disorder Neoplasia: Adenoma Nervous System: Confusion, paresthesia, subdural hematoma, tremor Respiratory System: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion Special Senses: Cataract Thrombosis: Thrombosis leg Urogenital System: Cystitis, kidney calculus, menstrual disorder Juvenile Idiopathic Arthritis Clinical Studies In general, the adverse reactions in the adalimumab-treated patients in the polyarticular juvenile idiopathic arthritis (JIA) trials (Studies JIA-I and JIA-II) [see Clinical Studies (14.2)] were similar in frequency and type to those seen in adult patients [see Warnings and Precautions (5), Adverse Reactions (6)]. Important findings and differences from adults are discussed in the following paragraphs. In Study JIA-I, adalimumab was studied in 171 patients who were 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, and appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with adalimumab and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. In Study JIA-I, 45% of patients experienced an infection while receiving adalimumab with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in adalimumab-treated patients were generally similar to those commonly seen in polyarticular JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in this patient population treated with adalimumab were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in patients receiving adalimumab was granuloma annulare which did not lead to discontinuation of adalimumab treatment. In the first 48 weeks of treatment in Study JIA-I, non-serious hypersensitivity reactions were seen in approximately 6% of patients and included primarily localized allergic hypersensitivity reactions and allergic rash. In Study JIA-I, 10% of patients treated with adalimumab who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial. 18 Reference ID: 5498630 Approximately 15% of patients treated with adalimumab developed mild-to-moderate elevations of creatine phosphokinase (CPK) in Study JIA-I. Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK concentrations decreased or returned to normal in all patients. Most patients were able to continue adalimumab without interruption. In Study JIA-II, adalimumab was studied in 32 patients who were 2 to <4 years of age or 4 years of age and older weighing <15 kg with polyarticular JIA. The safety profile for this patient population was similar to the safety profile seen in patients 4 to 17 years of age with polyarticular JIA. In Study JIA-II, 78% of patients experienced an infection while receiving adalimumab. These included nasopharyngitis, bronchitis, upper respiratory tract infection, otitis media, and were mostly mild to moderate in severity. Serious infections were observed in 9% of patients receiving adalimumab in the study and included dental caries, rotavirus gastroenteritis, and varicella. In Study JIA-II, non-serious allergic reactions were observed in 6% of patients and included intermittent urticaria and rash, which were all mild in severity. Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies Adalimumab has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo- controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies [see Clinical Studies (14.3, 14.4)]. The safety profile for patients with PsA and AS treated with adalimumab 40 mg every other week was similar to the safety profile seen in patients with RA, adalimumab Studies RA-I through IV. Crohn’s Disease Clinical Studies Adults: The safety profile of adalimumab in 1478 adult patients with Crohn’s disease from four placebo-controlled and two open-label extension studies [see Clinical Studies (14.5)] was similar to the safety profile seen in patients with RA. Pediatric Patients 6 Years to 17 Years: The safety profile of adalimumab in 192 pediatric patients from one double-blind study (Study PCD-I) and one open-label extension study [see Clinical Studies (14.6)] was similar to the safety profile seen in adult patients with Crohn’s disease. During the 4-week open label induction phase of Study PCD-I, the most common adverse reactions occurring in the pediatric population treated with adalimumab were injection site pain and injection site reaction (6% and 5%, respectively). A total of 67% of children experienced an infection while receiving adalimumab in Study PCD-I. These included upper respiratory tract infection and nasopharyngitis. A total of 5% of children experienced a serious infection while receiving adalimumab in Study PCD-I. These included viral infection, device related sepsis (catheter), gastroenteritis, H1N1 influenza, and disseminated histoplasmosis. In Study PCD-I, allergic reactions were observed in 5% of children which were all non-serious and were primarily localized reactions. Ulcerative Colitis Clinical Studies Adults: The safety profile of adalimumab in 1010 adult patients with ulcerative colitis (UC) from two placebo-controlled studies and one open-label extension study [see Clinical Studies (14.7)] was similar to the safety profile seen in patients with RA. 19 Reference ID: 5498630 Plaque Psoriasis Clinical Studies Adalimumab has been studied in 1696 subjects with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies [see Clinical Studies (14.8)]. The safety profile for subjects with Ps treated with adalimumab was similar to the safety profile seen in subjects with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in Ps subjects, adalimumab-treated subjects had a higher incidence of arthralgia when compared to controls (3% vs. 1%). Hidradenitis Suppurativa Clinical Studies Adalimumab has been studied in 727 subjects with hidradenitis suppurativa (HS) in three placebo- controlled studies and one open-label extension study [see Clinical Studies (14.9)]. The safety profile for subjects with HS treated with adalimumab weekly was consistent with the known safety profile of adalimumab. Flare of HS, defined as ≥25% increase from baseline in abscesses and inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects who were withdrawn from adalimumab treatment following the primary efficacy timepoint in two studies. Uveitis Clinical Studies Adalimumab has been studied in 464 adult patients with uveitis (UV) in placebo-controlled and open-label extension studies (Study PUV-I) [see Clinical Studies (14.10)]. The safety profile for patients with UV treated with adalimumab was similar to the safety profile seen in patients with RA. 6.2 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti­ drugantibodies in other studies, including those of adalimumab or of other adalimumab products. There are two assays that have been used to measure anti-adalimumab antibodies. With the ELISA, antibodies to adalimumab could be detected only when serum adalimumab concentrations were < 2 mcg/mL. The ECL assay can detect anti-adalimumab antibody titers independent of adalimumab concentrations in the serum samples. The incidence of anti-adalimumab antibody (AAA) development in patients treated with adalimumab are presented in Table 2. 20 Reference ID: 5498630 Table 2: Anti-Adalimumab Antibody Development Determined by ELISA and ECL Assay in Patients Treated with adalimumab Indications Study Duration Anti-Adalimumab Antibody Incidence by ELISA (n/N) Anti-Adalimumab Antibody Incidence by ECL Assay (n/N) In all patients who received adalimumab In patients with serum adalimumab concentrations < 2 mcg/mL Rheumatoid Arthritisa 6 to 12 months 5% (58/1062) NR NA Juvenile Idiopathic Arthritis (JIA) 4 to 17 years of ageb 48 weeks 16% (27/171) NR NA 2 to 4 years of age or ≥ 4 years of age and weighing < 15 kg 24 weeks 7% (1/15)c NR NA Psoriatic Arthritisd 48 weekse 13% (24/178) NR NA Ankylosing Spondylitis 24 weeks 9% (16/185) NR NA Adult Crohn’s Disease 56 weeks 3% (7/269) 8% (7/86) NA Pediatric Crohn’s Disease 52 weeks 3% (6/182) 10% (6/58) NA Adult Ulcerative Colitis 52 weeks 5% (19/360) 21% (19/92) NA Plaque Psoriasisf Up to 52 weeksg 8% (77/920) 21% (77/372) NA Hidradenitis Suppurativa 36 weeks 7% (30/461) 28% (58/207)h 61% (272/445)i Non-infectious Uveitis 52 weeks 5% (12/249) 21% (12/57) 40% (99/249) j n: number of patients with anti-adalimumab antibody; NR: not reported; NA: Not applicable (not performed) a In patients receiving concomitant methotrexate (MTX), the incidence of anti-adalimumab antibody was 1% compared to 12% with adalimumab monotherapy b In patients receiving concomitant MTX, the incidence of anti-adalimumab antibody was 6% compared to 26% with adalimumab monotherapy c This patient received concomitant MTX d In patients receiving concomitant MTX, the incidence of antibody development was 7% compared to 1% in RA e Subjects enrolled after completing 2 previous studies of 24 weeks or 12 weeks of treatments. f In plaque psoriasis patients who were on adalimumab monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal g One 12-week Phase 2 study and one 52-week Phase 3 study h Among subjects in the 2 Phase 3 studies who stopped adalimumab treatment for up to 24 weeks and in whom adalimumab serum levels subsequently declined to <2 mcg/mL (approximately 22% of total subjects studied) i No apparent association between antibody development and safety was observed j No correlation of antibody development to safety or efficacy outcomes was observed 21 Reference ID: 5498630 Rheumatoid Arthritis and Psoriatic Arthritis: Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab using the ELISA during the 6- to 12­ month period. No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of adalimumab products is unknown. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of adalimumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to adalimumab products exposure. Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis General disorders and administration site conditions: Pyrexia Hepato-biliary disorders: Liver failure, hepatitis Immune system disorders: Sarcoidosis Neoplasms benign, malignant and unspecified (including cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin) Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia, lichenoid skin reaction Vascular disorders: Systemic vasculitis, deep vein thrombosis 7 DRUG INTERACTIONS 7.1 Methotrexate Adalimumab has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either Adalimumab-aacf or MTX [see Clinical Pharmacology (12.3)]. 7.2 Biological Products In clinical studies in patients with RA, an increased risk of serious infections has been observed with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of Adalimumab-aacf with abatacept or anakinra is not recommended in patients with RA [see 22 Reference ID: 5498630 Warnings and Precautions (5.7, 5.11)]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker. There is insufficient information regarding the concomitant use of Adalimumab-aacf and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of Adalimumab-aacf with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions. 7.3 Live Vaccines Avoid the use of live vaccines with Adalimumab-aacf [see Warnings and Precautions (5.10)]. 7.4 Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for products that antagonize cytokine activity, such as adalimumab products, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of Adalimumab-aacf in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available studies with use of adalimumab during pregnancy do not reliably establish an association between adalimumab and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry in pregnant women with rheumatoid arthritis (RA) or Crohn’s disease (CD) treated with adalimumab. Registry results showed a rate of 10% for major birth defects with first trimester use of adalimumab in pregnant women with RA or CD and a rate of 7.5% for major birth defects in the disease-matched comparison cohort. The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects (see Data). Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in-utero exposed infant (see Clinical Considerations). In an embryo-fetal perinatal development study conducted in cynomolgus monkeys, no fetal harm or malformations were observed with intravenous administration of adalimumab during organogenesis and later in gestation, at doses that produced exposures up to approximately 373 times the maximum recommended human dose (MRHD) of 40 mg subcutaneous without methotrexate (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations 23 Reference ID: 5498630 Disease-associated maternal and embryo/fetal risk Published data suggest that the risk of adverse pregnancy outcomes in women with RA or inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Fetal/Neonatal Adverse Reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester (see Data). Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to adalimumab products in utero [see Use in Specific Populations (8.4)]. Data Human Data A prospective cohort pregnancy exposure registry conducted by OTIS/MotherToBaby in the U.S. and Canada between 2004 and 2016 compared the risk of major birth defects in live-born infants of 221 women (69 RA, 152 CD) treated with adalimumab during the first trimester and 106 women (74 RA, 32 CD) not treated with adalimumab. The proportion of major birth defects among live-born infants in the adalimumab-treated and untreated cohorts was 10% (8.7% RA, 10.5% CD) and 7.5% (6.8% RA, 9.4% CD), respectively. The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects. This study cannot reliably establish whether there is an association between adalimumab and major birth defects because of methodological limitations of the registry, including small sample size, the voluntary nature of the study, and the non-randomized design. In an independent clinical study conducted in ten pregnant women with IBD treated with adalimumab, adalimumab concentrations were measured in maternal serum as well as in cord blood (n=10) and infant serum (n=8) on the day of birth. The last dose of adalimumab was given between 1 and 56 days prior to delivery. Adalimumab concentrations were 0.16-19.7 mcg/mL in cord blood, 4.28-17.7 mcg/mL in infant serum, and 0-16.1 mcg/mL in maternal serum. In all but one case, the cord blood concentration of adalimumab was higher than the maternal serum concentration, suggesting adalimumab actively crosses the placenta. In addition, one infant had serum concentrations at each of the following: 6 weeks (1.94 mcg/mL), 7 weeks (1.31 mcg/mL), 8 weeks (0.93 mcg/mL), and 11 weeks (0.53 mcg/mL), suggesting adalimumab can be detected in the serum of infants exposed in utero for at least 3 months from birth. Animal Data In an embryo-fetal perinatal development study, pregnant cynomolgus monkeys received adalimumab from gestation days 20 to 97 at doses that produced exposures up to 373 times that achieved with the MRHD without methotrexate (on an AUC basis with maternal IV doses up to 100 mg/kg/week). Adalimumab did not elicit harm to the fetuses or malformations. 8.2 Lactation Risk Summary Limited data from case reports in the published literature describe the presence of adalimumab in human milk at infant doses of 0.1% to 1% of the maternal serum concentration. Published data suggest that the systemic exposure to a breastfed infant is expected to be low because adalimumab 24 Reference ID: 5498630 is a large molecule and is degraded in the gastrointestinal tract. However, the effects of local exposure in the gastrointestinal tract are unknown. There are no reports of adverse effects of adalimumab products on the breastfed infant and no effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Adalimumab-aacf and any potential adverse effects on the breastfed child from Adalimumab-aacf or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Adalimumab-aacf have been established for: • reducing signs and symptoms of moderately to severely active polyarticular JIA in pediatric patients 2 years of age and older. • the treatment of moderately to severely active Crohn’s disease in pediatric patients 6 years of age and older. Pediatric assessments for Adalimumab-aacf demonstrate that Adalimumab-aacf is safe and effective for pediatric patients in indications for which HUMIRA (adalimumab) is approved. However, Adalimumab-aacf is not approved for such indications due to marketing exclusivity for HUMIRA (adalimumab). Due to their inhibition of TNFα, adalimumab products administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to adalimumab in utero suggest adalimumab crosses the placenta [see Use in Specific Populations (8.1)]. The clinical significance of elevated adalimumab concentrations in infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants. Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including adalimumab products [see Warnings and Precautions (5.2)]. Juvenile Idiopathic Arthritis In Study JIA-I, adalimumab was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age [see Clinical Studies (14.2)]. In Study JIA-II, the safety profile for patients 2 to <4 years of age was similar to the safety profile for patients 4 to 17 years of age with polyarticular JIA [see Adverse Reactions (6.1)]. Adalimumab products have not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg. The safety of adalimumab in patients in the polyarticular JIA trials was generally similar to that observed in adults with certain exceptions [see Adverse Reactions (6.1)]. The safety and effectiveness of Adalimumab-aacf have not been established in pediatric patients with JIA less than 2 years of age. Pediatric Crohn’s Disease The safety and effectiveness of Adalimumab-aacf for the treatment of moderately to severely active Crohn’s disease have been established in pediatric patients 6 years of age and older. Use of Adalimumab-aacf for this indication is supported by Adalimumab-aacf’s approval as a biosimilar to adalimumab and evidence from adequate and well-controlled studies in adults with additional data of adalimumab from a randomized, double-blind, 52-week clinical study of two dose 25 Reference ID: 5498630 ---- concentrations of adalimumab in 192 pediatric patients (6 years to 17 years of age) [see Adverse Reactions (6.1), Clinical Pharmacology (12.2, 12.3), Clinical Studies (14.6)]. The adverse reaction profile in patients 6 years to 17 years of age was similar to adults. The safety and effectiveness of Adalimumab-aacf have not been established in pediatric patients with Crohn’s disease less than 6 years of age. 8.5 Geriatric Use A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received adalimumab in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these patients and younger patients. The frequency of serious infection and malignancy among adalimumab treated patients 65 years of age and older was higher than for those less than 65 years of age. Consider the benefits and risks of Adalimumab-aacf in patients 65 years of age and older. In patients treated with Adalimumab­ aacf, closely monitor for the development of infection or malignancy [see Warnings and Precautions (5.1, 5.2)]. 10 OVERDOSAGE Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. 11 DESCRIPTION Adalimumab-aacf is a tumor necrosis factor blocker. Adalimumab-aacf is a recombinant human IgG1 monoclonal antibody created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1:k constant regions. Adalimumab-aacf is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary (CHO)) expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons. Adalimumab-aacf injection is supplied as a sterile, preservative-free solution for subcutaneous administration. The drug product is supplied as either a single-dose, prefilled pen (Adalimumab­ aacf Pen), as a single-dose, 1 mL or prefilled glass syringe or as a single dose institutional use vial kit. Enclosed within the pen is a single-dose, 1 mL prefilled glass syringe. The solution of Adalimumab-aacf is clear and colorless to pale yellow, with a pH of about 5.2. Each 40 mg/0.8 mL prefilled syringe or prefilled pen, or institutional use vial kit delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of Adalimumab-aacf contains adalimumab-aacf (40 mg) and glacial acetic acid (0.5 mg), trehalose (54.8 mg), polysorbate 80 (0.8 mg), sodium chloride (2.3 mg), and Water for Injection. Sodium hydroxide is added to adjust pH. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Adalimumab products bind specifically to TNF-alpha and block its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab products also lyse surface TNF expressing cells in 26 Reference ID: 5498630 vitro in the presence of complement. Adalimumab products do not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated concentrations of TNF are found in the synovial fluid of patients with RA, JIA, PsA, and AS and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased concentrations of TNF are also found in psoriasis plaques. In Ps, treatment with Adalimumab-aacf may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab products exert their clinical effects is unknown. Adalimumab products also modulate biological responses that are induced or regulated by TNF, including changes in the concentrations of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). 12.2 Pharmacodynamics After treatment with adalimumab, a decrease in concentrations of acute phase reactants of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. A decrease in CRP concentrations was also observed in patients with Crohn’s disease, ulcerative colitis and hidradenitis suppurativa. Serum concentrations of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration. 12.3 Pharmacokinetics The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10 mg/kg following administration of a single intravenous dose (adalimumab products are not approved for intravenous use). Following 20, 40, and 80 mg every other week and every week subcutaneous administration, adalimumab mean serum trough concentrations at steady state increased approximately proportionally with dose in RA patients. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Healthy subjects and patients with RA displayed similar adalimumab pharmacokinetics. Adalimumab exposure in patients treated with 80 mg every other week is estimated to be comparable with that in patients treated with 40 mg every week. Absorption The average absolute bioavailability of adalimumab following a single 40 mg subcutaneous dose was 64%. The mean time to reach the maximum concentration was 5.5 days (131 ± 56 hours) and the maximum serum concentration was 4.7 ± 1.6 mcg/mL in healthy subjects following a single 40 mg subcutaneous administration of adalimumab. Distribution The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. Elimination The single dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. 27 Reference ID: 5498630 Patient Population Rheumatoid Arthritis and Ankylosing Spondylitis: In patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations were approximately 5 mcg/mL and 8 to 9 mcg/mL, without and with MTX concomitant treatment, respectively. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum. The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA. Psoriatic Arthritis: In patients receiving 40 mg every other week, adalimumab mean steady-state trough concentrations were 6 to 10 mcg/mL and 8.5 to 12 mcg/mL, without and with MTX concomitant treatment, respectively. Plaque Psoriasis: Adalimumab mean steady-state trough concentration was approximately 5 to 6 mcg/mL during adalimumab 40 mg every other week treatment. Adult Uveitis: Adalimumab mean steady concentration was approximately 8 to 10 mcg/mL during adalimumab 40 mg every other week treatment. Adult Hidradenitis Suppurativa: Adalimumab trough concentrations were approximately 7 to 8 mcg/mL at Week 2 and Week 4, respectively, after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations at Week 12 through Week 36 were approximately 7 to 11 mcg/mL during adalimumab 40 mg every week treatment. Adult Crohn’s Disease: Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week 2 and Week 4 after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations were 7 mcg/mL at Week 24 and Week 56 during adalimumab 40 mg every other week treatment. Adult Ulcerative Colitis: Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week 2 and Week 4 after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations were approximately 8 mcg/mL and 15 mcg/mL at Week 52 after receiving a dose of adalimumab 40 mg every other week and 40 mg every week, respectively. Anti-Drug Antibody Effects on Pharmacokinetics Rheumatoid Arthritis: A trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies was identified. Hidradenitis Suppurativa: In subjects with moderate to severe HS, antibodies to adalimumab were associated with reduced serum adalimumab concentrations. In general, the extent of reduction in serum adalimumab concentrations is greater with increasing titers of antibodies to adalimumab. Specific Populations Geriatric Patients: A lower clearance with increasing age was observed in patients with RA aged 40 to >75 years. Pediatric Patients: Juvenile Idiopathic Arthritis: • 4 years to 17 years of age: The adalimumab mean steady-state trough concentrations were 6.8 mcg/mL and 10.9 mcg/mL in patients weighing <30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX, respectively. 28 Reference ID: 5498630 The adalimumab mean steady-state trough concentrations were 6.6 mcg/mL and 8.1 mcg/mL in patients weighing ≥30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with MTX concomitant treatment, respectively. • 2 years to <4 years of age or 4 years of age and older weighing <15 kg: The adalimumab mean steady-state trough adalimumab concentrations were 6.0 mcg/mL and 7.9 mcg/mL in patients receiving adalimumab subcutaneously every other week as monotherapy or with MTX concomitant treatment, respectively. Pediatric Crohn's Disease: Adalimumab mean ± SD concentrations were 15.7±6.5 mcg/mL at Week 4 following 160 mg at Week 0 and 80 mg at Week 2, and 10.5±6.0 mcg/mL at Week 52 following 40 mg every other week dosing in patients weighing ≥ 40 kg. Adalimumab mean ± SD concentrations were 10.6±6.1 mcg/mL at Week 4 following dosing 80 mg at Week 0 and 40 mg at Week 2, and 6.9±3.6 mcg/mL at Week 52 following 20 mg every other week dosing in patients weighing < 40 kg. Male and Female Patients: No gender-related pharmacokinetic differences were observed after correction for a patient’s body weight. Healthy subjects and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics. Patients with Renal or Hepatic Impairment: No pharmacokinetic data are available in patients with hepatic or renal impairment. Rheumatoid factor or CRP concentrations: Minor increases in apparent clearance were predicted in RA patients receiving doses lower than the recommended dose and in RA patients with high rheumatoid factor or CRP concentrations. These increases are not likely to be clinically important. Drug Interaction Studies: Methotrexate: MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA [see Drug Interactions (7.1)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies of adalimumab products have not been conducted to evaluate the carcinogenic potential or its effect on fertility. 14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis The efficacy and safety of adalimumab were assessed in five randomized, double-blind studies in patients ≥18 years of age with active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 6 swollen and 9 tender joints. Adalimumab was administered subcutaneously in combination with methotrexate (MTX) (12.5 to 25 mg, Studies RA-I, RA-III and RA-V) or as monotherapy (Studies RA-II and RA-V) or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study RA-IV). Study RA-I evaluated 271 patients who had failed therapy with at least one but no more than four DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks. Study RA-II evaluated 544 patients who had failed therapy with at least one DMARD. Doses of 29 Reference ID: 5498630 placebo, 20 or 40 mg of adalimumab were given as monotherapy every other week or weekly for 26 weeks. Study RA-III evaluated 619 patients who had an inadequate response to MTX. Patients received placebo, 40 mg of adalimumab every other week with placebo injections on alternate weeks, or 20 mg of adalimumab weekly for up to 52 weeks. Study RA-III had an additional primary endpoint at 52 weeks of inhibition of disease progression (as detected by X-ray results). Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was administered every other week for up to 5 years. Study RA-IV assessed safety in 636 patients who were either DMARD-naive or were permitted to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Patients were randomized to 40 mg of adalimumab or placebo every other week for 24 weeks. Study RA-V evaluated 799 patients with moderately to severely active RA of less than 3 years duration who were ≥18 years old and MTX naïve. Patients were randomized to receive either MTX (optimized to 20 mg/week by week 8), adalimumab 40 mg every other week or adalimumab/MTX combination therapy for 104 weeks. Patients were evaluated for signs and symptoms, and for radiographic progression of joint damage. The median disease duration among patients enrolled in the study was 5 months. The median MTX dose achieved was 20 mg. Clinical Response The percent of adalimumab treated patients achieving ACR 20, 50 and 70 responses in Studies RA-II and III are shown in Table 3. Table 3. ACR Responses in Studies RA-II and RA-III (Percent of Patients) Study RA-II Monotherapy (26 weeks) Study RA-III Methotrexate Combination (24 and 52 weeks) Response Placebo Adalimumab Adalimumab Placebo/MTX Adalimumab/MTX 40 mg every 40 mg weekly 40 mg every other week other week N=110 N=113 N=103 N=200 N=207 ACR20 Month 6 19% 46%* 53%* 30% 63%* Month 12 NA NA NA 24% 59%* ACR50 Month 6 8% 22%* 35%* 10% 39%* Month 12 NA NA NA 10% 42%* ACR70 Month 6 2% 12%* 18%* 3% 21%* Month 12 NA NA NA 5% 23%* * p<0.01, adalimumab vs.placebo 30 Reference ID: 5498630 The results of Study RA-I were similar to Study RA-III; patients receiving adalimumab 40 mg every other week in Study RA-I also achieved ACR 20, 50 and 70 response rates of 65%, 52% and 24%, respectively, compared to placebo responses of 13%, 7% and 3% respectively, at 6 months (p<0.01). The results of the components of the ACR response criteria for Studies RA-II and RA-III are shown in Table 4. ACR response rates and improvement in all components of ACR response were maintained to week 104. Over the 2 years in Study RA-III, 20% of adalimumab patients receiving 40 mg every other week achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6-month period. ACR responses were maintained in similar proportions of patients for up to 5 years with continuous adalimumab treatment in the open-label portion of Study RA-III. Table 4. Components of ACR Response in Studies RA-II and RA-III Study RA-II Study RA-III Parameter (median) Placebo N=110 Adalimumaba N=113 Placebo/MTX N=200 Adalimumaba/MTX N=207 Baseline Wk 26 Baseline Wk 26 Baseline Wk 24 Baseline Wk 24 Number of tender joints (0-68) 35 26 31 16* 26 15 24 8* Number of swollen joints (0-66) 19 16 18 10* 17 11 18 5* Physician global assessmentb 7.0 6.1 6.6 3.7* 6.3 3.5 6.5 2.0* Patient global assessmentb 7.5 6.3 7.5 4.5* 5.4 3.9 5.2 2.0* Painb 7.3 6.1 7.3 4.1* 6.0 3.8 5.8 2.1* Disability index (HAQ)c 2.0 1.9 1.9 1.5* 1.5 1.3 1.5 0.8* CRP (mg/dL) 3.9 4.3 4.6 1.8* 1.0 0.9 1.0 0.4* 40 mg adalimumab administered every other week b Visual analogue scale; 0 = best, 10 = worst c Disability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient’s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity * p<0.001, adalimumab vs. placebo, based on mean change from baseline The time course of ACR 20 response for Study RA-III is shown in Figure 1. In Study RA-III, 85% of patients with ACR 20 responses at week 24 maintained the response at 52 weeks. The time course of ACR 20 response for Study RA-I and Study RA-II were similar. 31 Reference ID: 5498630 ■ 40 mg evayolher ¥.eek - - -O - -Plar:elbo, 70 .,,, - o- o.. - - .o ,., - 410 0 16 2 · 32 40 48 liilm, iillfe ;71111 Figure 1. Study RA-III ACR 20 Responses over 52 Weeks In Study RA-IV, 53% of patients treated with adalimumab 40 mg every other week plus standard of care had an ACR 20 response at week 24 compared to 35% on placebo plus standard of care (p<0.001). No unique adverse reactions related to the combination of adalimumab and other DMARDs were observed. In Study RA-V with MTX naïve patients with recent onset RA, the combination treatment with adalimumab plus MTX led to greater percentages of patients achieving ACR responses than either MTX monotherapy or adalimumab monotherapy at Week 52 and responses were sustained at Week 104 (see Table 5). Table 5. ACR Response in Study RA-V (Percent of Patients) Response MTXb N=257 Adalimumabc N=274 Adalimumab/MT X N=268 ACR20 Week 52 Week 104 63% 56% 54% 49% 73% 69% ACR50 Week 52 Week 104 46% 43% 41% 37% 62% 59% ACR70 Week 52 Week 104 27% 28% 26% 28% 46% 47% Major Clinical Response a 28% 25% 49% a Major clinical response is defined as achieving an ACR70 response for a continuous six month period b p<0.05, adalimumab/MTX vs. MTX for ACR 20 p<0.001, adalimumab/MTX vs. MTX for ACR 50 and 70, and Major Clinical Response c p<0.001, adalimumab/MTX vs. adalimumab At Week 52, all individual components of the ACR response criteria for Study RA-V improved 32 Reference ID: 5498630 in the adalimumab/MTX group and improvements were maintained to Week 104. Radiographic Response In Study RA-III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score, at month 12 compared to baseline. At baseline, the median TSS was approximately 55 in the placebo and 40 mg every other week groups. The results are shown in Table 6. Adalimumab/MTX treated patients demonstrated less radiographic progression than patients receiving MTX alone at 52 weeks. Table 6. Radiographic Mean Changes Over 12 Months in Study RA-III Placebo/MTX Adalimumab/M TX 40 mg every other week Placebo/MTX-Adalimumab/MTX (95% Confidence Interval*) P-value** Total Sharp score 2.7 0.1 2.6 (1.4, 3.8) <0.001 Erosion score 1.6 0.0 1.6 (0.9, 2.2) <0.001 JSN score 1.0 0.1 0.9 (0.3, 1.4) 0.002 *95% confidence intervals for the differences in change scores between MTX and adalimumab. **Based on rank analysis In the open-label extension of Study RA-III, 77% of the original patients treated with any dose of adalimumab were evaluated radiographically at 2 years. Patients maintained inhibition of structural damage, as measured by the TSS. Fifty-four percent had no progression of structural damage as defined by a change in the TSS of zero or less. Fifty-five percent (55%) of patients originally treated with 40 mg adalimumab every other week have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage with 50% showing no progression of structural damage defined by a change in the TSS of zero or less. In Study RA-V, structural joint damage was assessed as in Study RA-III. Greater inhibition of radiographic progression, as assessed by changes in TSS, erosion score and JSN was observed in the adalimumab/MTX combination group as compared to either the MTX or adalimumab monotherapy group at Week 52 as well as at Week 104 (see Table 7). Table 7. Radiographic Mean Change* in Study RA-V MTXa N=257 Adalimumaba,b N=274 Adalimumab/MTX N=268 52 Weeks Total Sharp score 5.7 (4.2, 7.3) 3.0 (1.7, 4.3) 1.3 (0.5, 2.1) Erosion score 3.7 (2.7, 4.8) 1.7 (1.0, 2.4) 0.8 (0.4, 1.2) JSN score 2.0 (1.2, 2.8) 1.3 (0.5, 2.1) 0.5 (0.0, 1.0) 104 Weeks Total Sharp score 10.4 (7.7, 13.2) 5.5 (3.6, 7.4) 1.9 (0.9, 2.9) Erosion score 6.4 (4.6, 8.2) 3.0 (2.0, 4.0) 1.0 (0.4, 1.6) JSN score 4.1 (2.7, 5.4) 2.6 (1.5, 3.7) 0.9 (0.3, 1.5) 33 Reference ID: 5498630 *mean (95% confidence interval) a p<0.001, adalimumab /MTX vs. MTX at 52 and 104 weeks and for adalimumab /MTX vs adalimumab at 104 weeks b p<0.01, for adalimumab /MTX vs. adalimumab at 52 weeks Physical Function Response In studies RA-I through IV, adalimumab showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire (HAQ-DI) from baseline to the end of study, and significantly greater improvement than placebo in the health-outcomes as assessed by The Short Form Health Survey (SF 36). Improvement was seen in both the Physical Component Summary (PCS) and the Mental Component Summary (MCS). In Study RA-III, the mean (95% CI) improvement in HAQ-DI from baseline at week 52 was 0.60 (0.55, 0.65) for the adalimumab patients and 0.25 (0.17, 0.33) for placebo/MTX (p<0.001) patients. Sixty-three percent of adalimumab-treated patients achieved a 0.5 or greater improvement in HAQ-DI at week 52 in the double-blind portion of the study. Eighty-two percent of these patients maintained that improvement through week 104 and a similar proportion of patients maintained this response through week 260 (5 years) of open-label treatment. Mean improvement in the SF-36 was maintained through the end of measurement at week 156 (3 years). In Study RA-V, the HAQ-DI and the physical component of the SF-36 showed greater improvement (p<0.001) for the adalimumab/MTX combination therapy group versus either the MTX monotherapy or the adalimumab monotherapy group at Week 52, which was maintained through Week 104. 14.2 Juvenile Idiopathic Arthritis The safety and efficacy of adalimumab was assessed in two studies (Studies JIA-I and JIA-II) in patients with active polyarticular juvenile idiopathic arthritis (JIA). Study JIA-I The safety and efficacy of adalimumab were assessed in a multicenter, randomized, withdrawal, double-blind, parallel-group study in 171 patients who were 4 to 17 years of age with polyarticular JIA. In the study, the patients were stratified into two groups: MTX-treated or non-MTX-treated. All patients had to show signs of active moderate or severe disease despite previous treatment with NSAIDs, analgesics, corticosteroids, or DMARDS. Patients who received prior treatment with any biologic DMARDS were excluded from the study. The study included four phases: an open-label lead in phase (OL-LI; 16 weeks), a double-blind randomized withdrawal phase (DB; 32 weeks), an open-label extension phase (OLE-BSA; up to 136 weeks), and an open-label fixed dose phase (OLE-FD; 16 weeks). In the first three phases of the study, adalimumab was administered based on body surface area at a dose of 24 mg/m2 up to a maximum total body dose of 40 mg subcutaneously (SC) every other week. In the OLE-FD phase, the patients were treated with 20 mg of adalimumab SC every other week if their weight was less than 30 kg and with 40 mg of adalimumab SC every other week if their weight was 30 kg or greater. Patients remained on stable doses of NSAIDs and or prednisone (≤0.2 mg/kg/day or 10 mg/day maximum). Patients demonstrating a Pediatric ACR 30 response at the end of OL-LI phase were randomized into the double blind (DB) phase of the study and received either adalimumab or placebo every 34 Reference ID: 5498630 other week for 32 weeks or until disease flare. Disease flare was defined as a worsening of ≥30% from baseline in ≥3 of 6 Pediatric ACR core criteria, ≥2 active joints, and improvement of >30% in no more than 1 of the 6 criteria. After 32 weeks or at the time of disease flare during the DB phase, patients were treated in the open-label extension phase based on the BSA regimen (OLE­ BSA), before converting to a fixed dose regimen based on body weight (OLE-FD phase). Study JIA-I Clinical Response At the end of the 16-week OL-LI phase, 94% of the patients in the MTX stratum and 74% of the patients in the non-MTX stratum were Pediatric ACR 30 responders. In the DB phase significantly fewer patients who received adalimumab experienced disease flare compared to placebo, both without MTX (43% vs. 71%) and with MTX (37% vs. 65%). More patients treated with adalimumab continued to show pediatric ACR 30/50/70 responses at Week 48 compared to patients treated with placebo. Pediatric ACR responses were maintained for up to two years in the OLE phase in patients who received adalimumab throughout the study. Study JIA-II Adalimumab was assessed in an open-label, multicenter study in 32 patients who were 2 to <4 years of age or 4 years of age and older weighing <15 kg with moderately to severely active polyarticular JIA. Most patients (97%) received at least 24 weeks of adalimumab treatment dosed 24 mg/m2 up to a maximum of 20 mg every other week as a single SC injection up to a maximum of 120 weeks duration. During the study, most patients used concomitant MTX, with fewer reporting use of corticosteroids or NSAIDs. The primary objective of the study was evaluation of safety [see Adverse Reactions (6.1)]. 14.3 Psoriatic Arthritis The safety and efficacy of adalimumab was assessed in two randomized, double-blind, placebo controlled studies in 413 patients with psoriatic arthritis (PsA). Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg adalimumab was administered every other week. Study PsA-I enrolled 313 adult patients with moderately to severely active PsA (>3 swollen and >3 tender joints) who had an inadequate response to NSAID therapy in one of the following forms: (1) distal interphalangeal (DIP) involvement (N=23); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of plaque psoriasis) (N=210); (3) arthritis mutilans (N=1); (4) asymmetric PsA (N=77); or (5) AS-like (N=2). Patients on MTX therapy (158 of 313 patients) at enrollment (stable dose of ≤30 mg/week for >1 month) could continue MTX at the same dose. Doses of adalimumab 40 mg or placebo every other week were administered during the 24-week double-blind period of the study. Compared to placebo, treatment with adalimumab resulted in improvements in the measures of disease activity (see Tables 8 and 9). Among patients with PsA who received adalimumab, the clinical responses were apparent in some patients at the time of the first visit (two weeks) and were maintained up to 88 weeks in the ongoing open-label study. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. Patients with psoriatic involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses. At 24 weeks, the proportions of patients achieving a 75% or 90% improvement in the PASI were 59% and 42% respectively, in the adalimumab group (N=69), compared to 1% and 0% respectively, in the placebo group 35 Reference ID: 5498630 (N=69) (p<0.001). PASI responses were apparent in some patients at the time of the first visit (two weeks). Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. Table 8. ACR Response in Study PsA-I (Percent of Patients) Placebo N=162 Adalimumab* N=151 ACR20 Week 12 Week 24 14% 15% 58% 57% ACR50 Week 12 Week 24 4% 6% 36% 39% ACR70 Week 12 Week 24 1% 1% 20% 23% *p<0.001 for all comparisons between adalimumab and placebo Table 9. Components of Disease Activity in Study PsA-I Placebo N=162 Adalimumab* N=151 Parameter: median Baseline 24 weeks Baseline 24 weeks Number of tender jointsa 23.0 17.0 20.0 5.0 Number of swollen jointsb 11.0 9.0 11.0 3.0 Physician global assessmentc 53.0 49.0 55.0 16.0 Patient global assessmentc 49.5 49.0 48.0 20.0 Painc 49.0 49.0 54.0 20.0 Disability index (HAQ) d 1.0 0.9 1.0 0.4 CRP (mg/dL)e 0.8 0.7 0.8 0.2 *p<0.001 for adalimumab vs. placebo comparisons based on median changes a Scale 0-78 b Scale 0-76 c Visual analog scale; 0=best, 100=worst d Disability Index of the Health Assessment Questionnaire; 0=best, 3=worst; measures the patient’s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity. e Normal range: 0-0.287 mg/dL Similar results were seen in an additional, 12-week study in 100 patients with moderate to severe psoriatic arthritis who had suboptimal response to DMARD therapy as manifested by ≥3 tender joints and ≥3 swollen joints at enrollment. Radiographic Response Radiographic changes were assessed in the PsA studies. Radiographs of hands, wrists, and feet were obtained at baseline and Week 24 during the double-blind period when patients were on adalimumab or placebo and at Week 48 when all patients were on open-label adalimumab. A modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e., not 36 Reference ID: 5498630 identical to the TSS used for rheumatoid arthritis), was used by readers blinded to treatment group to assess the radiographs. Adalimumab-treated patients demonstrated greater inhibition of radiographic progression compared to placebo-treated patients and this effect was maintained at 48 weeks (see Table 10). Table 10. Change in Modified Total Sharp Score in Psoriatic Arthritis Placebo N=141 Adalimumab N=133 Week 24 Week 24 Week 48 Baseline mean 22.1 23.4 23.4 Mean Change ± SD 0.9 ± 3.1 -0.1 ± 1.7 -0.2 ± 4.9* * <0.001 for the difference between adalimumab, Week 48 and Placebo, Week 24 (primary analysis) Physical Function Response In Study PsA-I, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 40 mg of adalimumab every other week showed greater improvement from baseline in the HAQ-DI score (mean decreases of 47% and 49% at Weeks 12 and 24 respectively) in comparison to placebo (mean decreases of 1% and 3% at Weeks 12 and 24 respectively). At Weeks 12 and 24, patients treated with adalimumab showed greater improvement from baseline in the SF-36 Physical Component Summary score compared to patients treated with placebo, and no worsening in the SF-36 Mental Component Summary score. Improvement in physical function based on the HAQ-DI was maintained for up to 84 weeks through the open-label portion of the study. 14.4 Ankylosing Spondylitis The safety and efficacy of adalimumab 40 mg every other week was assessed in 315 adult patients in a randomized, 24 week double-blind, placebo-controlled study in patients with active ankylosing spondylitis (AS) who had an inadequate response to glucocorticoids, NSAIDs, analgesics, methotrexate or sulfasalazine. Active AS was defined as patients who fulfilled at least two of the following three criteria: (1) a Bath AS disease activity index (BASDAI) score ≥4 cm, (2) a visual analog score (VAS) for total back pain ≥ 40 mm, and (3) morning stiffness ≥ 1 hour. The blinded period was followed by an open-label period during which patients received adalimumab 40 mg every other week subcutaneously for up to an additional 28 weeks. Improvement in measures of disease activity was first observed at Week 2 and maintained through 24 weeks as shown in Figure 2 and Table 11. Responses of patients with total spinal ankylosis (n=11) were similar to those without total ankylosis. 37 Reference ID: 5498630 - - E>- - Placebo (N = 107) - Adalimumab (N = 208) 70 "' 60 "' C 0 50 0.. "' "' It: 40 0 N ti) 30 c( ti) c( 20 ::,e 0 ·o -- -- -o o -----e----- 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (Weeks) Figure 2. ASAS 20 Response By Visit, Study AS-I At 12 weeks, the ASAS 20/50/70 responses were achieved by 58%, 38%, and 23%, respectively, of patients receiving adalimumab, compared to 21%, 10%, and 5% respectively, of patients receiving placebo (p <0.001). Similar responses were seen at Week 24 and were sustained in patients receiving open-label adalimumab for up to 52 weeks. A greater proportion of patients treated with adalimumab (22%) achieved a low level of disease activity at 24 weeks (defined as a value <20 [on a scale of 0 to 100 mm] in each of the four ASAS response parameters) compared to patients treated with placebo (6%). Table 11. Components of Ankylosing Spondylitis Disease Activity Placebo N=107 Adalimumab N=208 Baseline mean Week 24 mean Baseline mean Week 24 mean ASAS 20 Response Criteria* Patient’s Global Assessment of Disease Activitya* 65 60 63 38 Total back pain* 67 58 65 37 Inflammationb* 6.7 5.6 6.7 3.6 BASFIc* 56 51 52 34 BASDAId score* 6.3 5.5 6.3 3.7 BASMIe score* 4.2 4.1 3.8 3.3 Tragus to wall (cm) 15.9 15.8 15.8 15.4 Lumbar flexion (cm) 4.1 4.0 4.2 4.4 Cervical rotation (degrees) 42.2 42.1 48.4 51.6 Lumbar side flexion (cm) 8.9 9.0 9.7 11.7 Intermalleolar distance (cm) 92.9 94.0 93.5 100.8 CRPf* 2.2 2.0 1.8 0.6 38 Reference ID: 5498630 a Percent of subjects with at least a 20% and 10-unit improvement measured on a Visual Analog Scale (VAS) with 0 = “none” and 100 = “severe” b mean of questions 5 and 6 of BASDAI (defined in ‘d’) c Bath Ankylosing Spondylitis Functional Index d Bath Ankylosing Spondylitis Disease Activity Index e Bath Ankylosing Spondylitis Metrology Index f C-Reactive Protein (mg/dL) *statistically significant for comparisons between adalimumab and placebo at Week 24 A second randomized, multicenter, double-blind, placebo-controlled study of 82 patients with ankylosing spondylitis showed similar results. Patients treated with adalimumab achieved improvement from baseline in the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score (-3.6 vs. -1.1) and in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) score (7.4 vs. 1.9) compared to placebo-treated patients at Week 24. 14.5 Adult Crohn’s Disease The safety and efficacy of multiple doses of adalimumab were assessed in adult patients with moderately to severely active Crohn’s disease, CD, (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in randomized, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted, and 79% of patients continued to receive at least one of these medications. Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies. In Study CD-I, 299 TNF-blocker naïve patients were randomized to one of four treatment groups: the placebo group received placebo at Weeks 0 and 2, the 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, the 80/40 group received 80 mg at Week 0 and 40 mg at Week 2, and the 40/20 group received 40 mg at Week 0 and 20 mg at Week 2. Clinical results were assessed at Week 4. In the second induction study, Study CD-II, 325 patients who had lost response to, or were intolerant to, previous infliximab therapy were randomized to receive either 160 mg adalimumab at Week 0 and 80 mg at Week 2, or placebo at Weeks 0 and 2. Clinical results were assessed at Week 4. Maintenance of clinical remission was evaluated in Study CD-III. In this study, 854 patients with active disease received open-label adalimumab, 80 mg at week 0 and 40 mg at Week 2. Patients were then randomized at Week 4 to 40 mg adalimumab every other week, 40 mg adalimumab every week, or placebo. The total study duration was 56 weeks. Patients in clinical response (decrease in CDAI ≥70) at Week 4 were stratified and analyzed separately from those not in clinical response at Week 4. Induction of Clinical Remission A greater percentage of the patients treated with 160/80 mg adalimumab achieved induction of clinical remission versus placebo at Week 4 regardless of whether the patients were TNF blocker naïve (CD-I), or had lost response to or were intolerant to infliximab (CD-II) (see Table 12). 39 Reference ID: 5498630 Table 12. Induction of Clinical Remission in Studies CD-I and CD-II (Percent of Patients) CD-I CD-II Placebo N=74 Adalimumab 160/80 mg N=76 Placebo N=166 Adalimumab 160/80 mg N=159 Week 4 Clinical remission 12% 36%* 7% 21%* Clinical response 34% 58%** 34% 52%** Clinical remission is CDAI score < 150; clinical response is decrease in CDAI of at least 70 points. * p<0.001 for adalimumab vs. placebo pairwise comparison of proportions ** p<0.01 for adalimumab vs. placebo pairwise comparison of proportions Maintenance of Clinical Remission In Study CD-III at Week 4, 58% (499/854) of patients were in clinical response and were assessed in the primary analysis. At Weeks 26 and 56, greater proportions of patients who were in clinical response at Week 4 achieved clinical remission in the adalimumab 40 mg every other week maintenance group compared to patients in the placebo maintenance group (see Table 13). The group that received adalimumab therapy every week did not demonstrate significantly higher remission rates compared to the group that received adalimumab every other week. Table 13. Maintenance of Clinical Remission in CD-III (Percent of Patients) Placebo 40 mg Adalimumab every other week N=170 N=172 Week 26 Clinical remission 17% 40%* Clinical response 28% 54%* Week 56 Clinical remission 12% 36%* Clinical response 18% 43%* Clinical remission is CDAI score < 150; clinical response is decrease in CDAI of at least 70 points. *p<0.001 for adalimumab vs. placebo pairwise comparisons of proportions Of those in response at Week 4 who attained remission during the study, patients in the adalimumab every other week group maintained remission for a longer time than patients in the placebo maintenance group. Among patients who were not in response by Week 12, therapy continued beyond 12 weeks did not result in significantly more responses. 14.6 Pediatric Crohn’s Disease A randomized, double-blind, 52-week clinical study of 2 dose concentrations of adalimumab (Study PCD-I) was conducted in 192 pediatric patients (6 to 17 years of age) with moderately to severely active Crohn’s disease (defined as Pediatric Crohn’s Disease Activity Index (PCDAI) score > 30). Enrolled patients had over the previous two year period an inadequate response to corticosteroids or an immunomodulator (i.e., azathioprine, 6-mercaptopurine, or methotrexate). 40 Reference ID: 5498630 Patients who had previously received a TNF blocker were allowed to enroll if they had previously had loss of response or intolerance to that TNF blocker. Patients received open-label induction therapy at a dose based on their body weight (≥40 kg and <40 kg). Patients weighing ≥40 kg received 160 mg (at Week 0) and 80 mg (at Week 2). Patients weighing <40 kg received 80 mg (at Week 0) and 40 mg (at Week 2). At Week 4, patients within each body weight category (≥40 kg and <40 kg) were randomized 1:1 to one of two maintenance dose regimens (high dose and low dose). The high dose was 40 mg every other week for patients weighing ≥40 kg and 20 mg every other week for patients weighing <40 kg. The low dose was 20 mg every other week for patients weighing ≥40 kg and 10 mg every other week for patients weighing <40 kg. Concomitant stable dosages of corticosteroids (prednisone dosage ≤40 mg/day or equivalent) and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted throughout the study. At Week 12, patients who experienced a disease flare (increase in PCDAI of ≥ 15 from Week 4 and absolute PCDAI > 30) or who were non-responders (did not achieve a decrease in the PCDAI of ≥ 15 from baseline for 2 consecutive visits at least 2 weeks apart) were allowed to dose-escalate (i.e., switch from blinded every other week dosing to blinded every week dosing); patients who dose-escalated were considered treatment failures. At baseline, 38% of patients were receiving corticosteroids, and 62% of patients were receiving an immunomodulator. Forty-four percent (44%) of patients had previously lost response or were intolerant to a TNF blocker. The median baseline PCDAI score was 40. Of the 192 patients total, 188 patients completed the 4 week induction period, 152 patients completed 26 weeks of treatment, and 124 patients completed 52 weeks of treatment. Fifty-one percent (51%) (48/95) of patients in the low maintenance dose group dose-escalated, and 38% (35/93) of patients in the high maintenance dose group dose-escalated. At Week 4, 28% (52/188) of patients were in clinical remission (defined as PCDAI ≤ 10). The proportions of patients in clinical remission (defined as PCDAI ≤ 10) and clinical response (defined as reduction in PCDAI of at least 15 points from baseline) were assessed at Weeks 26 and 52. At both Weeks 26 and 52, the proportion of patients in clinical remission and clinical response was numerically higher in the high dose group compared to the low dose group (Table 14). The recommended maintenance regimen is 20 mg every other week for patients weighing < 40 kg and 40 mg every other week for patients weighing ≥ 40 kg. Every week dosing is not the recommended maintenance dosing regimen [see Dosage and Administration (2.3)]. Table 14. Clinical Remission and Clinical Response in Study PCD-I Low Maintenance Dose† (20 or 10 mg every other week) N = 95 High Maintenance Dose# (40 or 20 mg every other week) N = 93 Week 26 Clinical Remission‡ 28% 39% Clinical Response§ 48% 59% Week 52 Clinical Remission‡ 23% 33% Clinical Response§ 28% 42% 41 Reference ID: 5498630 †The low maintenance dose was 20 mg every other week for patients weighing ≥ 40 kg and 10 mg every other week for patients weighing < 40 kg. #The high maintenance dose was 40 mg every other week for patients weighing ≥ 40 kg and 20 mg every other week for patients weighing < 40 kg. ‡Clinical remission defined as PCDAI ≤ 10. §Clinical response defined as reduction in PCDAI of at least 15 points from baseline. 14.7 Adult Ulcerative Colitis The safety and efficacy of adalimumab were assessed in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 on a 12 point scale, with an endoscopy subscore of 2 to 3 on a scale of 0 to 3) despite concurrent or prior treatment with immunosuppressants such as corticosteroids, azathioprine, or 6-MP in two randomized, double- blind, placebo-controlled clinical studies (Studies UC-I and UC-II). Both studies enrolled TNF- blocker naïve patients, but Study UC-II also allowed entry of patients who lost response to or were intolerant to TNF- blockers. Forty percent (40%) of patients enrolled in Study UC-II had previously used another TNF-blocker. Concomitant stable doses of aminosalicylates and immunosuppressants were permitted. In Studies UC-I and II, patients were receiving aminosalicylates (69%), corticosteroids (59%) and/or azathioprine or 6-MP (37%) at baseline. In both studies, 92% of patients received at least one of these medications. Induction of clinical remission (defined as Mayo score ≤ 2 with no individual subscores > 1) at Week 8 was evaluated in both studies. Clinical remission at Week 52 and sustained clinical remission (defined as clinical remission at both Weeks 8 and 52) were evaluated in Study UC-II. In Study UC-I, 390 TNF-blocker naïve patients were randomized to one of three treatment groups for the primary efficacy analysis. The placebo group received placebo at Weeks 0, 2, 4 and 6. The 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, and the 80/40 group received 80 mg adalimumab at Week 0 and 40 mg at Week 2. After Week 2, patients in both adalimumab treatment groups received 40 mg every other week. In Study UC-II, 518 patients were randomized to receive either adalimumab 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week starting at Week 4 through Week 50, or placebo starting at Week 0 and every other week through Week 50. Corticosteroid taper was permitted starting at Week 8. In both Studies UC-I and UC-II, a greater percentage of the patients treated with 160/80 mg of adalimumab compared to patients treated with placebo achieved induction of clinical remission. In Study UC-II, a greater percentage of the patients treated with 160/80 mg of adalimumab compared to patients treated with placebo achieved sustained clinical remission (clinical remission at both Weeks 8 and 52) (Table 15). Table 15. Induction of Clinical Remission in Studies UC-I and UC-II and Sustained Clinical Remission in Study UC-II (Percent of Patients) Study UC-I Study UC-II Placebo N=130 Adalimu mab 160/80 mg N=130 Treatment Difference (95% CI) Placebo N=246 Adalimu mab 160/80 mg N=248 Treatment Difference (95% CI) 42 Reference ID: 5498630 Induction of Clinical Remission (Clinical Remission at Week 8) 9.2% 18.5% 9.3%* (0.9%, 17.6%) 9.3% 16.5% 7.2%* (1.2%, 12.9%) Sustained Clinical Remission (Clinical Remission at both Weeks 8 and 52) N/A N/A N/A 4.1% 8.5% 4.4%* (0.1%, 8.6%) Clinical remission is defined as Mayo score ≤ 2 with no individual subscores > 1. CI=Confidence interval * p<0.05 for adalimumab vs. placebo pairwise comparison of proportions In Study UC-I, there was no statistically significant difference in clinical remission observed between the adalimumab 80/40 mg group and the placebo group at Week 8. In Study UC-II, 17.3% (43/248) in the adalimumab group were in clinical remission at Week 52 compared to 8.5% (21/246) in the placebo group (treatment difference: 8.8%; 95% confidence interval (CI): [2.8%, 14.5%]; p<0.05). In the subgroup of patients in Study UC-II with prior TNF-blocker use, the treatment difference for induction of clinical remission appeared to be lower than that seen in the whole study population, and the treatment differences for sustained clinical remission and clinical remission at Week 52 appeared to be similar to those seen in the whole study population. The subgroup of patients with prior TNF-blocker use achieved induction of clinical remission at 9% (9/98) in the adalimumab group versus 7% (7/101) in the placebo group, and sustained clinical remission at 5% (5/98) in the adalimumab group versus 1% (1/101) in the placebo group. In the subgroup of patients with prior TNF-blocker use, 10% (10/98) were in clinical remission at Week 52 in the adalimumab group versus 3% (3/101) in the placebo group. 14.8 Plaque Psoriasis The safety and efficacy of adalimumab were assessed in randomized, double-blind, placebo- controlled studies in 1696 adult subjects with moderate to severe chronic plaque psoriasis (Ps) who were candidates for systemic therapy or phototherapy. Study Ps-I evaluated 1212 subjects with chronic Ps with ≥10% body surface area (BSA) involvement, Physician’s Global Assessment (PGA) of at least moderate disease severity, and Psoriasis Area and Severity Index (PASI) ≥12 within three treatment periods. In period A, subjects received placebo or adalimumab at an initial dose of 80 mg at Week 0 followed by a dose of 40 mg every other week starting at Week 1. After 16 weeks of therapy, subjects who achieved at least a PASI 75 response at Week 16, defined as a PASI score improvement of at least 75% relative to baseline, entered period B and received open-label 40 mg adalimumab every other week. After 17 weeks of open label therapy, subjects who maintained at least a PASI 75 response at Week 33 and were originally randomized to active therapy in period A were re-randomized in period C to receive 40 mg adalimumab every other week or placebo for an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 19 and the baseline Physician’s Global Assessment score ranged from “moderate” (53%) to “severe” (41%) to “very severe” (6%). Study Ps-II evaluated 99 subjects randomized to adalimumab and 48 subjects randomized to placebo with chronic plaque psoriasis with ≥10% BSA involvement and PASI ≥12. Subjects received placebo, or an initial dose of 80 mg adalimumab at Week 0 followed by 40 mg every 43 Reference ID: 5498630 other week starting at Week 1 for 16 weeks. Across all treatment groups the mean baseline PASI score was 21 and the baseline PGA score ranged from “moderate” (41%) to “severe” (51%) to “very severe” (8%). Studies Ps-I and II evaluated the proportion of subjects who achieved “clear” or “minimal” disease on the 6-point PGA scale and the proportion of subjects who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at Week 16 (see Table 16 and 17). Additionally, Study Ps-I evaluated the proportion of subjects who maintained a PGA of “clear” or “minimal” disease or a PASI 75 response after Week 33 and on or before Week 52. Table 16. Efficacy Results at 16 Weeks in Study Ps-I Number of Subjects (%) Adalimumab 40 mg every other week Placebo N = 814 N = 398 PGA: Clear or minimal* 506 (62%) 17 (4%) PASI 75 578 (71%) 26 (7%) * Clear = no plaque elevation, no scale, plus or minus hyperpigmentation or diffuse pink or red coloration Minimal = possible but difficult to ascertain whether there is slight elevation of plaque above normal skin, plus or minus surface dryness with some white coloration, plus or minus up to red coloration Table 17. Efficacy Results at 16 Weeks in Study Ps-II Number of Subjects (%) Adalimumab 40 mg every other week Placebo N = 99 N = 48 PGA: Clear or minimal* 70 (71%) 5 (10%) PASI 75 77 (78%) 9 (19%) * Clear = no plaque elevation, no scale, plus or minus hyperpigmentation or diffuse pink or red coloration Minimal = possible but difficult to ascertain whether there is slight elevation of plaque above normal skin, plus or minus surface dryness with some white coloration, plus or minus up to red coloration Additionally, in Study Ps-I, subjects on adalimumab who maintained a PASI 75 were re- randomized to adalimumab (N = 250) or placebo (N = 240) at Week 33. After 52 weeks of treatment with adalimumab, more subjects on adalimumab maintained efficacy when compared to subjects who were re-randomized to placebo based on maintenance of PGA of “clear” or “minimal” disease (68% vs. 28%) or a PASI 75 (79% vs. 43%). A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. Median time to relapse (decline to PGA “moderate” or worse) was approximately 5 months. During the withdrawal period, no subject experienced transformation to either pustular or erythrodermic psoriasis. A total of 178 subjects who relapsed re-initiated treatment with 80 mg of adalimumab, then 40 mg every other week beginning at week 1. At week 16, 69% (123/178) of subjects had a response of PGA “clear” or “minimal”. A randomized, double-blind study (Study Ps-III) compared the efficacy and safety of adalimumab versus placebo in 217 adult subjects. Subjects in the study had to have chronic plaque psoriasis of at least moderate severity on the PGA scale, fingernail involvement of at least moderate severity on a 5-point Physician’s Global Assessment of Fingernail Psoriasis (PGA-F) 44 Reference ID: 5498630 scale, a Modified Nail Psoriasis Severity Index (mNAPSI) score for the target-fingernail of ≥ 8, and either a BSA involvement of at least 10% or a BSA involvement of at least 5% with a total mNAPSI score for all fingernails of ≥ 20. Subjects received an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeks followed by open-label adalimumab treatment for an additional 26 weeks. This study evaluated the proportion of subjects who achieved “clear” or “minimal” assessment with at least a 2-grade improvement on the PGA-F scale and the proportion of subjects who achieved at least a 75% improvement from baseline in the mNAPSI score (mNAPSI 75) at Week 26. At Week 26, a higher proportion of subjects in the adalimumab group than in the placebo group achieved the PGA-F endpoint. Furthermore, a higher proportion of subjects in the adalimumab group than in the placebo group achieved mNAPSI 75 at Week 26 (see Table 18). Table 18. Efficacy Results at 26 Weeks Endpoint Adalimumab 40 mg every other week* N=109 Placebo N=108 PGA-F: ≥2-grade improvement and clear or minimal 49% 7% mNAPSI 75 47% 3% *Subjects received 80 mg of adalimumab at Week 0, followed by 40 mg every other week starting at Week 1. Nail pain was also evaluated and improvement in nail pain was observed in Study Ps-III. 14.9 Hidradenitis Suppurativa Two randomized, double-blind, placebo-controlled studies (Studies HS-I and II) evaluated the safety and efficacy of adalimumab in a total of 633 adult subjects with moderate to severe hidradenitis suppurativa (HS) with Hurley Stage II or III disease and with at least 3 abscesses or inflammatory nodules. In both studies, subjects received placebo or adalimumab at an initial dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every week starting at Week 4 and continued through Week 11. Subjects used topical antiseptic wash daily. Concomitant oral antibiotic use was allowed in Study HS-II. Both studies evaluated Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12. HiSCR was defined as at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count relative to baseline (see Table 18). Reduction in HS-related skin pain was assessed using a Numeric Rating Scale in patients who entered the study with an initial baseline score of 3 or greater on a 11 point scale. In both studies, a higher proportion of adalimumab- than placebo-treated subjects achieved HiSCR (see Table 19). Table 19. Efficacy Results at 12 Weeks in Subjects with Moderate to Severe Hidradenitis Suppurativa HS Study I HS Study II* Placebo Adalimumab 40 mg Weekly Placebo Adalimumab 40 mg Weekly 45 Reference ID: 5498630 I I I I Hidradenitis Suppurativa Clinical Response (HiSCR) N = 154 40 (26%) N = 153 64 (42%) N=163 45 (28%) N=163 96 (59%) *19.3% of subjects in Study HS-II continued baseline oral antibiotic therapy during the study. In both studies, from Week 12 to Week 35 (Period B), subjects who had received adalimumab were re-randomized to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 40 mg every other week, or placebo). Subjects who had been randomized to placebo were assigned to receive adalimumab 40 mg every week (Study HS-I) or placebo (Study HS-II). During Period B, flare of HS, defined as ≥25% increase from baseline in abscesses and inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects who were withdrawn from adalimumab treatment following the primary efficacy timepoint in two studies. 14.10 Adult Uveitis The safety and efficacy of adalimumab were assessed in adult patients with non-infectious intermediate, posterior and panuveitis excluding patients with isolated anterior uveitis, in two randomized, double-masked, placebo-controlled studies (UV I and II). Patients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week after the initial dose. The primary efficacy endpoint in both studies was ´time to treatment failure´. Treatment failure was a multi-component outcome defined as the development of new inflammatory chorioretinal and/or inflammatory retinal vascular lesions, an increase in anterior chamber (AC) cell grade or vitreous haze (VH) grade or a decrease in best corrected visual acuity (BCVA). Study UV I evaluated 217 patients with active uveitis while being treated with corticosteroids (oral prednisone at a dose of 10 to 60 mg/day). All patients received a standardized dose of prednisone 60 mg/day at study entry followed by a mandatory taper schedule, with complete corticosteroid discontinuation by Week 15. Study UV II evaluated 226 patients with inactive uveitis while being treated with corticosteroids (oral prednisone 10 to 35 mg/day) at baseline to control their disease. Patients subsequently underwent a mandatory taper schedule, with complete corticosteroid discontinuation by Week 19. Clinical Response Results from both studies demonstrated statistically significant reduction of the risk of treatment failure in patients treated with adalimumab versus patients receiving placebo. In both studies, all components of the primary endpoint contributed cumulatively to the overall difference between adalimumab and placebo groups (Table 20). Table 20. Time to Treatment Failure in Studies UV I and UV II UV I UV II Placebo (N = 107) ADALIMUMAB (N = 110) HR [95% CI]a Placebo (N = 111) ADALIMUMAB (N = 115) HR [95% CI]a Failureb n (%) 84 (78.5) 60 (54.5) 0.50 [0.36, 0.70] 61 (55.0) 45 (39.1) 0.57 [0.39, 0.84] 46 Reference ID: 5498630 100 l I 80 Ill ~ $0 _, ~ i 40 :!: s ~ fE O< 100 ft !ii IMI = .. = 60 :, .. ;! ""' 411 ~ ; 20 e ,o __ .../· ,- - J'. --­ ~- _J )_/ 0 2 4 8 9 10 12 NIIM0<7 3!JU &lt.lS N/111 lllllf14 82111 a:)111 A,omo jM)2 4'W54 -~2 S4l3,S ~m ~ TIM!E lMOlffllS) TR£ATMBIT - FILACliiBO ~--~------.---- 0 2 4 6 8 10 '112 1'#0/llH 116.11111 3""116 46150 411141 5,1,133 5!W2II Al!OJUS &1105 ~YQ2 32161 31159 40151 4!41112 l'lM.E [MON'll'HSI JIIEA.TMENT - Pl.ACEBO {4 16 03/1 fjM G0/17 &0/1$ ADAUMU.MAB u 61121 45.1:11 ADAUI.IUMAB UI 114/4 W 12 20 &1111 E0/11 20 '6"0 45.10 Median Time to Failure (Months) [95% CI] 3.0 [2.7, 3.7] 5.6 [3.9, 9.2] N/A 8.3 [4.8, 12.0] NEc N/A ª HR of adalimumab versus placebo from proportional hazards regression with treatment as factor. b Treatment failure at or after Week 6 in Study UV I, or at or after Week 2 in Study UV II, was counted as event. Subjects who discontinued the study were censored at the time of dropping out. c NE = not estimable. Fewer than half of at-risk subjects had an event. Figure 3: Kaplan-Meier Curves Summarizing Time to Treatment Failure on or after Week 6 (Study UV I) or Week 2 (Study UV II) Study UV I Study UV II Note: P# = Placebo (Number of Events/Number at Risk); A# = adalimumab (Number of Events/Number at Risk). 15 REFERENCES 1. National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Incidence Crude Rates, 17 Registries, 2000-2007. 16 HOW SUPPLIED/STORAGE AND HANDLING Adalimumab-aacf injection is supplied as a preservative-free, sterile, clear and colorless to pale yellow solution for subcutaneous administration. The following packaging configurations are available. • Adalimumab-aacf Pen Carton - 40 mg/0.8 mL (2 count) 47 Reference ID: 5498630 Adalimumab-aacf is supplied in a carton containing 2 alcohol preps and one tray. The tray contains two single-dose pens, each containing a 1 mL prefilled glass syringe with a 29 gauge staked ½ inch needle, providing 40 mg/0.8 mL of Adalimumab-aacf. The syringe plunger stopper and needle cover are not made with natural rubber latex. The NDC number is 65219-612­ 99. • Adalimumab-aacf Pen 40 mg/0.8 mL - Starter Package for Plaque Psoriasis or Uveitis (4 Count) Adalimumab-aacf is supplied in a carton containing 4 alcohol preps and 2 trays (Starter Package for Plaque Psoriasis or Uveitis). Each tray contains two single-dose pens, each pen containing a 1 mL prefilled glass syringe with a 29 gauge staked ½ inch needle, providing 40 mg/0.8 mL of Adalimumab-aacf. The syringe plunger stopper and needle cover are not made with natural rubber latex. The NDC number is 65219-612-69. • Adalimumab-aacf Pen 40 mg/0.8 mL - Starter Package for Crohn's Disease, Ulcerative Colitis, or Hidradenitis Suppurativa (6 Count) Adalimumab-aacf is supplied in a carton containing 6 alcohol preps and 3 trays (Starter Package for Crohn’s Disease, Ulcerative Colitis, or Hidradenitis Suppurativa). Each tray contains two single-dose pens, each pen containing a 1 mL prefilled glass syringe with a 29 gauge staked ½ inch needle, providing 40 mg/0.8 mL of Adalimumab-aacf. The syringe plunger stopper and needle cover are not made with natural rubber latex. The NDC number is 65219-612-89. • Adalimumab-aacf Prefilled Syringe Carton - 40 mg/0.8 mL (2 count) Adalimumab-aacf is supplied in a carton containing 2 alcohol preps and one tray. The tray contains two single-dose, 1 mL prefilled glass syringes with a 29 gauge staked ½ inch needle, each syringe providing 40 mg/0.8 mL of Adalimumab-aacf. The syringe plunger stopper and needle cover are not made with natural rubber latex. The NDC number is 65219-620-20. • Adalimumab-aacf Single-Dose Institutional Use Vial Kit - 40 mg/0.8 mL. Adalimumab-aacf is supplied in a carton containing 1 sterile single-use syringe, 1 sterile needle, 1 vial adapter, 2 alcohol preps and 1 glass vial providing 40 mg/0.8 mL of Adalimumab-aacf. The vial stopper is not made with natural rubber latex. The NDC number is 65219-628-89. Storage and Stability Do not use beyond the expiration date on the container. Adalimumab-aacf must be refrigerated at 36°F to 46°F (2°C to 8°C). DO NOT FREEZE. Do not use if frozen even if it has been thawed. Store in original carton until time of administration to protect from light. If needed, for example when traveling, Adalimumab-aacf may be stored at room temperature up to a maximum of 77°F (25°C) for a period of up to 28 days, with protection from light. Adalimumab-aacf should be discarded if not used within the 28-day period. Record the date when Adalimumab-aacf is first removed from the refrigerator in the spaces provided on the carton. Do not store Adalimumab-aacf in extreme heat or cold. 48 Reference ID: 5498630 17 PATIENT COUNSELING INFORMATION Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Infections Inform patients that Adalimumab-aacf may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections [see Warnings and Precautions (5.1, 5.2, 5.4)]. Malignancies Counsel patients about the risk of malignancies while receiving Adalimumab-aacf [see Warnings and Precautions (5.2)] Hypersensitivity Reactions Advise patients to seek immediate medical attention if they experience any symptoms of severe hypersensitivity reactions. Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever [see Warnings and Precautions (5.5, 5.6, 5.8, 5.9)]. Instructions on Injection Technique Inform patients that the first injection is to be performed under the supervision of a qualified health care professional. If a patient or caregiver is to administer Adalimumab-aacf, instruct them in injection techniques and assess their ability to inject subcutaneously to ensure the proper administration of Adalimumab-aacf [see Instructions for Use]. For patients who will use the Adalimumab-aacf Pen, tell them to: • Remove the needle cap of the Pen and push and hold the Pen firmly against the skin on the chosen injection site. • Activate Pen by pressing the injection button. The click means the start of the injection. • Keep holding the Adalimumab-aacf Pen against their skin until the injection has finished. • Will know that the injection has finished when the syringe plunger moves all the way down to the bottom of the transparent syringe housing to enable the safety guard to cover the needle Instruct patients to dispose of their used needles and syringes or used Pen in a FDA-cleared sharps disposal container immediately after use. Instruct patients not to dispose of loose needles and syringes or Pens in their household trash. Instruct patients that if they do not have a FDA-cleared sharps disposal container, they may use a household container that is made of a heavy-duty plastic, can be closed with a tight-fitting and puncture-resistant lid without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. Instruct patients that when their sharps disposal container is almost full, they will need to follow their community guidelines for the correct way to dispose of their sharps disposal container. Instruct patients that there may be state or local laws regarding disposal of used needles and syringes. Refer patients to the FDA’s website at http://www.fda.gov/safesharpsdisposal for more 49 Reference ID: 5498630 information about safe sharps disposal, and for specific information about sharps disposal in the state that they live in. Instruct patients not to dispose of their used sharps disposal container in their household trash unless their community guidelines permit this. Instruct patients not to recycle their used sharps disposal container. Manufactured by: Fresenius Kabi USA, LLC Lake Zurich, IL 60047, U.S.A US License Number 2146 50 Reference ID: 5498630 MEDICATION GUIDE Adalimumab-aacf (ada-LIM-u-mab aacf) injection, for subcutaneous use This product is IDACIO® (adalimumab-aacf). Read the Medication Guide that comes with Adalimumab-aacf before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment. What is the most important information I should know about Adalimumab-aacf? Adalimumab-aacf is a medicine that affects your immune system. Adalimumab-aacf can lower the ability of your immune system to fight infections. Serious infections have happened in people taking adalimumab products. These serious infections include tuberculosis (TB) and infections caused by viruses, fungi or bacteria that have spread throughout the body. Some people have died from these infections. • Your healthcare provider should test you for TB before starting Adalimumab-aacf. • Your healthcare provider should check you closely for signs and symptoms of TB during treatment with Adalimumab­ aacf. You should not start taking Adalimumab-aacf if you have any kind of infection unless your healthcare provider says it is okay. Before starting Adalimumab-aacf, tell your healthcare provider if you: • think you have an infection or have symptoms of an infection such as: o fever, sweats, or chills o diarrhea or stomach pain o muscle aches o burning when you urinate or urinate more often o cough than normal o shortness of breath o feel very tired o blood in phlegm o weight loss o warm, red, or painful skin or sores on your body • are being treated for an infection. • get a lot of infections or have infections that keep coming back. • have diabetes • have TB or have been in close contact with someone with TB. • were born in, lived in, or traveled to countries where there is more risk for getting TB. Ask your healthcare provider if you are not sure. • live or have lived in certain parts of the country (such as the Ohio and Mississippi River valleys) where there is an increased risk for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, or blastomycosis). These infections may happen or become more severe if you use Adalimumab-aacf. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common. • have or have had hepatitis B • use the medicine ORENCIA (abatacept), KINERET (anakinra), RITUXAN (rituximab), IMURAN (azathioprine), or PURINETHOL (6–mercaptopurine, 6-MP). • are scheduled to have major surgery. After starting Adalimumab-aacf, call your healthcare provider right away if you have an infection, or any sign of an infection. Adalimumab-aacf can make you more likely to get infections or make any infection that you may have worse. Cancer • For children and adults taking Tumor Necrosis Factor (TNF)-blockers, including Adalimumab-aacf, the chances of getting cancer may increase. • There have been cases of unusual cancers in children, teenagers, and young adults using TNF-blockers. • People with rheumatoid arthritis (RA), especially more serious RA, may have a higher chance for getting a kind of cancer called lymphoma. • If you use TNF blockers including Adalimumab-aacf your chance of getting two types of skin cancer may increase (basal cell cancer and squamous cell cancer of the skin). These types of cancer are generally not life-threatening if treated. Tell your healthcare provider if you have a bump or open sore that does not heal. • Some people receiving TNF blockers including Adalimumab-aacf developed a rare type of cancer called hepatosplenic T-cell lymphoma. This type of cancer often results in death. Most of these people were male teenagers or young men. Also, most people were being treated for Crohn’s disease or ulcerative colitis with another medicine called IMURAN (azathioprine) or PURINETHOL (6-mercaptopurine, 6–MP). 51 Reference ID: 5498630 What is Adalimumab-aacf? Adalimumab-aacf is a medicine called a Tumor Necrosis Factor (TNF) blocker. Adalimumab-aacf is used: • To reduce the signs and symptoms of: o moderate to severe RA in adults. Adalimumab-aacf can be used alone, with methotrexate, or with certain other medicines. o moderate to severe polyarticular juvenile idiopathic arthritis (JIA) in children 2 years and older. Adalimumab-aacf can be used alone, or with methotrexate. o psoriatic arthritis (PsA) in adults. Adalimumab-aacf can be used alone or with certain other medicines. o ankylosing spondylitis (AS) in adults. o moderate to severe hidradenitis suppurativa (HS) in adults. • To treat moderate to severe Crohn’s disease (CD) in adults and children 6 years of age and older. • To treat moderate to severe ulcerative colitis (UC) in adults. It is not known if adalimumab products are effective in people who stopped responding to or could not tolerate TNF-blocker medicines. • To treat moderate to severe chronic (lasting a long time) plaque psoriasis (Ps) in adults who have the condition in many areas of their body and who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills). • To treat non-infectious intermediate, posterior, and panuveitis in adults. What should I tell my healthcare provider before taking Adalimumab-aacf? Adalimumab-aacf may not be right for you. Before starting Adalimumab-aacf, tell your healthcare provider about all of your medical conditions, including if you: • have an infection. See “What is the most important information I should know about Adalimumab-aacf?” • have or have had cancer. • have any numbness or tingling or have a disease that affects your nervous system such as multiple sclerosis or Guillain-Barré syndrome. • have or had heart failure. • have recently received or are scheduled to receive a vaccine. You may receive vaccines, except for live vaccines while using Adalimumab-aacf. Children should be brought up to date with all vaccines before starting Adalimumab-aacf. • are allergic to Adalimumab-aacf or to any of its ingredients. See the end of this Medication Guide for a list of ingredients in Adalimumab-aacf. • are pregnant or plan to become pregnant, breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you should take Adalimumab-aacf while you are pregnant or breastfeeding. • have a baby and you were using Adalimumab-aacf during your pregnancy. Tell your baby’s healthcare provider before your baby receives any vaccines. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you use: • ORENCIA (abatacept), KINERET (anakinra), REMICADE (infliximab), ENBREL (etanercept), CIMZIA (certolizumab pegol) or SIMPONI (golimumab), because you should not use Adalimumab-aacf while you are also using one of these medicines. • RITUXAN (rituximab). Your healthcare provider may not want to give you Adalimumab-aacf if you have received RITUXAN (rituximab) recently. • IMURAN (azathioprine) or PURINETHOL (6–mercaptopurine, 6-MP). Keep a list of your medicines with you to show your healthcare provider and pharmacist each time you get a new medicine. How should I take Adalimumab-aacf? • Adalimumab-aacf is given by an injection under the skin. Your healthcare provider will tell you how often to take an injection of Adalimumab-aacf. This is based on your condition to be treated. Do not inject Adalimumab-aacf more often than you were prescribed. • See the Instructions for Use inside the carton for complete instructions for the right way to prepare and inject Adalimumab-aacf. • Make sure you have been shown how to inject Adalimumab-aacf before you do it yourself. If you have any questions about giving yourself an injection, you can call your healthcare provider or the patient support program at 1-833-522­ 4227. Someone you know can also help you with your injection after they have been shown how to prepare and inject Adalimumab-aacf. • Do not try to inject Adalimumab-aacf yourself until you have been shown the right way to give the injections. If your healthcare provider decides that you or a caregiver may be able to give your injections of Adalimumab-aacf at home, you should receive training on the right way to prepare and inject Adalimumab-aacf. • Do not miss any doses of Adalimumab-aacf unless your healthcare provider says it is okay. If you forget to take Adalimumab-aacf, inject a dose as soon as you remember. Then, take your next dose at your regular scheduled time. 52 Reference ID: 5498630 This will put you back on schedule. In case you are not sure when to inject Adalimumab-aacf, call your healthcare provider or pharmacist. • If you take more Adalimumab-aacf than you were told to take, call your healthcare provider. What are the possible side effects of Adalimumab-aacf? Adalimumab-aacf can cause serious side effects, including: See “What is the most important information I should know about Adalimumab-aacf?” • Serious Infections. Your healthcare provider will examine you for TB and perform a test to see if you have TB. If your healthcare provider feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with Adalimumab-aacf and during treatment with Adalimumab-aacf. Even if your TB test is negative your healthcare provider should carefully monitor you for TB infections while you are taking Adalimumab-aacf. People who had a negative TB skin test before receiving adalimumab products have developed active TB. Tell your healthcare provider if you have any of the following symptoms while taking or after taking Adalimumab-aacf: o cough that does not go away o low grade fever o weight loss o loss of body fat and muscle (wasting) • Hepatitis B infection in people who carry the virus in their blood. If you are a carrier of the hepatitis B virus (a virus that affects the liver), the virus can become active while you use Adalimumab-aacf. Your healthcare provider should do blood tests before you start treatment, while you are using Adalimumab-aacf, and for several months after you stop treatment with Adalimumab-aacf. Tell your healthcare provider if you have any of the following symptoms of a possible hepatitis B infection: o muscle aches o clay-colored bowel movements o feel very tired o fever o dark urine o chills o skin or eyes look yellow o stomach discomfort o little or no appetite o skin rash o vomiting • Allergic reactions. Allergic reactions can happen in people who use Adalimumab-aacf. Call your healthcare provider or get medical help right away if you have any of these symptoms of a serious allergic reaction: o Hives o swelling of your face, eyes, lips or mouth o trouble breathing • Nervous system problems. Signs and symptoms of a nervous system problem include numbness or tingling, problems with your vision, weakness in your arms or legs, and dizziness. • Blood problems. Your body may not make enough of the blood cells that help fight infections or help to stop bleeding. Symptoms include a fever that does not go away, bruising or bleeding very easily, or looking very pale. • New heart failure or worsening of heart failure you already have. Call your healthcare provider right away if you get new worsening symptoms of heart failure while taking Adalimumab-aacf, including: o shortness of breath o swelling of your ankles or feet o sudden weight gain • Immune reactions including a lupus-like syndrome. Symptoms include chest discomfort or pain that does not go away, shortness of breath, joint pain, or a rash on your cheeks or arms that gets worse in the sun. Symptoms may improve when you stop Adalimumab-aacf. • Liver Problems. Liver problems can happen in people who use TNF-blocker medicines. These problems can lead to liver failure and death. Call your healthcare provider right away if you have any of these symptoms: o feel very tired o skin or eyes look yellow o poor appetite or vomiting o pain on the right side of your stomach (abdomen) • Psoriasis. Some people using adalimumab products had new psoriasis or worsening of psoriasis they already had. Tell your healthcare provider if you develop red scaly patches or raised bumps that are filled with pus. Your healthcare provider may decide to stop your treatment with Adalimumab-aacf. Call your healthcare provider or get medical care right away if you develop any of the above symptoms. Your treatment with Adalimumab-aacf may be stopped. The most common side effects of Adalimumab-aacf include: • injection site reactions: redness, rash, swelling, itching, or bruising. These symptoms usually will go away within a few days. Call your healthcare provider right away if you have pain, redness or swelling around the injection site that does not go away within a few days or gets worse. • upper respiratory infections (including sinus infections). • headaches. 53 Reference ID: 5498630 • rash. These are not all the possible side effects with Adalimumab-aacf. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Adalimumab-aacf? • Store Adalimumab-aacf in the refrigerator at 36ºF to 46ºF (2ºC to 8ºC). Store Adalimumab-aacf in the original carton until use to protect it from light. • Do not freeze Adalimumab-aacf. Do not use Adalimumab-aacf if frozen, even if it has been thawed. • Refrigerated Adalimumab-aacf may be used until the expiration date printed on the Adalimumab-aacf carton. Pen or prefilled syringe. Do not use Adalimumab-aacf after the expiration date. • If needed, for example when you are traveling, you may also store Adalimumab-aacf at room temperature up to 77°F (25°C) for up to 28 days. Store Adalimumab-aacf in the original carton until use, to protect it from light. • Throw away Adalimumab-aacf if it has been kept at room temperature and not been used within 28 days. • Record the date you first remove Adalimumab-aacf from the refrigerator in the spaces provided on the carton. • Do not store Adalimumab-aacf in extreme heat or cold. • Do not use a Pen or prefilled syringe if the liquid is cloudy, discolored, or has flakes or particles in it. • Do not drop or crush Adalimumab-aacf. The prefilled syringe is glass. Keep Adalimumab-aacf, injection supplies, and all other medicines out of the reach of children. General information about the safe and effective use of Adalimumab-aacf. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Adalimumab­ aacf for a condition for which it was not prescribed. Do not give Adalimumab-aacf to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about Adalimumab-aacf. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Adalimumab-aacf that is written for health professionals. What are the ingredients in Adalimumab-aacf? Active ingredient: adalimumab-aacf Adalimumab-aacf 40 mg/0.8 mL Pen, Adalimumab-aacf 40 mg/0.8 mL prefilled syringe and Adalimumab-aacf 40 mg/0.8 mL institutional use vial kit. Inactive ingredients: glacial acetic acid, trehalose, polysorbate 80, sodium chloride and Water for Injection. Sodium hydroxide is added as necessary to adjust pH. Manufactured by: Fresenius Kabi USA, LLC, Lake Zurich, IL 60047, U.S.A. You can enroll in a patient support program by calling 1-833-522-4227 or visiting the patient support program website: https://kabicare.us/. U.S. License number 2146 This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 06/2024 54 Reference ID: 5498630
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2025-02-12T15:47:53.362058
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INVOKANA safely and effectively. See full prescribing information for INVOKANA. INVOKANA® (canagliflozin) tablets, for oral use Initial U.S. Approval: 2013 -------------------------RECENT MAJOR CHANGES----------------------------­ Indications and Usage (1) 12/2024 Dosage and Administration (2.2, 2.3) 12/2024 Dosage and Administration (2.5) 08/2024 Warnings and Precautions (5.1) 08/2024 Warnings and Precautions (5.2) 08/2024 ----------------------------INDICATIONS AND USAGE---------------------------­ INVOKANA is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated:  As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus (1).  To reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (1).  To reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria (1). Limitations of Use:  Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus (1).  Not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2 (1). -----------------------DOSAGE AND ADMINISTRATION----------------------­  Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating (2.1).  The recommended starting dosage in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus is 100 mg orally once daily, taken before the first meal of the day to improve glycemic control. The dosage can be increased to 300 mg once daily in patients tolerating 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control (2.2).  For all other indications in adults, the recommended dosage of INVOKANA is 100 mg orally once daily (2.2).  Dosage adjustments for patients with renal impairment may be required (2.3).  See full prescribing information for INVOKANA dosage modifications due to drug interactions (2.4).  Withhold INVOKANA at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting (2.5). ----------------------DOSAGE FORMS AND STRENGTHS--------------------­ Tablets: 100 mg, 300 mg (3) -------------------------------CONTRAINDICATIONS------------------------------­  Serious hypersensitivity reaction to INVOKANA (4) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Prior to Initiation of INVOKANA 2.2 Recommended Dosage and Administration 2.3 Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment 2.4 Concomitant Use with UDP-Glucuronosyl transferase (UGT) Enzyme Inducers 2.5 Temporary Interruption for Surgery 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS --------------------------WARNINGS AND PRECAUTIONS-----------------­  Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue INVOKANA if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting (5.1).  Lower Limb Amputation: Monitor patients for infection or ulcers of lower limb and discontinue if these occur (5.2).  Volume Depletion: May result in acute kidney injury. Before initiating INVOKANA, assess and correct volume status in patients with renal impairment, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy (5.3).  Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (5.4).  Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues: Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with INVOKANA (5.5).  Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment (5.6).  Genital Mycotic Infections: Monitor and treat if indicated (5.7)  Hypersensitivity Reactions: Discontinue INVOKANA and monitor until signs and symptoms resolve (5.8).  Bone Fracture: Consider factors that contribute to fracture risk before initiating INVOKANA (5.9). ------------------------------ADVERSE REACTIONS------------------------------­ Most common adverse reactions (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------­ See full prescribing information for information on drug interactions and interference of INVOKANA with laboratory tests (7). -----------------------USE IN SPECIFIC POPULATIONS-----------------------­  Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters (8.1).  Lactation: Not recommended when breastfeeding (8.2).  Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume (8.5).  Renal Impairment: Higher incidence of adverse reactions related to hypotension and renal function (8.6).  Hepatic Impairment: Not recommended in patients with severe hepatic impairment (8.7). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 12/2024 5 WARNINGS AND PRECAUTIONS 5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis 5.2 Lower Limb Amputation 5.3 Volume Depletion 5.4 Urosepsis and Pyelonephritis 5.5 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues 5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) 5.7 Genital Mycotic Infections 5.8 Hypersensitivity Reactions Reference ID: 5499136 1 5.9 Bone Fracture 13 NONCLINICAL TOXICOLOGY 6 7 8 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience DRUG INTERACTIONS USE IN SPECIFIC POPULATIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 14.2 Glycemic Control Trial in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus 14.3 Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus and Atherosclerotic 10 11 12 8.6 Renal Impairment 8.7 Hepatic Impairment OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY Cardiovascular Disease 14.4 Renal and Cardiovascular Outcomes in Adults with Diabetic Nephropathy and Albuminuria 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5499136 2 1-------- FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE INVOKANA (canagliflozin) is indicated:  as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.  to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).  to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day. Limitations of Use INVOKANA is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.1)]. INVOKANA is not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2. INVOKANA is likely to be ineffective in this setting based upon its mechanism of action. 2 DOSAGE AND ADMINISTRATION 2.1 Prior to Initiation of INVOKANA Assess renal function before initiating INVOKANA and as clinically indicated [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)]. In patients with volume depletion, correct this condition before initiating INVOKANA [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5, 8.6)]. 2.2 Recommended Dosage and Administration Recommended Dosage for Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older  The recommended starting dosage of INVOKANA is 100 mg orally once daily to improve glycemic control, taken before the first meal of the day.  For additional glycemic control, the dosage of INVOKANA may be increased to the maximum recommended dosage of 300 mg once daily. Recommended Dosage for Other Indications in Adults Reference ID: 5499136 3 The recommended dosage of INVOKANA is 100 mg orally once daily for the following indications in adults:  to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).  to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day. 2.3 Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment Table 1 provides dosage recommendations for adults and pediatric patients aged 10 years and older with renal impairment, based on estimated glomerular filtration rate (eGFR). Table 1: Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment Estimated Glomerular Filtration Rate [eGFR (mL/min/1.73 m2)] Recommended Dosage eGFR 30 to less than 60 The maximum recommended dosage is 100 mg orally once daily. eGFR less than 30  Initiation is not recommended  Adult patients taking INVOKANA with albuminuria greater than 300 mg/day may continue INVOKANA 100 mg once daily to reduce the risk of ESKD, doubling of serum creatinine, CV death, and hospitalization for heart failure [see Indications and Usage (1) and Use in Specific Populations (8.6)]. 2.4 Concomitant Use with UDP-Glucuronosyl transferase (UGT) Enzyme Inducers When co-administering INVOKANA with an inducer of UGT (e.g., rifampin, phenytoin, phenobarbital, ritonavir), increase the dosage of INVOKANA based on renal function [see Drug Interactions (7)]:  In patients with eGFR 60 mL/min/1.73 m2 or greater, increase the dosage to 200 mg orally once daily in patients currently tolerating INVOKANA 100 mg once daily. The maximum recommended dosage of INVOKANA is 300 mg once daily.  In patients with eGFR less than 60 mL/min/1.73 m2, increase to a maximum recommended dosage of 200 mg orally once daily in patients currently tolerating INVOKANA 100 mg once daily. Reference ID: 5499136 4 2.5 Temporary Interruption for Surgery Withhold INVOKANA at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume INVOKANA when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)]. 3 DOSAGE FORMS AND STRENGTHS  INVOKANA 100 mg tablets are yellow, capsule-shaped, tablets with “CFZ” on one side and “100” on the other side.  INVOKANA 300 mg tablets are white, capsule-shaped, tablets with “CFZ” on one side and “300” on the other side. 4 CONTRAINDICATIONS INVOKANA is contraindicated in patients with a serious hypersensitivity reaction to INVOKANA, such as anaphylaxis or angioedema [see Warnings and Precautions (5.8) and Adverse Reactions (6.1, 6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, INVOKANA significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may be greater with higher doses of INVOKANA. INVOKANA is not indicated for glycemic control in patients with type 1 diabetes mellitus. Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKANA. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under­ insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Reference ID: 5499136 5 Urinary glucose excretion persists for 3 days after discontinuing INVOKANA [see Clinical Pharmacology (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INVOKANA, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKANA. Withhold INVOKANA, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKANA when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.5)]. Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKANA and seek medical attention immediately if signs and symptoms occur. 5.2 Lower Limb Amputation An increased risk of lower limb amputations associated with INVOKANA use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating adult patients with type 2 diabetes mellitus who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower limb amputations was observed at both the 100 mg and 300 mg once daily dosage regimens. The amputation data for CANVAS and CANVAS-R are shown in Tables 3 and 4, respectively [see Adverse Reactions (6.1)]. Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving INVOKANA in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving INVOKANA in the two trials). Some patients had multiple amputations, some involving both lower limbs. Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving INVOKANA for signs and symptoms of infection (including osteomyelitis), new pain Reference ID: 5499136 6 or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKANA if these complications occur. 5.3 Volume Depletion INVOKANA can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There have been post-marketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKANA in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy. 5.4 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving INVOKANA. Treatment with INVOKANA increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)]. 5.5 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)]. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with INVOKANA presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if Reference ID: 5499136 7 necessary, surgical debridement. Discontinue INVOKANA, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control. 5.7 Genital Mycotic Infections INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately. 5.8 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with INVOKANA. These reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat and monitor until signs and symptoms resolve [see Contraindications (4) and Adverse Reactions (6.1, 6.2)]. 5.9 Bone Fracture An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in adult patients using INVOKANA in the CANVAS trial [see Clinical Studies (14.3)]. Consider factors that contribute to fracture risk prior to initiating INVOKANA [see Adverse Reactions (6.1)]. 6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling:  Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [see Warnings and Precautions (5.1)]  Lower Limb Amputation [see Warnings and Precautions (5.2)]  Volume Depletion [see Warnings and Precautions (5.3)]  Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4)]  Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.5)]  Necrotizing Fasciitis of the Perineum (Fournier’s gangrene) [see Warnings and Precautions (5.6)]  Genital Mycotic Infections [see Warnings and Precautions (5.7)]  Hypersensitivity Reactions [see Warnings and Precautions (5.8)]  Bone Fracture [see Warnings and Precautions (5.9)] Reference ID: 5499136 8 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. INVOKANA has been evaluated in clinical trials in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Additionally, INVOKANA has been studied in clinical trials in adult patients with type 2 diabetes mellitus who also have heart failure or chronic kidney disease. The overall safety profile of INVOKANA was consistent across the studied indications. Clinical Trials in Adult Patients with Type 2 Diabetes Mellitus Pool of Placebo-Controlled Trials for Glycemic Control The data in Table 2 are derived from four 26-week placebo-controlled trials where INVOKANA was used as monotherapy in one trial and as add-on therapy in three trials. These data reflect exposure of 1,667 adult patients to INVOKANA and a mean duration of exposure to INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were White, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2). Table 2 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg. Reference ID: 5499136 9 Table 2: Adverse Reactions from Pool of Four 26−Week Placebo-Controlled Trials Reported in ≥ 2% of INVOKANA-Treated Adult Patients * Adverse Reaction Placebo N=646 INVOKANA 100 mg N=833 INVOKANA 300 mg N=834 Urinary tract infections‡ 3.8% 5.9% 4.4% Increased urination§ 0.7% 5.1% 4.6% Thirst# 0.1% 2.8% 2.4% Constipation 0.9% 1.8% 2.4% Nausea 1.6% 2.1% 2.3% N=312 N=425 N=430 Female genital mycotic infections† 2.8% 10.6% 11.6% Vulvovaginal pruritus 0.0% 1.6% 3.2% N=334 N=408 N=404 Male genital mycotic infections¶ 0.7% 4.2% 3.8% * The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin HCl, metformin HCl and sulfonylurea, or metformin HCl and pioglitazone. † Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. ‡ Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. § Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. ¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. # Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. Note: Percentages were weighted by studies. Trial weights were proportional to the harmonic mean of the three treatment sample sizes. Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Placebo-Controlled Trial in Diabetic Nephropathy The occurrence of adverse reactions for INVOKANA was evaluated in patients participating in CREDENCE, a trial in adult patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria ˃ 300 mg/day [see Clinical Studies (14.4)]. These data reflect exposure of 2,201 adult patients to INVOKANA and a mean duration of exposure to INVOKANA of 137 weeks.  The rate of lower limb amputations associated with the use of INVOKANA 100 mg relative to placebo was 12.3 vs 11.2 events per 1,000 patient-years, respectively, with 2.6 years mean duration of follow-up.  The incidence of hypotension was 2.8% and 1.5% on INVOKANA 100 mg and placebo, respectively. Reference ID: 5499136 10 Pool of Placebo- and Active-Controlled Trials for Glycemic Control and Cardiovascular Outcomes in Adult Patients The occurrence of adverse reactions for INVOKANA was evaluated in adult patients participating in placebo- and active-controlled trials and in an integrated analysis of two cardiovascular trials, CANVAS and CANVAS-R. The types and frequency of common adverse reactions observed in the pool of eight clinical trials (which reflect an exposure of 6,177 adult patients to INVOKANA) were consistent with those listed in Table 2. Percentages were weighted by trials. Trial weights were proportional to the harmonic mean of the three treatment sample sizes. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.8%, 2.2%, and 2.0% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively) and loss of strength or energy (i.e., asthenia) (0.6%, 0.7%, and 1.1% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively). In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.1%, 0.2%, and 0.1% receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of adult patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated. Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Other adverse reactions occurring more frequently on INVOKANA than on comparator were: Lower Limb Amputation An increased risk of lower limb amputations associated with INVOKANA use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating adult patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. Patients in CANVAS and CANVAS-R were followed for an Reference ID: 5499136 11 average of 5.7 and 2.1 years, respectively [see Clinical Studies (14.3)]. The amputation data for CANVAS and CANVAS-R are shown in Tables 3 and 4, respectively. Table 3: Amputations in the CANVAS Trial in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Placebo N=1,441 INVOKANA 100 mg N=1,445 INVOKANA 300 mg N=1,441 INVOKANA (Pooled) N=2,886 Patients with an amputation, n (%) 22 (1.5) 50 (3.5) 45 (3.1) 95 (3.3) Total amputations 33 83 79 162 Amputation incidence rate (per 1,000 patient-years) 2.8 6.2 5.5 5.9 Hazard Ratio (95% CI) -­ 2.24 (1.36, 3.69) 2.01 (1.20, 3.34) 2.12 (1.34, 3.38) Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. Table 4: Amputations in the CANVAS-R Trial in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Placebo N=2,903 INVOKANA 100 mg (with up-titration to 300 mg) N=2,904 Patients with an amputation, n (%) 25 (0.9) 45 (1.5) Total amputations 36 59 Amputation incidence rate (per 1,000 patient-years) 4.2 7.5 Hazard Ratio (95% CI) -­ 1.80 (1.10, 2.93) Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. Renal Cell Carcinoma In the CANVAS trial in adults (mean duration of follow-up of 5.7 years) [see Clinical Studies (14.3)], the incidence of renal cell carcinoma was 0.15% (2/1,331) and 0.29% (8/2,716) for placebo and INVOKANA, respectively, excluding patients with less than 6 months of follow­ up, less than 90 days of treatment, or a history of renal cell carcinoma. A causal relationship to INVOKANA could not be established due to the limited number of cases. Volume Depletion-Related Adverse Reactions INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical trials for glycemic control, treatment with INVOKANA was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in adult patients on the 300 mg dose. The three factors Reference ID: 5499136 12 associated with the largest increase in volume depletion-related adverse reactions in these trials were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and age 75 years and older (Table 5) [see Use in Specific Populations (8.5 and 8.6)]. Table 5: Proportion of Adult Patients with at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials for Glycemic Control) Baseline Characteristic Comparator Group* % INVOKANA 100 mg % INVOKANA 300 mg % Overall population 1.5% 2.3% 3.4% 75 years of age and older† 2.6% 4.9% 8.7% eGFR less than 60 mL/min/1.73 m2† 2.5% 4.7% 8.1% Use of loop diuretic† 4.7% 3.2% 8.8% * Includes placebo and active-comparator groups † Patients could have more than 1 of the listed risk factors Falls In a pool of nine clinical trials in adults with mean duration of exposure to INVOKANA of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. The higher risk of falls for patients treated with INVOKANA was observed within the first few weeks of treatment. Genital Mycotic Infections In the pool of four placebo-controlled clinical trials in adults for glycemic control, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 2.8%, 10.6%, and 11.6% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti­ microbial agents. In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and INVOKANA, respectively. In the pool of four placebo-controlled clinical trials in adults, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.7%, 4.2%, and 3.8% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA versus none on placebo) and require treatment with oral or topical antifungal agents and anti-microbial Reference ID: 5499136 13 agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and INVOKANA, respectively. In the pooled analysis of 8 randomized trials in adults evaluating glycemic control, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis. Hypoglycemia In all glycemic control trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials of glycemic control in adults [see Clinical Studies (14.1)], episodes of hypoglycemia occurred at a higher rate when INVOKANA was co- administered with insulin or sulfonylureas (Table 6). Table 6: Incidence of Hypoglycemia* in Randomized Clinical Trials of Glycemic Control in Adults Monotherapy (26 weeks) Placebo (N=192) INVOKANA 100 mg (N=195) INVOKANA 300 mg (N=197) Overall [N (%)] 5 (2.6) 7 (3.6) 6 (3.0) In Combination with Metformin HCl (26 weeks) Placebo + Metformin HCl (N=183) INVOKANA 100 mg + Metformin HCl (N=368) INVOKANA 300 mg + Metformin HCl (N=367) Overall [N (%)] 3 (1.6) 16 (4.3) 17 (4.6) Severe [N (%)]† 0 (0) 1 (0.3) 1 (0.3) In Combination with Metformin HCl (52 weeks) Glimepiride + Metformin HCl (N=482) INVOKANA 100 mg + Metformin HCl (N=483) INVOKANA 300 mg + Metformin HCl (N=485) Overall [N (%)] 165 (34.2) 27 (5.6) 24 (4.9) Severe [N (%)]† 15 (3.1) 2 (0.4) 3 (0.6) In Combination with Sulfonylurea (18 weeks) Placebo + Sulfonylurea (N=69) INVOKANA 100 mg + Sulfonylurea (N=74) INVOKANA 300 mg + Sulfonylurea (N=72) Overall [N (%)] 4 (5.8) 3 (4.1) 9 (12.5) In Combination with Metformin HCl + Sulfonylurea (26 weeks) Placebo + Metformin HCl + Sulfonylurea (N=156) INVOKANA 100 mg + Metformin HCl + Sulfonylurea (N=157) INVOKANA 300 mg + Metformin HCl + Sulfonylurea (N=156) Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1) Severe [N (%)]† 1 (0.6) 1 (0.6) 0 In Combination with Metformin HCl + Sulfonylurea (52 weeks) Sitagliptin + Metformin HCl + Sulfonylurea (N=378) INVOKANA 300 mg + Metformin HCl + Sulfonylurea (N=377) Overall [N (%)] 154 (40.7) 163 (43.2) Severe [N (%)]† 13 (3.4) 15 (4.0) In Combination with Placebo + INVOKANA 100 mg + INVOKANA 300 mg + Reference ID: 5499136 14 Metformin HCl + Pioglitazone (26 weeks) Metformin HCl + Pioglitazone (N=115) Metformin HCl + Pioglitazone (N=113) Metformin HCl + Pioglitazone (N=114) Overall [N (%)] 3 (2.6) 3 (2.7) 6 (5.3) In Combination with Insulin (18 weeks) Placebo (N=565) INVOKANA 100 mg (N=566) INVOKANA 300 mg (N=587) Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6) Severe [N (%)]† 14 (2.5) 10 (1.8) 16 (2.7) * Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population † Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) Bone Fracture In the CANVAS trial in adults [see Clinical Studies (14.3)], the incidence rates of all adjudicated bone fracture were 1.09, 1.59, and 1.79 events per 100 patient-years of follow-up to placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. The fracture imbalance was observed within the first 26 weeks of therapy and remained through the end of the trial. Fractures were more likely to be low trauma (e.g., fall from no more than standing height), and affect the distal portion of upper and lower extremities. Laboratory and Imaging Tests Increases in Serum Creatinine and Decreases in eGFR Initiation of INVOKANA causes an increase in serum creatinine and decrease in estimated GFR. In adult patients with moderate renal impairment, the increase in serum creatinine generally does not exceed 0.2 mg/dL, occurs within the first 6 weeks of starting therapy, and then stabilizes. Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Clinical Pharmacology (12.1)]. The acute effect on eGFR reverses after treatment discontinuation suggesting acute hemodynamic changes may play a role in the renal function changes observed with INVOKANA. Increases in Serum Potassium In a pooled population of adult patients (N=723) in glycemic control trials with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 m2), increases in serum potassium to greater than 5.4 mEq/L and 15% above baseline occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with INVOKANA 100 mg, and 1.3% of patients treated with INVOKANA 300 mg. In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% Reference ID: 5499136 15 were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Use in Specific Populations (8.6)]. In CREDENCE, no difference in serum potassium, no increase in adverse events of hyperkalemia, and no increase in absolute (> 6.5 mEq/L) or relative (> upper limit of normal and > 15% increase from baseline) increases in serum potassium were observed in adults treated with INVOKANA 100 mg relative to placebo. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C) In the pool of four glycemic control placebo-controlled trials in adults, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups. Dose-related increases in non-HDL-C with INVOKANA were observed in adults. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups. Increases in Hemoglobin In the pool of four placebo-controlled trials of glycemic control in adults, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal. Decreases in Bone Mineral Density Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years) [see Clinical Studies (14.1)]. At 2 years, adult patients randomized to INVOKANA 100 mg and INVOKANA 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both INVOKANA doses and 0.4% at the distal forearm for patients randomized to INVOKANA 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to INVOKANA 100 mg was 0%. Reference ID: 5499136 16 Clinical Trial in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus INVOKANA was administered to 84 pediatric patients in a double-blind, placebo-controlled trial of 171 pediatric patients aged 10 to 17 years with a mean exposure to INVOKANA of 48.3 weeks [see Clinical Studies (14.2)]. At baseline, background therapies included metformin monotherapy (46%), metformin and insulin (29%), diet and exercise only (14%), and insulin monotherapy (11%). Approximately 42% were Asian, 42% were White, 11% were Black or African American, 5% were American Indian/Alaska Native, and 36% identified as Hispanic or Latino ethnicity. The mean baseline eGFR was 157.3 mL/min/1.73 m2, and approximately 16% (24/151) of the trial population with measurements had microalbuminuria or macroalbuminuria. The safety profile of pediatric patients treated with INVOKANA was similar to that observed in adults with type 2 diabetes mellitus. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of INVOKANA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Metabolism and Nutrition Ketoacidosis Renal and Urinary Acute Kidney Injury Immune System Anaphylaxis Skin and Subcutaneous Tissue Angioedema Infections Urosepsis and Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s gangrene) 7 DRUG INTERACTIONS Table 7: Clinically Significant Drug Interactions with INVOKANA UGT Enzyme Inducers Clinical Impact: UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKANA. Intervention: For patients with eGFR 60 mL/min/1.73 m2 or greater, if an inducer of UGTs is administered with INVOKANA, increase the dosage to 200 mg daily in patients currently tolerating INVOKANA 100 mg daily. The total daily dosage may be increased to 300 mg Reference ID: 5499136 17 daily in patients currently tolerating INVOKANA 200 mg daily who require additional glycemic control. For patients with eGFR less than 60 mL/min/1.73 m2, if an inducer of UGTs is administered with INVOKANA, increase the dosage to 200 mg daily in patients currently tolerating INVOKANA 100 mg daily. Consider adding another antihyperglycemic agent in patients who require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Examples: Rifampin, phenytoin, phenobarbital, ritonavir Insulin or Insulin Secretagogues Clinical Impact: The risk of hypoglycemia is increased when INVOKANA is used concomitantly with insulin secretagogues (e.g., sulfonylurea) or insulin. Intervention: Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. Digoxin Clinical Impact: Canagliflozin increases digoxin exposure [see Clinical Pharmacology (12.3)]. Intervention: Monitor patients taking INVOKANA with concomitant digoxin for a need to adjust the dosage of digoxin. Lithium Clinical Impact: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention: Monitor serum lithium concentration more frequently during INVOKANA initiation and dosage changes. Drug/Laboratory Test Interference Positive Urine Glucose Test Clinical Impact: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. Intervention: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention: Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on juvenile animal data showing adverse renal effects, INVOKANA is not recommended during the second and third trimesters of pregnancy. Limited data with INVOKANA in pregnant women are not sufficient to determine a drug- associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. Reference ID: 5499136 18 In juvenile animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at an exposure 0.5-times the 300 mg clinical dose, based on AUC. The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1C >7 and has been reported to be as high as 20-25% in women with a HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre­ eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Animal Data Canagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg increased kidney weights and dose dependently increased the incidence and severity of renal pelvic and tubular dilatation at all doses tested. Exposure at the lowest dose was greater than or equal to 0.5-times the 300 mg clinical dose, based on AUC. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. The renal pelvic dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period. In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities independent of maternal toxicity were observed when canagliflozin was administered at doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits during embryonic organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on AUC. 8.2 Lactation Risk Summary There is no information regarding the presence of INVOKANA in human milk, the effects on the breastfed infant, or the effects on milk production. Canagliflozin is present in the milk of Reference ID: 5499136 19 --- lactating rats [see Data]. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of INVOKANA is not recommended while breastfeeding. Data Animal Data Radiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. 8.4 Pediatric Use The safety and effectiveness of INVOKANA as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of INVOKANA for this indication is supported by evidence from a 52-week double-blind, placebo-controlled trial in 171 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus and in a pediatric pharmacokinetic study [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. The safety profile of pediatric patients treated with INVOKANA was similar to that observed in adults with type 2 diabetes mellitus. The safety and effectiveness of INVOKANA for glycemic control in patients with type 2 diabetes have not been established in pediatric patients under 10 years of age. The safety and effectiveness of INVOKANA have not been established in pediatric patients to reduce the risk of:  major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in patients with type 2 diabetes mellitus and established cardiovascular disease (CVD).  end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day. Reference ID: 5499136 20 8.5 Geriatric Use In 13 clinical trials of INVOKANA, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to INVOKANA [see Clinical Studies (14.1)]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) and Adverse Reactions (6.1)]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo). 8.6 Renal Impairment The efficacy and safety of INVOKANA for glycemic control were evaluated in a trial that included adult patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2) [see Clinical Studies (14.1)]. These patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of the trial. Patients with renal impairment using INVOKANA for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury [see Warnings and Precautions (5.3)]. Efficacy and safety trials with INVOKANA did not enroll adult patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2 [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In the event of an overdose, contact the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. Reference ID: 5499136 21 F OH OH 11 DESCRIPTION INVOKANA® (canagliflozin) contains canagliflozin, an inhibitor of SGLT2, the transporter responsible for reabsorbing the majority of glucose filtered by the kidney. Canagliflozin, the active ingredient of INVOKANA, is chemically known as (1S)-1,5-anhydro-1-[3-[[5-(4­ fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate and its molecular formula and weight are C24H25FO5S1/2 H2O and 453.53, respectively. The structural formula for canagliflozin is: Canagliflozin is practically insoluble in aqueous media from pH 1.1 to 12.9. INVOKANA is supplied as film-coated tablets for oral administration, containing 102 and 306 mg of canagliflozin in each tablet strength, corresponding to 100 mg and 300 mg of canagliflozin (anhydrous), respectively. Inactive ingredients of the core tablet are croscarmellose sodium (E468), hydroxypropyl cellulose (E463), lactose anhydrous, magnesium stearate (E572), and microcrystalline cellulose (E460[i]). The magnesium stearate is vegetable-sourced. The tablets are finished with a commercially available film-coating consisting of the following excipients: iron oxide yellow (E172) (100 mg tablet only), macrogol/PEG3350 (E1521), polyvinyl alcohol (E1203) (partially hydrolyzed), talc (E553b), and titanium dioxide (E171). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action SGLT2, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE). Reference ID: 5499136 22 Canagliflozin increases the delivery of sodium to the distal tubule by blocking SGLT2-dependent glucose and sodium reabsorption. This is believed to increase tubuloglomerular feedback and reduce intraglomerular pressure. 12.2 Pharmacodynamics Following single and multiple oral doses of canagliflozin in adult patients with type 2 diabetes, dose-dependent decreases in RTG and increases in urinary glucose excretion were observed. From a starting RTG value of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg once daily suppressed RTG throughout the 24-hour period. Data from single oral doses of canagliflozin in healthy volunteers indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for doses up to 300 mg once daily. Maximal suppression of mean RTG over the 24-hour period was seen with the 300 mg daily dose to approximately 70 to 90 mg/dL in patients with type 2 diabetes in Phase 1 trials. The reductions in RTG led to increases in mean UGE of approximately 100 g/day in patients with type 2 diabetes treated with either 100 mg or 300 mg of canagliflozin. In patients with type 2 diabetes given 100 to 300 mg once daily over a 16-day dosing period, reductions in RTG and increases in urinary glucose excretion were observed over the dosing period. In this trial, plasma glucose declined in a dose-dependent fashion within the first day of dosing. In single-dose trials in healthy and type 2 diabetic patients, treatment with canagliflozin 300 mg before a mixed-meal delayed intestinal glucose absorption and reduced postprandial glucose. Cardiac Electrophysiology In a randomized, double-blind, placebo-controlled, active-comparator, 4-way crossover trial, 60 healthy adult subjects were administered a single oral dose of canagliflozin 300 mg, canagliflozin 1,200 mg (4 times the maximum recommended dose), moxifloxacin, and placebo. No meaningful changes in QTc interval were observed with either the recommended dose of 300 mg or the 1,200 mg dose. 12.3 Pharmacokinetics The pharmacokinetics of canagliflozin is similar in healthy subjects and patients with type 2 diabetes. Following single-dose oral administration of 100 mg and 300 mg of INVOKANA, peak plasma concentrations (median Tmax) of canagliflozin occurs within 1 to 2 hours post-dose. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. The apparent terminal half-life (t1/2) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after 4 to 5 days of once-daily dosing with canagliflozin 100 mg to 300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics and accumulated in plasma up to 36% following multiple doses of 100 mg and 300 mg. Reference ID: 5499136 23 Absorption The mean absolute oral bioavailability of canagliflozin is approximately 65%. Co-administration of a high-fat meal with canagliflozin had no effect on the pharmacokinetics of canagliflozin; therefore, INVOKANA may be taken with or without food. However, based on the potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, it is recommended that INVOKANA be taken before the first meal of the day [see Dosage and Administration (2.2)]. Distribution The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 83.5 L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. Metabolism O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans. Excretion Following administration of a single oral [14C] canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible. Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O-glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min. Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration. Specific Populations Pediatric Patients The pharmacokinetics and pharmacodynamics of canagliflozin were investigated in pediatric patients aged 10 years and older with type 2 diabetes mellitus. Oral administration of Reference ID: 5499136 24 canagliflozin at 100 mg and 300 mg resulted in exposures and responses consistent with those found in adult patients. Patients with Renal Impairment A single-dose, open-label trial evaluated the pharmacokinetics of canagliflozin 200 mg in adult subjects with varying degrees of renal impairment (classified using the MDRD-eGFR formula) compared to healthy subjects. Renal impairment did not affect the Cmax of canagliflozin. Compared to healthy adult subjects (N=3; eGFR greater than or equal to 90 mL/min/1.73 m2), plasma AUC of canagliflozin was increased by approximately 15%, 29%, and 53% in subjects with mild (N=10), moderate (N=9), and severe (N=10) renal impairment, respectively, (eGFR 60 to less than 90, 30 to less than 60, and 15 to less than 30 mL/min/1.73 m2, respectively), but was similar for ESKD (N=8) subjects and healthy subjects. Increases in canagliflozin AUC of this magnitude are not considered clinically relevant. The glucose lowering pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment [see Contraindications (4) and Warnings and Precautions (5.3)]. Canagliflozin was negligibly removed by hemodialysis. Patients with Hepatic Impairment Relative to adult subjects with normal hepatic function, the geometric mean ratios for Cmax and AUC∞ of canagliflozin were 107% and 110%, respectively, in subjects with Child-Pugh class A (mild hepatic impairment) and 96% and 111%, respectively, in subjects with Child-Pugh class B (moderate hepatic impairment) following administration of a single 300 mg dose of canagliflozin. These differences are not considered to be clinically meaningful. There is no clinical experience in adult patients with Child-Pugh class C (severe) hepatic impairment [see Use in Specific Populations (8.7)]. Pharmacokinetic Effects of Age, Body Mass Index (BMI)/Weight, Gender and Race Based on the population PK analysis with data collected from 1,526 adult subjects, age, body mass index (BMI)/weight, gender, and race do not have a clinically meaningful effect on the pharmacokinetics of canagliflozin [see Use in Specific Populations (8.5)]. Drug Interaction Studies In Vitro Assessment of Drug Interactions Canagliflozin did not induce CYP450 enzyme expression (3A4, 2C9, 2C19, 2B6, and 1A2) in cultured human hepatocytes. Canagliflozin did not inhibit the CYP450 isoenzymes (1A2, 2A6, Reference ID: 5499136 25 2C19, 2D6, or 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes. Canagliflozin is a weak inhibitor of P-gp. Canagliflozin is also a substrate of drug transporters P-glycoprotein (P-gp) and MRP2. In Vivo Assessment of Drug Interactions Table 8: Effect of Co−Administered Drugs on Systemic Exposures of Canagliflozin Co-Administered Drug Dose of Co-Administered Drug* Dose of Canagliflozin* Geometric Mean Ratio (Ratio With/Without Co-Administered Drug) No Effect = 1.0 AUC† (90% CI) Cmax (90% CI) See Drug Interactions (7) for the clinical relevance of the following: Rifampin 600 mg QD for 8 days 300 mg 0.49 (0.44; 0.54) 0.72 (0.61; 0.84) No dose adjustments of INVOKANA required for the following: Cyclosporine 400 mg 300 mg QD for 8 days 1.23 (1.19; 1.27) 1.01 (0.91; 1.11) Ethinyl estradiol and levonorgestrel 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel 200 mg QD for 6 days 0.91 (0.88; 0.94) 0.92 (0.84; 0.99) Hydrochlorothiazide 25 mg QD for 35 days 300 mg QD for 7 days 1.12 (1.08; 1.17) 1.15 (1.06; 1.25) Metformin HCl 2,000 mg 300 mg QD for 8 days 1.10 (1.05; 1.15) 1.05 (0.96; 1.16) Probenecid 500 mg BID for 3 days 300 mg QD for 17 days 1.21 (1.16; 1.25) 1.13 (1.00; 1.28) * Single dose unless otherwise noted † AUCinf for drugs given as a single dose and AUC24h for drugs given as multiple doses QD = once daily; BID = twice daily Table 9: Effect of Canagliflozin on Systemic Exposure of Co-Administered Drugs Co-Administered Drug Dose of Co- Administered Drug* Dose of Canagliflozin* Geometric Mean Ratio (Ratio With/Without Co-Administered Drug) No Effect = 1.0 AUC† (90% CI) Cmax (90% CI) See Drug Interactions (7) for the clinical relevance of the following: Digoxin 0.5 mg QD first day followed by 300 mg QD for 7 days Digoxin 1.20 (1.12; 1.28) 1.36 (1.21; 1.53) Reference ID: 5499136 26 0.25 mg QD for 6 days No dose adjustments of co-administered drug required for the following: Acetaminophen 1,000 mg 300 mg BID for 25 days Acetaminophen 1.06‡ (0.98; 1.14) 1.00 (0.92; 1.09) Ethinyl estradiol and levonorgestrel 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel 200 mg QD for 6 days ethinyl estradiol 1.07 (0.99; 1.15) 1.22 (1.10; 1.35) Levonorgestrel 1.06 (1.00; 1.13) 1.22 (1.11; 1.35) Glyburide 1.25 mg 200 mg QD for 6 days Glyburide 1.02 (0.98; 1.07) 0.93 (0.85; 1.01) 3-cis-hydroxy­ glyburide 1.01 (0.96; 1.07) 0.99 (0.91; 1.08) 4-trans-hydroxy­ glyburide 1.03 (0.97; 1.09) 0.96 (0.88; 1.04) Hydrochlorothiazide 25 mg QD for 35 days 300 mg QD for 7 days Hydrochlorothiazide 0.99 (0.95; 1.04) 0.94 (0.87; 1.01) Metformin HCl 2,000 mg 300 mg QD for 8 days Metformin HCl 1.20 (1.08; 1.34) 1.06 (0.93; 1.20) Simvastatin 40 mg 300 mg QD for 7 days Simvastatin 1.12 (0.94; 1.33) 1.09 (0.91; 1.31) simvastatin acid 1.18 (1.03; 1.35) 1.26 (1.10; 1.45) Warfarin 30 mg 300 mg QD for 12 days (R)-warfarin 1.01 (0.96; 1.06) 1.03 (0.94; 1.13) (S)-warfarin 1.06 (1.00; 1.12) 1.01 (0.90; 1.13) INR 1.00 (0.98; 1.03) 1.05 (0.99; 1.12) * Single dose unless otherwise noted † AUCinf for drugs given as a single dose and AUC24h for drugs given as multiple doses ‡ AUC0-12h QD = once daily; BID = twice daily; INR = International Normalized Ratio 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Sprague-Dawley rats. Canagliflozin did not increase the incidence of tumors in mice dosed at 10, 30, or 100 mg/kg (less than or equal to 14 times exposure from a 300 mg clinical dose). Testicular Leydig cell tumors, considered secondary to increased luteinizing hormone (LH), increased significantly in male rats at all doses tested (10, 30, and 100 mg/kg). In a 12-week clinical trial, LH did not increase in males treated with canagliflozin. Reference ID: 5499136 27 Renal tubular adenoma and carcinoma increased significantly in male and female rats dosed at 100 mg/kg, or approximately 12-times exposure from a 300 mg clinical dose. Also, adrenal pheochromocytoma increased significantly in males and numerically in females dosed at 100 mg/kg. Carbohydrate malabsorption associated with high doses of canagliflozin was considered a necessary proximal event in the emergence of renal and adrenal tumors in rats. Clinical trials have not demonstrated carbohydrate malabsorption in humans at canagliflozin doses of up to 2-times the recommended clinical dose of 300 mg. Mutagenesis Canagliflozin was not mutagenic with or without metabolic activation in the Ames assay. Canagliflozin was mutagenic in the in vitro mouse lymphoma assay with but not without metabolic activation. Canagliflozin was not mutagenic or clastogenic in an in vivo oral micronucleus assay in rats and an in vivo oral Comet assay in rats. Impairment of Fertility Canagliflozin had no effects on the ability of rats to mate and sire or maintain a litter up to the high dose of 100 mg/kg (approximately 14 times and 18 times the 300 mg clinical dose in males and females, respectively), although there were minor alterations in a number of reproductive parameters (decreased sperm velocity, increased number of abnormal sperm, slightly fewer corpora lutea, fewer implantation sites, and smaller litter sizes) at the highest dosage administered. 14 CLINICAL STUDIES 14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus INVOKANA (canagliflozin) has been studied as monotherapy, in combination with metformin HCl, sulfonylurea, metformin HCl and sulfonylurea, metformin HCl and sitagliptin, metformin HCl and a thiazolidinedione (i.e., pioglitazone), and in combination with insulin (with or without other anti-hyperglycemic agents). The efficacy of INVOKANA was compared to a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin), both as add-on combination therapy with metformin HCl and sulfonylurea, and a sulfonylurea (glimepiride), both as add-on combination therapy with metformin HCl. INVOKANA was also evaluated in adults 55 to 80 years of age and patients with moderate renal impairment. Monotherapy A total of 584 adult patients with type 2 diabetes inadequately controlled on diet and exercise participated in a 26-week double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA. The mean age was 55 years, 44% of patients were male, and the mean baseline eGFR was 87 mL/min/1.73 m2. Patients taking other antihyperglycemic agents (N=281) discontinued the agent and underwent an 8-week washout followed by a 2-week, single-blind, Reference ID: 5499136 28 placebo run-in period. Patients not taking oral antihyperglycemic agents (N=303) entered the 2-week, single-blind, placebo run-in period directly. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily for 26 weeks. At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo (see Table 10). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -3.7 mmHg and -5.4 mmHg with INVOKANA 100 mg and 300 mg, respectively. Table 10: Results from 26-Week Placebo-Controlled Clinical Trial with INVOKANA as Monotherapy in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo (N=192) INVOKANA 100 mg (N=195) INVOKANA 300 mg (N=197) HbA1C (%) Baseline (mean) 7.97 8.06 8.01 Change from baseline (adjusted mean) 0.14 -0.77 -1.03 Difference from placebo (adjusted mean) (95% CI)† -0.91‡ (-1.09; -0.73) -1.16‡ (-1.34; -0.99) Percent of Patients Achieving HbA1C < 7% 21 45‡ 62‡ Fasting Plasma Glucose (mg/dL) Baseline (mean) 166 172 173 Change from baseline (adjusted mean) 8 -27 -35 Difference from placebo (adjusted mean) (95% CI)† -36‡ (-42; -29) -43‡ (-50; -37) 2-hour Postprandial Glucose (mg/dL) Baseline (mean) 229 250 254 Change from baseline (adjusted mean) 5 -43 -59 Difference from placebo (adjusted mean) (95% CI)† -48‡ (-59.1; -37.0) -64‡ (-75.0; -52.9) Body Weight Baseline (mean) in kg 87.5 85.9 86.9 % change from baseline (adjusted mean) -0.6 -2.8 -3.9 Difference from placebo (adjusted mean) (95% CI)† -2.2‡ (-2.9; -1.6) -3.3‡ (-4.0; -2.6) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001 Reference ID: 5499136 29 Add-on Combination Therapy with Metformin HCl A total of 1,284 adult patients with type 2 diabetes inadequately controlled on metformin HCl monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 26-week, double-blind, placebo- and active-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin HCl. The mean age was 55 years, 47% of patients were male, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the required metformin HCl dose (N=1,009) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients taking less than the required metformin HCl dose or patients on metformin HCl in combination with another antihyperglycemic agent (N=275) were switched to metformin HCl monotherapy (at doses described above) for at least 8 weeks before entering the 2-week, single-blind, placebo run-in. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, sitagliptin 100 mg, or placebo, administered once daily as add-on therapy to metformin HCl. At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo when added to metformin HCl (see Table 11). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -5.4 mmHg and -6.6 mmHg with INVOKANA 100 mg and 300 mg, respectively. Table 11: Results from 26-Week Placebo-Controlled Clinical Trial of INVOKANA in Combination with Metformin HCl in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Metformin HCl (N=183) INVOKANA 100 mg + Metformin HCl (N=368) INVOKANA 300 mg + Metformin HCl (N=367) HbA1C (%) Baseline (mean) 7.96 7.94 7.95 Change from baseline (adjusted mean) -0.17 -0.79 -0.94 Difference from placebo (adjusted mean) (95% CI)† -0.62‡ (-0.76; -0.48) -0.77‡ (-0.91; -0.64) Percent of patients achieving HbA1C < 7% 30 46‡ 58‡ Fasting Plasma Glucose (mg/dL) Baseline (mean) 164 169 173 Change from baseline (adjusted mean) 2 -27 -38 Difference from placebo (adjusted mean) (95% CI)† -30‡ (-36; -24) -40‡ (-46; -34) Reference ID: 5499136 30 2-hour Postprandial Glucose (mg/dL) Baseline (mean) 249 258 262 Change from baseline (adjusted mean) -10 -48 -57 Difference from placebo (adjusted mean) (95% CI)† -38‡ (-49; -27) -47‡ (-58; -36) Body Weight Baseline (mean) in kg 86.7 88.7 85.4 % change from baseline (adjusted mean) -1.2 -3.7 -4.2 Difference from placebo (adjusted mean) (95% CI)† -2.5‡ (-3.1; -1.9) -2.9‡ (-3.5; -2.3) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001 Initial Combination Therapy with Metformin HCl Extended-Release A total of 1,186 adult patients with type 2 diabetes inadequately controlled with diet and exercise participated in a 26-week double-blind, active-controlled, parallel-group, 5-arm, multicenter trial to evaluate the efficacy and safety of initial therapy with INVOKANA in combination with metformin HCl extended-release. The median age was 56 years, 48% of patients were male, and the mean baseline eGFR was 87.6 mL/min/1.73 m2. The median duration of diabetes was 1.6 years, and 72% of patients were treatment naïve. After completing a 2-week single-blind placebo run-in period, patients were randomly assigned for a double-blind treatment period of 26 weeks to 1 of 5 treatment groups (Table 12). The metformin HCl extended-release dose was initiated at 500 mg/day for the first week of treatment and then increased to 1,000 mg/day. Metformin HCl extended-release or matching placebo was up-titrated every 2-3 weeks during the next 8 weeks of treatment to a maximum daily dose of 1,500 to 2,000 mg/day, as tolerated; about 90% of patients reached 2,000 mg/day. At the end of treatment, INVOKANA 100 mg and INVOKANA 300 mg in combination with metformin HCl extended-release resulted in a statistically significant greater improvement in HbA1C compared to their respective INVOKANA doses (100 mg and 300 mg) alone or metformin HCl extended-release alone. Table 12: Results from 26-Week Active-Controlled Clinical Trial of INVOKANA Alone or INVOKANA as Initial Combination Therapy with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Metformin HCl extended- release (N=237) INVOKANA 100 mg (N=237) INVOKANA 300 mg (N=238) INVOKANA 100 mg + Metformin HCl extended-release (N=237) INVOKANA 300 mg + Metformin HCl extended-release (N=237) HbA1C (%) Baseline (mean) 8.81 8.78 8.77 8.83 8.90 Change from -1.30 -1.37 -1.42 -1.77 -1.78 Reference ID: 5499136 31 baseline (adjusted mean)¶ Difference from canagliflozin 100 mg (adjusted mean) (95% CI)† -0.40‡ (-0.59, -0.21) Difference from canagliflozin 300 mg (adjusted mean) (95% CI)† -0.36‡ (-0.56, -0.17) Difference from metformin HCl extended- release (adjusted mean) (95% CI)† -0.06‡‡ (-0.26, 0.13) -0.11‡‡ (-0.31, 0.08) -0.46‡ (-0.66, -0.27) -0.48‡ (-0.67, -0.28) Percent of patients achieving HbA1C < 7% 38 34 39 47§§ 51§§ * Intent-to-treat population † Least squares mean adjusted for covariates including baseline value and stratification factor ‡ Adjusted p=0.001 for superiority ‡‡ Adjusted p=0.001 for non-inferiority §§ Adjusted p<0.05 ¶ There were 121 patients without week 26 efficacy data. Analyses addressing missing data gave consistent results with the results provided in this table. INVOKANA Compared to Glimepiride, Both as Add-on Combination With Metformin HCl A total of 1,450 adult patients with type 2 diabetes inadequately controlled on metformin HCl monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 52-week, double-blind, active-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin HCl. The mean age was 56 years, 52% of patients were male, and the mean baseline eGFR was 90 mL/min/1.73 m2. Patients tolerating maximally required metformin HCl dose (N=928) were randomized after completing a 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin HCl monotherapy (at doses described above) for at least 10 weeks, then completed a 2-week single-blind run-in period. After the 2-week run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or glimepiride Reference ID: 5499136 32 (titration allowed throughout the 52-week trial to 6 or 8 mg), administered once daily as add-on therapy to metformin HCl. As shown in Table 13 and Figure 1, at the end of treatment, INVOKANA 100 mg provided similar reductions in HbA1C from baseline compared to glimepiride when added to metformin HCl therapy. INVOKANA 300 mg provided a greater reduction from baseline in HbA1C compared to glimepiride, and the relative treatment difference was -0.12% (95% CI: −0.22; −0.02). As shown in Table 13, treatment with INVOKANA 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride. Table 13: Results from 52−Week Clinical Trial Comparing INVOKANA to Glimepiride in Combination with Metformin HCl in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter INVOKANA 100 mg + Metformin HCl (N=483) INVOKANA 300 mg + Metformin HCl (N=485) Glimepiride (titrated) + Metformin HCl (N=482) HbA1C (%) Baseline (mean) 7.78 7.79 7.83 Change from baseline (adjusted mean) -0.82 -0.93 -0.81 Difference from glimepiride (adjusted mean) (95% CI)† -0.01‡ (-0.11; 0.09) -0.12‡ (-0.22; -0.02) Percent of patients achieving HbA1C < 7% 54 60 56 Fasting Plasma Glucose (mg/dL) Baseline (mean) 165 164 166 Change from baseline (adjusted mean) -24 -28 -18 Difference from glimepiride (adjusted mean) (95% CI)† -6 (-10; -2) -9 (-13; -5) Body Weight Baseline (mean) in kg 86.8 86.6 86.6 % change from baseline (adjusted mean) -4.2 -4.7 1.0 Difference from glimepiride (adjusted mean) (95% CI)† -5.2§ (-5.7; -4.7) -5.7§ (-6.2; -5.1) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ INVOKANA + metformin HCl is considered non-inferior to glimepiride + metformin HCl because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%. § p<0.001 Reference ID: 5499136 33 12 18 26 36 44 Study Week -- Canagliflozin 1 DO mg • -- Canagliflozin 300 mg 52 Wk52 LOCF • - - Glimepiride Figure 1: Mean HbA1C Change in Adults with Type 2 Diabetes Mellitus Treated with INVOKANA or Glimepiride in Combination with Metformin HCl at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population) Add-on Combination Therapy with Sulfonylurea A total of 127 adult patients with type 2 diabetes inadequately controlled on sulfonylurea monotherapy participated in an 18-week, double-blind, placebo-controlled sub-trial to evaluate the efficacy and safety of INVOKANA in combination with sulfonylurea. The mean age was 65 years, 57% of patients were male, and the mean baseline eGFR was 69 mL/min/1.73 m2. Patients treated with sulfonylurea monotherapy on a stable protocol-specified dose (greater than or equal to 50% maximal dose) for at least 10 weeks completed a 2-week, single-blind, placebo run-in period. After the run-in period, patients with inadequate glycemic control were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to sulfonylurea. As shown in Table 14, at the end of treatment, INVOKANA 100 mg and 300 mg daily provided statistically significant (p<0.001 for both doses) improvements in HbA1C relative to placebo when added to sulfonylurea. INVOKANA 300 mg once daily compared to placebo resulted in a greater proportion of patients achieving an HbA1C less than 7%, (33% vs 5%), greater reductions in fasting plasma glucose (-36 mg/dL vs +12 mg/dL), and greater percent body weight reduction (-2.0% vs -0.2%). Table 14: Results from 18-Week Placebo−Controlled Clinical Trial of INVOKANA in Combination with Sulfonylurea in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Sulfonylurea (N=45) INVOKANA 100 mg + Sulfonylurea (N=42) INVOKANA 300 mg + Sulfonylurea (N=40) HbA1C (%) Baseline (mean) 8.49 8.29 8.28 Reference ID: 5499136 34 Change from baseline (adjusted mean) 0.04 -0.70 -0.79 Difference from placebo (adjusted mean) (95% CI)† -0.74‡ (-1.15; -0.33) -0.83‡ (-1.24; -0.41) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value ‡ p<0.001 Add-on Combination Therapy with Metformin HCl and Sulfonylurea A total of 469 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (maximal or near-maximal effective dose) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin HCl and sulfonylurea. The mean age was 57 years, 51% of patients were male, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the protocol-specified doses of metformin HCl and sulfonylurea (N=372) entered a 2-week, single- blind, placebo run-in period. Other patients (N=97) were required to be on a stable protocol- specified dose of metformin HCl and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to metformin HCl and sulfonylurea. At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl and sulfonylurea. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in a significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin HCl and sulfonylurea (see Table 15). Table 15: Results from 26-Week Placebo-Controlled Clinical Trial of INVOKANA in Combination with Metformin HCl and Sulfonylurea in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Metformin HCl and Sulfonylurea (N=156) INVOKANA 100 mg + Metformin HCl and Sulfonylurea (N=157) INVOKANA 300 mg + Metformin HCl and Sulfonylurea (N=156) HbA1C (%) Baseline (mean) 8.12 8.13 8.13 Change from baseline (adjusted mean) -0.13 -0.85 -1.06 Difference from placebo (adjusted mean) (95% CI)† -0.71‡ (-0.90; -0.52) -0.92‡ (-1.11; -0.73) Percent of patients achieving A1C < 7% 18 43‡ 57‡ Fasting Plasma Glucose (mg/dL) Baseline (mean) 170 173 168 Reference ID: 5499136 35 Change from baseline (adjusted mean) 4 -18 -31 Difference from placebo (adjusted mean) (95% CI)† -22‡ (-31; -13) -35‡ (-44; -25) Body Weight Baseline (mean) in kg 90.8 93.5 93.5 % change from baseline (adjusted mean) -0.7 -2.1 -2.6 Difference from placebo (adjusted mean) (95% CI)† -1.4‡ (-2.1; -0.7) -2.0‡ (-2.7; -1.3) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001 Add-on Combination Therapy with Metformin HCl and Sitagliptin A total of 217 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 1,500 mg/day) and sitagliptin 100 mg/day (or equivalent fixed-dose combination) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin HCl and sitagliptin. The mean age was 57 years, 58% of patients were male, 73% of patients were White, 15% were Asian, and 12% were Black or African American. The mean baseline eGFR was 90 mL/min/1.73 m2 and the mean baseline BMI was 32 kg/m2. The mean duration of diabetes was 10 years. Eligible patients entered a 2-week, single-blind, placebo run-in period and were subsequently randomized to INVOKANA 100 mg or placebo, administered once daily as add-on to metformin HCl and sitagliptin. Patients with a baseline eGFR of 70 mL/min/1.73 m2 or greater who were tolerating INVOKANA 100 mg and who required additional glycemic control (fasting finger stick 100 mg/dL or greater at least twice within 2 weeks) were up-titrated to INVOKANA 300 mg. While up-titration occurred as early as Week 4, most (90%) patients randomized to INVOKANA were up-titrated to INVOKANA 300 mg by 6 to 8 weeks. At the end of 26 weeks, INVOKANA resulted in a statistically significant improvement in HbA1C (p<0.001) compared to placebo when added to metformin HCl and sitagliptin. Table 16: Results from 26−Week Placebo-Controlled Clinical Trial of INVOKANA in Combination with Metformin HCl and Sitagliptin in Adults with Type 2 Diabetes Mellitus Efficacy Parameter Placebo + Metformin HCl and Sitagliptin (N=108*) INVOKANA + Metformin HCl and Sitagliptin (N=109*) HbA1C (%) Baseline (mean) 8.40 8.50 Change from baseline (adjusted mean) -0.03 -0.83 Difference from placebo (adjusted mean) (95% CI)†§ -0.81# (-1.11; -0.51) Percent of patients achieving HbA1C < 7%‡ 9 28 Reference ID: 5499136 36 Fasting Plasma Glucose (mg/dL)¶ Baseline (mean) 180 185 Change from baseline (adjusted mean) -3 -28 Difference from placebo (adjusted mean) (95% CI) -25# (-39; -11) * To preserve the integrity of randomization, all randomized patients were included in the analysis. The patient who was randomized once to each arm was analyzed on INVOKANA. † Early treatment discontinuation before week 26, occurred in 11.0% and 24.1% of INVOKANA and placebo patients, respectively. ‡ Patients without week 26 efficacy data were considered as non-responders when estimating the proportion achieving HbA1C < 7%. § Estimated using a multiple imputation method modeling a “wash-out” of the treatment effect for patients having missing data who discontinued treatment. Missing data was imputed only at week 26 and analyzed using ANCOVA. ¶ Estimated using a multiple imputation method modeling a “wash-out” of the treatment effect for patients having missing data who discontinued treatment. A mixed model for repeated measures was used to analyze the imputed data. # p<0.001 INVOKANA Compared to Sitagliptin, Both as Add-on Combination Therapy with Metformin HCl and Sulfonylurea A total of 755 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (near-maximal or maximal effective dose) participated in a 52-week, double-blind, active-controlled trial to compare the efficacy and safety of INVOKANA 300 mg versus sitagliptin 100 mg in combination with metformin HCl and sulfonylurea. The mean age was 57 years, 56% of patients were male, and the mean baseline eGFR was 88 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin HCl and sulfonylurea (N=716) entered a 2-week single-blind, placebo run-in period. Other patients (N=39) were required to be on a stable protocol-specified dose of metformin HCl and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 300 mg or sitagliptin 100 mg as add-on to metformin HCl and sulfonylurea. As shown in Table 17 and Figure 2, at the end of treatment, INVOKANA 300 mg provided greater HbA1C reduction compared to sitagliptin 100 mg when added to metformin HCl and sulfonylurea (p<0.05). INVOKANA 300 mg resulted in a mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. A mean change in systolic blood pressure from baseline of -5.06 mmHg was observed with INVOKANA 300 mg compared to +0.85 mmHg with sitagliptin 100 mg. Table 17: Results from 52-Week Clinical Trial Comparing INVOKANA to Sitagliptin in Combination with Metformin HCl and Sulfonylurea in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter INVOKANA 300 mg + Metformin HCl and Sulfonylurea (N=377) Sitagliptin 100 mg + Metformin HCl and Sulfonylurea (N=378) HbA1C (%) Baseline (mean) 8.12 8.13 Reference ID: 5499136 37 0.0 + -.----------------------------------, w en -0.2 ]' -0.4 ID g>~ ~ ~ -0 .6 (.) (I] C E :i ~ -0.8 (/)~ _J tr ~ -1 .0 I C -1.2 - 1.4 12 18 26 34 42 52 Study Week Canagliflozin 300 mg • - - • Sitagliptin 100 mg Wk52 LOCF Change from baseline (adjusted mean) -1.03 -0.66 Difference from sitagliptin (adjusted mean) (95% CI)† -0.37‡ (-0.50; -0.25) Percent of patients achieving HbA1C < 7% 48 35 Fasting Plasma Glucose (mg/dL) Baseline (mean) 170 164 Change from baseline (adjusted mean) -30 -6 Difference from sitagliptin (adjusted mean) (95% CI)† -24 (-30; -18) Body Weight Baseline (mean) in kg 87.6 89.6 % change from baseline (adjusted mean) -2.5 0.3 Difference from sitagliptin (adjusted mean) (95% CI)† -2.8§ (-3.3; -2.2) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ INVOKANA + metformin HCl+ sulfonylurea is considered non-inferior to sitagliptin + metformin HCl + sulfonylurea because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%. § p<0.001 Figure 2: Mean HbA1C Change in Adults with Type 2 Diabetes Mellitus Treated with INVOKANA or Sitagliptin in Combination with Metformin HCl and Sulfonylurea at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population) Add-on Combination Therapy with Metformin HCl and Pioglitazone A total of 342 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and pioglitazone (30 or 45 mg/day) participated in a 26-week, double-blind, placebo- controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin HCl and pioglitazone. The mean age was 57 years, 63% of patients were male, and the mean baseline eGFR was 86 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin HCl and pioglitazone (N=163) entered a 2-week, single-blind, placebo run-in period. Reference ID: 5499136 38 Other patients (N=181) were required to be on stable protocol-specified doses of metformin HCl and pioglitazone for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to metformin HCl and pioglitazone. At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl and pioglitazone. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG) and in percent body weight reduction compared to placebo when added to metformin HCl and pioglitazone (see Table 18). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -4.1 mmHg and -3.5 mmHg with INVOKANA 100 mg and 300 mg, respectively. Table 18: Results from 26-Week Placebo-Controlled Clinical Trial of INVOKANA in Combination with Metformin HCl and Pioglitazone in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Metformin HCl and Pioglitazone (N=115) INVOKANA 100 mg + Metformin HCl and Pioglitazone (N=113) INVOKANA 300 mg + Metformin HCl and Pioglitazone (N=114) HbA1C (%) Baseline (mean) 8.00 7.99 7.84 Change from baseline (adjusted mean) -0.26 -0.89 -1.03 Difference from placebo (adjusted mean) (95% CI)† -0.62‡ (-0.81; -0.44) -0.76‡ (-0.95; -0.58) Percent of patients achieving HbA1C < 7% 33 47‡ 64‡ Fasting Plasma Glucose (mg/dL) Baseline (mean) 164 169 164 Change from baseline (adjusted mean) 3 -27 -33 Difference from placebo (adjusted mean) (95% CI)† -29‡ (-37; -22) -36‡ (-43; -28) Body Weight Baseline (mean) in kg 94.0 94.2 94.4 % change from baseline (adjusted mean) -0.1 -2.8 -3.8 Difference from placebo (adjusted mean) (95% CI)† -2.7‡ (-3.6; -1.8) -3.7‡ (-4.6; -2.8) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001 Add-On Combination Therapy with Insulin (With or Without Other Antihyperglycemic Agents) A total of 1,718 adult patients with type 2 diabetes inadequately controlled on insulin greater than or equal to 30 units/day or insulin in combination with other antihyperglycemic agents Reference ID: 5499136 39 participated in an 18-week, double-blind, placebo-controlled subtrial of a cardiovascular trial to evaluate the efficacy and safety of INVOKANA in combination with insulin. The mean age was 63 years, 66% of patients were male, and the mean baseline eGFR was 75 mL/min/1.73 m2. Patients on basal, bolus, or basal/bolus insulin for at least 10 weeks entered a 2-week, single- blind, placebo run-in period. Approximately 70% of patients were on a background basal/bolus insulin regimen. After the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to insulin. The mean daily insulin dose at baseline was 83 units, which was similar across treatment groups. At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to insulin. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reductions in fasting plasma glucose (FPG), and in percent body weight reductions compared to placebo (see Table 19). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -2.6 mmHg and -4.4 mmHg with INVOKANA 100 mg and 300 mg, respectively. Table 19: Results from 18-Week Placebo-Controlled Clinical Trial of INVOKANA in Combination with Insulin ≥ 30 Units/Day (With or Without Other Oral Antihyperglycemic Agents) in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Insulin (N=565) INVOKANA 100 mg + Insulin (N=566) INVOKANA 300 mg + Insulin (N=587) HbA1C (%) Baseline (mean) 8.20 8.33 8.27 Change from baseline (adjusted mean) 0.01 -0.63 -0.72 Difference from placebo (adjusted mean) (95% CI)† -0.65‡ (-0.73; -0.56) -0.73‡ (-0.82; -0.65) Percent of patients achieving HbA1C < 7% 8 20‡ 25‡ Fasting Plasma Glucose (mg/dL) Baseline 169 170 168 Change from baseline (adjusted mean) 4 -19 -25 Difference from placebo (adjusted mean) (97.5% CI)† -23‡ (-29; -16) -29‡ (-35; -23) Body Weight Baseline (mean) in kg 97.7 96.9 96.7 % change from baseline (adjusted mean) 0.1 -1.8 -2.3 Difference from placebo (adjusted mean) (97.5% CI)† -1.9‡ (-2.2; -1.6) -2.4‡ (-2.7; -2.1) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001 Reference ID: 5499136 40 Trial in Patients Ages 55 to 80 A total of 714 type 2 diabetes patients ages 55 to 80 years and inadequately controlled on current diabetes therapy (either diet and exercise alone or in combination with oral or parenteral agents) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with current diabetes treatment. The mean age was 64 years, 55% of patients were male, and the mean baseline eGFR was 77 mL/min/1.73 m2. Patients were randomized in a 1:1:1 ratio to the addition of INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily. At the end of treatment, INVOKANA provided statistically significant improvements from baseline relative to placebo in HbA1C (p<0.001 for both doses) of -0.57% (95% CI: -0.71%; -0.44%) for INVOKANA 100 mg and -0.70% (95% CI: -0.84%; -0.57%) for INVOKANA 300 mg [see Use in Specific Populations (8.5)]. Glycemic Control in Patients with Moderate Renal Impairment A total of 269 adult patients with type 2 diabetes and a baseline eGFR of 30 mL/min/1.73 m2 to less than 50 mL/min/1.73 m2 inadequately controlled on current diabetes therapy participated in a 26-week, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of INVOKANA in combination with current diabetes treatment (diet or antihyperglycemic agent therapy, with 95% of patients on insulin and/or sulfonylurea). The mean age was 68 years, 61% of patients were male, and the mean baseline eGFR was 39 mL/min/1.73 m2. Patients were randomized in a 1:1:1 ratio to the addition of INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily. At the end of treatment, INVOKANA 100 mg and INVOKANA 300 mg daily provided greater reductions in HbA1C relative to placebo (-0.30% [95% CI: -0.53%; -0.07%] and -0.40%, [95% CI: -0.64%; -0.17%], respectively) [see Warnings and Precautions (5.3), Adverse Reactions (6.1), Use in Specific Populations (8.6), and Clinical Studies (14.4)]. 14.2 Glycemic Control Trial in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus In a double-blind, placebo-controlled, parallel-group pediatric trial (NCT03170518), 171 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus (HbA1C ≥6.5% and ≤11.0%) were randomized to INVOKANA (84 patients) or placebo (87 patients) as add-on to diet and exercise, metformin HCl (≥1,000 mg per day or maximally tolerated dosage), insulin, or a combination of metformin HCl and insulin, for a total of 52­ weeks. At Week 13, patients in the INVOKANA arm whose HbA1C was ≥7.0% and eGFR ≥60 mL/min/1.73m2 were re-randomized to either continue on INVOKANA 100 mg orally once daily (n=16) or to up-titrate to INVOKANA 300 mg orally once daily (n=17). Reference ID: 5499136 41 At baseline, background therapies included diet and exercise only (14%), insulin monotherapy (11%), metformin HCl and insulin (29%), and metformin HCl monotherapy (46%). The mean HbA1C at baseline was 8.0% and the mean duration of type 2 diabetes mellitus was 2 years. The mean eGFR at baseline was 157.3 mL/min/1.73 m2, and approximately 16% (24/151) of the trial population with measurements had microalbuminuria or macroalbuminuria. Patients with an eGFR less than 60 mL/min/1.73 m2 were not enrolled in the trial; no patients in the trial reached an eGFR < 60 mL/min/1.73m2. The mean age was 14.3 years, 47% were under 15 years of age, and 68% were female. Approximately 42% were Asian, 42% were White, 11% were Black or African American, 5% were American Indian/Alaska Native, and 36% were of Hispanic or Latino ethnicity. The mean BMI was 30.8 kg/m2 (range 18-57 kg/m2) and the mean BMI Z-score was 1.84. At Week 26, treatment with canagliflozin provided statistically significant improvement in HbA1C from baseline, compared with placebo (see Table 20). Table 20: Results at Week 26 in a Placebo-Controlled Trial of INVOKANA in Combination with Metformin HCl and/or Insulin or as Monotherapy in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo (N=87) INVOKANA (N=84) HbA1C (%) Baseline (mean) 8.3 7.8 Change from baseline †‡ 0.34 -0.38 Difference from placebo 95% CI †‡ -0.73 (-1.26, -0.19) § FPG (mg/dL) Baseline (mean) 156.5 154.8 Change from baseline †‡ 17.29 -8.22 Difference from placebo 95% CI †‡ -25.51 (-49.55, -1.47) ¶ * Modified intent-to-treat set (All randomized and treated patients with baseline HbA1C measurement). † Multiple imputation using retrieved dropout approach with 1000 iterations for missing data (canagliflozin N=7 (8.3%), placebo N=7 (8.1%) for HbA1C and canagliflozin N=9 (10.7%), placebo N=7 (8.1%) for FPG). ‡ Least-Square Mean from Analysis of Covariance (ANCOVA) adjusted for baseline value, baseline age stratum (< 15 years vs 15 to < 18 years) and baseline antihyperglycemic agent (AHA) background (i.e, diet and exercise only, metformin monotherapy, insulin monotherapy, or combination of insulin and metformin). § P-value=0.008 (two-sided) ¶ Not evaluated for statistical significance, not part of sequential testing procedure. 14.3 Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease The CANVAS and CANVAS-R trials were multicenter, multi-national, randomized, double- blind parallel group, with similar inclusion and exclusion criteria. Patients eligible for enrollment in both CANVAS and CANVAS-R trials were: 30 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease (66% of the enrolled Reference ID: 5499136 42 population) or were 50 years of age or older and had two or more other specified risk factors for cardiovascular disease (34% of the enrolled population). The integrated analysis of the CANVAS and CANVAS-R trials compared the risk of Major Adverse Cardiovascular Event (MACE) between canagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. In CANVAS, patients were randomly assigned 1:1:1 to canagliflozin 100 mg, canagliflozin 300 mg, or matching placebo. In CANVAS-R, patients were randomly assigned 1:1 to canagliflozin 100 mg or matching placebo, and titration to 300 mg was permitted at the investigator’s discretion (based on tolerability and glycemic needs) after Week 13. Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases. A total of 10,134 adult patients were treated (4,327 in CANVAS and 5,807 in CANVAS-R; total of 4,344 randomly assigned to placebo and 5,790 to canagliflozin) for a mean exposure duration of 149 weeks (223 weeks [4.3 years] in CANVAS and 94 weeks [1.8 years] in CANVAS-R). Approximately 78% of the trial population was White, 13% was Asian, and 3% was Black or African American. The mean age was 63 years and approximately 64% were male. The mean HbA1C at baseline was 8.2% and mean duration of diabetes was 13.5 years with 70% of patients having had diabetes for 10 years or more. Approximately 31%, 21% and 17% reported a past history of neuropathy, retinopathy and nephropathy, respectively, and the mean eGFR 76 mL/min/1.73 m2. At baseline, patients were treated with one (19%) or more (80%) antidiabetic medications including metformin HCl (77%), insulin (50%), and sulfonylurea (43%). At baseline, the mean systolic blood pressure was 137 mmHg, the mean diastolic blood pressure was 78 mmHg, the mean LDL was 89 mg/dL, the mean HDL was 46 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 115 mg/g. At baseline, approximately 80% of patients were treated with renin angiotensin system inhibitors, 53% with beta-blockers, 13% with loop diuretics, 36% with non-loop diuretics, 75% with statins, and 74% with antiplatelet agents (mostly aspirin). During the trial, investigators could modify anti-diabetic and cardiovascular therapies to achieve local standard of care treatment targets with respect to blood glucose, lipid, and blood pressure. More patients receiving canagliflozin compared to placebo initiated anti­ thrombotics (5.2% vs 4.2%) and statins (5.8% vs 4.8%) during the trial. Reference ID: 5499136 43 24 22 HR (95%CI) Cana vs. Placebo 0.86 (0 75, 097) 20 18 ~ 16 C ru ,jj 14 ~ ~ 12 :g- 10 (/) ;f!. l~6~i:bol 0 26 52 78 104 130 156 182 208 234 260 286 312 338 Time (Weeks) SubJecls Placebo 4347 4239 4153 4061 2942 1626 1240 1217 1187 1156 1120 1095 789 216 Cana 5795 5672 5566 5447 4343 2984 2555 2513 2460 2419 2363 2311 1661 448 For the primary analysis, a stratified Cox proportional hazards model was used to test for non- inferiority against a pre-specified risk margin of 1.3 for the hazard ratio of MACE. In the integrated analysis of CANVAS and CANVAS-R trials, canagliflozin reduced the risk of first occurrence of MACE. The estimated hazard ratio (95% CI) for time to first MACE was 0.86 (0.75, 0.97). Refer to Table 21. Vital status was obtained for 99.6% of patients across the trials. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 3. Table 21: Treatment Effect for the Primary Composite Endpoint, MACE, and its Components in the Integrated Analysis of CANVAS and CANVAS-R Trials in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease* Placebo N=4,347(%) Canagliflozin N=5,795 (%) Hazard ratio (95% C.I.)¶ Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)†, ‡, § 426 (10.4) 585 (9.2) 0.86 (0.75, 0.97) Non-fatal myocardial infarction‡, § 159 (3.9) 215 (3.4) 0.85 (0.69, 1.05) Non-fatal Stroke‡, § 116 (2.8) 158 (2.5) 0.90 (0.71, 1.15) Cardiovascular Death‡, § 185 (4.6) 268 (4.1) 0.87 (0.72, 1.06) * Intent-To-Treat Analysis Set † P-value for superiority (2-sided) = 0.0158 ‡ Number and percentage of first events § Due to pooling of unequal randomization ratios, Cochran-Mantel-Haenszel weights were applied to calculate percentages ¶ Stratified Cox-proportional hazards model with treatment as a factor and stratified by the trial and by prior CV disease Figure 3: Time to First Occurrence of MACE in Adults with Type 2 Diabetes Mellitus 44 Reference ID: 5499136 14.4 Renal and Cardiovascular Outcomes in Adults with Diabetic Nephropathy and Albuminuria The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial (CREDENCE) was a multinational, randomized, double-blind, placebo- controlled trial comparing canagliflozin with placebo in adult patients with type 2 diabetes mellitus, an eGFR ≥ 30 to < 90 mL/min/1.73 m2 and albuminuria (urine albumin/creatinine ˃ 300 to ≤ 5,000 mg/g) who were receiving standard of care including a maximum-tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The primary objective of CREDENCE was to assess the efficacy of canagliflozin relative to placebo in reducing the composite endpoint of end stage kidney disease (ESKD), doubling of serum creatinine, and renal or CV death. Patients were randomized to receive canagliflozin 100 mg (N=2,202) or placebo (N=2,199) and treatment was continued until the initiation of dialysis or renal transplantation. The median follow-up duration for the 4,401 randomized subjects was 137 weeks. Vital status was obtained for 99.9% of subjects. The population was 67% White, 20% Asian, and 5% Black or African American; 32% were of Hispanic or Latino ethnicity. The mean age was 63 years and 66% were male. At randomization, the mean HbA1C was 8.3%, the median urine albumin/creatinine was 927 mg/g, the mean eGFR was 56.2 mL/min/1.73 m2, 50% had prior CV disease, and 15% reported a history of heart failure. The most frequent antihyperglycemic agents (AHA) medications used at baseline were insulin (66%), biguanides (58%), and sulfonylureas (29%). Nearly all subjects (99.9%) were on ACEi or ARB at randomization, approximately 60% were taking an anti-thrombotic agent (including aspirin), and 69% were on a statin. The primary composite endpoint in the CREDENCE trial was the time to first occurrence of ESKD (defined as an eGFR < 15 mL/min/1.73 m2, initiation of chronic dialysis or renal transplant), doubling of serum creatinine, and renal or CV death. Canagliflozin 100 mg significantly reduced the risk of the primary composite endpoint based on a time-to-event analysis [HR: 0.70; 95% CI: 0.59, 0.82; p<0.0001] (see Figure 4). The treatment effect reflected a reduction in progression to ESKD, doubling of serum creatinine and cardiovascular death as shown in Table 22 and Figure 4. There were few renal deaths during the trial. Canagliflozin 100 mg also significantly reduced the risk of hospitalization for heart failure [HR: 0.61; 95% CI: 0.47 to 0.80; p<0.001]. Reference ID: 5499136 45 Table 22: Analysis of Primary Endpoint (including the Individual Components) and Secondary Endpoints from the CREDENCE Trial in Adults with Diabetic Nephropathy and Albuminuria Placebo canagliflozin Endpoint N=2,199 (%) Event Rate* N=2,202 (%) Event Rate* HR† (95% CI) Primary Composite Endpoint (ESKD, doubling of serum creatinine, renal death, or CV death) 340 (15.5) 6.1 245 (11.1) 4.3 0.70 (0.59, 0.82) ‡ ESKD 165 (7.5) 2.9 116 (5.3) 2.0 0.68 (0.54, 0.86) Doubling of serum creatinine 188 (8.5) 3.4 118 (5.4) 2.1 0.60 (0.48, 0.76) Renal death 5 (0.2) 0.1 2 (0.1) 0.0 CV death 140 (6.4) 2.4 110 (5.0) 1.9 0.78 (0.61, 1.00) CV death or hospitalization for heart failure 253 (11.5) 4.5 179 (8.1) 3.1 0.69 (0.57, 0.83) § CV death, non-fatal myocardial infarction or non­ fatal stroke 269 (12.2) 4.9 217 (9.9) 3.9 0.80 (0.67, 0.95) ¶ Non-fatal myocardial infarction 87 (4.0) 1.6 71 (3.2) 1.3 0.81 (0.59, 1.10) Non-fatal stroke 66 (3.0) 1.2 53 (2.4) 0.9 0.80 (0.56, 1.15) Hospitalization for heart failure 141 (6.4) 2.5 89 (4.0) 1.6 0.61 (0.47, 0.80) § ESKD, doubling of serum creatinine or renal death 224 (10.2) 4.0 153 (6.9) 2.7 0.66 (0.53, 0.81) ‡ Intent-To-Treat Analysis Set (time to first occurrence) t Analysis Set (time to first occurrence) time to first occurrence) The individual components do not represent a breakdown of the composite outcomes, but rather the total number of subjects experiencing an event during the course of the trial. * Event rate per 100 patient-years. † Hazard ratio (canagliflozin compared to placebo), 95% CI and p-value are estimated using a stratified Cox proportional hazards model including treatment as the explanatory variable and stratified by screening eGFR (≥ 30 to < 45, ≥ 45 to < 60, ≥ 60 to < 90 mL/min/1.73 m2). HR is not presented for renal death due to the small number of events in each group. ‡ P-value <0.0001 § P-value <0.001 ¶ P-value <0.02 The Kaplan-Meier curve (Figure 4) shows time to first occurrence of the primary composite endpoint of ESKD, doubling of serum creatinine, renal death, or CV death. The curves begin to separate by Week 52 and continue to diverge thereafter. Reference ID: 5499136 46 30 28 HR (95%CI) Cana vs. Placebo 0 70 (0.59, 0.82) 26 24 22 _f!l 20 C Q) > 18 UJ j 16 ,-' {'l 14 Q) E 12 :J Cf) ,?. 10 8 6 4 2 0 1~ 6~~=bol 0 26 52 78 104 130 156 182 Time (Weeks) Subjects at risk Placebo 2199 2178 2132 2047 1725 1129 621 170 Cana 2202 2181 2145 2081 1786 1211 646 196 Figure 4: CREDENCE: Time to First Occurrence of the Primary Composite Endpoint 16 HOW SUPPLIED/STORAGE AND HANDLING INVOKANA® (canagliflozin) tablets are available in the strengths and packages listed below: 100 mg tablets are yellow, capsule-shaped, film-coated tablets with “CFZ” on one side and “100” on the other side. NDC 50458-140-30 Bottle of 30 NDC 50458-140-90 Bottle of 90 NDC 50458-140-50 Bottle of 500 300 mg tablets are white, capsule-shaped, film-coated tablets with “CFZ” on one side and “300” on the other side. NDC 50458-141-30 Bottle of 30 NDC 50458-141-90 Bottle of 90 NDC 50458-141-50 Bottle of 500 Storage and Handling Keep out of reach of children. Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Reference ID: 5499136 47 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis Inform patients that INVOKANA can cause potentially fatal ketoacidosis and that type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors. Educate all patients on precipitating factors (such as insulin dose reduction or missed doses, infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform patients that blood glucose may be normal even in the presence of ketoacidosis. Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur, instruct patients to discontinue INVOKANA and seek medical attention immediately [see Warnings and Precautions (5.1)]. Lower Limb Amputation Inform patients that INVOKANA is associated with an increased risk of amputations. Counsel patients about the importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop [see Warnings and Precautions (5.2)]. Volume Depletion Inform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions (5.3)]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake. Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Inform patients that hypoglycemia has been reported when INVOKANA is used with insulin or insulin secretagogues. Educate patients or caregivers on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.5)]. Serious Urinary Tract Infections Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.4)]. Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Inform patients that necrotizing infections of the perineum (Fournier’s gangrene) have occurred with INVOKANA. Counsel patients to promptly seek medical attention if they develop pain or Reference ID: 5499136 48 tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.6)]. Genital Mycotic Infections in Females (e.g., Vulvovaginitis) Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.7)]. Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.7)]. Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions, such as urticaria, rash, anaphylaxis, and angioedema, have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction, and to discontinue drug until they have consulted prescribing physicians [see Warnings and Precautions (5.8)]. Bone Fracture Inform patients that bone fractures have been reported in adult patients taking INVOKANA. Provide them with information on factors that may contribute to fracture risk [see Warnings and Precautions (5.9)]. Pregnancy Advise pregnant women, and females of reproductive potential of the potential risk to a fetus with treatment with INVOKANA [see Use in Specific Populations (8.1)]. Instruct females of reproductive potential to report pregnancies to their physicians as soon as possible. Lactation Advise women that breastfeeding is not recommended during treatment with INVOKANA [see Use in Specific Populations (8.2)]. Laboratory Tests Inform patients that due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine [see Drug Interactions (7)]. Reference ID: 5499136 49 Missed Dose If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time. Active ingredient made in Belgium Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA Licensed from Mitsubishi Tanabe Pharma Corporation For patent information: www.janssenpatents.com © Johnson & Johnson and its affiliates 2013 – 2024 Reference ID: 5499136 50 Medication Guide INVOKANA® (in-vo-KAHN-uh) (canagliflozin) tablets, for oral use What is the most important information I should know about INVOKANA? INVOKANA can cause serious side effects, including:  Diabetic ketoacidosis (increased ketones in your blood or urine) in people with type 1 and other ketoacidosis. INVOKANA can cause ketoacidosis that can be life-threatening and may lead to death. Ketoacidosis is a serious condition which needs to be treated in a hospital. People with type 1 diabetes have a high risk of getting ketoacidosis. People with type 2 diabetes or pancreas problems also have an increased risk of getting ketoacidosis. Ketoacidosis can also happen in people who: are sick, cannot eat or drink as usual, skip meals, are on a diet high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount of insulin or miss insulin doses, drink too much alcohol, have a loss of too much fluid from the body (volume depletion), or who have surgery or a procedure that requires not having food for a long time (prolonged fasting). Ketoacidosis can happen even if your blood sugar is less than 250 mg/dL. Your healthcare provider may ask you to periodically check ketones in your urine or blood.  Stop taking INVOKANA and call your healthcare provider or get medical help right away if you get any of the following. If possible, check for ketones in your urine or blood, even if your blood sugar is less than 250 mg/dL: o nausea o tiredness o vomiting o trouble breathing o stomach-area (abdominal) pain o ketones in your urine or blood  Amputations. INVOKANA may increase your risk of lower limb amputations. Amputations mainly involve removal of the toe or part of the foot, however, amputations involving the leg, below and above the knee, have also occurred. Some people had more than one amputation, some on both sides of the body. You may be at a higher risk of lower limb amputation if you: o have a history of amputation o have heart disease or are at risk for heart disease o have had blocked or narrowed blood vessels, usually in your leg o have damage to the nerves (neuropathy) in your leg o have had diabetic foot ulcers or sores Call your healthcare provider right away if you have new pain or tenderness, any sores, ulcers, or infections in your leg or foot. Your healthcare provider may decide to stop your INVOKANA for a while if you have any of these signs or symptoms. Talk to your healthcare provider about proper foot care.  Dehydration. INVOKANA can cause some people to become dehydrated (the loss of too much body water). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden worsening of kidney function in people with type 2 diabetes who are taking INVOKANA. You may be at higher risk of dehydration if you: o take medicines to lower your blood pressure, including diuretics (water pill) o are on a low sodium (salt) diet o have kidney problems o are 65 years of age or older Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should drink on a daily basis. Call your healthcare provider right away if you reduce the amount of food or liquid you drink, for example if you cannot eat or you start to lose liquids from your body, for example from vomiting, diarrhea, or being in the sun too long.  Vaginal yeast infection. Women who take INVOKANA may get vaginal yeast infections. Yeast infections can be a serious but common side effect of INVOKANA. Symptoms of a vaginal yeast infection include: o vaginal odor o white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese) o vaginal itching  Yeast infection of the skin around the penis (balanitis or balanoposthitis). Men who take INVOKANA may get a yeast infection of the skin around the penis. Men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include: o redness, itching, or swelling of the penis o rash of the penis Reference ID: 5499136 1 o foul smelling discharge from the penis o pain in the skin around penis Talk to your healthcare provider about what to do if you get symptoms of a yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medication and your symptoms do not go away. What is INVOKANA?  INVOKANA is a prescription medicine used: o along with diet and exercise to lower blood sugar (glucose) in adults and children aged 10 years and older with type 2 diabetes. o to reduce the risk of major cardiovascular events such as heart attack, stroke or death in adults with type 2 diabetes who have known cardiovascular disease. o to reduce the risk of end stage kidney disease (ESKD), worsening of kidney function, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes and diabetic kidney disease (nephropathy) with a certain amount of protein in the urine.  INVOKANA is not recommended to decrease blood sugar (glucose) in people with type 1 diabetes.  INVOKANA is not recommended to decrease blood sugar (glucose) in people with type 2 diabetes with severe kidney problems.  It is not known if INVOKANA is safe and effective in children under 10 years of age. Do not take INVOKANA if you:  are allergic to canagliflozin or any of the ingredients in INVOKANA. See the end of this Medication Guide for a list of ingredients in INVOKANA. Symptoms of allergic reaction to INVOKANA may include: o rash o raised red patches on your skin (hives) o swelling of the face, lips, mouth, tongue, and throat that may cause difficulty in breathing or swallowing Before taking INVOKANA, tell your healthcare provider about all of your medical conditions, including if you:  have type 1 diabetes or have had diabetic ketoacidosis.  have a decrease in your insulin dose.  have a serious infection.  have a history of infection of the vagina or penis.  have a history of amputation.  have had blocked or narrowed blood vessels, usually in your leg.  have damage to the nerves (neuropathy) in your leg.  have had diabetic foot ulcers or sores.  have kidney problems.  have liver problems.  have a history of urinary tract infections or problems with urination.  are on a low sodium (salt) diet. Your healthcare provider may change your diet or your dose of INVOKANA.  are going to have surgery or a procedure that requires not having food for a long time (prolonged fasting). Your healthcare provider may stop your INVOKANA before you have surgery. Talk to your healthcare provider if you are having surgery about when to stop taking INVOKANA and when to start it again.  are eating less or there is a change in your diet.  are dehydrated.  have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.  drink alcohol very often, or drink a lot of alcohol in the short-term (“binge” drinking).  have ever had an allergic reaction to INVOKANA.  are pregnant or plan to become pregnant. INVOKANA may harm your unborn baby. If you become pregnant while taking INVOKANA, tell your healthcare provider as soon as possible. Talk with your healthcare provider about the best way to control your blood sugar while you are pregnant.  are breastfeeding or plan to breastfeed. INVOKANA may pass into your breast milk and may harm your baby. Talk with your healthcare provider about the best way to feed your baby if you are taking INVOKANA. Do not breastfeed while taking INVOKANA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. INVOKANA may affect the way other medicines work, and other medicines may affect how INVOKANA works. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. Reference ID: 5499136 2 How should I take INVOKANA?  Take INVOKANA by mouth 1 time each day exactly as your healthcare provider tells you to take it.  Your healthcare provider will tell you how much INVOKANA to take and when to take it. Your healthcare provider may change your dose if needed.  It is best to take INVOKANA before the first meal of the day.  Your healthcare provider may tell you to take INVOKANA along with other diabetes medicines. Low blood sugar can happen more often when INVOKANA is taken with certain other diabetes medicines. See “What are the possible side effects of INVOKANA?”  Your healthcare provider may tell you to stop taking INVOKANA at least 3 days before any surgery or procedure that requires not having food or water for a long time (prolonged fasting).  If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take two doses of INVOKANA at the same time. Talk to your healthcare provider if you have questions about a missed dose.  If you take too much INVOKANA, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away.  When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you have any of these conditions and follow your healthcare provider’s instructions.  INVOKANA will cause your urine to test positive for glucose.  Your healthcare provider may do certain blood tests before you start INVOKANA and during treatment as needed. Your healthcare provider may change your dose of INVOKANA based on the results of your blood tests. What are the possible side effects of INVOKANA? INVOKANA may cause serious side effects including: See “What is the most important information I should know about INVOKANA?”  serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking INVOKANA. Tell your healthcare provider if you have any signs or symptoms of a urinary tract infection such as a burning feeling when passing urine, a need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people may also have a fever, back pain, nausea, or vomiting.  low blood sugar (hypoglycemia). If you take INVOKANA with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take INVOKANA. Signs and symptoms of low blood sugar may include: o headache o drowsiness o weakness o confusion o dizziness o irritability o hunger o fast heartbeat o sweating o shaking or feeling jittery  a rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in people who take INVOKANA. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around your anus and genitals: o pain or tenderness o swelling o redness of the skin (erythema)  serious allergic reaction. If you have any symptoms of a serious allergic reaction, stop taking INVOKANA and call your healthcare provider right away or go to the nearest hospital emergency room. See “Do not take INVOKANA if you:”. Your healthcare provider may give you a medicine for your allergic reaction and prescribe a different medicine for your diabetes.  broken bones (fractures). Bone fractures have been seen in patients taking INVOKANA. Talk to your healthcare provider about factors that may increase your risk of bone fracture. The most common side effects of INVOKANA include:  vaginal yeast infections and yeast infections of the penis (See “What is the most important information I should know about INVOKANA?”)  changes in urination, including urgent need to urinate more often, in larger amounts, or at night These are not all the possible side effects of INVOKANA. Reference ID: 5499136 3 Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc. at 1-800-526-7736. How should I store INVOKANA?  Store INVOKANA at room temperature between 68 °F to 77 °F (20 °C to 25 °C).  Keep INVOKANA and all medicines out of the reach of children. General information about the safe and effective use of INVOKANA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use INVOKANA for a condition for which it was not prescribed. Do not give INVOKANA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about INVOKANA that is written for health professionals. What are the ingredients in INVOKANA? Active ingredient: canagliflozin Inactive ingredients: croscarmellose sodium (E468), hydroxypropyl cellulose (E463), lactose anhydrous, magnesium stearate (E572), and microcrystalline cellulose (E460[i]). In addition, the tablet coating contains iron oxide yellow (E172) (100 mg tablet only), macrogol/PEG3350 (E1521), polyvinyl alcohol (E1203) (partially hydrolyzed), talc (E553b), and titanium dioxide (E171). Active ingredient made in Belgium. Manufactured for: Janssen Pharmaceuticals, Inc., Titusville, NJ 08560, USA. Licensed from Mitsubishi Tanabe Pharma Corporation. For patent information: www.janssenpatents.com © Johnson & Johnson and its affiliates 2013 - 2024 For more information about INVOKANA, call 1-800-526-7736 or visit our website at www.invokana.com. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2024 Reference ID: 5499136 4
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2025-02-12T15:47:54.146661
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INVOKAMET or INVOKAMET XR safely and effectively. See full prescribing information for INVOKAMET or INVOKAMET XR. INVOKAMET® (canagliflozin and metformin hydrochloride) tablets, for oral use INVOKAMET® XR (canagliflozin and metformin hydrochloride) extended-release tablets, for oral use Initial U.S. Approval: 2014 WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.  Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. (5.1)  Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. (5.1)  If lactic acidosis is suspected, discontinue INVOKAMET or INVOKAMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1) -------------------------RECENT MAJOR CHANGES----------------------------­ Indications and Usage (1) 12/2024 Dosage and Administration (2.2, 2.3, 2.4) 12/2024 Dosage and Administration (2.6) 08/2024 Warnings and Precautions (5.3) 01/2024 ----------------------------INDICATIONS AND USAGE--------------------------­ INVOKAMET and INVOKAMET XR are a combination of canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus (1). Canagliflozin Canagliflozin, when used as a component of INVOKAMET or INVOKAMET XR is indicated in adults with type 2 diabetes mellitus to reduce the risk of:  Major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (1).  End-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria (1). Limitations of Use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus (1). -----------------------DOSAGE AND ADMINISTRATION----------------------­  Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating (2.1).  Individualize starting dose based on the patient’s current regimen and renal function . See Table 1 in the full prescribing information for recommended starting dosages based on the current regimen (2.2, 2.3).  The maximum recommended total daily dosage is 300 mg of canagliflozin and 2,000 mg of metformin HCl (2.2).  Initiation of INVOKAMET or INVOKAMET XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m2, due to the metformin HCl component (2.3).  INVOKAMET: take one tablet orally twice daily with meals (2.2).  INVOKAMET XR: take two tablets orally once daily with the morning meal. Swallow whole. Never crush, cut, or chew (2.2)  Gradually escalate the dosage of metformin HCl in INVOKAMET or INVOKAMET XR to reduce the risk of gastrointestinal adverse reactions with metformin HCl (2.2).  Dose adjustment for patients with renal impairment may be required (2.3)  See full prescribing information for INVOKAMET and INVOKAMET XR dosage modifications due to drug interactions (2.4).  May need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.5).  Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting (2.6). --------------------DOSAGE FORMS AND STRENGTHS---------------------­ INVOKAMET tablets:  Canagliflozin 50 mg and metformin HCl 500 mg (3)  Canagliflozin 50 mg and metformin HCl 1,000 mg (3)  Canagliflozin 150 mg and metformin HCl 500 mg (3)  Canagliflozin 150 mg and metformin HCl 1,000 mg (3) INVOKAMET XR extended-release tablets:  Canagliflozin 50 mg and metformin HCl 500 mg (3)  Canagliflozin 50 mg and metformin HCl 1,000 mg (3)  Canagliflozin 150 mg and metformin HCl 500 mg (3)  Canagliflozin 150 mg and metformin HCl 1,000 mg (3) -------------------------------CONTRAINDICATIONS-----------------------------­  Severe renal impairment (eGFR less than 30 mL/min/1.73 m2) (4)  Metabolic acidosis, including diabetic ketoacidosis (4)  Serious hypersensitivity reaction to canagliflozin or metformin HCl (4) ---------------------------WARNINGS AND PRECAUTIONS-------------------­  Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue INVOKAMET or INVOKAMET XR if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting (5.2).  Lower Limb Amputation: Monitor patients for infection or ulcers of lower limb and discontinue if these occur (5.3).  Volume Depletion: May result in acute kidney injury. Before initiating, assess and correct volume status in patients with renal impairment, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy (5.4).  Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (5.5).  Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues: Consider a lower dose of insulin or insulin secretagogue to reduce the risk of hypoglycemia when used in combination (5.6).  Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment (5.7).  Genital Mycotic Infections: Monitor and treat if indicated (5.8).  Hypersensitivity Reactions: Discontinue and monitor until signs and symptoms resolve (5.9).  Bone Fracture: Consider factors that contribute to fracture risk before initiating INVOKAMET or INVOKAMET XR (5.10).  Vitamin B12 Deficiency: Metformin HCl may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2- to 3-year intervals and manage any abnormalities (5.11). ------------------------------ADVERSE REACTIONS---------------------------­  Most common adverse reactions associated with canagliflozin (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination (6.1).  Most common adverse reactions associated with metformin HCl (5% or greater incidence) are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS-----------------------------­ Reference ID: 5499136 1  Carbonic Anhydrase Inhibitors: May increase risk of lactic acidosis. Consider more frequent monitoring (7)  Drugs that Reduce Metformin Clearance: May increase risk of lactic acidosis. Consider benefits and risks of concomitant use (7)  See full prescribing information for additional drug interactions and information on interference of INVOKAMET and INVOKAMET XR with laboratory tests. (7) -----------------------USE IN SPECIFIC POPULATIONS----------------------­  Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters (8.1)  Lactation: Not recommended when breastfeeding (8.2) FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: LACTIC ACIDOSIS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Prior to Initiation of INVOKAMET or INVOKAMET XR 2.2 Recommended Dosage and Administration 2.3 Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment 2.4 Concomitant Use with UDP- Glucuronosyltransferase (UGT) Enzyme Inducers 2.5 Discontinuation for Iodinated Contrast Imaging Procedures 2.6 Temporary Interruption for Surgery 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Lactic Acidosis 5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis 5.3 Lower Limb Amputation 5.4 Volume Depletion 5.5 Urosepsis and Pyelonephritis 5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues 5.7 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) 5.8 Genital Mycotic Infections 5.9 Hypersensitivity Reactions 5.10 Bone Fracture 5.11 Vitamin B12 Levels 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience  Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy (8.3)  Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume. Assess renal function more frequently (8.5)  Renal Impairment: Higher incidence of adverse reactions related to hypotension and renal function (8.6)  Hepatic Impairment: Avoid use in patients with hepatic impairment (8.7) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 12/2024 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus 14.2 Glycemic Control Trial in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus 14.3 Canagliflozin Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease 14.4 Canagliflozin Renal and Cardiovascular Outcomes in Adults with Diabetic Nephropathy and Albuminuria 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5499136 2 FULL PRESCRIBING INFORMATION WARNING: LACTIC ACIDOSIS  Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin­ associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].  Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment [see Warnings and Precautions (5.1)].  Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2, 2.3), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].  If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET or INVOKAMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE INVOKAMET INVOKAMET is a combination of canagliflozin and metformin HCl immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. INVOKAMET XR INVOKAMET XR is a combination of canagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Canagliflozin Reference ID: 5499136 3 Canagliflozin, when used as a component of INVOKAMET or INVOKAMET XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of :  Major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).  End-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day. Limitations of Use INVOKAMET or INVOKAMET XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Prior to Initiation of INVOKAMET or INVOKAMET XR Assess renal function before initiating INVOKAMET or INVOKAMET XR and as clinically indicated [see Dosage and Administration (2.3), Contraindications (4), and Warnings and Precautions (5.1, 5.4)]. In patients with volume depletion, correct this condition before initiating INVOKAMET or INVOKAMET XR [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5, 8.6)]. 2.2 Recommended Dosage and Administration INVOKAMET and INVOKAMET XR  INVOKAMET and INVOKAMET XR contain canagliflozin and metformin HCl. For the available strengths of the canagliflozin and metformin HCl components in INVOKAMET and INVOKAMET XR, see Dosage Forms and Strengths (3).  Individualize the starting dosage of INVOKAMET or INVOKAMET XR based on the patient’s current regimen as presented in Table 1 and based on renal function as presented in Table 2 [see Dosage and Administration (2.3]. INVOKAMET Take one tablet of INVOKAMET orally twice daily with meals. INVOKAMET XR Take two tablets of INVOKAMET XR orally once daily with the morning meal. Swallow each tablet whole and never crush, cut, or chew. Reference ID: 5499136 4 Table 1 presents the recommended starting dosage of INVOKAMET and INVOKAMET XR based on the patient’s current regimen. Table 1: Recommended Starting Dosage Based on the Current Regimen Current Regimen INVOKAMET Recommended Dosage INVOKAMET XR Recommended Dosage Not treated with either canagliflozin or metformin HCl Total daily dosage is canagliflozin 100 mg and metformin HCl 1,000 mg Metformin HCl* Total daily dosage is canagliflozin 100 mg and the nearest appropriate total daily dosage of metformin HCl Canagliflozin The same total daily dosage of canagliflozin and a total daily dosage of metformin HCl 1,000 mg Canagliflozin and metformin HCl* The same total daily dosage of canagliflozin and the nearest appropriate total daily dosage of metformin HCl * For patients taking an evening dosage of metformin HCl extended-release tablets, skip the last dose before starting INVOKAMET or INVOKAMET XR the following morning. Recommended Dosage for Additional Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older INVOKAMET The dosage of canagliflozin in INVOKAMET may be increased to the maximum total daily dosage of 300 mg (150 mg orally twice daily) in patients tolerating a dosage of 100 mg (50 mg twice daily) of canagliflozin. The dosage of metformin HCl in INVOKAMET may be increased to the maximum total daily dosage of 2,000 mg (1,000 mg orally twice daily), with gradual escalation to reduce the risk of gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1)]. INVOKAMET XR The dosage of canagliflozin in INVOKAMET XR may be increased to the maximum total daily dosage of 300 mg orally once daily in patients tolerating a 100 mg once daily dosage of canagliflozin. The dosage of metformin HCl in INVOKAMET XR may be increased to the maximum total daily dosage of 2,000 mg once daily, with gradual escalation to reduce the risk of gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1)]. Reference ID: 5499136 5 2.3 Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment  Initiation of INVOKAMET or INVOKAMET XR is not recommended in adults or pediatric patients aged 10 years and older with an eGFR less than 45 mL/min/1.73 m2, due to the metformin component.  Table 2 provides dosage recommendations for adults and pediatric patients aged 10 years and older with renal impairment, based on eGFR [see Use in Specific Populations (8.6) and Clinical Studies (14.4)]. Table 2: Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment Estimated Glomerular Filtration Rate Recommended Dosage of INVOKAMET or INVOKAMET XR* [eGFR (mL/min/1.73 m2)] eGFR 45 to less than 60 The maximum total daily dosage of canagliflozin is 100 mg. eGFR 30 to less than 45 Assess the benefit risk of continuing INVOKAMET or INVOKAMET XR. The maximum total daily dosage of canagliflozin is 100 mg. eGFR less than 30 Contraindicated. If eGFR falls below 30 during treatment; discontinue INVOKAMET or INVOKAMET XR [see Contraindications (4)]. * For the dosing frequency of INVOKAMET and INVOKAMET XR, see Dosage and Administration (2.2). 2.4 Concomitant Use with UDP-Glucuronosyltransferase (UGT) Enzyme Inducers When co-administering INVOKAMET or INVOKAMET XR with an inducer of UGT (e.g., rifampin, phenytoin, phenobarbital, ritonavir), increase the total daily dosage of canagliflozin based on renal function [see Drug Interactions (7)]:  In patients with eGFR 60 mL/min/1.73 m2 or greater, increase the total daily dosage of canagliflozin to 200 mg in patients currently tolerating a total daily dosage of canagliflozin 100 mg. The maximum total daily dosage of canagliflozin is 300 mg.  In patients with eGFR less than 60 mL/min/1.73 m2, increase the total daily dosage of canagliflozin to a maximum of 200 mg in patients currently tolerating a total daily dosage of canagliflozin 100 mg. 2.5 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue INVOKAMET or INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of less than 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart INVOKAMET or INVOKAMET XR if renal function is stable [see Warnings and Precautions (5.1)]. Reference ID: 5499136 6 2.6 Temporary Interruption for Surgery Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume INVOKAMET or INVOKAMET XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)]. 3 DOSAGE FORMS AND STRENGTHS INVOKAMET (canagliflozin and metformin HCl) tablets are available as follows: Canagliflozin Strength Metformin HCl Strength Color/Shape Tablet Identifiers* 50 mg 500 mg white/capsule-shaped CM 155 50 mg 1,000 mg beige/capsule-shaped CM 551 150 mg 500 mg yellow/capsule-shaped CM 215 150 mg 1,000 mg purple/capsule-shaped CM 611 * Embossing appears on both sides of tablet. INVOKAMET XR (canagliflozin and metformin HCl) extended-release tablets are available as follows: Canagliflozin Strength Metformin HCl Strength Color/Shape Tablet Identifiers* 50 mg 500 mg almost white to light orange/oblong, biconvex CM1 50 mg 1,000 mg pink/oblong, biconvex CM3 150 mg 500 mg orange/oblong, biconvex CM2 150 mg 1,000 mg reddish brown/oblong, biconvex CM4 * Embossing appears on one side only of tablet. 4 CONTRAINDICATIONS INVOKAMET or INVOKAMET XR is contraindicated in patients with:  Severe renal impairment (eGFR less than 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].  Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.2)].  Serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema [see Warnings and Precautions (5.9) and Adverse Reactions (6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Lactic Acidosis There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as Reference ID: 5499136 7 malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET or INVOKAMET XR. In INVOKAMET or INVOKAMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue INVOKAMET or INVOKAMET XR and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].  Before initiating INVOKAMET or INVOKAMET XR, obtain an estimated glomerular filtration rate (eGFR).  INVOKAMET or INVOKAMET XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)].  Obtain an eGFR at least annually in all patients taking INVOKAMET or INVOKAMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. Drug Interactions: The concomitant use of INVOKAMET or INVOKAMET XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase Reference ID: 5499136 8 metformin accumulation (e.g. cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients. Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)]. Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop INVOKAMET or INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart INVOKAMET or INVOKAMET XR if renal function is stable. Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. INVOKAMET or INVOKAMET XR should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur, discontinue INVOKAMET or INVOKAMET XR. Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving INVOKAMET or INVOKAMET XR. Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of INVOKAMET or INVOKAMET XR in patients with clinical or laboratory evidence of hepatic disease. 5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, INVOKAMET or INVOKAMET XR significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may be greater with higher doses of Reference ID: 5499136 9 INVOKAMET or INVOKAMET XR. INVOKAMET or INVOKAMET XR is not indicated for glycemic control in patients with type 1 diabetes mellitus. Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKAMET or INVOKAMET XR. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under­ insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INVOKAMET or INVOKAMET XR [see Clinical Pharmacology (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INVOKAMET or INVOKAMET XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKAMET or INVOKAMET XR. Withhold INVOKAMET or INVOKAMET XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKAMET or INVOKAMET XR when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.7)]. Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKAMET or INVOKAMET XR and seek medical attention immediately if signs and symptoms occur. 5.3 Lower Limb Amputation An increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET or INVOKAMET XR, versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating adult patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower limb amputations was observed at both the 100 mg and Reference ID: 5499136 10 300 mg once daily dosage regimens. The amputation data for CANVAS and CANVAS-R are shown in Tables 4 and 5, respectively [see Adverse Reactions (6.1)]. Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving canagliflozin in the two trials). Some patients had multiple amputations, some involving both lower limbs. Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving INVOKAMET or INVOKAMET XR for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKAMET or INVOKAMET XR if these complications occur. 5.4 Volume Depletion Canagliflozin can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There have been post-marketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKAMET or INVOKAMET XR in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy. 5.5 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving canagliflozin. Treatment with INVOKAMET or INVOKAMET XR increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)]. 5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKAMET or INVOKAMET XR may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)]. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. Reference ID: 5499136 11 5.7 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with INVOKAMET or INVOKAMET XR presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKAMET or INVOKAMET XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control. 5.8 Genital Mycotic Infections Canagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately. 5.9 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with canagliflozin. These reactions generally occurred within hours to days after initiating canagliflozin. If hypersensitivity reactions occur, discontinue use of INVOKAMET or INVOKAMET XR; treat and monitor until signs and symptoms resolve [see Contraindications (4) and Adverse Reactions (6.1, 6.2)]. 5.10 Bone Fracture An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in adult patients using canagliflozin in the CANVAS trial [see Clinical Studies (14.3)]. Consider factors that contribute to fracture risk prior to initiating INVOKAMET or INVOKAMET XR [see Adverse Reactions (6.1)]. 5.11 Vitamin B12 Levels In metformin HCl clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin HCl or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on INVOKAMET or INVOKAMET XR and manage any abnormalities [see Adverse Reactions (6.1)]. Reference ID: 5499136 12 6 ADVERSE REACTIONS The following important adverse reactions are also discussed elsewhere in the labeling:  Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1, 5.4)]  Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [see Warnings and Precautions (5.2)]  Lower Limb Amputation [see Warnings and Precautions (5.3)]  Volume Depletion [see Warnings and Precautions (5.4)]  Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)]  Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.6)]  Necrotizing Fasciitis of the Perineum (Fournier’s gangrene) [see Warnings and Precautions (5.7)]  Genital Mycotic Infections [see Warnings and Precautions (5.8)]  Hypersensitivity Reactions [see Warnings and Precautions (5.9)]  Bone Fracture [see Warnings and Precautions (5.10)]  Vitamin B12 Deficiency [see Warnings and Precautions (5.11)] 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Canagliflozin has been evaluated in clinical trials in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Additionally, canagliflozin has been studied in clinical trials in adult patients with type 2 diabetes mellitus who also have heart failure or chronic kidney disease. The overall safety profile of canagliflozin was consistent across the studied indications. Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Placebo-Controlled Trials for Glycemic Control Canagliflozin The data in Table 3 are derived from four 26-week placebo-controlled trials where canagliflozin was used as monotherapy in one trial and as add-on therapy in three trials. These data reflect exposure of 1,667 adult patients to canagliflozin and a mean duration of exposure to Reference ID: 5499136 13 canagliflozin of 24 weeks with 1,275 patients exposed to a combination of canagliflozin and metformin HCl. Patients received canagliflozin 100 mg (N=833), canagliflozin 300 mg (N=834) or placebo (N=646) once daily. The mean daily dose of metformin HCl was 2,138 mg (SD 337.3) for the 1,275 patients in the three placebo-controlled metformin HCl add-on trials. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were White, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2). Table 3 shows common adverse reactions associated with the use of canagliflozin. These adverse reactions were not present at baseline, occurred more commonly on canagliflozin than on placebo, and occurred in at least 2% of patients treated with either canagliflozin 100 mg or canagliflozin 300 mg. Table 3: Adverse Reactions from Pool of Four 26−Week Placebo-Controlled Trials Reported in ≥ 2% of Canagliflozin-Treated Adult Patients* Adverse Reaction Placebo N=646 Canagliflozin 100 mg N=833 Canagliflozin 300 mg N=834 Urinary tract infections‡ 3.8% 5.9% 4.4% Increased urination§ 0.7% 5.1% 4.6% Thirst# 0.1% 2.8% 2.4% Constipation 0.9% 1.8% 2.4% Nausea 1.6% 2.1% 2.3% N=312 N=425 N=430 Female genital mycotic infections† 2.8% 10.6% 11.6% Vulvovaginal pruritus 0.0% 1.6% 3.2% N=334 N=408 N=404 Male genital mycotic infections¶ 0.7% 4.2% 3.8% * The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin HCl, metformin HCl and sulfonylurea, or metformin HCl and pioglitazone. † Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. ‡ Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. § Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. ¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. # Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. Note: Percentages were weighted by trials. Trial weights were proportional to the harmonic mean of the three treatment sample sizes. Abdominal pain was also more commonly reported in patients taking canagliflozin 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Canagliflozin and Metformin HCl The incidence and type of adverse reactions in the three 26-week placebo-controlled metformin HCl tablets add-on trials in adults, representing a majority of data from the four 26-week placebo-controlled trials, was similar to the adverse reactions described in Table 3. There were no additional adverse reactions identified in the pooling of these three Reference ID: 5499136 14 placebo-controlled trials that included metformin HCl tablets relative to the four placebo-controlled trials. In a trial in adults with canagliflozin as initial combination therapy with metformin HCl [see Clinical Studies (14.1)], an increased incidence of diarrhea was observed in the canagliflozin and metformin HCl combination groups (4.2%) compared to canagliflozin or metformin HCl monotherapy groups (1.7%). Placebo-Controlled Trial in Diabetic Nephropathy The occurrence of adverse reactions for canagliflozin was evaluated in patients participating in CREDENCE, a trial in adult patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria ˃ 300 mg/day [see Clinical Studies (14.4)]. These data reflect exposure of 2,201 adult patients to canagliflozin and a mean duration of exposure to canagliflozin of 137 weeks. The rate of lower limb amputations associated with the use of canagliflozin 100 mg relative to placebo was 12.3 vs 11.2 events per 1,000 patient-years, respectively, with 2.6 years mean duration of follow-up. The incidence of hypotension was 2.8% and 1.5% on canagliflozin 100 mg and placebo, respectively. Pool of Placebo- and Active-Controlled Trials for Glycemic Control and Cardiovascular Outcomes The occurrence of adverse reactions for canagliflozin was evaluated in adult patients participating in placebo- and active-controlled trials and in an integrated analysis of two cardiovascular trials, CANVAS and CANVAS-R. The types and frequency of common adverse reactions observed in the pool of eight clinical trials (which reflect an exposure of 6,177 adult patients to canagliflozin) were consistent with those listed in Table 3. Percentages were weighted by trials. Trial weights were proportional to the harmonic mean of the three treatment sample sizes. In this pool, canagliflozin was also associated with the adverse reactions of fatigue (1.8%, 2.2%, and 2.0% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively) and loss of strength or energy (i.e., asthenia) (0.6%, 0.7%, and 1.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively). In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.1%, 0.2%, and 0.1% receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) was 3.0%, 3.8%, and 4.2% of adult patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Five patients Reference ID: 5499136 15 experienced serious adverse reactions of hypersensitivity with canagliflozin, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to canagliflozin. Among these patients, 2 patients discontinued canagliflozin. One patient with urticaria had recurrence when canagliflozin was re-initiated. Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Other adverse reactions occurring more frequently on canagliflozin than on comparator were: Lower Limb Amputation An increased risk of lower limb amputations associated with canagliflozin was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating adult patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. Patients in CANVAS and CANVAS-R were followed for an average of 5.7 and 2.1 years, respectively [see Clinical Studies (14.3)]. The amputation data for CANVAS and CANVAS-R are shown in Tables 4 and 5, respectively. Table 4: Amputations in the CANVAS Trial in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Placebo N=1,441 Canagliflozin 100 mg N=1,445 Canagliflozin 300 mg N=1,441 Canagliflozin (Pooled) N=2,886 Patients with an amputation, n (%) 22 (1.5) 50 (3.5) 45 (3.1) 95 (3.3) Total amputations 33 83 79 162 Amputation incidence rate (per 1,000 patient-years) 2.8 6.2 5.5 5.9 Hazard Ratio (95% CI) -­ 2.24 (1.36, 3.69) 2.01 (1.20, 3.34) 2.12 (1.34, 3.38) Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. Table 5: Amputations in the CANVAS-R Trial in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Placebo N=2,903 Canagliflozin 100 mg (with up-titration to 300 mg) N=2,904 Patients with an amputation, n (%) 25 (0.9) 45 (1.5) Total amputations 36 59 Amputation incidence rate (per 1,000 patient-years) 4.2 7.5 Hazard Ratio (95% CI) -­ 1.80 (1.10, 2.93) Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. Reference ID: 5499136 16 Renal Cell Carcinoma In the CANVAS trial in adults (mean duration of follow-up of 5.7 years) [see Clinical Studies (14.3)], the incidence of renal cell carcinoma was 0.15% (2/1,331) and 0.29% (8/2,716) for placebo and canagliflozin, respectively, excluding patients with less than 6 months of follow­ up, less than 90 days of treatment, or a history of renal cell carcinoma. A causal relationship to canagliflozin could not be established due to the limited number of cases. Volume Depletion-Related Adverse Reactions Canagliflozin results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical trials for glycemic control, treatment with canagliflozin was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in adult patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions in these trials were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and age 75 years and older (Table 6) [see Use in Specific Populations (8.5 and 8.6)]. Table 6: Adult Patients with at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials for Glycemic Control) Baseline Characteristic Comparator Group* % Canagliflozin 100 mg % Canagliflozin 300 mg % Overall population 1.5% 2.3% 3.4% 75 years of age and older† 2.6% 4.9% 8.7% eGFR less than 60 mL/min/1.73 m2† 2.5% 4.7% 8.1% Use of loop diuretic† 4.7% 3.2% 8.8% * Includes placebo and active-comparator groups † Patients could have more than 1 of the listed risk factors Falls In a pool of nine clinical trials in adults with mean duration of exposure to canagliflozin of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The higher risk of falls for patients treated with canagliflozin was observed within the first few weeks of treatment. Genital Mycotic Infections In the pool of four placebo-controlled clinical trials in adults for glycemic control, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 2.8%, 10.6%, and 11.6% of females treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on canagliflozin. Female patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrence and require treatment with oral or topical antifungal agents and Reference ID: 5499136 17 anti-microbial agents. In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and canagliflozin, respectively. In the pool of four placebo-controlled clinical trials in adults, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.7%, 4.2%, and 3.8% of males treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrent infections (22% on canagliflozin versus none on placebo) and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and canagliflozin, respectively. In the pooled analysis of 8 randomized trials in adults evaluating glycemic control, phimosis was reported in 0.3% of uncircumcised male patients treated with canagliflozin and 0.2% required circumcision to treat the phimosis. Hypoglycemia In canagliflozin glycemic control trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials of glycemic control in adults [see Clinical Studies (14.1)], episodes of hypoglycemia occurred at a higher rate when canagliflozin was co- administered with insulin or sulfonylureas (Table 7). Table 7: Incidence of Hypoglycemia* in Randomized Clinical Trials of Glycemic Control in Adults Monotherapy (26 weeks) Placebo (N=192) Canagliflozin 100 mg (N=195) Canagliflozin 300 mg (N=197) Overall [N (%)] 5 (2.6) 7 (3.6) 6 (3.0) In Combination with Metformin HCl (26 weeks) Placebo + Metformin HCl (N=183) Canagliflozin 100 mg + Metformin HCl (N=368) Canagliflozin 300 mg + Metformin HCl (N=367) Overall [N (%)] 3 (1.6) 16 (4.3) 17 (4.6) Severe [N (%)]† 0 (0) 1 (0.3) 1 (0.3) In Combination with Metformin HCl (18 weeks)‡ Placebo (N=93) Canagliflozin 100 mg (N=93) Canagliflozin 300 mg (N=93) Overall [N (%)] 3 (3.2) 4 (4.3) 3 (3.2) In Combination with Metformin HCl + Sulfonylurea (26 weeks) Placebo + Metformin HCl + Sulfonylurea (N=156) Canagliflozin 100 mg + Metformin HCl + Sulfonylurea (N=157) Canagliflozin 300 mg + Metformin HCl + Sulfonylurea (N=156) Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1) Reference ID: 5499136 18 Severe [N (%)]† 1 (0.6) 1 (0.6) 0 In Combination with Metformin HCl + Pioglitazone (26 weeks) Placebo + Metformin HCl + Pioglitazone (N=115) Canagliflozin 100 mg + Metformin HCl + Pioglitazone (N=113) Canagliflozin 300 mg + Metformin HCl + Pioglitazone (N=114) Overall [N (%)] 3 (2.6) 3 (2.7) 6 (5.3) In Combination with Insulin (18 weeks) Placebo (N=565) Canagliflozin 100 mg (N=566) Canagliflozin 300 mg (N=587) Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6) Severe [N (%)]† 14 (2.5) 10 (1.8) 16 (2.7) In Combination with Insulin and Metformin HCl (18 weeks)§ Placebo (N=145) Canagliflozin 100 mg (N=139) Canagliflozin 300 mg (N=148) Overall [N (%)] 66 (45.5) 58 (41.7) 70 (47.3) Severe [N (%)]† 4 (2.8) 1 (0.7) 3 (2.0) * Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population † Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) ‡ Phase 2 clinical trial with twice daily dosing (50 mg or 150 mg twice daily in combination with metformin HCl) § Subgroup of patients (N=287) from insulin subtrial on canagliflozin in combination with metformin HCl and insulin (with or without other antiglycemic agents) Bone Fracture In the CANVAS trial in adults [see Clinical Studies (14.3)], the incidence rates of all adjudicated bone fracture were 1.09, 1.59, and 1.79 events per 100 patient-years of follow-up to placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The fracture imbalance was observed within the first 26 weeks of therapy and remained through the end of the trial. Fractures were more likely to be low trauma (e.g., fall from no more than standing height), and affect the distal portion of upper and lower extremities. Metformin HCl The most common adverse reactions (5% or greater incidence) due to initiation of metformin HCl in adults are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of adult patients. Laboratory and Imaging Tests Increases in Serum Creatinine and Decreases in eGFR Initiation of canagliflozin causes an increase in serum creatinine and decrease in estimated GFR. In patients with moderate renal impairment, the increase in serum creatinine generally does not exceed 0.2 mg/dL, occurs within the first 6 weeks of starting therapy, and then stabilizes. Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Clinical Pharmacology (12.1)]. The acute effect on eGFR reverses after Reference ID: 5499136 19 treatment discontinuation suggesting acute hemodynamic changes may play a role in the renal function changes observed with canagliflozin. Increases in Serum Potassium In a pooled population of adult patients (N=723) in glycemic control trials with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 m2), increases in serum potassium to greater than 5.4 mEq/L and 15% above occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with canagliflozin 100 mg, and 1.3% of patients treated with canagliflozin 300 mg. In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Use in Specific Populations (8.6)]. In CREDENCE, no difference in serum potassium, no increase in adverse events of hyperkalemia, and no increase in absolute (> 6.5 mEq/L) or relative (> upper limit of normal and > 15% increase from baseline) increases in serum potassium were observed in adult patients treated with canagliflozin 100 mg relative to placebo. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C) In the pool of four glycemic control placebo-controlled trials in adults, dose-related increases in LDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with canagliflozin 100 mg and canagliflozin 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups. Dose-related increases in non-HDL-C with canagliflozin were observed in adults. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with canagliflozin 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups. Increases in Hemoglobin In the pool of four placebo-controlled trials in adults of glycemic control, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with canagliflozin 100 mg, and 0.51 g/dL (3.8%) with canagliflozin 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively, had hemoglobin above the upper limit of normal. Reference ID: 5499136 20 Decreases in Bone Mineral Density Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years) [see Clinical Studies (14.1)]. At 2 years, adult patients randomized to canagliflozin 100 mg and canagliflozin 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both canagliflozin doses and 0.4% at the distal forearm for patients randomized to canagliflozin 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to canagliflozin 100 mg was 0%. Clinical Trials in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus Canagliflozin Canagliflozin was administered to 84 pediatric patients in a double-blind, placebo-controlled trial of 171 pediatric patients aged 10 to 17 years with a mean exposure to canagliflozin of 48.3 weeks [see Clinical Studies (14.2)]. At baseline, background therapies included metformin monotherapy (46%), metformin and insulin (29%), diet and exercise only (14%), and insulin monotherapy (11%). Approximately 42% were Asian, 42% were White, 11% were Black or African American, 5% were American Indian/Alaska Native, and 36% identified as Hispanic or Latino ethnicity. The mean baseline eGFR was 157.3 mL/min/1.73 m2, and approximately 16% (24/151) of the trial population with measurements had microalbuminuria or macroalbuminuria. The safety profile of pediatric patients treated with canagliflozin was similar to that observed in adults with type 2 diabetes mellitus. Metformin HCl In clinical trials with metformin HCl immediate-release tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of canagliflozin and/or metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Canagliflozin Metabolism and Nutrition Ketoacidosis Renal and Urinary Acute Kidney Injury Reference ID: 5499136 21 Immune System Anaphylaxis Skin and Subcutaneous Tissue Angioedema Infections Urosepsis and Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s gangrene) Metformin HCl Hepatobiliary Cholestatic, hepatocellular, and mixed hepatocellular liver injury 7 DRUG INTERACTIONS Table 8: Clinically Significant Drug Interactions with INVOKAMET or INVOKAMET XR Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET or INVOKAMET XR may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) Drugs That Reduce Metformin Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)]. Intervention: Consider the benefits and risks of concomitant use. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving INVOKAMET or INVOKAMET XR. UGT Enzyme Inducers Clinical Impact: UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKAMET or INVOKAMET XR. Intervention: For patients with eGFR 60 mL/min/1.73 m2 or greater, if an inducer of UGTs is co-administered with INVOKAMET or INVOKAMET XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating INVOKAMET or INVOKAMET XR with a total daily dose of canagliflozin 100 mg. The total daily dose of canagliflozin may be increased to 300 mg in patients currently tolerating canagliflozin 200 mg and who require additional glycemic control. For patients with eGFR less than 60 mL/min/1.73 m2, if an inducer of UGTs is co-administered with INVOKAMET or INVOKAMET XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating canagliflozin 100 mg [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. Examples: Rifampin, phenytoin, phenobarbital, ritonavir Reference ID: 5499136 22 Insulin or Insulin Secretagogues Clinical Impact: The risk of hypoglycemia is increased when INVOKAMET or INVOKAMET XR is used concomitantly with insulin secretagogues (e.g., sulfonylurea) or insulin. Intervention: Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: When such drugs are administered to a patient receiving INVOKAMET or INVOKAMET XR, monitor for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET or INVOKAMET XR, monitor for hypoglycemia. Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. Digoxin Clinical Impact: Canagliflozin increases digoxin exposure [see Clinical Pharmacology (12.3)]. Intervention: Monitor patients taking INVOKAMET or INVOKAMET XR with concomitant digoxin for a need to adjust the dosage of digoxin. Lithium Clinical Impact: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention: Monitor serum lithium concentration more frequently during INVOKAMET or INVOKAMET XR initiation and dosage changes. Drug/Laboratory Test Interference Positive Urine Glucose Test Clinical Impact: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. Intervention: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention: Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on juvenile animal data showing adverse renal effects from canagliflozin, INVOKAMET or INVOKAMET XR is not recommended during the second and third trimesters of pregnancy. Limited data with INVOKAMET, INVOKAMET XR or canagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin HCl use during pregnancy have not reported a clear association with metformin HCl and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. In juvenile animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered during a period of renal development Reference ID: 5499136 23 corresponding to the late second and third trimesters of human pregnancy, at an exposure 0.5­ times the 300 mg clinical dose, based on AUC. No adverse developmental effects were observed when metformin HCl was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 6-times, respectively, a 2,000 mg clinical dose, based on body surface area [see Data]. The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1C >7 and has been reported to be as high as 20-25% in women with a HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre­ eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin HCl and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin HCl was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Canagliflozin Canagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg increased kidney weights and dose dependently increased the incidence and severity of renal pelvic and tubular dilatation at all doses tested. Exposure at the lowest dose was greater than or equal to 0.5-times the 300 mg clinical dose, based on AUC. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. The renal pelvic dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period. In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities independent of maternal toxicity were observed when canagliflozin was administered at doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits during embryonic organogenesis or during a study in which maternal rats were dosed from gestation day Reference ID: 5499136 24 (GD) 6 through PND 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on AUC. Metformin HCl Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2,000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively. Canagliflozin and Metformin HCl No adverse developmental effects were observed when canagliflozin and metformin HCl were co-administered to pregnant rats during the period of organogenesis at exposures up to 11 and 13 times, respectively, the 300 mg and 2,000 mg clinical doses of canagliflozin and metformin HCl based on AUC. 8.2 Lactation Risk Summary There is no information regarding the presence of INVOKAMET, INVOKAMET XR or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information on the effects of metformin HCl on the breastfed infant and no available information on the effects of metformin HCl on milk production. Canagliflozin is present in the milk of lactating rats [see Data]. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of INVOKAMET or INVOKAMET XR is not recommended while breastfeeding. Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin HCl during lactation because of small sample size and limited adverse event data collected in infants. Radiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Reference ID: 5499136 25 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women. 8.4 Pediatric Use The safety and effectiveness of INVOKAMET and INVOKAMET XR as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of INVOKAMET and INVOKAMET XR for this indication is supported by evidence from a 52-week double-blind, placebo-controlled trial of canagliflozin in 171 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus and in a pediatric pharmacokinetic study [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. The safety profile of pediatric patients treated with canagliflozin was similar to that observed in adults with type 2 diabetes mellitus. The use of INVOKAMET and INVOKAMET XR for this indication is also supported by evidence from adequate and well-controlled trials of metformin HCl immediate-release tablets in adults with additional data from a controlled clinical trial using metformin HCl immediate- release tablets in pediatric patients 10 to 16 years old with type 2 diabetes mellitus, and pharmacokinetic data with metformin HCl extended-release tablets in adults [see Clinical Pharmacology (12.3) and Clinical Studies (14.1, 14.2)]. In the clinical trial with pediatric patients receiving metformin HCl immediate-release tablets, adverse reactions with metformin HCl immediate-release tablets were similar to those described in adults [see Adverse Reactions (6.1)]. The safety and effectiveness of INVOKAMET or INVOKAMET XR for glycemic control in patients with type 2 diabetes mellitus have not been established in pediatric patients under 10 years of age. The safety and effectiveness of INVOKAMET or INVOKAMET XR have not been established in pediatric patients to reduce the risk of:  major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in patients with type 2 diabetes mellitus and established cardiovascular disease (CVD).  end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day. Reference ID: 5499136 26 8.5 Geriatric Use INVOKAMET and INVOKAMET XR Because renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, monitor renal function more frequently after initiating INVOKAMET or INVOKAMET XR in the elderly and then adjust dose based on renal function [see Dosage and Administration (2.4) and Warnings and Precautions (5.1, 5.4)]. Canagliflozin In 13 clinical trials of canagliflozin, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to canagliflozin. Of these patients, 1,534 patients 65 years and older and 196 patients 75 years and older were exposed to the combination of canagliflozin and metformin HCl [see Clinical Studies (14.1)]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with canagliflozin (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) and Adverse Reactions (6.1)]. Smaller reductions in HbA1C with canagliflozin relative to placebo were seen in older (65 years and older; -0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg relative to placebo) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg relative to placebo). Metformin HCl Controlled clinical trials of metformin HCl did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. The initial and maintenance dosing of metformin HCl should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications (4), Warnings and Precautions (5.4), and Clinical Pharmacology (12.3)]. 8.6 Renal Impairment Canagliflozin The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included adult patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2). These patients had less overall glycemic efficacy, and patients treated with canagliflozin 300 mg per day had increases in serum potassium, which were transient and similar by the end of the trial. Patients with renal impairment using canagliflozin for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury [see Warnings and Precautions (5.4)]. Reference ID: 5499136 27 Efficacy and safety trials with canagliflozin did not enroll adult patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2 [see Clinical Pharmacology (12.3)]. Metformin HCl Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. INVOKAMET or INVOKAMET XR is contraindicated in severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or in patients on dialysis [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Use of metformin HCl in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET or INVOKAMET XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)]. 10 OVERDOSAGE Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl use has been established. Lactic acidosis has been reported in approximately 32% of metformin HCl overdose cases [see Warnings and Precautions (5.1)]. In the event of an overdose with INVOKAMET or INVOKAMET XR, contact the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom INVOKAMET or INVOKAMET XR overdosage is suspected. 11 DESCRIPTION INVOKAMET® (canagliflozin and metformin HCl immediate-release tablets) and INVOKAMET® XR (canagliflozin and metformin HCl extended-release tablets) contain canagliflozin and metformin HCl. Canagliflozin Canagliflozin is an inhibitor of SGLT2, the transporter responsible for reabsorbing the majority of glucose filtered by the kidney. Canagliflozin is chemically known as (1S)-1,5-anhydro-1-[3­ [[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate and its molecular formula and weight are C24H25FO5S1/2 H2O and 453.53, respectively. The structural formula for canagliflozin is: Reference ID: 5499136 28 F OH OH Canagliflozin is practically insoluble in aqueous media from pH 1.1 to 12.9. Metformin HCl Metformin HCl is a biguanide chemically known as 1,1-Dimethylbiguanide HCl and its molecular formula and weight are C4H11N5 ● HCl and 165.62, respectively. The structural formula for metformin HCl is: NH NH H2N NH N CH3 HCl CH3 INVOKAMET and INVOKAMET XR INVOKAMET or INVOKAMET XR are supplied as film-coated tablets for oral administration. Each 50 mg/500 mg tablet and 50 mg/1,000 mg tablet contains 51 mg of canagliflozin equivalent to 50 mg canagliflozin (anhydrous) and 500 mg or 1,000 mg metformin HCl (equivalent to metformin 389.93 mg and 779.86 mg, respectively). Each 150 mg/500 mg tablet and 150 mg/1,000 mg tablet contains 153 mg of canagliflozin equivalent to 150 mg canagliflozin (anhydrous) and 500 mg or 1,000 mg metformin HCl (equivalent to metformin 389.93 mg and 779.86 mg, respectively). INVOKAMET contains the following inactive ingredients: croscarmellose sodium (E468), hypromellose, magnesium stearate (E572), and microcrystalline cellulose (E460[i]). The magnesium stearate is vegetable-sourced. The tablets are finished with a commercially available film-coating consisting of the following inactive ingredients: macrogol/PEG3350 (E1521), polyvinyl alcohol (E1203) (partially hydrolyzed), talc (E553b), titanium dioxide (E171), iron oxide yellow (E172) (50 mg/1,000 mg and 150 mg/500 mg tablets only), iron oxide red (E172) Reference ID: 5499136 29 (50 mg/1,000 mg, 150 mg/500 mg and 150 mg/1,000 mg tablets only), and iron oxide black (E172) (150 mg/1,000 mg tablets only). INVOKAMET XR contains the following inactive ingredients: croscarmellose sodium (E468), hydroxypropyl cellulose (E463), hypromellose, lactose anhydrous, magnesium stearate (E572) (vegetable-sourced), microcrystalline cellulose (E460[i]), polyethylene oxide, and silicified microcrystalline cellulose (50 mg/500 mg and 50 mg/1,000 mg tablets only). The tablets are finished with a commercially available film-coating consisting of the following inactive ingredients: macrogol/PEG3350 (E1521), polyvinyl alcohol (E1203) (partially hydrolyzed), talc (E553b), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172), and iron oxide black (E172) (50 mg/1,000 mg and 150 mg/1,000 mg tablets only). INVOKAMET XR tablets provide canagliflozin for immediate-release and metformin HCl for extended-release. Each bilayer tablet is compressed from two separate granulates, one for each active ingredient of the tablet, and finished with a film-coating. The metformin HCl extended-release layer is based on a polymer matrix which controls the drug release by passive diffusion through the swollen matrix in combination with tablet erosion. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Canagliflozin SGLT2, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE). Canagliflozin increases the delivery of sodium to the distal tubule by blocking SGLT2-dependent glucose and sodium reabsorption. This is believed to increase tubuloglomerular feedback and reduce intraglomerular pressure. Metformin HCl Metformin HCl is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease. 12.2 Pharmacodynamics Canagliflozin Following single and multiple oral doses of canagliflozin in adult patients with type 2 diabetes, dose-dependent decreases in RTG and increases in urinary glucose excretion were observed. From a starting RTG value of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg Reference ID: 5499136 30 once daily suppressed RTG throughout the 24-hour period. Data from single oral doses of canagliflozin in healthy volunteers indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for doses up to 300 mg once daily. Maximal suppression of mean RTG over the 24-hour period was seen with the 300 mg daily dose to approximately 70 to 90 mg/dL in patients with type 2 diabetes in Phase 1 trials. The reductions in RTG led to increases in mean UGE of approximately 100 g/day in patients with type 2 diabetes treated with either 100 mg or 300 mg of canagliflozin. The 24-h mean RTG at steady state was similar following once daily and twice daily dosing regimens at the same total daily dose of 100 mg or 300 mg. In patients with type 2 diabetes given 100 to 300 mg once daily over a 16-day dosing period, reductions in RTG and increases in urinary glucose excretion were observed over the dosing period. In this trial, plasma glucose declined in a dose-dependent fashion within the first day of dosing. Cardiac Electrophysiology In a randomized, double-blind, placebo-controlled, active-comparator, 4-way crossover trial, 60 healthy adult subjects were administered a single oral dose of canagliflozin 300 mg, canagliflozin 1,200 mg (4 times the maximum recommended dose), moxifloxacin, and placebo. No meaningful changes in QTc interval were observed with either the recommended dose of 300 mg or the 1,200 mg dose. 12.3 Pharmacokinetics INVOKAMET Administration of INVOKAMET 150 mg/1,000 mg fixed-dose combination with food resulted in no change in overall exposure of canagliflozin. There was no change in metformin AUC; however, the mean peak plasma concentration of metformin was decreased by 16% when administered with food. A delayed time to peak plasma concentration was observed for both components (a delay of 2 hours for canagliflozin and 1 hour for metformin) under fed conditions. These changes are not likely to be clinically meaningful. INVOKAMET XR After administration of INVOKAMET XR tablets with a high-fat breakfast, the peak (Cmax) and total (AUC) exposure of canagliflozin were not altered relative to dosing in the fasted state. However, the AUC of metformin increased by approximately 61% and Cmax increased by approximately 13%. Canagliflozin The pharmacokinetics of canagliflozin is essentially similar in healthy subjects and patients with type 2 diabetes. Following single-dose oral administration of 100 mg and 300 mg of canagliflozin, peak plasma concentrations (median Tmax) of canagliflozin occurs within 1 to 2 hours post-dose. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. The apparent terminal half-life (t1/2) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after 4 to Reference ID: 5499136 31 5 days of once-daily dosing with canagliflozin 100 mg to 300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics and accumulated in plasma up to 36% following multiple doses of 100 mg and 300 mg. The mean systemic exposure (AUC) at steady state was similar following once daily and twice daily dosing regimens at the same total daily dose of 100 mg or 300 mg. Absorption Canagliflozin The mean absolute oral bioavailability of canagliflozin is approximately 65%. Metformin HCl The absolute bioavailability of a metformin HCl 500 mg tablet given under fasting conditions is approximately 50% to 60%. Trials using single oral doses of metformin HCl 500 to 1,500 mg, and 850 to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Following a single oral dose of 1,000 mg metformin HCl extended-release tablets (two 500 mg tablets) after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7-8 hours. In both single and multiple-dose trials in healthy subjects, once daily 1,000 mg (two 500 mg tablets) dosing results in up to 35% higher Cmax, of metformin relative to the immediate-release given as 500 mg twice daily without any change in overall systemic exposure, as measured by AUC. Distribution Canagliflozin The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 83.5 L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. Metformin HCl The apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl 850 mg immediate-release tablets averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. Metabolism Canagliflozin O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4­ mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans. Reference ID: 5499136 32 Metformin HCl Intravenous single-dose trials in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Excretion Canagliflozin Following administration of a single oral [14C] canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible. Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O­ glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min. Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration. Metformin HCl Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Specific Populations Trials characterizing the pharmacokinetics of canagliflozin and metformin after administration of INVOKAMET or INVOKAMET XR were not conducted in patients with renal and hepatic impairment. Descriptions of the individual components in this patient population are described below. Pediatric Patients Canagliflozin The pharmacokinetics and pharmacodynamics of canagliflozin were investigated in pediatric patients aged 10 years and older with type 2 diabetes mellitus. Oral administration of canagliflozin at 100 mg and 300 mg resulted in exposures and responses consistent with those found in adult patients. Reference ID: 5499136 33 Metformin HCl After administration of a single oral metformin 500 mg immediate-release tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12-16 years of age) and gender-and weight-matched healthy adults (20­ 45 years of age), all with normal renal function. Patients with Renal Impairment Canagliflozin A single-dose, open-label trial evaluated the pharmacokinetics of canagliflozin 200 mg in adult subjects with varying degrees of renal impairment (classified using the MDRD-eGFR formula) compared to healthy subjects. Renal impairment did not affect the Cmax of canagliflozin. Compared to healthy adult subjects (N=3; eGFR greater than or equal to 90 mL/min/1.73 m2), plasma AUC of canagliflozin was increased by approximately 15%, 29%, and 53% in subjects with mild (N=10), moderate (N=9), and severe (N=10) renal impairment, respectively, (eGFR 60 to less than 90, 30 to less than 60, and 15 to less than 30 mL/min/1.73 m2, respectively), but was similar for ESKD (N=8) subjects and healthy subjects. Increases in canagliflozin AUC of this magnitude are not considered clinically relevant. The glucose lowering pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment [see Contraindications (4) and Warnings and Precautions (5.4)]. Canagliflozin was negligibly removed by hemodialysis. Metformin HCl In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (4) and Warnings and Precautions (5.1)]. Following a single dose administration of metformin HCl extended-release tablets 500 mg in patients with mild and moderate renal failure (based on measured creatinine clearance), the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively [see Warnings and Precautions (5.4)]. Metformin peak and systemic exposure was 27% and 61% greater, respectively in mild renal impaired and 74% and 2.36-fold greater in moderate renal impaired patients as compared to healthy subjects [see Contraindications (4) and Warnings and Precautions (5.1)]. Patients with Hepatic Impairment Canagliflozin Relative to adult subjects with normal hepatic function, the geometric mean ratios for Cmax and AUC∞ of canagliflozin were 107% and 110%, respectively, in subjects with Child-Pugh class A (mild hepatic impairment) and 96% and 111%, respectively, in subjects with Child-Pugh class B Reference ID: 5499136 34 (moderate hepatic impairment) following administration of a single 300 mg dose of canagliflozin. These differences are not considered to be clinically meaningful. There is no clinical experience in adult patients with Child-Pugh class C (severe) hepatic impairment [see Warnings and Precautions (5.1)]. Metformin HCl No pharmacokinetic trials of metformin HCl tablets have been conducted in patients with hepatic insufficiency [see Warnings and Precautions (5.1)]. Pharmacokinetic Effects of Age, Body Mass Index (BMI)/Weight, Gender and Race Canagliflozin Based on the population PK analysis with data collected from 1,526 adult subjects, age, body mass index (BMI)/weight, gender, and race do not have a clinically meaningful effect on the pharmacokinetics of canagliflozin [see Use in Specific Populations (8.5)]. Metformin HCl Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender. No trials of metformin pharmacokinetic parameters according to race have been performed. Canagliflozin Age had no clinically meaningful effect on the pharmacokinetics of canagliflozin based on a population pharmacokinetic analysis [see Adverse Reactions (6.1) and Use in Specific Populations (8.5)]. Metformin HCl Limited data from controlled pharmacokinetic trials of metformin HCl tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared with healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function [see Warnings and Precautions (5.1, 5.4) and Use in Specific Populations (8.5)]. Drug Interaction Studies INVOKAMET and INVOKAMET XR Pharmacokinetic drug interaction trials with INVOKAMET or INVOKAMET XR have not been performed; however, such trials have been conducted with the individual components canagliflozin and metformin HCl. Reference ID: 5499136 35 I I Co-administration of multiple doses of canagliflozin (300 mg) and metformin HCl (2,000 mg) given once daily did not meaningfully alter the pharmacokinetics of either canagliflozin or metformin in healthy subjects. Canagliflozin In Vitro Assessment of Drug Interactions Canagliflozin did not induce CYP450 enzyme expression (3A4, 2C9, 2C19, 2B6, and 1A2) in cultured human hepatocytes. Canagliflozin did not inhibit the CYP450 isoenzymes (1A2, 2A6, 2C19, 2D6, or 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes. Canagliflozin is a weak inhibitor of P-gp. Canagliflozin is also a substrate of drug transporters P-glycoprotein (P-gp) and MRP2. In Vivo Assessment of Drug Interactions Table 9: Effect of Co−Administered Drugs on Systemic Exposures of Canagliflozin Co-Administered Drug Dose of Co-Administered Drug* Dose of Canagliflozin* Geometric Mean Ratio (Ratio With/Without Co-Administered Drug) No Effect = 1.0 AUC† (90% CI) Cmax (90% CI) See Drug Interactions (7) for the clinical relevance of the following: Rifampin 600 mg QD for 8 days 300 mg 0.49 (0.44; 0.54) 0.72 (0.61; 0.84) No dose adjustments of canagliflozin required for the following: Cyclosporine 400 mg 300 mg QD for 8 days 1.23 (1.19; 1.27) 1.01 (0.91; 1.11) Ethinyl estradiol and levonorgestrel 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel 200 mg QD for 6 days 0.91 (0.88; 0.94) 0.92 (0.84; 0.99) Hydrochlorothiazide 25 mg QD for 35 days 300 mg QD for 7 days 1.12 (1.08; 1.17) 1.15 (1.06; 1.25) Metformin HCl 2,000 mg 300 mg QD for 8 days 1.10 (1.05; 1.15) 1.05 (0.96; 1.16) Probenecid 500 mg BID for 3 days 300 mg QD for 17 days 1.21 (1.16; 1.25) 1.13 (1.00; 1.28) * Single dose unless otherwise noted † AUCinf for drugs given as a single dose and AUC24h for drugs given as multiple doses QD = once daily; BID = twice daily Table 10: Effect of Canagliflozin on Systemic Exposure of Co-Administered Drugs Co-Administered Drug Dose of Co-Administered Drug* Dose of Canagliflozin* Geometric Mean Ratio (Ratio With/Without Co-Administered Drug) No Effect = 1.0 AUC† (90% CI) Cmax (90% CI) See Drug Interactions (7) for the clinical relevance of the following: Reference ID: 5499136 36 Digoxin 0.5 mg QD first day followed by 0.25 mg QD for 6 days 300 mg QD for 7 days Digoxin 1.20 (1.12; 1.28) 1.36 (1.21; 1.53) No dose adjustments of co-administered drug required for the following: Acetaminophen 1,000 mg 300 mg BID for 25 days Acetaminophen 1.06‡ (0.98; 1.14) 1.00 (0.92; 1.09) Ethinyl estradiol and levonorgestrel 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel 200 mg QD for 6 days ethinyl estradiol 1.07 (0.99; 1.15) 1.22 (1.10; 1.35) Levonorgestrel 1.06 (1.00; 1.13) 1.22 (1.11; 1.35) Glyburide 1.25 mg 200 mg QD for 6 days Glyburide 1.02 (0.98; 1.07) 0.93 (0.85; 1.01) 3-cis-hydroxy­ glyburide 1.01 (0.96; 1.07) 0.99 (0.91; 1.08) 4-trans-hydroxy­ glyburide 1.03 (0.97; 1.09) 0.96 (0.88; 1.04) Hydrochlorothiazide 25 mg QD for 35 days 300 mg QD for 7 days Hydrochlorothiazide 0.99 (0.95; 1.04) 0.94 (0.87; 1.01) Metformin HCl 2,000 mg 300 mg QD for 8 days Metformin 1.20 (1.08; 1.34) 1.06 (0.93; 1.20) Simvastatin 40 mg 300 mg QD for 7 days Simvastatin 1.12 (0.94; 1.33) 1.09 (0.91; 1.31) simvastatin acid 1.18 (1.03; 1.35) 1.26 (1.10; 1.45) Warfarin 30 mg 300 mg QD for 12 days (R)-warfarin 1.01 (0.96; 1.06) 1.03 (0.94; 1.13) (S)-warfarin 1.06 (1.00; 1.12) 1.01 (0.90; 1.13) INR 1.00 (0.98; 1.03) 1.05 (0.99; 1.12) * Single dose unless otherwise noted † AUCinf for drugs given as a single dose and AUC24h for drugs given as multiple doses ‡ AUC0-12h QD = once daily; BID = twice daily; INR = International Normalized Ratio Metformin HCl Table 11: Effect of Co−Administered Drugs on Plasma Metformin Systemic Exposures Co-Administered Drug Dose of Co-Administered Drug* Dose of Metformin HCl* Geometric Mean Ratio (Ratio With/Without Co-Administered Drug) Reference ID: 5499136 37 No Effect = 1.00 AUC† Cmax No dose adjustments required for the following: Glyburide 5 mg 500 mg‡ 0.98§ 0.99§ Furosemide 40 mg 850 mg 1.09§ 1.22§ Nifedipine 10 mg 850 mg 1.16 1.21 Propranolol 40 mg 850 mg 0.90 0.94 Ibuprofen 400 mg 850 mg 1.05§ 1.07§ Drugs that are eliminated by renal tubular secretion increase the accumulation of metformin [see Warnings and Precautions (5) and Drug Interactions (7)] Cimetidine 400 mg 850 mg 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) and Drug Interactions (7)] Topiramate¶ 100 mg 500 mg 1.25# 1.18 * Single dose unless otherwise noted † AUC = AUC0-∞ ‡ Metformin HCl extended-release tablets 500 mg § Ratio of arithmetic means ¶ Healthy volunteer study at steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours for 7 days. Study conducted to assess pharmacokinetics only # Steady state AUC0-12h. Table 12: Effect of Metformin HCl on Co-Administered Drug Systemic Exposures Co-Administered Drug Dose of Co-Administered Drug* Dose of Metformin HCl* Geometric Mean Ratio (Ratio With/Without Co-Administered Drug) No Effect = 1.00 AUC† Cmax No dose adjustments required for the following: Glyburide 5 mg 500 mg‡ 0.78§ 0.63§ Furosemide 40 mg 850 mg 0.87§ 0.69§ Nifedipine 10 mg 850 mg 1.10‡ 1.08 Propranolol 40 mg 850 mg 1.01‡ 0.94 Ibuprofen 400 mg 850 mg 0.97¶ 1.01¶ Cimetidine 400 mg 850 mg 0.95‡ 1.01 * Single dose unless otherwise noted † AUC = AUC0-∞ ‡ AUC0-24 hr reported § Ratio of arithmetic means, p-value of difference <0.05 ¶ Ratio of arithmetic means. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility INVOKAMET and INVOKAMET XR No animal studies have been conducted with the combined products in INVOKAMET or INVOKAMET XR to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The Reference ID: 5499136 38 following data are based on findings in studies with canagliflozin and metformin HCl individually. Canagliflozin Carcinogenesis Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Sprague-Dawley rats. Canagliflozin did not increase the incidence of tumors in mice dosed at 10, 30, or 100 mg/kg (less than or equal to 14 times exposure from a 300 mg clinical dose). Testicular Leydig cell tumors, considered secondary to increased luteinizing hormone (LH), increased significantly in male rats at all doses tested (10, 30, and 100 mg/kg). In a 12-week clinical trial, LH did not increase in males treated with canagliflozin. Renal tubular adenoma and carcinoma increased significantly in male and female rats dosed at 100 mg/kg, or approximately 12-times exposure from a 300 mg clinical dose. Also, adrenal pheochromocytoma increased significantly in males and numerically in females dosed at 100 mg/kg. Carbohydrate malabsorption associated with high doses of canagliflozin was considered a necessary proximal event in the emergence of renal and adrenal tumors in rats. Clinical trials have not demonstrated carbohydrate malabsorption in humans at canagliflozin doses of up to 2-times the recommended clinical dose of 300 mg. Mutagenesis Canagliflozin was not mutagenic with or without metabolic activation in the Ames assay. Canagliflozin was mutagenic in the in vitro mouse lymphoma assay with but not without metabolic activation. Canagliflozin was not mutagenic or clastogenic in an in vivo oral micronucleus assay in rats and an in vivo oral Comet assay in rats. Metformin HCl Carcinogenesis Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin HCl was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin HCl in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. Mutagenesis There was no evidence of a mutagenic potential of metformin HCl in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Reference ID: 5499136 39 Impairment of Fertility Canagliflozin had no effects on the ability of rats to mate and sire or maintain a litter up to the high dose of 100 mg/kg (approximately 14 times and 18 times the 300 mg clinical dose in males and females, respectively), although there were minor alterations in a number of reproductive parameters (decreased sperm velocity, increased number of abnormal sperm, slightly fewer corpora lutea, fewer implantation sites, and smaller litter sizes) at the highest dosage administered. Fertility of male or female rats was unaffected by metformin HCl when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons. 14 CLINICAL STUDIES 14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus The effectiveness of INVOKAMET and INVOKAMET XR have been established in clinical trials with canagliflozin in combination with metformin HCl alone, metformin HCl and sulfonylurea, metformin HCl and sitagliptin, metformin HCl and a thiazolidinedione (i.e., pioglitazone), and metformin HCl and insulin (with or without other anti-hyperglycemic agents). The efficacy of canagliflozin was compared to a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin), both as add-on combination therapy with metformin HCl and sulfonylurea, and a sulfonylurea (glimepiride), both as add-on combination therapy with metformin HCl. Canagliflozin as Initial Combination Therapy with Metformin HCl Extended-Release A total of 1,186 adult patients with type 2 diabetes inadequately controlled with diet and exercise participated in a 26-week double-blind, active-controlled, parallel-group, 5-arm, multicenter trial to evaluate the efficacy and safety of initial therapy with canagliflozin in combination with metformin HCl extended-release. The median age was 56 years, 48% of patients were male, and the mean baseline eGFR was 87.6 mL/min/1.73 m2. The median duration of diabetes was 1.6 years, and 72% of patients were treatment naïve. After completing a 2-week single-blind placebo run-in period, patients were randomly assigned for a double-blind treatment period of 26 weeks to 1 of 5 treatment groups (Table 13). The metformin HCl extended-release dose was initiated at 500 mg/day for the first week of treatment and then increased to 1,000 mg/day. Metformin HCl extended-release or matching placebo was up-titrated every 2-3 weeks during the next 8 weeks of treatment to a maximum daily dose of 1,500 to 2,000 mg/day, as tolerated; about 90% of patients reached 2,000 mg/day. At the end of treatment, canagliflozin 100 mg and canagliflozin 300 mg in combination with metformin HCl extended-release resulted in a statistically significant greater improvement in HbA1C compared to their respective canagliflozin doses (100 mg and 300 mg) alone or metformin HCl extended-release alone. Reference ID: 5499136 40 Table 13: Results from 26-Week Active-Controlled Clinical Trial of Canagliflozin Alone or Canagliflozin as Initial Combination Therapy with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Metformin HCl extended-release (N=237) Canagliflozin 100 mg (N=237) Canagliflozin 300 mg (N=238) Canagliflozin 100 mg + Metformin HCl extended- release (N=237) Canagliflozin 300 mg + Metformin HCl extended- release (N=237) HbA1C (%) Baseline (mean) 8.81 8.78 8.77 8.83 8.90 Change from baseline (adjusted mean)¶ -1.30 -1.37 -1.42 -1.77 -1.78 Difference from canagliflozin 100 mg (adjusted mean) (95% CI)† -0.40‡ (-0.59, -0.21) Difference from canagliflozin 300 mg (adjusted mean) (95% CI)† -0.36‡ (-0.56, -0.17) Difference from metformin HCl extended- release (adjusted mean) (95% CI)† -0.46‡ (-0.66, -0.27) -0.48‡ (-0.67, -0.28) Percent of patients achieving HbA1C < 7% 38 34 39 47§§ 51§§ * Intent-to-treat population † Least squares mean adjusted for covariates including baseline value and stratification factor ‡ Adjusted p=0.001 §§ Adjusted p<0.05 ¶ There were 121 patients without week 26 efficacy data. Analyses addressing missing data gave consistent results with the results provided in this table. Canagliflozin as Add-on Combination Therapy with Metformin HCl A total of 1,284 adult patients with type 2 diabetes inadequately controlled on metformin HCl monotherapy (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) participated in a 26-week, double-blind, placebo- and active-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl. The mean age was Reference ID: 5499136 41 55 years, 47% of patients were male, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the required metformin HCl dose (N=1,009) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients taking less than the required metformin HCl dose or patients on metformin HCl in combination with another antihyperglycemic agent (N=275) were switched to metformin HCl monotherapy (at doses described above) for at least 8 weeks before entering the 2-week, single-blind, placebo run-in. After the placebo run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, sitagliptin 100 mg, or placebo, administered once daily as add-on therapy to metformin HCl. At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo when added to metformin HCl (see Table 14). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -5.4 mmHg and -6.6 mmHg with canagliflozin 100 mg and 300 mg, respectively. Table 14: Results from 26-Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Metformin HCl (N=183) Canagliflozin 100 mg + Metformin HCl (N=368) Canagliflozin 300 mg + Metformin HCl (N=367) HbA1C (%) Baseline (mean) 7.96 7.94 7.95 Change from baseline (adjusted mean) -0.17 -0.79 -0.94 Difference from placebo (adjusted mean) (95% CI)† -0.62‡ (-0.76, -0.48) -0.77‡ (-0.91, -0.64) Percent of patients achieving HbA1C < 7% 30 46‡ 58‡ Fasting Plasma Glucose (mg/dL) Baseline (mean) 164 169 173 Change from baseline (adjusted mean) 2 -27 -38 Difference from placebo (adjusted mean) (95% CI)† -30‡ (-36, -24) -40‡ (-46, -34) 2-hour Postprandial Glucose (mg/dL) Baseline (mean) 249 258 262 Change from baseline (adjusted mean) -10 -48 -57 Difference from placebo (adjusted mean) (95% CI)† -38‡ (-49, -27) -47‡ (-58, -36) Body Weight Baseline (mean) in kg 86.7 88.7 85.4 % change from baseline (adjusted mean) -1.2 -3.7 -4.2 Difference from placebo (adjusted mean) (95% CI)† -2.5‡ (-3.1, -1.9) -2.9‡ (-3.5, -2.3) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors Reference ID: 5499136 42 ‡ p<0.001 Canagliflozin Compared to Glimepiride, Both as Add-on Combination Therapy with Metformin HCl A total of 1,450 adult patients with type 2 diabetes inadequately controlled on metformin HCl monotherapy (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) participated in a 52-week, double-blind, active-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl. The mean age was 56 years, 52% of patients were male, and the mean baseline eGFR was 90 mL/min/1.73 m2. Patients tolerating maximally required metformin HCl dose (N=928) were randomized after completing a 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin HCl monotherapy (at doses described above) for at least 10 weeks, then completed a 2-week single-blind run-in period. After the 2-week run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride (titration allowed throughout the 52-week trial to 6 or 8 mg), administered once daily as add-on therapy to metformin HCl. As shown in Table 15 and Figure 1, at the end of treatment, canagliflozin 100 mg provided similar reductions in HbA1C from baseline compared to glimepiride when added to metformin HCl therapy. Canagliflozin 300 mg provided a greater reduction from baseline in HbA1C compared to glimepiride, and the relative treatment difference was -0.12% (95% CI: −0.22; −0.02). As shown in Table 15, treatment with canagliflozin 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride. Table 15: Results from 52−Week Clinical Trial Comparing Canagliflozin to Glimepiride in Combination with Metformin HCl in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Canagliflozin 100 mg + Metformin HCl (N=483) Canagliflozin 300 mg + Metformin HCl (N=485) Glimepiride (titrated) + Metformin HCl (N=482) HbA1C (%) Baseline (mean) 7.78 7.79 7.83 Change from baseline (adjusted mean) -0.82 -0.93 -0.81 Difference from glimepiride (adjusted mean) (95% CI)† -0.01‡ (-0.11, 0.09) -0.12‡ (-0.22, -0.02) Percent of patients achieving HbA1C < 7% 54 60 56 Fasting Plasma Glucose (mg/dL) Baseline (mean) 165 164 166 Change from baseline (adjusted mean) -24 -28 -18 Difference from glimepiride (adjusted mean) (95% CI)† -6 (-10, -2) -9 (-13, -5) Body Weight Baseline (mean) in kg 86.8 86.6 86.6 % change from baseline (adjusted mean) -4.2 -4.7 1.0 Reference ID: 5499136 43 12 18 26 36 44 Study Week -- Canagliflozin 1 00 mg ~ -- Canaghflozin 300 mg 52 Wk52 LOCF + - - Glimepiride Difference from glimepiride (adjusted mean) (95% CI)† -5.2§ (-5.7, -4.7) -5.7§ (-6.2, -5.1) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ Canagliflozin + metformin HCl is considered non-inferior to glimepiride + metformin HCl because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%. § p<0.001 Figure 1: Mean HbA1C Change in Adults with Type 2 Diabetes Mellitus Treated with Canagliflozin or Glimepiride in Combination with Metformin HCl at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population) Canagliflozin as Add-on Combination Therapy with Metformin HCl and Sitagliptin A total of 217 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 1,500 mg/day) and sitagliptin 100 mg/day (or equivalent fixed-dose combination) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl and sitagliptin. The mean age was 57 years, 58% of patients were male, 73% of patients were White, 15% were Asian, and 12% were Black or African American. The mean baseline eGFR was 90 mL/min/1.73 m2 and the mean baseline BMI was 32 kg/m2. The mean duration of diabetes was 10 years. Eligible patients entered a 2-week, single-blind, placebo run-in period and were subsequently randomized to canagliflozin 100 mg or placebo, administered once daily as add-on to metformin HCl and sitagliptin. Patients with a baseline eGFR of 70 mL/min/1.73 m2 or greater who were tolerating canagliflozin 100 mg and who required additional glycemic control (fasting finger stick 100 mg/dL or greater at least twice within 2 weeks) were up-titrated to canagliflozin 300 mg. While up-titration occurred as early as Week 4, most (90%) patients randomized to canagliflozin were up-titrated to canagliflozin 300 mg by 6 to 8 weeks. At the end of 26 weeks, canagliflozin once daily resulted in a statistically significant improvement in HbA1C (p<0.001) compared to placebo when added to metformin HCl and sitagliptin (see Table 16). Reference ID: 5499136 44 Table 16: Results from 26−Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl and Sitagliptin in Adults with Type 2 Diabetes Mellitus Efficacy Parameter Placebo + Metformin HCl and Sitagliptin (N=108*) Canagliflozin + Metformin HCl and Sitagliptin (N=109*) HbA1C (%) Baseline (mean) 8.40 8.50 Change from baseline (adjusted mean) -0.03 -0.83 Difference from placebo (adjusted mean) (95% CI)†§ -0.81# (-1.11; -0.51) Percent of patients achieving HbA1C < 7%‡ 9 28 Fasting Plasma Glucose (mg/dL)¶ Baseline (mean) 180 185 Change from baseline (adjusted mean) -3 -28 Difference from placebo (adjusted mean) (95% CI) -25# (-39; -11) * To preserve the integrity of randomization, all randomized patients were included in the analysis. The patient who was randomized once to each arm was analyzed on canagliflozin. † Early treatment discontinuation before week 26, occurred in 11.0% and 24.1% of canagliflozin and placebo patients, respectively. ‡ Patients without week 26 efficacy data were considered as non-responders when estimating the proportion achieving HbA1C < 7%. § Estimated using a multiple imputation method modeling a “wash-out” of the treatment effect for patients having missing data who discontinued treatment. Missing data was imputed only at week 26 and analyzed using ANCOVA. ¶ Estimated using a multiple imputation method modeling a “wash-out” of the treatment effect for patients having missing data who discontinued treatment. A mixed model for repeated measures was used to analyze the imputed data. # p<0.001 Canagliflozin as Add-on Combination Therapy with Metformin HCl and Sulfonylurea A total of 469 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (maximal or near-maximal effective dose) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl and sulfonylurea. The mean age was 57 years, 51% of patients were male, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the protocol-specified doses of metformin HCl and sulfonylurea (N=372) entered a 2-week, single-blind, placebo run-in period. Other patients (N=97) were required to be on a stable protocol-specified dose of metformin HCl and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo administered once daily as add-on to metformin HCl and sulfonylurea. At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl and sulfonylurea. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7.0%, in a significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin HCl and sulfonylurea (see Table 17). Reference ID: 5499136 45 Table 17: Results from 26−Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl and Sulfonylurea in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Metformin HCl and Sulfonylurea (N=156) Canagliflozin 100 mg + Metformin HCl and Sulfonylurea (N=157) Canagliflozin 300 mg + Metformin HCl and Sulfonylurea (N=156) HbA1C (%) Baseline (mean) 8.12 8.13 8.13 Change from baseline (adjusted mean) -0.13 -0.85 -1.06 Difference from placebo (adjusted mean) (95% CI)† -0.71‡ (-0.90, -0.52) -0.92‡ (-1.11, -0.73) Percent of patients achieving HbA1C < 7% 18 43‡ 57‡ Fasting Plasma Glucose (mg/dL) Baseline (mean) 170 173 168 Change from baseline (adjusted mean) 4 -18 -31 Difference from placebo (adjusted mean) (95% CI)† -22‡ (-31, -13) -35‡ (-44, -25) Body Weight Baseline (mean) in kg 90.8 93.5 93.5 % change from baseline (adjusted mean) -0.7 -2.1 -2.6 Difference from placebo (adjusted mean) (95% CI)† -1.4‡ (-2.1, -0.7) -2.0‡ (-2.7, -1.3) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001 Canagliflozin Compared to Sitagliptin, Both as Add-on Combination Therapy with Metformin HCl and Sulfonylurea A total of 755 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (near-maximal or maximal effective dose) participated in a 52 week, double-blind, active-controlled trial to compare the efficacy and safety of canagliflozin 300 mg versus sitagliptin 100 mg in combination with metformin HCl and sulfonylurea. The mean age was 57 years, 56% of patients were male, and the mean baseline eGFR was 88 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin HCl and sulfonylurea (N=716) entered a 2-week single-blind, placebo run-in period. Other patients (N=39) were required to be on a stable protocol-specified dose of metformin HCl and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to canagliflozin 300 mg or sitagliptin 100 mg as add-on to metformin HCl and sulfonylurea. As shown in Table 18 and Figure 2, at the end of treatment, canagliflozin 300 mg provided greater HbA1C reduction compared to sitagliptin 100 mg when added to metformin HCl and sulfonylurea (p<0.05). Canagliflozin 300 mg resulted in a mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. A mean change in systolic blood pressure from baseline of -5.06 mmHg was observed with canagliflozin 300 mg compared to +0.85 mmHg with sitagliptin 100 mg. Reference ID: 5499136 46 w U) 0.0 -0.2 i -0 .4 ID ID C ai= C ID 2 ~ -0.6 0 (0 C E :i ~ -0.8 (()~ _J rS ~ -1 .0 I C -1.2 -1 .4 12 18 26 34 42 52 Study Week canagliflozin 300 mg • - - • Sitagliptin 1 oo mg Wk52 LOCF Table 18: Results from 52−Week Clinical Trial Comparing Canagliflozin to Sitagliptin in Combination with Metformin HCl and Sulfonylurea in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Canagliflozin 300 mg + Metformin HCl and Sulfonylurea (N=377) Sitagliptin 100 mg + Metformin HCl and Sulfonylurea (N=378) HbA1C (%) Baseline (mean) 8.12 8.13 Change from baseline (adjusted mean) -1.03 -0.66 Difference from sitagliptin (adjusted mean) (95% CI)† -0.37‡ (-0.50, -0.25) Percent of patients achieving HbA1C < 7% 48 35 Fasting Plasma Glucose (mg/dL) Baseline (mean) 170 164 Change from baseline (adjusted mean) -30 -6 Difference from sitagliptin (adjusted mean) (95% CI)† -24 (-30, -18) Body Weight Baseline (mean) in kg 87.6 89.6 % change from baseline (adjusted mean) -2.5 0.3 Difference from sitagliptin (adjusted mean) (95% CI)† -2.8§ (-3.3, -2.2) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ Canagliflozin + metformin HCl + sulfonylurea is considered non-inferior to sitagliptin + metformin HCl + sulfonylurea because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%. § p<0.001 Figure 2: Mean HbA1C Change in Adults with Type 2 Diabetes Mellitus Treated with Canagliflozin or Sitagliptin in Combination with Metformin HCl and Sulfonylurea at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population) Canagliflozin as Add-on Combination Therapy with Metformin HCl and Pioglitazone A total of 342 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not Reference ID: 5499136 47 tolerated) and pioglitazone (30 or 45 mg/day) participated in a 26-week, double--blind, placebo- controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl and pioglitazone. The mean age was 57 years, 63% of patients were male, and the mean baseline eGFR was 86 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin HCl and pioglitazone (N=163) entered a 2-week, single-blind, placebo run-in period. Other patients (N=181) were required to be on stable protocol-specified doses of metformin HCl and pioglitazone for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo, administered once daily as add-on to metformin HCl and pioglitazone. At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl and pioglitazone. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin HCl and pioglitazone (see Table 19). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -4.1 mmHg and -3.5 mmHg with canagliflozin 100 mg and 300 mg, respectively. Table 19: Results from 26−Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl and Pioglitazone in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Metformin HCl and Pioglitazone (N=115) Canagliflozin 100 mg + Metformin HCl and Pioglitazone (N=113) Canagliflozin 300 mg + Metformin HCl and Pioglitazone (N=114) HbA1C (%) Baseline (mean) 8.00 7.99 7.84 Change from baseline (adjusted mean) -0.26 -0.89 -1.03 Difference from placebo (adjusted mean) (95% CI)† -0.62‡ (-0.81, -0.44) -0.76‡ (-0.95, -0.58) Percent of patients achieving HbA1C < 7% 33 47‡ 64‡ Fasting Plasma Glucose (mg/dL) Baseline (mean) 164 169 164 Change from baseline (adjusted mean) 3 -27 -33 Difference from placebo (adjusted mean) (95% CI)† -29‡ (-37, -22) -36‡ (-43, -28) Body Weight Baseline (mean) in kg 94.0 94.2 94.4 % change from baseline (adjusted mean) -0.1 -2.8 -3.8 Difference from placebo (adjusted mean) (95% CI)† -2.7‡ (-3.6, -1.8) -3.7‡ (-4.6, -2.8) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001 Reference ID: 5499136 48 Canagliflozin as Add-on Combination Therapy with Insulin (With or Without Other Anti-Hyperglycemic Agents, Including Metformin HCl) A total of 1,718 adult patients with type 2 diabetes inadequately controlled on insulin greater than or equal to 30 units/day or insulin in combination with other antihyperglycemic agents participated in an 18-week, double-blind, placebo-controlled subtrial of a cardiovascular trial to evaluate the efficacy and safety of canagliflozin in combination with insulin. Of these patients, a subgroup of 432 patients with inadequate glycemic control received canagliflozin or placebo plus metformin HCl and ≥ 30 units/day of insulin over 18 weeks. In this subgroup, the mean age was 61 years, 67% of patients were male, and the mean baseline eGFR was 81 mL/min/1.73 m2. Patients on metformin HCl in combination with basal, bolus, or basal/bolus insulin for at least 10 weeks entered a 2-week, single-blind, placebo run-in period. Approximately 74% of these patients were on a background of metformin HCl and basal/bolus insulin regimen. After the run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo, administered once daily as add-on to metformin HCl and insulin. The mean daily insulin dose at baseline was 93 units, which was similar across treatment groups. At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl and insulin. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reductions in fasting plasma glucose (FPG), and in percent body weight reductions compared to placebo (see Table 20). Statistically significant (p=0.023 for the 100 mg and p<0.001 for the 300 mg dose) mean change from baseline in systolic blood pressure relative to placebo was –3.5 mmHg and -6 mmHg with canagliflozin 100 mg and 300 mg, respectively. Fewer patients on canagliflozin in combination with metformin HCl and insulin required glycemic rescue therapy: 3.6% of patients receiving canagliflozin 100 mg, 2.7% of patients receiving canagliflozin 300 mg, and 6.2% of patients receiving placebo. An increased incidence of hypoglycemia was observed in this trial, which is consistent with the expected increase of hypoglycemia when an agent not associated with hypoglycemia is added to insulin [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)]. Reference ID: 5499136 49 Table 20: Results from 18−Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl and Insulin ≥ 30 Units/Day in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Metformin HCl + Insulin (N=145) Canagliflozin 100 mg + Metformin HCl + Insulin (N=139) Canagliflozin 300 mg + Metformin HCl + Insulin (N=148) HbA1C (%) Baseline (mean) 8.15 8.20 8.22 Change from baseline (adjusted mean) 0.03 -0.64 -0.79 Difference from placebo (adjusted mean) (95% CI)† -0.66‡ (-0.81, -0.51) -0.82‡ (-0.96, -0.67) Percent of patients achieving HbA1C < 7% 9 19§ 29‡ Fasting Plasma Glucose (mg/dL) Baseline 163 168 167 Change from baseline (adjusted mean) 1 -16 -24 Difference from placebo (adjusted mean) (97.5% CI)† -16‡ (-28, -5) -25‡ (-36, -14) Body Weight Baseline (mean) in kg 102.3 99.7 101.1 % change from baseline (adjusted mean) 0.0 -1.7 -2.7 Difference from placebo (adjusted mean) (97.5% CI)† -1.7‡ (-2.4, -1.0) -2.7‡ (-3.4, -2.0) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p≤0.001 § p≤0.01 14.2 Glycemic Control Trial in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus Glycemic Control Trial of Canagliflozin in Pediatric Patients Aged 10 years and Older with Type 2 Diabetes Mellitus In a double-blind, placebo-controlled, parallel-group pediatric trial (NCT03170518), 171 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus (HbA1C >6.5% and <11.0%) were randomized to canagliflozin (84 patients) or placebo (87 patients) as add-on to diet and exercise, metformin HCl (>1,000 mg per day or maximally tolerated dosage), insulin, or a combination of metformin HCl and insulin, for a total of 52­ weeks. At Week 13, patients in the canagliflozin arm whose HbA1C was ≥7.0% and eGFR ≥60 mL/min/1.73m2 were re-randomized to either continue on canagliflozin 100 mg orally once daily (n=16) or to up-titrate to 300 mg orally once daily (n=17). At baseline, background therapies included diet and exercise only (14%), insulin monotherapy (11%), metformin HCl and insulin (29%), and metformin HCl monotherapy (46%). The mean HbA1C at baseline was 8.0% and the mean duration of type 2 diabetes mellitus was 2 years. The mean eGFR at baseline was 157.3 mL/min/1.73 m2, and approximately 16% (24/151) of the trial population with measurements had microalbuminuria or macroalbuminuria. Patients with an eGFR less than 60 mL/min/1.73 m2 were not enrolled in the trial; no patients in the trial reached an eGFR < 60 mL/min/1.72m2. The mean age was 14.3 years, 47% were under 15 years of age, Reference ID: 5499136 50 and 68% were female. Approximately 42% were Asian, 42% were White, 11% were Black or African American, 5% were American Indian/Alaska Native, and 36% were of Hispanic or Latino ethnicity. The mean BMI was 30.8 kg/m2 (range 18-57 kg/m2) and the mean BMI Z-score was 1.84. At Week 26, treatment with canagliflozin provided statistically significant improvement in HbA1C from baseline, compared with placebo (see Table 21). The treatment effect with canagliflozin was consistent in the subgroup of patients with metformin with or without insulin as background therapy [adjusted mean change in HbA1C relative to placebo from baseline to Week 26 was –0.74% (95% CI -1.37, -0.11; p = 0.02)]. Table 21: Results at Week 26 in a Placebo-Controlled Trial of Canagliflozin in Combination with Metformin HCl and/or Insulin or as Monotherapy in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo (N=87) Canagliflozin (N=84) HbA1C (%) Baseline (mean) 8.3 7.8 Change from baseline†‡ 0.34 -0.38 Difference from placebo 95% CI†‡ -0.73 (-1.26, -0.19)§ FPG (mg/dL) Baseline (mean) 156.5 154.8 Change from baseline†‡ 17.29 -8.22 Difference from placebo 95% CI†‡ -25.51 (-49.55, -1.47) ¶ * Modified intent-to-treat set (All randomized and treated patients with baseline HbA1C measurement). † Multiple imputation using retrieved dropout approach with 1,000 iterations for missing data (canagliflozin N=7 (8.3%), placebo N=7 (8.1%) for HbA1C and canagliflozin N=9 (10.7%), placebo N=7 (8.1%) for FPG). ‡ Least-Square Mean from Analysis of Covariance (ANCOVA) adjusted for baseline value, baseline age stratum (< 15 years vs 15 to < 18 years) and baseline antihyperglycemic agent (AHA) background (i.e., diet and exercise only, metformin monotherapy, insulin monotherapy, or combination of insulin and metformin). § P-value=0.008 (two-sided) ¶ Not evaluated for statistical significance, not part of sequential testing procedure. Glycemic Control Trial of Metformin HCl Immediate-Release in Pediatric Patients Aged 10 to 16 Years with Type 2 Diabetes Mellitus A double-blind, placebo-controlled trial was conducted in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), where patients were treated with metformin HCl immediate-release tablets (up to 2,000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks). The results are displayed in Table 22. Table 22: Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin HCl versus Placebo in Pediatric Patientsa with Type 2 Diabetes Mellitus Metformin HCl Placebo p-value FPG (n=37) (n=36) Baseline 162.4 192.3 Change at Final Visit -42.9 21.4 <0.001 a Pediatric patients mean age 13.8 years (range 10-16 years) Reference ID: 5499136 51 Mean baseline body weight was 205 lbs and 189 lbs in the metformin HCl immediate-release and placebo arms, respectively. Mean change in body weight from baseline to week 16 was ­ 3.3 lbs and -2.0 lbs in the metformin HCl and placebo arms, respectively. 14.3 Canagliflozin Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD). The CANVAS and CANVAS-R trials were multicenter, multi-national, randomized, double-blind parallel group, with similar inclusion and exclusion criteria. Patients eligible for enrollment in both CANVAS and CANVAS-R trials were: 30 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease (66% of the enrolled population) or were 50 years of age or older and had two or more other specified risk factors for cardiovascular disease (34% of the enrolled population). The integrated analysis of the CANVAS and CANVAS-R trials compared the risk of Major Adverse Cardiovascular Event (MACE) between canagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. In CANVAS, patients were randomly assigned 1:1:1 to canagliflozin 100 mg, canagliflozin 300 mg, or matching placebo. In CANVAS-R, patients were randomly assigned 1:1 to canagliflozin 100 mg or matching placebo, and titration to 300 mg was permitted at the investigator’s discretion (based on tolerability and glycemic needs) after Week 13. Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases. A total of 10,134 adult patients were treated (4,327 in CANVAS and 5,807 in CANVAS-R; total of 4,344 randomly assigned to placebo and 5,790 to canagliflozin) for a mean exposure duration of 149 weeks (223 weeks [4.3 years] in CANVAS and 94 weeks [1.8 years] in CANVAS-R). Approximately 78% of the trial population was White, 13% was Asian, and 3% was Black or African American. The mean age was 63 years and approximately 64% were male. The mean HbA1C at baseline was 8.2% and mean duration of diabetes was 13.5 years with 70% of patients having had diabetes for 10 years or more. Approximately 31%, 21% and 17% reported a past history of neuropathy, retinopathy and nephropathy, respectively, and the mean eGFR 76 mL/min/1.73 m2. At baseline, patients were treated with one (19%) or more (80%) antidiabetic medications including metformin HCl (77%), insulin (50%), and sulfonylurea (43%). Reference ID: 5499136 52 At baseline, the mean systolic blood pressure was 137 mmHg, the mean diastolic blood pressure was 78 mmHg, the mean LDL was 89 mg/dL, the mean HDL was 46 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 115 mg/g. At baseline, approximately 80% of patients were treated with renin angiotensin system inhibitors, 53% with beta-blockers, 13% with loop diuretics, 36% with non-loop diuretics, 75% with statins, and 74% with antiplatelet agents (mostly aspirin). During the trial, investigators could modify anti-diabetic and cardiovascular therapies to achieve local standard of care treatment targets with respect to blood glucose, lipid, and blood pressure. More patients receiving canagliflozin compared to placebo initiated anti-thrombotics (5.2% vs 4.2%) and statins (5.8% vs 4.8%) during the trial. For the primary analysis, a stratified Cox proportional hazards model was used to test for non-inferiority against a pre-specified risk margin of 1.3 for the hazard ratio of MACE. In the integrated analysis of CANVAS and CANVAS-R trials, canagliflozin reduced the risk of first occurrence of MACE. The estimated hazard ratio (95% CI) for time to first MACE was 0.86 (0.75, 0.97). Refer to Table 23. Vital status was obtained for 99.6% of patients across the trials. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 3. Reference ID: 5499136 53 24 22 20 18 ~ 16 ~ w 14 12 Subjects Placebo Cana Cana vs. Placebo 0 26 52 4347 4239 4153 5795 5672 5566 HR (95%CI) 0.86 (0.75, 0.97) 78 104 130 4061 2942 1626 5447 4343 2984 l~6~~=bol 156 182 208 234 260 286 312 338 Time (Weeks) 1240 1217 11 87 1156 1120 1095 789 216 2555 2513 2460 2419 2363 2311 1661 448 Table 23: Treatment Effect for the Primary Composite Endpoint, MACE, and its Components in the Integrated Analysis of CANVAS and CANVAS-R Trials in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease* Placebo N=4,347 (%) Canagliflozin N=5,795 (%) Hazard ratio (95% CI)¶ Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)†, ‡, §, 426 (10.4) 585 (9.2) 0.86 (0.75, 0.97) Non-fatal myocardial infarction‡, § 159 (3.9) 215 (3.4) 0.85 (0.69, 1.05) Non-fatal Stroke‡, § 116 (2.8) 158 (2.5) 0.90 (0.71, 1.15) Cardiovascular Death‡, § 185 (4.6) 268 (4.1) 0.87 (0.72, 1.06) * Intent-To-Treat Analysis Set † P-value for superiority (2-sided) = 0.0158 ‡ Number and percentage of first events § Due to pooling of unequal randomization ratios, Cochran-Mantel-Haenszel weights were applied to calculate percentages ¶ Stratified Cox-proportional hazards model with treatment as a factor and stratified by the trial and by prior CV disease Figure 3: Time to First Occurrence of MACE 14.4 Canagliflozin Renal and Cardiovascular Outcomes in Adults with Diabetic Nephropathy and Albuminuria Canagliflozin is indicated to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria ˃ 300 mg/day. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial (CREDENCE) was a multinational, randomized, double-blind, placebo-controlled trial comparing canagliflozin with placebo in adult patients with type 2 diabetes mellitus, an eGFR ≥ 30 to < 90 mL/min/1.73 m2 and albuminuria (urine albumin/creatinine ˃ 300 to ≤ 5,000 mg/g) who were receiving standard of care including a Reference ID: 5499136 54 maximum-tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The primary objective of CREDENCE was to assess the efficacy of canagliflozin relative to placebo in reducing the composite endpoint of end stage kidney disease (ESKD), doubling of serum creatinine, and renal or CV death. Patients were randomized to receive canagliflozin 100 mg (N=2,202) or placebo (N=2,199) and treatment was continued until the initiation of dialysis or renal transplantation. The median follow-up duration for the 4,401 randomized subjects was 137 weeks. Vital status was obtained for 99.9% of subjects. The population was 67% White, 20% Asian, and 5% Black or African American; 32% were of Hispanic or Latino ethnicity. The mean age was 63 years and 66% were male. At randomization, the mean HbA1C was 8.3%, the median urine albumin/creatinine was 927 mg/g, the mean eGFR was 56.2 mL/min/1.73 m2, 50% had prior CV disease, and 15% reported a history of heart failure. The most frequent antihyperglycemic agents (AHA) medications used at baseline were insulin (66%), biguanides (58%), and sulfonylureas (29%). Nearly all subjects (99.9%) were on ACEi or ARB at randomization, approximately 60% were taking an anti-thrombotic agent (including aspirin), and 69% were on a statin. The primary composite endpoint in the CREDENCE trial was the time to first occurrence of ESKD (defined as an eGFR < 15 mL/min/1.73 m2, initiation of chronic dialysis or renal transplant), doubling of serum creatinine, and renal or CV death. Canagliflozin 100 mg significantly reduced the risk of the primary composite endpoint based on a time-to-event analysis [HR: 0.70; 95% CI: 0.59, 0.82; p<0.0001] (see Figure 4). The treatment effect reflected a reduction in progression to ESKD, doubling of serum creatinine and cardiovascular death as shown in Table 24 and Figure 4. There were few renal deaths during the trial. Canagliflozin 100 mg also significantly reduced the risk of hospitalization for heart failure [HR: 0.61; 95% CI: 0.47 to 0.80; p<0.001]. Reference ID: 5499136 55 Table 24: Analysis of Primary Endpoint (including the Individual Components) and Secondary Endpoints from the CREDENCE Trial in Adults with Diabetic Nephropathy and Albuminuria Placebo canagliflozin Endpoint N=2,199 (%) Event Rate* N=2,202 (%) Event Rate* HR† (95% CI) Primary Composite Endpoint (ESKD, doubling of serum creatinine, renal death, or CV death) 340 (15.5) 6.1 245 (11.1) 4.3 0.70 (0.59, 0.82)‡ ESKD 165 (7.5) 2.9 116 (5.3) 2.0 0.68 (0.54, 0.86) Doubling of serum creatinine 188 (8.5) 3.4 118 (5.4) 2.1 0.60 (0.48, 0.76) Renal death 5 (0.2) 0.1 2 (0.1) 0.0 CV death 140 (6.4) 2.4 110 (5.0) 1.9 0.78 (0.61, 1.00) CV death or hospitalization for heart failure 253 (11.5) 4.5 179 (8.1) 3.1 0.69 (0.57, 0.83)§ CV death, non-fatal myocardial infarction or non­ fatal stroke 269 (12.2) 4.9 217 (9.9) 3.9 0.80 (0.67, 0.95)¶ Non-fatal myocardial infarction 87 (4.0) 1.6 71 (3.2) 1.3 0.81 (0.59, 1.10) Non-fatal stroke 66 (3.0) 1.2 53 (2.4) 0.9 0.80 (0.56, 1.15) Hospitalization for heart failure 141 (6.4) 2.5 89 (4.0) 1.6 0.61 (0.47, 0.80)§ ESKD, doubling of serum creatinine or renal death 224 (10.2) 4.0 153 (6.9) 2.7 0.66 (0.53, 0.81)‡ Intent-To-Treat Analysis Set (time to first occurrence) The individual components do not represent a breakdown of the composite outcomes, but rather the total number of subjects experiencing an event during the course of the trial. * Event rate per 100 patient-years. † Hazard ratio (canagliflozin compared to placebo), 95% CI and p-value are estimated using a stratified Cox proportional hazards model including treatment as the explanatory variable and stratified by screening eGFR (≥ 30 to < 45, ≥ 45 to < 60, ≥ 60 to < 90 mL/min/1.73 m2). HR is not presented for renal death due to the small number of events in each group. ‡ P-value <0.0001 § P-value <0.001 ¶ P-value <0.02 The Kaplan-Meier curve (Figure 4) shows time to first occurrence of the primary composite endpoint of ESKD, doubling of serum creatinine, renal death, or CV death. The curves begin to separate by Week 52 and continue to diverge thereafter. Reference ID: 5499136 56 30 28 Cana vs. Placebo 26 24 22 2l 20 C: Q) > 18 w ~ 16 tl 14 Q) E 12 :, (f) °$. 10 8 6 4 2 0 0 26 Subjects at risk Placebo 2199 2178 Cana 2202 2181 HR (95%C I) 0. 70 (0.59, 0.82) 52 78 104 Time (Weeks) 2132 2047 1725 2145 2081 1786 130 1129 1211 , --·­ ·-' 1~ 6~~=bol 156 182 621 170 646 196 Figure 4: CREDENCE: Time to First Occurrence of the Primary Composite Endpoint 16 HOW SUPPLIED/STORAGE AND HANDLING INVOKAMET® tablets are available in bottles of 60 in the strengths listed below: INVOKAMET TABLET STRENGTH canagliflozin/metformin HCl tablets 50 mg/500 mg 50 mg/1,000 mg 150 mg/500 mg 150 mg/1,000 mg Color White Beige Yellow Purple CM CM CM CM Tablet Identification 155 551 215 611 Capsule-shaped, film-coated tablets NDC 50458-540-60 50458-541-60 50458-542-60 50458-543-60 INVOKAMET® XR tablets are available in bottles of 60 in the strengths listed below: INVOKAMET XR TABLET STRENGTH canagliflozin/metformin HCl extended-release tablets 50 mg/500 mg 50 mg/1,000 mg 150 mg/500 mg 150 mg/1,000 mg Color Almost White to Light Orange Pink Orange Reddish Brown Tablet Identification CM1 CM3 CM2 CM4 Oblong, biconvex, film-coated tablets, a thin line on the tablet side may be visible. NDC 50458-940-01 50458-941-01 50458-942-01 50458-943-01 Storage and Handling Keep out of reach of children. Reference ID: 5499136 57 Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30°C (59 °F to 86 °F) [see USP Controlled Room Temperature]. Store and dispense in the original container. Storage in a pill box or pill organizer is allowed for up to 30 days. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-Approved Patient Labeling (Medication Guide). Lactic Acidosis Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in Warnings and Precautions (5.1). Advise patients to discontinue INVOKAMET or INVOKAMET XR immediately and to promptly notify their health care provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Once a patient is stabilized on INVOKAMET or INVOKAMET XR, gastrointestinal symptoms, which are common during initiation of metformin HCl, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Counsel patients against excessive alcohol intake while receiving INVOKAMET or INVOKAMET XR. Inform patients about importance of regular testing of renal function and hematological parameters while receiving INVOKAMET or INVOKAMET XR. Instruct patients to inform their doctor that they are taking INVOKAMET or INVOKAMET XR prior to any surgical or radiological procedure, as temporary discontinuation of INVOKAMET or INVOKAMET XR may be required until renal function has been confirmed to be normal [see Warnings and Precautions (5.1)]. Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis Inform patients that INVOKAMET or INVOKAMET XR can cause potentially fatal ketoacidosis and that type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors. Educate all patients on precipitating factors (such as insulin dose reduction or missed doses, infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform patients that blood glucose may be normal even in the presence of ketoacidosis. Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur, instruct patients to discontinue INVOKAMET or INVOKAMET XR and seek medical attention immediately [see Warnings and Precautions (5.2)]. Reference ID: 5499136 58 Lower Limb Amputation Inform patients that INVOKAMET or INVOKAMET XR is associated with an increased risk of amputations. Counsel patients about the importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop [see Warnings and Precautions (5.3)]. Volume Depletion Inform patients that symptomatic hypotension may occur with INVOKAMET or INVOKAMET XR and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions (5.4)]. Inform patients that dehydration may increase the risk for hypotension and to have adequate fluid intake. Serious Urinary Tract Infections Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.5)]. Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Inform patients that hypoglycemia has been reported when INVOKAMET or INVOKAMET XR is used with insulin or insulin secretagogues. Educate patients or caregivers on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.6)]. Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Inform patients that necrotizing infections of the perineum (Fournier’s gangrene) have occurred with INVOKAMET or INVOKAMET XR. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.7)]. Genital Mycotic Infections in Females (e.g., Vulvovaginitis) Inform female patients that vaginal yeast infection (e.g., vulvovaginitis) may occur and provide them with information on the signs and symptoms of a vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.8)]. Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.8)]. Reference ID: 5499136 59 Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions, such as urticaria, rash, anaphylaxis, and angioedema, have been reported with canagliflozin. Advise patients to report immediately any signs or symptoms suggesting allergic reaction and to discontinue drug until they have consulted prescribing physicians [see Warnings and Precautions (5.9)]. Bone Fracture Inform patients that bone fractures have been reported in adult patients taking canagliflozin. Provide them with information on factors that may contribute to fracture risk [see Warnings and Precautions (5.10)]. Vitamin B12 Deficiency Inform patients about importance of regular hematological parameters while receiving INVOKAMET or INVOKAMET XR [see Warnings and Precautions (5.11)]. Laboratory Tests Inform patients that they will test positive for glucose in their urine while on INVOKAMET or INVOKAMET XR [see Drug Interactions (7)]. Females of Reproductive Age Advise pregnant women, and females of reproductive potential of the potential risk to a fetus with treatment with INVOKAMET or INVOKAMET XR [see Use in Specific Populations (8.1)]. Instruct females of reproductive potential to report pregnancies to their physicians as soon as possible. Inform females that treatment with INVOKAMET or INVOKAMET XR may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)]. Lactation Advise women that breastfeeding is not recommended during treatment with INVOKAMET or INVOKAMET XR [see Use in Specific Populations (8.2)]. Administration Instruct patients to keep INVOKAMET or INVOKAMET XR in the original bottle to protect from moisture. Advise patients that storage in a pill box or pill organizer is allowed for up to 30 days. Instruct patients to take INVOKAMET only as prescribed twice daily with food. If a dose is missed, advise patients not to take two doses of INVOKAMET at the same time. Instruct patients to take INVOKAMET XR only as prescribed once daily with the morning meal. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time Reference ID: 5499136 60 for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take more than two tablets of INVOKAMET XR at the same time. Instruct patients that INVOKAMET XR must be swallowed whole and never crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet. Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA Licensed from Mitsubishi Tanabe Pharma Corporation For patent information: www.janssenpatents.com  Johnson & Johnson and its affiliates 2014 – 2024 Reference ID: 5499136 61 Medication Guide INVOKAMET® (in vok’ a met) (canagliflozin and metformin hydrochloride) tablets, for oral use and INVOKAMET® (in vok’ a met) XR (canagliflozin and metformin hydrochloride) extended-release tablets, for oral use What is the most important information I should know about INVOKAMET or INVOKAMET XR? INVOKAMET and INVOKAMET XR can cause serious side effects, including:  Lactic Acidosis. Metformin, one of the medicines in INVOKAMET and INVOKAMET XR, can cause a rare but serious condition called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital. Stop taking INVOKAMET or INVOKAMET XR and call your healthcare provider right away if you have any of the following symptoms of lactic acidosis: o feel cold in your hands or feet o have a slow or irregular heartbeat o feel very weak or tired o have unusual (not normal) muscle pain o have trouble breathing o have unusual sleepiness or sleep longer than usual o have stomach pains, nausea, or vomiting o feel dizzy or lightheaded Most people who have had lactic acidosis had other conditions that, in combination with metformin use, led to the lactic acidosis. Tell your healthcare provider if you have any of the following, because you have a higher chance for getting lactic acidosis with INVOKAMET or INVOKAMET XR if you: o have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye. o have liver problems. o drink alcohol very often or drink a lot of alcohol in short-term "binge" drinking. o get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids. o have surgery. o have new or worsening symptoms of congestive heart failure such as shortness of breath or increased fluid or swelling of the legs. o have a heart attack, severe infection, or stroke. o are 65 years of age or older. The best way to keep from having a problem with lactic acidosis from metformin is to tell your healthcare provider if you have any of the problems in the list above. Your healthcare provider will decide to stop your INVOKAMET or INVOKAMET XR for a while if you have any of these things.  Diabetic ketoacidosis (increased ketones in your blood or urine) in people with type 1 and other ketoacidosis. INVOKAMET and INVOKAMET XR can cause ketoacidosis that can be life-threatening and may lead to death. Ketoacidosis is a serious condition which needs to be treated in a hospital. People with type 1 diabetes have a high risk of getting ketoacidosis. People with type 2 diabetes or pancreas problems also have an increased risk of getting ketoacidosis. Ketoacidosis can also happen in people who: are sick, cannot eat or drink as usual, skip meals, are on a diet high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount of insulin or miss insulin doses, drink too much alcohol, have a loss of too much fluid from the body (volume depletion), or who have surgery or a procedure that requires not having food for a long time (prolonged fasting). Ketoacidosis can happen even if your blood sugar is less than 250 mg/dL. Your health care provider may ask you to periodically check ketones in your urine or blood.  Stop taking INVOKAMET or INVOKAMET XR and call your health care provider or get medical help right away if you get any of the following. If possible, check for ketones in your urine or blood, even if your blood sugar is less than 250 mg/dL: o nausea o tiredness o vomiting o trouble breathing o stomach-area (abdominal) pain o ketones in your urine or blood  Amputations. INVOKAMET or INVOKAMET XR may increase your risk of lower limb amputations. Amputations mainly involve removal of the toe or part of the foot, however, amputations involving the leg, below and above the knee, have also occurred. Some people had more than one amputation, some on both sides of the body. You may be at a higher risk of lower limb amputation if you: Reference ID: 5499136 1 o have a history of amputation o have heart disease or are at risk for heart disease o have had blocked or narrowed blood vessels, usually in your leg o have damage to the nerves (neuropathy) in your leg o have had diabetic foot ulcers or sores Call your healthcare provider right away if you have new pain or tenderness, any sores, ulcers, or infections in your leg or foot. Your healthcare provider may decide to stop your INVOKAMET or INVOKAMET XR for a while if you have any of these signs or symptoms. Talk to your healthcare provider about proper foot care.  Dehydration. INVOKAMET or INVOKAMET XR can cause some people to become dehydrated (the loss of too much body water). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden worsening of kidney function in people with type 2 diabetes who are taking canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. You may be at higher risk of dehydration if you: o take medicines to lower your blood pressure, including diuretics (water pill) o are on a low sodium (salt) diet o have kidney problems o are 65 years of age or older Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should drink on a daily basis. Call your health care provider right away if you reduce the amount of food or liquid you drink, for example if you cannot eat or you start to lose liquids from your body, for example from vomiting, diarrhea, or being in the sun too long.  Vaginal yeast infection. Women who take INVOKAMET or INVOKAMET XR may get vaginal yeast infections. Yeast infections can be a serious but common side effect of INVOKAMET or INVOKAMET XR. Symptoms of a vaginal yeast infection include: o vaginal odor o white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese) o vaginal itching  Yeast infection of the skin around the penis (balanitis or balanoposthitis). Men who take INVOKAMET or INVOKAMET XR may get a yeast infection of the skin around the penis. Men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include: o redness, itching, or swelling of the penis o rash of the penis o foul smelling discharge from the penis o pain in the skin around the penis Talk to your healthcare provider about what to do if you get symptoms of a yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medication and your symptoms do not go away. INVOKAMET or INVOKAMET XR can have other serious side effects. See “What are the possible side effects of INVOKAMET or INVOKAMET XR?” What is INVOKAMET or INVOKAMET XR?  INVOKAMET contains 2 prescription medicines called canagliflozin (INVOKANA) and metformin hydrochloride (HCl).  INVOKAMET XR contains 2 prescription medicines called canagliflozin (INVOKANA) and metformin HCL extended- release.  INVOKAMET or INVOKAMET XR can be used along with diet and exercise to lower blood sugar (glucose) in adults and children aged 10 years and older with type 2 diabetes. o One of the medicines in INVOKAMET or INVOKAMET XR, canagliflozin (INVOKANA), can also be used in adults with type 2 diabetes who have: o cardiovascular disease and canagliflozin is needed to reduce the risk of major cardiovascular events such as heart attack, stroke, or death. o diabetic kidney disease (nephropathy) with a certain amount of protein in the urine, and canagliflozin is needed to reduce the risk of end stage kidney disease (ESKD), worsening of kidney function, cardiovascular death, and hospitalization for heart failure.  INVOKAMET or INVOKAMET XR is not used to lower blood sugar (glucose) in people with type 1 diabetes.  It is not known if INVOKAMET or INVOKAMET XR is safe and effective in children under 10 years of age. Do not take INVOKAMET or INVOKAMET XR if you: Reference ID: 5499136 2  have severe kidney problems  have a condition called metabolic acidosis, including diabetic ketoacidosis (increased ketones in the blood or urine).  are allergic to canagliflozin, metformin, or any of the ingredients in INVOKAMET or INVOKAMET XR. See the end of this Medication Guide for a list of ingredients in INVOKAMET and INVOKAMET XR. Symptoms of an allergic reaction to INVOKAMET and INVOKAMET XR may include: o rash o raised red patches on your skin (hives) o swelling of the face, lips, mouth, tongue, and throat that may cause difficulty in breathing or swallowing Before taking INVOKAMET or INVOKAMET XR, tell your healthcare provider about all of your medical conditions, including if you:  have type 1 diabetes or have had diabetic ketoacidosis.  have a decrease in your insulin dose.  have a serious infection.  have a history of infection of the vagina or penis.  have a history of amputation.  have had blocked or narrowed blood vessels, usually in your leg.  have damage to the nerves (neuropathy) in your leg.  have had diabetic foot ulcers or sores.  have moderate to severe kidney problems.  have liver problems.  have a history of urinary tract infections or problems with urination.  are on a low sodium (salt) diet. Your healthcare provider may change your diet or your dose of INVOKAMET or INVOKAMET XR.  have ever had an allergic reaction to INVOKAMET or INVOKAMET XR.  are going to get an injection of dye or contrast agents for an x-ray procedure. INVOKAMET or INVOKAMET XR may need to be stopped for a short time. Talk to your healthcare provider about when you should stop INVOKAMET or INVOKAMET XR and when you should start INVOKAMET or INVOKAMET XR again. See "What is the most important information I should know about INVOKAMET or INVOKAMET XR?”  have heart problems, including congestive heart failure.  are going to have surgery or a procedure that requires not having food for a long time (prolonged fasting). Your healthcare provider may stop your INVOKAMET or INVOKAMET XR before you have surgery. Talk to your healthcare provider if you are having surgery about when to stop taking INVOKAMET or INVOKAMET XR and when to start it again.  are eating less or there is a change in your diet.  are dehydrated.  have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.  drink alcohol very often or drink a lot of alcohol in the short-term ("binge" drinking).  have low levels of vitamin B12 or calcium in your blood.  are pregnant or plan to become pregnant. INVOKAMET or INVOKAMET XR may harm your unborn baby. If you become pregnant while taking INVOKAMET or INVOKAMET XR, tell your healthcare provider as soon as possible. Talk with your healthcare provider about the best way to control your blood sugar while you are pregnant.  are premenopausal (before the “change of life”), and do not have periods regularly or at all. INVOKAMET or INVOKAMET XR may increase your chance of becoming pregnant. Talk to your healthcare provider about birth control choices while taking INVOKAMET or INVOKAMET XR, if you are not planning to become pregnant. Tell your healthcare provider right away if you become pregnant while taking INVOKAMET or INVOKAMET XR.  are breastfeeding or plan to breastfeed. INVOKAMET or INVOKAMET XR may pass into your breast milk and may harm your baby. Talk with your healthcare provider about the best way to feed your baby if you are taking INVOKAMET or INVOKAMET XR. Do not breastfeed while taking INVOKAMET or INVOKAMET XR. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. INVOKAMET or INVOKAMET XR may affect the way other medicines work and other medicines may affect how INVOKAMET or INVOKAMET XR works. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. Reference ID: 5499136 3 How should I take INVOKAMET or INVOKAMET XR?  If you are prescribed INVOKAMET, take by mouth 2 times each day with meals exactly as your healthcare provider tells you to take it. Taking INVOKAMET with meals may lower your chance of having an upset stomach.  If you are prescribed INVOKAMET XR, take by mouth 1 time each day with the morning meal exactly as your healthcare provider tells you to take it. Taking INVOKAMET XR with a meal may lower your chance of having an upset stomach.  Swallow INVOKAMET XR whole. Do not crush, cut, or chew.  You may sometimes pass a soft mass in your stools (bowel movement) that looks like INVOKAMET XR tablets. It is normal to see this in your stool.  Your healthcare provider may change your dose if needed.  Your healthcare provider may tell you to take INVOKAMET or INVOKAMET XR along with other diabetes medicines. Low blood sugar can happen more often when INVOKAMET or INVOKAMET XR is taken with certain other diabetes medicines. See “What are the possible side effects of INVOKAMET or INVOKAMET XR?”  Your healthcare provider may tell you to stop taking INVOKAMET or INVOKAMET XR at least 3 days before any surgery or procedure that requires not having food for a long time (prolonged fasting).  If you miss a dose of INVOKAMET, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take 2 tablets of INVOKAMET at the same time. Talk to your healthcare provider if you have questions about a missed dose.  If you miss a dose of INVOKAMET XR, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take more than 2 tablets of INVOKAMET XR at the same time. Talk to your healthcare provider if you have questions about a missed dose.  If you take too much INVOKAMET or INVOKAMET XR, call your healthcare provider or Poison Help line at 1-800-222­ 1222 or go to the nearest hospital emergency room right away.  When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you have any of these conditions and follow your healthcare provider’s instructions.  INVOKAMET and INVOKAMET XR will cause your urine to test positive for glucose.  Your healthcare provider may do certain blood tests before you start INVOKAMET or INVOKAMET XR and during treatment as needed. Your healthcare provider may change your dose of INVOKAMET or INVOKAMET XR based on the results of your blood tests. What should I avoid while taking INVOKAMET or INVOKAMET XR?  Avoid drinking alcohol very often or drinking a lot of alcohol in a short period of time (“binge” drinking). It can increase your chances of getting serious side effects. What are the possible side effects of INVOKAMET or INVOKAMET XR? INVOKAMET or INVOKAMET XR may cause serious side effects including:  See "What is the most important information I should know about INVOKAMET or INVOKAMET XR?”  serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. Tell your healthcare provider if you have any signs or symptoms of a urinary tract infection such as a burning feeling when passing urine, a need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people may also have a fever, back pain, nausea, or vomiting.  low blood sugar (hypoglycemia). If you take INVOKAMET or INVOKAMET XR with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take INVOKAMET or INVOKAMET XR. Signs and symptoms of low blood sugar may include: o headache o drowsiness o weakness o confusion o dizziness o irritability o hunger o fast heartbeat o sweating o shaking or feeling jittery  a rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in people who take canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention Reference ID: 5499136 4 immediately if you have a fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around your anus and genitals: o pain or tenderness o swelling o redness of the skin (erythema)  serious allergic reaction. If you have any symptoms of a serious allergic reaction, stop taking INVOKAMET or INVOKAMET XR and call your healthcare provider right away or go to the nearest hospital emergency room. See “Do not take INVOKAMET or INVOKAMET XR if you:”. Your healthcare provider may give you a medicine for your allergic reaction and prescribe a different medicine for your diabetes.  broken bones (fractures). Bone fractures have been seen in patients taking canagliflozin. Talk to your healthcare provider about factors that may increase your risk of bone fracture.  low vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause a decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 blood levels before. Your healthcare provider may order blood tests to check your vitamin B12 levels. Other common side effects of INVOKAMET or INVOKAMET XR include:  nausea and vomiting  diarrhea  weakness  gas  upset stomach  indigestion  headache  changes in urination, including urgent need to urinate more often, in larger amounts, or at night These are not all the possible side effects of INVOKAMET or INVOKAMET XR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc. at 1-800-526-7736. How should I store INVOKAMET or INVOKAMET XR?  Store INVOKAMET or INVOKAMET XR at room temperature between 68 °F to 77 °F (20 °C to 25 °C).  Store INVOKAMET or INVOKAMET XR in the original container to protect from moisture. Storage in a pill box or pill organizer is allowed for up to 30 days. Keep INVOKAMET and INVOKAMET XR and all medicines out of the reach of children. General information about the safe and effective use of INVOKAMET or INVOKAMET XR. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use INVOKAMET or INVOKAMET XR for a condition for which it was not prescribed. Do not give INVOKAMET or INVOKAMET XR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about INVOKAMET or INVOKAMET XR that is written for health professionals. What are the ingredients in INVOKAMET? Active ingredients: canagliflozin and metformin HCl Inactive ingredients: The tablet core contains croscarmellose sodium (E468), hypromellose, magnesium stearate (E572), and microcrystalline cellulose (E460[i]). The magnesium stearate is vegetable-sourced. In addition, the tablet coating contains Macrogol/PEG3350 (E1521), polyvinyl alcohol (E1203) (partially hydrolyzed), talc (E553b), titanium dioxide (E171), iron oxide yellow (E172) (50 mg/1,000 mg and 150 mg/500 mg tablets only), iron oxide red (E172) (50 mg/1,000 mg, 150 mg/500 mg and 150 mg/1,000 mg tablets only), and iron oxide black (E172) (150 mg/1,000 mg tablets only). What are the ingredients of INVOKAMET XR? Active ingredients: canagliflozin and metformin HCl Inactive ingredients: The tablet core contains croscarmellose sodium (E468), hydroxypropyl cellulose (E463), hypromellose, lactose anhydrous, magnesium stearate (E572) (vegetable-sourced), microcrystalline cellulose (E460[i]), polyethylene oxide, and silicified microcrystalline cellulose (50 mg/500 mg and 50 mg/1,000 mg tablets only). In addition, the tablet coating contains macrogol/PEG3350 (E1521), polyvinyl alcohol (E1203) (partially hydrolyzed), talc (E553b), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172), and iron oxide black (E172) (50 mg/1,000 mg and 150 mg/1,000 mg tablets only). Manufactured for: Janssen Pharmaceuticals, Inc., Titusville, NJ 08560, USA. Licensed from Mitsubishi Tanabe Pharma Corporation. For patent information: www.janssenpatents.com © Johnson & Johnson and its affiliates 2014 - 2024 For more information about INVOKAMET or INVOKAMET XR, call 1-800-526-7736 or visit our websites at www.invokamet.com or www.invokametxr.com. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2024 Reference ID: 5499136 5
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2025-02-12T15:47:54.706256
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use INVOKAMET or INVOKAMET XR safely and effectively. See full prescribing information for INVOKAMET or INVOKAMET XR. INVOKAMET® (canagliflozin and metformin hydrochloride) tablets, for oral use INVOKAMET® XR (canagliflozin and metformin hydrochloride) extended-release tablets, for oral use Initial U.S. Approval: 2014 WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.  Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. (5.1)  Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. (5.1)  If lactic acidosis is suspected, discontinue INVOKAMET or INVOKAMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1) -------------------------RECENT MAJOR CHANGES----------------------------­ Indications and Usage (1) 12/2024 Dosage and Administration (2.2, 2.3, 2.4) 12/2024 Dosage and Administration (2.6) 08/2024 Warnings and Precautions (5.3) 01/2024 ----------------------------INDICATIONS AND USAGE--------------------------­ INVOKAMET and INVOKAMET XR are a combination of canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus (1). Canagliflozin Canagliflozin, when used as a component of INVOKAMET or INVOKAMET XR is indicated in adults with type 2 diabetes mellitus to reduce the risk of:  Major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (1).  End-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria (1). Limitations of Use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus (1). -----------------------DOSAGE AND ADMINISTRATION----------------------­  Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating (2.1).  Individualize starting dose based on the patient’s current regimen and renal function . See Table 1 in the full prescribing information for recommended starting dosages based on the current regimen (2.2, 2.3).  The maximum recommended total daily dosage is 300 mg of canagliflozin and 2,000 mg of metformin HCl (2.2).  Initiation of INVOKAMET or INVOKAMET XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m2, due to the metformin HCl component (2.3).  INVOKAMET: take one tablet orally twice daily with meals (2.2).  INVOKAMET XR: take two tablets orally once daily with the morning meal. Swallow whole. Never crush, cut, or chew (2.2)  Gradually escalate the dosage of metformin HCl in INVOKAMET or INVOKAMET XR to reduce the risk of gastrointestinal adverse reactions with metformin HCl (2.2).  Dose adjustment for patients with renal impairment may be required (2.3)  See full prescribing information for INVOKAMET and INVOKAMET XR dosage modifications due to drug interactions (2.4).  May need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.5).  Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting (2.6). --------------------DOSAGE FORMS AND STRENGTHS---------------------­ INVOKAMET tablets:  Canagliflozin 50 mg and metformin HCl 500 mg (3)  Canagliflozin 50 mg and metformin HCl 1,000 mg (3)  Canagliflozin 150 mg and metformin HCl 500 mg (3)  Canagliflozin 150 mg and metformin HCl 1,000 mg (3) INVOKAMET XR extended-release tablets:  Canagliflozin 50 mg and metformin HCl 500 mg (3)  Canagliflozin 50 mg and metformin HCl 1,000 mg (3)  Canagliflozin 150 mg and metformin HCl 500 mg (3)  Canagliflozin 150 mg and metformin HCl 1,000 mg (3) -------------------------------CONTRAINDICATIONS-----------------------------­  Severe renal impairment (eGFR less than 30 mL/min/1.73 m2) (4)  Metabolic acidosis, including diabetic ketoacidosis (4)  Serious hypersensitivity reaction to canagliflozin or metformin HCl (4) ---------------------------WARNINGS AND PRECAUTIONS-------------------­  Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue INVOKAMET or INVOKAMET XR if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting (5.2).  Lower Limb Amputation: Monitor patients for infection or ulcers of lower limb and discontinue if these occur (5.3).  Volume Depletion: May result in acute kidney injury. Before initiating, assess and correct volume status in patients with renal impairment, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy (5.4).  Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (5.5).  Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues: Consider a lower dose of insulin or insulin secretagogue to reduce the risk of hypoglycemia when used in combination (5.6).  Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment (5.7).  Genital Mycotic Infections: Monitor and treat if indicated (5.8).  Hypersensitivity Reactions: Discontinue and monitor until signs and symptoms resolve (5.9).  Bone Fracture: Consider factors that contribute to fracture risk before initiating INVOKAMET or INVOKAMET XR (5.10).  Vitamin B12 Deficiency: Metformin HCl may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2- to 3-year intervals and manage any abnormalities (5.11). ------------------------------ADVERSE REACTIONS---------------------------­  Most common adverse reactions associated with canagliflozin (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination (6.1).  Most common adverse reactions associated with metformin HCl (5% or greater incidence) are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS-----------------------------­ Reference ID: 5499136 1  Carbonic Anhydrase Inhibitors: May increase risk of lactic acidosis. Consider more frequent monitoring (7)  Drugs that Reduce Metformin Clearance: May increase risk of lactic acidosis. Consider benefits and risks of concomitant use (7)  See full prescribing information for additional drug interactions and information on interference of INVOKAMET and INVOKAMET XR with laboratory tests. (7) -----------------------USE IN SPECIFIC POPULATIONS----------------------­  Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters (8.1)  Lactation: Not recommended when breastfeeding (8.2) FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: LACTIC ACIDOSIS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Prior to Initiation of INVOKAMET or INVOKAMET XR 2.2 Recommended Dosage and Administration 2.3 Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment 2.4 Concomitant Use with UDP- Glucuronosyltransferase (UGT) Enzyme Inducers 2.5 Discontinuation for Iodinated Contrast Imaging Procedures 2.6 Temporary Interruption for Surgery 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Lactic Acidosis 5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis 5.3 Lower Limb Amputation 5.4 Volume Depletion 5.5 Urosepsis and Pyelonephritis 5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues 5.7 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) 5.8 Genital Mycotic Infections 5.9 Hypersensitivity Reactions 5.10 Bone Fracture 5.11 Vitamin B12 Levels 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience  Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy (8.3)  Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume. Assess renal function more frequently (8.5)  Renal Impairment: Higher incidence of adverse reactions related to hypotension and renal function (8.6)  Hepatic Impairment: Avoid use in patients with hepatic impairment (8.7) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 12/2024 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus 14.2 Glycemic Control Trial in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus 14.3 Canagliflozin Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease 14.4 Canagliflozin Renal and Cardiovascular Outcomes in Adults with Diabetic Nephropathy and Albuminuria 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5499136 2 FULL PRESCRIBING INFORMATION WARNING: LACTIC ACIDOSIS  Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin­ associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].  Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment [see Warnings and Precautions (5.1)].  Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2, 2.3), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].  If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET or INVOKAMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE INVOKAMET INVOKAMET is a combination of canagliflozin and metformin HCl immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. INVOKAMET XR INVOKAMET XR is a combination of canagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Canagliflozin Reference ID: 5499136 3 Canagliflozin, when used as a component of INVOKAMET or INVOKAMET XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of :  Major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).  End-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day. Limitations of Use INVOKAMET or INVOKAMET XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Prior to Initiation of INVOKAMET or INVOKAMET XR Assess renal function before initiating INVOKAMET or INVOKAMET XR and as clinically indicated [see Dosage and Administration (2.3), Contraindications (4), and Warnings and Precautions (5.1, 5.4)]. In patients with volume depletion, correct this condition before initiating INVOKAMET or INVOKAMET XR [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5, 8.6)]. 2.2 Recommended Dosage and Administration INVOKAMET and INVOKAMET XR  INVOKAMET and INVOKAMET XR contain canagliflozin and metformin HCl. For the available strengths of the canagliflozin and metformin HCl components in INVOKAMET and INVOKAMET XR, see Dosage Forms and Strengths (3).  Individualize the starting dosage of INVOKAMET or INVOKAMET XR based on the patient’s current regimen as presented in Table 1 and based on renal function as presented in Table 2 [see Dosage and Administration (2.3]. INVOKAMET Take one tablet of INVOKAMET orally twice daily with meals. INVOKAMET XR Take two tablets of INVOKAMET XR orally once daily with the morning meal. Swallow each tablet whole and never crush, cut, or chew. Reference ID: 5499136 4 Table 1 presents the recommended starting dosage of INVOKAMET and INVOKAMET XR based on the patient’s current regimen. Table 1: Recommended Starting Dosage Based on the Current Regimen Current Regimen INVOKAMET Recommended Dosage INVOKAMET XR Recommended Dosage Not treated with either canagliflozin or metformin HCl Total daily dosage is canagliflozin 100 mg and metformin HCl 1,000 mg Metformin HCl* Total daily dosage is canagliflozin 100 mg and the nearest appropriate total daily dosage of metformin HCl Canagliflozin The same total daily dosage of canagliflozin and a total daily dosage of metformin HCl 1,000 mg Canagliflozin and metformin HCl* The same total daily dosage of canagliflozin and the nearest appropriate total daily dosage of metformin HCl * For patients taking an evening dosage of metformin HCl extended-release tablets, skip the last dose before starting INVOKAMET or INVOKAMET XR the following morning. Recommended Dosage for Additional Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older INVOKAMET The dosage of canagliflozin in INVOKAMET may be increased to the maximum total daily dosage of 300 mg (150 mg orally twice daily) in patients tolerating a dosage of 100 mg (50 mg twice daily) of canagliflozin. The dosage of metformin HCl in INVOKAMET may be increased to the maximum total daily dosage of 2,000 mg (1,000 mg orally twice daily), with gradual escalation to reduce the risk of gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1)]. INVOKAMET XR The dosage of canagliflozin in INVOKAMET XR may be increased to the maximum total daily dosage of 300 mg orally once daily in patients tolerating a 100 mg once daily dosage of canagliflozin. The dosage of metformin HCl in INVOKAMET XR may be increased to the maximum total daily dosage of 2,000 mg once daily, with gradual escalation to reduce the risk of gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1)]. Reference ID: 5499136 5 2.3 Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment  Initiation of INVOKAMET or INVOKAMET XR is not recommended in adults or pediatric patients aged 10 years and older with an eGFR less than 45 mL/min/1.73 m2, due to the metformin component.  Table 2 provides dosage recommendations for adults and pediatric patients aged 10 years and older with renal impairment, based on eGFR [see Use in Specific Populations (8.6) and Clinical Studies (14.4)]. Table 2: Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment Estimated Glomerular Filtration Rate Recommended Dosage of INVOKAMET or INVOKAMET XR* [eGFR (mL/min/1.73 m2)] eGFR 45 to less than 60 The maximum total daily dosage of canagliflozin is 100 mg. eGFR 30 to less than 45 Assess the benefit risk of continuing INVOKAMET or INVOKAMET XR. The maximum total daily dosage of canagliflozin is 100 mg. eGFR less than 30 Contraindicated. If eGFR falls below 30 during treatment; discontinue INVOKAMET or INVOKAMET XR [see Contraindications (4)]. * For the dosing frequency of INVOKAMET and INVOKAMET XR, see Dosage and Administration (2.2). 2.4 Concomitant Use with UDP-Glucuronosyltransferase (UGT) Enzyme Inducers When co-administering INVOKAMET or INVOKAMET XR with an inducer of UGT (e.g., rifampin, phenytoin, phenobarbital, ritonavir), increase the total daily dosage of canagliflozin based on renal function [see Drug Interactions (7)]:  In patients with eGFR 60 mL/min/1.73 m2 or greater, increase the total daily dosage of canagliflozin to 200 mg in patients currently tolerating a total daily dosage of canagliflozin 100 mg. The maximum total daily dosage of canagliflozin is 300 mg.  In patients with eGFR less than 60 mL/min/1.73 m2, increase the total daily dosage of canagliflozin to a maximum of 200 mg in patients currently tolerating a total daily dosage of canagliflozin 100 mg. 2.5 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue INVOKAMET or INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of less than 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart INVOKAMET or INVOKAMET XR if renal function is stable [see Warnings and Precautions (5.1)]. Reference ID: 5499136 6 2.6 Temporary Interruption for Surgery Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume INVOKAMET or INVOKAMET XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)]. 3 DOSAGE FORMS AND STRENGTHS INVOKAMET (canagliflozin and metformin HCl) tablets are available as follows: Canagliflozin Strength Metformin HCl Strength Color/Shape Tablet Identifiers* 50 mg 500 mg white/capsule-shaped CM 155 50 mg 1,000 mg beige/capsule-shaped CM 551 150 mg 500 mg yellow/capsule-shaped CM 215 150 mg 1,000 mg purple/capsule-shaped CM 611 * Embossing appears on both sides of tablet. INVOKAMET XR (canagliflozin and metformin HCl) extended-release tablets are available as follows: Canagliflozin Strength Metformin HCl Strength Color/Shape Tablet Identifiers* 50 mg 500 mg almost white to light orange/oblong, biconvex CM1 50 mg 1,000 mg pink/oblong, biconvex CM3 150 mg 500 mg orange/oblong, biconvex CM2 150 mg 1,000 mg reddish brown/oblong, biconvex CM4 * Embossing appears on one side only of tablet. 4 CONTRAINDICATIONS INVOKAMET or INVOKAMET XR is contraindicated in patients with:  Severe renal impairment (eGFR less than 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].  Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.2)].  Serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema [see Warnings and Precautions (5.9) and Adverse Reactions (6)]. 5 WARNINGS AND PRECAUTIONS 5.1 Lactic Acidosis There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as Reference ID: 5499136 7 malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET or INVOKAMET XR. In INVOKAMET or INVOKAMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue INVOKAMET or INVOKAMET XR and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].  Before initiating INVOKAMET or INVOKAMET XR, obtain an estimated glomerular filtration rate (eGFR).  INVOKAMET or INVOKAMET XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)].  Obtain an eGFR at least annually in all patients taking INVOKAMET or INVOKAMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. Drug Interactions: The concomitant use of INVOKAMET or INVOKAMET XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase Reference ID: 5499136 8 metformin accumulation (e.g. cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients. Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)]. Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop INVOKAMET or INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart INVOKAMET or INVOKAMET XR if renal function is stable. Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. INVOKAMET or INVOKAMET XR should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur, discontinue INVOKAMET or INVOKAMET XR. Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving INVOKAMET or INVOKAMET XR. Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of INVOKAMET or INVOKAMET XR in patients with clinical or laboratory evidence of hepatic disease. 5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, INVOKAMET or INVOKAMET XR significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may be greater with higher doses of Reference ID: 5499136 9 INVOKAMET or INVOKAMET XR. INVOKAMET or INVOKAMET XR is not indicated for glycemic control in patients with type 1 diabetes mellitus. Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKAMET or INVOKAMET XR. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under­ insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INVOKAMET or INVOKAMET XR [see Clinical Pharmacology (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INVOKAMET or INVOKAMET XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKAMET or INVOKAMET XR. Withhold INVOKAMET or INVOKAMET XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKAMET or INVOKAMET XR when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.7)]. Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKAMET or INVOKAMET XR and seek medical attention immediately if signs and symptoms occur. 5.3 Lower Limb Amputation An increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET or INVOKAMET XR, versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating adult patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower limb amputations was observed at both the 100 mg and Reference ID: 5499136 10 300 mg once daily dosage regimens. The amputation data for CANVAS and CANVAS-R are shown in Tables 4 and 5, respectively [see Adverse Reactions (6.1)]. Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving canagliflozin in the two trials). Some patients had multiple amputations, some involving both lower limbs. Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving INVOKAMET or INVOKAMET XR for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKAMET or INVOKAMET XR if these complications occur. 5.4 Volume Depletion Canagliflozin can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There have been post-marketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKAMET or INVOKAMET XR in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy. 5.5 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving canagliflozin. Treatment with INVOKAMET or INVOKAMET XR increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)]. 5.6 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKAMET or INVOKAMET XR may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)]. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. Reference ID: 5499136 11 5.7 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with INVOKAMET or INVOKAMET XR presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKAMET or INVOKAMET XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control. 5.8 Genital Mycotic Infections Canagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately. 5.9 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with canagliflozin. These reactions generally occurred within hours to days after initiating canagliflozin. If hypersensitivity reactions occur, discontinue use of INVOKAMET or INVOKAMET XR; treat and monitor until signs and symptoms resolve [see Contraindications (4) and Adverse Reactions (6.1, 6.2)]. 5.10 Bone Fracture An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in adult patients using canagliflozin in the CANVAS trial [see Clinical Studies (14.3)]. Consider factors that contribute to fracture risk prior to initiating INVOKAMET or INVOKAMET XR [see Adverse Reactions (6.1)]. 5.11 Vitamin B12 Levels In metformin HCl clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin HCl or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on INVOKAMET or INVOKAMET XR and manage any abnormalities [see Adverse Reactions (6.1)]. Reference ID: 5499136 12 6 ADVERSE REACTIONS The following important adverse reactions are also discussed elsewhere in the labeling:  Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1, 5.4)]  Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [see Warnings and Precautions (5.2)]  Lower Limb Amputation [see Warnings and Precautions (5.3)]  Volume Depletion [see Warnings and Precautions (5.4)]  Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)]  Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.6)]  Necrotizing Fasciitis of the Perineum (Fournier’s gangrene) [see Warnings and Precautions (5.7)]  Genital Mycotic Infections [see Warnings and Precautions (5.8)]  Hypersensitivity Reactions [see Warnings and Precautions (5.9)]  Bone Fracture [see Warnings and Precautions (5.10)]  Vitamin B12 Deficiency [see Warnings and Precautions (5.11)] 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Canagliflozin has been evaluated in clinical trials in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Additionally, canagliflozin has been studied in clinical trials in adult patients with type 2 diabetes mellitus who also have heart failure or chronic kidney disease. The overall safety profile of canagliflozin was consistent across the studied indications. Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Placebo-Controlled Trials for Glycemic Control Canagliflozin The data in Table 3 are derived from four 26-week placebo-controlled trials where canagliflozin was used as monotherapy in one trial and as add-on therapy in three trials. These data reflect exposure of 1,667 adult patients to canagliflozin and a mean duration of exposure to Reference ID: 5499136 13 canagliflozin of 24 weeks with 1,275 patients exposed to a combination of canagliflozin and metformin HCl. Patients received canagliflozin 100 mg (N=833), canagliflozin 300 mg (N=834) or placebo (N=646) once daily. The mean daily dose of metformin HCl was 2,138 mg (SD 337.3) for the 1,275 patients in the three placebo-controlled metformin HCl add-on trials. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were White, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2). Table 3 shows common adverse reactions associated with the use of canagliflozin. These adverse reactions were not present at baseline, occurred more commonly on canagliflozin than on placebo, and occurred in at least 2% of patients treated with either canagliflozin 100 mg or canagliflozin 300 mg. Table 3: Adverse Reactions from Pool of Four 26−Week Placebo-Controlled Trials Reported in ≥ 2% of Canagliflozin-Treated Adult Patients* Adverse Reaction Placebo N=646 Canagliflozin 100 mg N=833 Canagliflozin 300 mg N=834 Urinary tract infections‡ 3.8% 5.9% 4.4% Increased urination§ 0.7% 5.1% 4.6% Thirst# 0.1% 2.8% 2.4% Constipation 0.9% 1.8% 2.4% Nausea 1.6% 2.1% 2.3% N=312 N=425 N=430 Female genital mycotic infections† 2.8% 10.6% 11.6% Vulvovaginal pruritus 0.0% 1.6% 3.2% N=334 N=408 N=404 Male genital mycotic infections¶ 0.7% 4.2% 3.8% * The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin HCl, metformin HCl and sulfonylurea, or metformin HCl and pioglitazone. † Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. ‡ Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. § Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. ¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. # Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. Note: Percentages were weighted by trials. Trial weights were proportional to the harmonic mean of the three treatment sample sizes. Abdominal pain was also more commonly reported in patients taking canagliflozin 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Canagliflozin and Metformin HCl The incidence and type of adverse reactions in the three 26-week placebo-controlled metformin HCl tablets add-on trials in adults, representing a majority of data from the four 26-week placebo-controlled trials, was similar to the adverse reactions described in Table 3. There were no additional adverse reactions identified in the pooling of these three Reference ID: 5499136 14 placebo-controlled trials that included metformin HCl tablets relative to the four placebo-controlled trials. In a trial in adults with canagliflozin as initial combination therapy with metformin HCl [see Clinical Studies (14.1)], an increased incidence of diarrhea was observed in the canagliflozin and metformin HCl combination groups (4.2%) compared to canagliflozin or metformin HCl monotherapy groups (1.7%). Placebo-Controlled Trial in Diabetic Nephropathy The occurrence of adverse reactions for canagliflozin was evaluated in patients participating in CREDENCE, a trial in adult patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria ˃ 300 mg/day [see Clinical Studies (14.4)]. These data reflect exposure of 2,201 adult patients to canagliflozin and a mean duration of exposure to canagliflozin of 137 weeks. The rate of lower limb amputations associated with the use of canagliflozin 100 mg relative to placebo was 12.3 vs 11.2 events per 1,000 patient-years, respectively, with 2.6 years mean duration of follow-up. The incidence of hypotension was 2.8% and 1.5% on canagliflozin 100 mg and placebo, respectively. Pool of Placebo- and Active-Controlled Trials for Glycemic Control and Cardiovascular Outcomes The occurrence of adverse reactions for canagliflozin was evaluated in adult patients participating in placebo- and active-controlled trials and in an integrated analysis of two cardiovascular trials, CANVAS and CANVAS-R. The types and frequency of common adverse reactions observed in the pool of eight clinical trials (which reflect an exposure of 6,177 adult patients to canagliflozin) were consistent with those listed in Table 3. Percentages were weighted by trials. Trial weights were proportional to the harmonic mean of the three treatment sample sizes. In this pool, canagliflozin was also associated with the adverse reactions of fatigue (1.8%, 2.2%, and 2.0% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively) and loss of strength or energy (i.e., asthenia) (0.6%, 0.7%, and 1.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively). In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.1%, 0.2%, and 0.1% receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) was 3.0%, 3.8%, and 4.2% of adult patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Five patients Reference ID: 5499136 15 experienced serious adverse reactions of hypersensitivity with canagliflozin, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to canagliflozin. Among these patients, 2 patients discontinued canagliflozin. One patient with urticaria had recurrence when canagliflozin was re-initiated. Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Other adverse reactions occurring more frequently on canagliflozin than on comparator were: Lower Limb Amputation An increased risk of lower limb amputations associated with canagliflozin was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating adult patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. Patients in CANVAS and CANVAS-R were followed for an average of 5.7 and 2.1 years, respectively [see Clinical Studies (14.3)]. The amputation data for CANVAS and CANVAS-R are shown in Tables 4 and 5, respectively. Table 4: Amputations in the CANVAS Trial in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Placebo N=1,441 Canagliflozin 100 mg N=1,445 Canagliflozin 300 mg N=1,441 Canagliflozin (Pooled) N=2,886 Patients with an amputation, n (%) 22 (1.5) 50 (3.5) 45 (3.1) 95 (3.3) Total amputations 33 83 79 162 Amputation incidence rate (per 1,000 patient-years) 2.8 6.2 5.5 5.9 Hazard Ratio (95% CI) -­ 2.24 (1.36, 3.69) 2.01 (1.20, 3.34) 2.12 (1.34, 3.38) Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. Table 5: Amputations in the CANVAS-R Trial in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Placebo N=2,903 Canagliflozin 100 mg (with up-titration to 300 mg) N=2,904 Patients with an amputation, n (%) 25 (0.9) 45 (1.5) Total amputations 36 59 Amputation incidence rate (per 1,000 patient-years) 4.2 7.5 Hazard Ratio (95% CI) -­ 1.80 (1.10, 2.93) Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. Reference ID: 5499136 16 Renal Cell Carcinoma In the CANVAS trial in adults (mean duration of follow-up of 5.7 years) [see Clinical Studies (14.3)], the incidence of renal cell carcinoma was 0.15% (2/1,331) and 0.29% (8/2,716) for placebo and canagliflozin, respectively, excluding patients with less than 6 months of follow­ up, less than 90 days of treatment, or a history of renal cell carcinoma. A causal relationship to canagliflozin could not be established due to the limited number of cases. Volume Depletion-Related Adverse Reactions Canagliflozin results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical trials for glycemic control, treatment with canagliflozin was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in adult patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions in these trials were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and age 75 years and older (Table 6) [see Use in Specific Populations (8.5 and 8.6)]. Table 6: Adult Patients with at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials for Glycemic Control) Baseline Characteristic Comparator Group* % Canagliflozin 100 mg % Canagliflozin 300 mg % Overall population 1.5% 2.3% 3.4% 75 years of age and older† 2.6% 4.9% 8.7% eGFR less than 60 mL/min/1.73 m2† 2.5% 4.7% 8.1% Use of loop diuretic† 4.7% 3.2% 8.8% * Includes placebo and active-comparator groups † Patients could have more than 1 of the listed risk factors Falls In a pool of nine clinical trials in adults with mean duration of exposure to canagliflozin of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The higher risk of falls for patients treated with canagliflozin was observed within the first few weeks of treatment. Genital Mycotic Infections In the pool of four placebo-controlled clinical trials in adults for glycemic control, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 2.8%, 10.6%, and 11.6% of females treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on canagliflozin. Female patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrence and require treatment with oral or topical antifungal agents and Reference ID: 5499136 17 anti-microbial agents. In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and canagliflozin, respectively. In the pool of four placebo-controlled clinical trials in adults, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.7%, 4.2%, and 3.8% of males treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on canagliflozin were more likely to experience recurrent infections (22% on canagliflozin versus none on placebo) and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and canagliflozin, respectively. In the pooled analysis of 8 randomized trials in adults evaluating glycemic control, phimosis was reported in 0.3% of uncircumcised male patients treated with canagliflozin and 0.2% required circumcision to treat the phimosis. Hypoglycemia In canagliflozin glycemic control trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials of glycemic control in adults [see Clinical Studies (14.1)], episodes of hypoglycemia occurred at a higher rate when canagliflozin was co- administered with insulin or sulfonylureas (Table 7). Table 7: Incidence of Hypoglycemia* in Randomized Clinical Trials of Glycemic Control in Adults Monotherapy (26 weeks) Placebo (N=192) Canagliflozin 100 mg (N=195) Canagliflozin 300 mg (N=197) Overall [N (%)] 5 (2.6) 7 (3.6) 6 (3.0) In Combination with Metformin HCl (26 weeks) Placebo + Metformin HCl (N=183) Canagliflozin 100 mg + Metformin HCl (N=368) Canagliflozin 300 mg + Metformin HCl (N=367) Overall [N (%)] 3 (1.6) 16 (4.3) 17 (4.6) Severe [N (%)]† 0 (0) 1 (0.3) 1 (0.3) In Combination with Metformin HCl (18 weeks)‡ Placebo (N=93) Canagliflozin 100 mg (N=93) Canagliflozin 300 mg (N=93) Overall [N (%)] 3 (3.2) 4 (4.3) 3 (3.2) In Combination with Metformin HCl + Sulfonylurea (26 weeks) Placebo + Metformin HCl + Sulfonylurea (N=156) Canagliflozin 100 mg + Metformin HCl + Sulfonylurea (N=157) Canagliflozin 300 mg + Metformin HCl + Sulfonylurea (N=156) Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1) Reference ID: 5499136 18 Severe [N (%)]† 1 (0.6) 1 (0.6) 0 In Combination with Metformin HCl + Pioglitazone (26 weeks) Placebo + Metformin HCl + Pioglitazone (N=115) Canagliflozin 100 mg + Metformin HCl + Pioglitazone (N=113) Canagliflozin 300 mg + Metformin HCl + Pioglitazone (N=114) Overall [N (%)] 3 (2.6) 3 (2.7) 6 (5.3) In Combination with Insulin (18 weeks) Placebo (N=565) Canagliflozin 100 mg (N=566) Canagliflozin 300 mg (N=587) Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6) Severe [N (%)]† 14 (2.5) 10 (1.8) 16 (2.7) In Combination with Insulin and Metformin HCl (18 weeks)§ Placebo (N=145) Canagliflozin 100 mg (N=139) Canagliflozin 300 mg (N=148) Overall [N (%)] 66 (45.5) 58 (41.7) 70 (47.3) Severe [N (%)]† 4 (2.8) 1 (0.7) 3 (2.0) * Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population † Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) ‡ Phase 2 clinical trial with twice daily dosing (50 mg or 150 mg twice daily in combination with metformin HCl) § Subgroup of patients (N=287) from insulin subtrial on canagliflozin in combination with metformin HCl and insulin (with or without other antiglycemic agents) Bone Fracture In the CANVAS trial in adults [see Clinical Studies (14.3)], the incidence rates of all adjudicated bone fracture were 1.09, 1.59, and 1.79 events per 100 patient-years of follow-up to placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. The fracture imbalance was observed within the first 26 weeks of therapy and remained through the end of the trial. Fractures were more likely to be low trauma (e.g., fall from no more than standing height), and affect the distal portion of upper and lower extremities. Metformin HCl The most common adverse reactions (5% or greater incidence) due to initiation of metformin HCl in adults are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of adult patients. Laboratory and Imaging Tests Increases in Serum Creatinine and Decreases in eGFR Initiation of canagliflozin causes an increase in serum creatinine and decrease in estimated GFR. In patients with moderate renal impairment, the increase in serum creatinine generally does not exceed 0.2 mg/dL, occurs within the first 6 weeks of starting therapy, and then stabilizes. Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Clinical Pharmacology (12.1)]. The acute effect on eGFR reverses after Reference ID: 5499136 19 treatment discontinuation suggesting acute hemodynamic changes may play a role in the renal function changes observed with canagliflozin. Increases in Serum Potassium In a pooled population of adult patients (N=723) in glycemic control trials with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 m2), increases in serum potassium to greater than 5.4 mEq/L and 15% above occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with canagliflozin 100 mg, and 1.3% of patients treated with canagliflozin 300 mg. In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Use in Specific Populations (8.6)]. In CREDENCE, no difference in serum potassium, no increase in adverse events of hyperkalemia, and no increase in absolute (> 6.5 mEq/L) or relative (> upper limit of normal and > 15% increase from baseline) increases in serum potassium were observed in adult patients treated with canagliflozin 100 mg relative to placebo. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C) In the pool of four glycemic control placebo-controlled trials in adults, dose-related increases in LDL-C with canagliflozin were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with canagliflozin 100 mg and canagliflozin 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups. Dose-related increases in non-HDL-C with canagliflozin were observed in adults. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with canagliflozin 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups. Increases in Hemoglobin In the pool of four placebo-controlled trials in adults of glycemic control, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with canagliflozin 100 mg, and 0.51 g/dL (3.8%) with canagliflozin 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively, had hemoglobin above the upper limit of normal. Reference ID: 5499136 20 Decreases in Bone Mineral Density Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years) [see Clinical Studies (14.1)]. At 2 years, adult patients randomized to canagliflozin 100 mg and canagliflozin 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both canagliflozin doses and 0.4% at the distal forearm for patients randomized to canagliflozin 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to canagliflozin 100 mg was 0%. Clinical Trials in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus Canagliflozin Canagliflozin was administered to 84 pediatric patients in a double-blind, placebo-controlled trial of 171 pediatric patients aged 10 to 17 years with a mean exposure to canagliflozin of 48.3 weeks [see Clinical Studies (14.2)]. At baseline, background therapies included metformin monotherapy (46%), metformin and insulin (29%), diet and exercise only (14%), and insulin monotherapy (11%). Approximately 42% were Asian, 42% were White, 11% were Black or African American, 5% were American Indian/Alaska Native, and 36% identified as Hispanic or Latino ethnicity. The mean baseline eGFR was 157.3 mL/min/1.73 m2, and approximately 16% (24/151) of the trial population with measurements had microalbuminuria or macroalbuminuria. The safety profile of pediatric patients treated with canagliflozin was similar to that observed in adults with type 2 diabetes mellitus. Metformin HCl In clinical trials with metformin HCl immediate-release tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of canagliflozin and/or metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Canagliflozin Metabolism and Nutrition Ketoacidosis Renal and Urinary Acute Kidney Injury Reference ID: 5499136 21 Immune System Anaphylaxis Skin and Subcutaneous Tissue Angioedema Infections Urosepsis and Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s gangrene) Metformin HCl Hepatobiliary Cholestatic, hepatocellular, and mixed hepatocellular liver injury 7 DRUG INTERACTIONS Table 8: Clinically Significant Drug Interactions with INVOKAMET or INVOKAMET XR Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET or INVOKAMET XR may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) Drugs That Reduce Metformin Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)]. Intervention: Consider the benefits and risks of concomitant use. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving INVOKAMET or INVOKAMET XR. UGT Enzyme Inducers Clinical Impact: UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKAMET or INVOKAMET XR. Intervention: For patients with eGFR 60 mL/min/1.73 m2 or greater, if an inducer of UGTs is co-administered with INVOKAMET or INVOKAMET XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating INVOKAMET or INVOKAMET XR with a total daily dose of canagliflozin 100 mg. The total daily dose of canagliflozin may be increased to 300 mg in patients currently tolerating canagliflozin 200 mg and who require additional glycemic control. For patients with eGFR less than 60 mL/min/1.73 m2, if an inducer of UGTs is co-administered with INVOKAMET or INVOKAMET XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating canagliflozin 100 mg [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. Examples: Rifampin, phenytoin, phenobarbital, ritonavir Reference ID: 5499136 22 Insulin or Insulin Secretagogues Clinical Impact: The risk of hypoglycemia is increased when INVOKAMET or INVOKAMET XR is used concomitantly with insulin secretagogues (e.g., sulfonylurea) or insulin. Intervention: Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: When such drugs are administered to a patient receiving INVOKAMET or INVOKAMET XR, monitor for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET or INVOKAMET XR, monitor for hypoglycemia. Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. Digoxin Clinical Impact: Canagliflozin increases digoxin exposure [see Clinical Pharmacology (12.3)]. Intervention: Monitor patients taking INVOKAMET or INVOKAMET XR with concomitant digoxin for a need to adjust the dosage of digoxin. Lithium Clinical Impact: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention: Monitor serum lithium concentration more frequently during INVOKAMET or INVOKAMET XR initiation and dosage changes. Drug/Laboratory Test Interference Positive Urine Glucose Test Clinical Impact: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. Intervention: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention: Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on juvenile animal data showing adverse renal effects from canagliflozin, INVOKAMET or INVOKAMET XR is not recommended during the second and third trimesters of pregnancy. Limited data with INVOKAMET, INVOKAMET XR or canagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin HCl use during pregnancy have not reported a clear association with metformin HCl and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. In juvenile animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered during a period of renal development Reference ID: 5499136 23 corresponding to the late second and third trimesters of human pregnancy, at an exposure 0.5­ times the 300 mg clinical dose, based on AUC. No adverse developmental effects were observed when metformin HCl was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 6-times, respectively, a 2,000 mg clinical dose, based on body surface area [see Data]. The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1C >7 and has been reported to be as high as 20-25% in women with a HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre­ eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin HCl and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin HCl was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Canagliflozin Canagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg increased kidney weights and dose dependently increased the incidence and severity of renal pelvic and tubular dilatation at all doses tested. Exposure at the lowest dose was greater than or equal to 0.5-times the 300 mg clinical dose, based on AUC. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. The renal pelvic dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period. In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities independent of maternal toxicity were observed when canagliflozin was administered at doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits during embryonic organogenesis or during a study in which maternal rats were dosed from gestation day Reference ID: 5499136 24 (GD) 6 through PND 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on AUC. Metformin HCl Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2,000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively. Canagliflozin and Metformin HCl No adverse developmental effects were observed when canagliflozin and metformin HCl were co-administered to pregnant rats during the period of organogenesis at exposures up to 11 and 13 times, respectively, the 300 mg and 2,000 mg clinical doses of canagliflozin and metformin HCl based on AUC. 8.2 Lactation Risk Summary There is no information regarding the presence of INVOKAMET, INVOKAMET XR or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information on the effects of metformin HCl on the breastfed infant and no available information on the effects of metformin HCl on milk production. Canagliflozin is present in the milk of lactating rats [see Data]. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of INVOKAMET or INVOKAMET XR is not recommended while breastfeeding. Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin HCl during lactation because of small sample size and limited adverse event data collected in infants. Radiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Reference ID: 5499136 25 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women. 8.4 Pediatric Use The safety and effectiveness of INVOKAMET and INVOKAMET XR as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of INVOKAMET and INVOKAMET XR for this indication is supported by evidence from a 52-week double-blind, placebo-controlled trial of canagliflozin in 171 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus and in a pediatric pharmacokinetic study [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. The safety profile of pediatric patients treated with canagliflozin was similar to that observed in adults with type 2 diabetes mellitus. The use of INVOKAMET and INVOKAMET XR for this indication is also supported by evidence from adequate and well-controlled trials of metformin HCl immediate-release tablets in adults with additional data from a controlled clinical trial using metformin HCl immediate- release tablets in pediatric patients 10 to 16 years old with type 2 diabetes mellitus, and pharmacokinetic data with metformin HCl extended-release tablets in adults [see Clinical Pharmacology (12.3) and Clinical Studies (14.1, 14.2)]. In the clinical trial with pediatric patients receiving metformin HCl immediate-release tablets, adverse reactions with metformin HCl immediate-release tablets were similar to those described in adults [see Adverse Reactions (6.1)]. The safety and effectiveness of INVOKAMET or INVOKAMET XR for glycemic control in patients with type 2 diabetes mellitus have not been established in pediatric patients under 10 years of age. The safety and effectiveness of INVOKAMET or INVOKAMET XR have not been established in pediatric patients to reduce the risk of:  major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in patients with type 2 diabetes mellitus and established cardiovascular disease (CVD).  end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day. Reference ID: 5499136 26 8.5 Geriatric Use INVOKAMET and INVOKAMET XR Because renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, monitor renal function more frequently after initiating INVOKAMET or INVOKAMET XR in the elderly and then adjust dose based on renal function [see Dosage and Administration (2.4) and Warnings and Precautions (5.1, 5.4)]. Canagliflozin In 13 clinical trials of canagliflozin, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to canagliflozin. Of these patients, 1,534 patients 65 years and older and 196 patients 75 years and older were exposed to the combination of canagliflozin and metformin HCl [see Clinical Studies (14.1)]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with canagliflozin (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) and Adverse Reactions (6.1)]. Smaller reductions in HbA1C with canagliflozin relative to placebo were seen in older (65 years and older; -0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg relative to placebo) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg relative to placebo). Metformin HCl Controlled clinical trials of metformin HCl did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. The initial and maintenance dosing of metformin HCl should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications (4), Warnings and Precautions (5.4), and Clinical Pharmacology (12.3)]. 8.6 Renal Impairment Canagliflozin The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included adult patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2). These patients had less overall glycemic efficacy, and patients treated with canagliflozin 300 mg per day had increases in serum potassium, which were transient and similar by the end of the trial. Patients with renal impairment using canagliflozin for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury [see Warnings and Precautions (5.4)]. Reference ID: 5499136 27 Efficacy and safety trials with canagliflozin did not enroll adult patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2 [see Clinical Pharmacology (12.3)]. Metformin HCl Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. INVOKAMET or INVOKAMET XR is contraindicated in severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or in patients on dialysis [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Use of metformin HCl in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET or INVOKAMET XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)]. 10 OVERDOSAGE Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl use has been established. Lactic acidosis has been reported in approximately 32% of metformin HCl overdose cases [see Warnings and Precautions (5.1)]. In the event of an overdose with INVOKAMET or INVOKAMET XR, contact the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom INVOKAMET or INVOKAMET XR overdosage is suspected. 11 DESCRIPTION INVOKAMET® (canagliflozin and metformin HCl immediate-release tablets) and INVOKAMET® XR (canagliflozin and metformin HCl extended-release tablets) contain canagliflozin and metformin HCl. Canagliflozin Canagliflozin is an inhibitor of SGLT2, the transporter responsible for reabsorbing the majority of glucose filtered by the kidney. Canagliflozin is chemically known as (1S)-1,5-anhydro-1-[3­ [[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate and its molecular formula and weight are C24H25FO5S1/2 H2O and 453.53, respectively. The structural formula for canagliflozin is: Reference ID: 5499136 28 F OH OH Canagliflozin is practically insoluble in aqueous media from pH 1.1 to 12.9. Metformin HCl Metformin HCl is a biguanide chemically known as 1,1-Dimethylbiguanide HCl and its molecular formula and weight are C4H11N5 ● HCl and 165.62, respectively. The structural formula for metformin HCl is: NH NH H2N NH N CH3 HCl CH3 INVOKAMET and INVOKAMET XR INVOKAMET or INVOKAMET XR are supplied as film-coated tablets for oral administration. Each 50 mg/500 mg tablet and 50 mg/1,000 mg tablet contains 51 mg of canagliflozin equivalent to 50 mg canagliflozin (anhydrous) and 500 mg or 1,000 mg metformin HCl (equivalent to metformin 389.93 mg and 779.86 mg, respectively). Each 150 mg/500 mg tablet and 150 mg/1,000 mg tablet contains 153 mg of canagliflozin equivalent to 150 mg canagliflozin (anhydrous) and 500 mg or 1,000 mg metformin HCl (equivalent to metformin 389.93 mg and 779.86 mg, respectively). INVOKAMET contains the following inactive ingredients: croscarmellose sodium (E468), hypromellose, magnesium stearate (E572), and microcrystalline cellulose (E460[i]). The magnesium stearate is vegetable-sourced. The tablets are finished with a commercially available film-coating consisting of the following inactive ingredients: macrogol/PEG3350 (E1521), polyvinyl alcohol (E1203) (partially hydrolyzed), talc (E553b), titanium dioxide (E171), iron oxide yellow (E172) (50 mg/1,000 mg and 150 mg/500 mg tablets only), iron oxide red (E172) Reference ID: 5499136 29 (50 mg/1,000 mg, 150 mg/500 mg and 150 mg/1,000 mg tablets only), and iron oxide black (E172) (150 mg/1,000 mg tablets only). INVOKAMET XR contains the following inactive ingredients: croscarmellose sodium (E468), hydroxypropyl cellulose (E463), hypromellose, lactose anhydrous, magnesium stearate (E572) (vegetable-sourced), microcrystalline cellulose (E460[i]), polyethylene oxide, and silicified microcrystalline cellulose (50 mg/500 mg and 50 mg/1,000 mg tablets only). The tablets are finished with a commercially available film-coating consisting of the following inactive ingredients: macrogol/PEG3350 (E1521), polyvinyl alcohol (E1203) (partially hydrolyzed), talc (E553b), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172), and iron oxide black (E172) (50 mg/1,000 mg and 150 mg/1,000 mg tablets only). INVOKAMET XR tablets provide canagliflozin for immediate-release and metformin HCl for extended-release. Each bilayer tablet is compressed from two separate granulates, one for each active ingredient of the tablet, and finished with a film-coating. The metformin HCl extended-release layer is based on a polymer matrix which controls the drug release by passive diffusion through the swollen matrix in combination with tablet erosion. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Canagliflozin SGLT2, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE). Canagliflozin increases the delivery of sodium to the distal tubule by blocking SGLT2-dependent glucose and sodium reabsorption. This is believed to increase tubuloglomerular feedback and reduce intraglomerular pressure. Metformin HCl Metformin HCl is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin HCl decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease. 12.2 Pharmacodynamics Canagliflozin Following single and multiple oral doses of canagliflozin in adult patients with type 2 diabetes, dose-dependent decreases in RTG and increases in urinary glucose excretion were observed. From a starting RTG value of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg Reference ID: 5499136 30 once daily suppressed RTG throughout the 24-hour period. Data from single oral doses of canagliflozin in healthy volunteers indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for doses up to 300 mg once daily. Maximal suppression of mean RTG over the 24-hour period was seen with the 300 mg daily dose to approximately 70 to 90 mg/dL in patients with type 2 diabetes in Phase 1 trials. The reductions in RTG led to increases in mean UGE of approximately 100 g/day in patients with type 2 diabetes treated with either 100 mg or 300 mg of canagliflozin. The 24-h mean RTG at steady state was similar following once daily and twice daily dosing regimens at the same total daily dose of 100 mg or 300 mg. In patients with type 2 diabetes given 100 to 300 mg once daily over a 16-day dosing period, reductions in RTG and increases in urinary glucose excretion were observed over the dosing period. In this trial, plasma glucose declined in a dose-dependent fashion within the first day of dosing. Cardiac Electrophysiology In a randomized, double-blind, placebo-controlled, active-comparator, 4-way crossover trial, 60 healthy adult subjects were administered a single oral dose of canagliflozin 300 mg, canagliflozin 1,200 mg (4 times the maximum recommended dose), moxifloxacin, and placebo. No meaningful changes in QTc interval were observed with either the recommended dose of 300 mg or the 1,200 mg dose. 12.3 Pharmacokinetics INVOKAMET Administration of INVOKAMET 150 mg/1,000 mg fixed-dose combination with food resulted in no change in overall exposure of canagliflozin. There was no change in metformin AUC; however, the mean peak plasma concentration of metformin was decreased by 16% when administered with food. A delayed time to peak plasma concentration was observed for both components (a delay of 2 hours for canagliflozin and 1 hour for metformin) under fed conditions. These changes are not likely to be clinically meaningful. INVOKAMET XR After administration of INVOKAMET XR tablets with a high-fat breakfast, the peak (Cmax) and total (AUC) exposure of canagliflozin were not altered relative to dosing in the fasted state. However, the AUC of metformin increased by approximately 61% and Cmax increased by approximately 13%. Canagliflozin The pharmacokinetics of canagliflozin is essentially similar in healthy subjects and patients with type 2 diabetes. Following single-dose oral administration of 100 mg and 300 mg of canagliflozin, peak plasma concentrations (median Tmax) of canagliflozin occurs within 1 to 2 hours post-dose. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. The apparent terminal half-life (t1/2) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after 4 to Reference ID: 5499136 31 5 days of once-daily dosing with canagliflozin 100 mg to 300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics and accumulated in plasma up to 36% following multiple doses of 100 mg and 300 mg. The mean systemic exposure (AUC) at steady state was similar following once daily and twice daily dosing regimens at the same total daily dose of 100 mg or 300 mg. Absorption Canagliflozin The mean absolute oral bioavailability of canagliflozin is approximately 65%. Metformin HCl The absolute bioavailability of a metformin HCl 500 mg tablet given under fasting conditions is approximately 50% to 60%. Trials using single oral doses of metformin HCl 500 to 1,500 mg, and 850 to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Following a single oral dose of 1,000 mg metformin HCl extended-release tablets (two 500 mg tablets) after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7-8 hours. In both single and multiple-dose trials in healthy subjects, once daily 1,000 mg (two 500 mg tablets) dosing results in up to 35% higher Cmax, of metformin relative to the immediate-release given as 500 mg twice daily without any change in overall systemic exposure, as measured by AUC. Distribution Canagliflozin The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 83.5 L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. Metformin HCl The apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl 850 mg immediate-release tablets averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. Metabolism Canagliflozin O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4­ mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans. Reference ID: 5499136 32 Metformin HCl Intravenous single-dose trials in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Excretion Canagliflozin Following administration of a single oral [14C] canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible. Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O­ glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min. Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration. Metformin HCl Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Specific Populations Trials characterizing the pharmacokinetics of canagliflozin and metformin after administration of INVOKAMET or INVOKAMET XR were not conducted in patients with renal and hepatic impairment. Descriptions of the individual components in this patient population are described below. Pediatric Patients Canagliflozin The pharmacokinetics and pharmacodynamics of canagliflozin were investigated in pediatric patients aged 10 years and older with type 2 diabetes mellitus. Oral administration of canagliflozin at 100 mg and 300 mg resulted in exposures and responses consistent with those found in adult patients. Reference ID: 5499136 33 Metformin HCl After administration of a single oral metformin 500 mg immediate-release tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12-16 years of age) and gender-and weight-matched healthy adults (20­ 45 years of age), all with normal renal function. Patients with Renal Impairment Canagliflozin A single-dose, open-label trial evaluated the pharmacokinetics of canagliflozin 200 mg in adult subjects with varying degrees of renal impairment (classified using the MDRD-eGFR formula) compared to healthy subjects. Renal impairment did not affect the Cmax of canagliflozin. Compared to healthy adult subjects (N=3; eGFR greater than or equal to 90 mL/min/1.73 m2), plasma AUC of canagliflozin was increased by approximately 15%, 29%, and 53% in subjects with mild (N=10), moderate (N=9), and severe (N=10) renal impairment, respectively, (eGFR 60 to less than 90, 30 to less than 60, and 15 to less than 30 mL/min/1.73 m2, respectively), but was similar for ESKD (N=8) subjects and healthy subjects. Increases in canagliflozin AUC of this magnitude are not considered clinically relevant. The glucose lowering pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment [see Contraindications (4) and Warnings and Precautions (5.4)]. Canagliflozin was negligibly removed by hemodialysis. Metformin HCl In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (4) and Warnings and Precautions (5.1)]. Following a single dose administration of metformin HCl extended-release tablets 500 mg in patients with mild and moderate renal failure (based on measured creatinine clearance), the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively [see Warnings and Precautions (5.4)]. Metformin peak and systemic exposure was 27% and 61% greater, respectively in mild renal impaired and 74% and 2.36-fold greater in moderate renal impaired patients as compared to healthy subjects [see Contraindications (4) and Warnings and Precautions (5.1)]. Patients with Hepatic Impairment Canagliflozin Relative to adult subjects with normal hepatic function, the geometric mean ratios for Cmax and AUC∞ of canagliflozin were 107% and 110%, respectively, in subjects with Child-Pugh class A (mild hepatic impairment) and 96% and 111%, respectively, in subjects with Child-Pugh class B Reference ID: 5499136 34 (moderate hepatic impairment) following administration of a single 300 mg dose of canagliflozin. These differences are not considered to be clinically meaningful. There is no clinical experience in adult patients with Child-Pugh class C (severe) hepatic impairment [see Warnings and Precautions (5.1)]. Metformin HCl No pharmacokinetic trials of metformin HCl tablets have been conducted in patients with hepatic insufficiency [see Warnings and Precautions (5.1)]. Pharmacokinetic Effects of Age, Body Mass Index (BMI)/Weight, Gender and Race Canagliflozin Based on the population PK analysis with data collected from 1,526 adult subjects, age, body mass index (BMI)/weight, gender, and race do not have a clinically meaningful effect on the pharmacokinetics of canagliflozin [see Use in Specific Populations (8.5)]. Metformin HCl Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender. No trials of metformin pharmacokinetic parameters according to race have been performed. Canagliflozin Age had no clinically meaningful effect on the pharmacokinetics of canagliflozin based on a population pharmacokinetic analysis [see Adverse Reactions (6.1) and Use in Specific Populations (8.5)]. Metformin HCl Limited data from controlled pharmacokinetic trials of metformin HCl tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared with healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function [see Warnings and Precautions (5.1, 5.4) and Use in Specific Populations (8.5)]. Drug Interaction Studies INVOKAMET and INVOKAMET XR Pharmacokinetic drug interaction trials with INVOKAMET or INVOKAMET XR have not been performed; however, such trials have been conducted with the individual components canagliflozin and metformin HCl. Reference ID: 5499136 35 I I Co-administration of multiple doses of canagliflozin (300 mg) and metformin HCl (2,000 mg) given once daily did not meaningfully alter the pharmacokinetics of either canagliflozin or metformin in healthy subjects. Canagliflozin In Vitro Assessment of Drug Interactions Canagliflozin did not induce CYP450 enzyme expression (3A4, 2C9, 2C19, 2B6, and 1A2) in cultured human hepatocytes. Canagliflozin did not inhibit the CYP450 isoenzymes (1A2, 2A6, 2C19, 2D6, or 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes. Canagliflozin is a weak inhibitor of P-gp. Canagliflozin is also a substrate of drug transporters P-glycoprotein (P-gp) and MRP2. In Vivo Assessment of Drug Interactions Table 9: Effect of Co−Administered Drugs on Systemic Exposures of Canagliflozin Co-Administered Drug Dose of Co-Administered Drug* Dose of Canagliflozin* Geometric Mean Ratio (Ratio With/Without Co-Administered Drug) No Effect = 1.0 AUC† (90% CI) Cmax (90% CI) See Drug Interactions (7) for the clinical relevance of the following: Rifampin 600 mg QD for 8 days 300 mg 0.49 (0.44; 0.54) 0.72 (0.61; 0.84) No dose adjustments of canagliflozin required for the following: Cyclosporine 400 mg 300 mg QD for 8 days 1.23 (1.19; 1.27) 1.01 (0.91; 1.11) Ethinyl estradiol and levonorgestrel 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel 200 mg QD for 6 days 0.91 (0.88; 0.94) 0.92 (0.84; 0.99) Hydrochlorothiazide 25 mg QD for 35 days 300 mg QD for 7 days 1.12 (1.08; 1.17) 1.15 (1.06; 1.25) Metformin HCl 2,000 mg 300 mg QD for 8 days 1.10 (1.05; 1.15) 1.05 (0.96; 1.16) Probenecid 500 mg BID for 3 days 300 mg QD for 17 days 1.21 (1.16; 1.25) 1.13 (1.00; 1.28) * Single dose unless otherwise noted † AUCinf for drugs given as a single dose and AUC24h for drugs given as multiple doses QD = once daily; BID = twice daily Table 10: Effect of Canagliflozin on Systemic Exposure of Co-Administered Drugs Co-Administered Drug Dose of Co-Administered Drug* Dose of Canagliflozin* Geometric Mean Ratio (Ratio With/Without Co-Administered Drug) No Effect = 1.0 AUC† (90% CI) Cmax (90% CI) See Drug Interactions (7) for the clinical relevance of the following: Reference ID: 5499136 36 Digoxin 0.5 mg QD first day followed by 0.25 mg QD for 6 days 300 mg QD for 7 days Digoxin 1.20 (1.12; 1.28) 1.36 (1.21; 1.53) No dose adjustments of co-administered drug required for the following: Acetaminophen 1,000 mg 300 mg BID for 25 days Acetaminophen 1.06‡ (0.98; 1.14) 1.00 (0.92; 1.09) Ethinyl estradiol and levonorgestrel 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel 200 mg QD for 6 days ethinyl estradiol 1.07 (0.99; 1.15) 1.22 (1.10; 1.35) Levonorgestrel 1.06 (1.00; 1.13) 1.22 (1.11; 1.35) Glyburide 1.25 mg 200 mg QD for 6 days Glyburide 1.02 (0.98; 1.07) 0.93 (0.85; 1.01) 3-cis-hydroxy­ glyburide 1.01 (0.96; 1.07) 0.99 (0.91; 1.08) 4-trans-hydroxy­ glyburide 1.03 (0.97; 1.09) 0.96 (0.88; 1.04) Hydrochlorothiazide 25 mg QD for 35 days 300 mg QD for 7 days Hydrochlorothiazide 0.99 (0.95; 1.04) 0.94 (0.87; 1.01) Metformin HCl 2,000 mg 300 mg QD for 8 days Metformin 1.20 (1.08; 1.34) 1.06 (0.93; 1.20) Simvastatin 40 mg 300 mg QD for 7 days Simvastatin 1.12 (0.94; 1.33) 1.09 (0.91; 1.31) simvastatin acid 1.18 (1.03; 1.35) 1.26 (1.10; 1.45) Warfarin 30 mg 300 mg QD for 12 days (R)-warfarin 1.01 (0.96; 1.06) 1.03 (0.94; 1.13) (S)-warfarin 1.06 (1.00; 1.12) 1.01 (0.90; 1.13) INR 1.00 (0.98; 1.03) 1.05 (0.99; 1.12) * Single dose unless otherwise noted † AUCinf for drugs given as a single dose and AUC24h for drugs given as multiple doses ‡ AUC0-12h QD = once daily; BID = twice daily; INR = International Normalized Ratio Metformin HCl Table 11: Effect of Co−Administered Drugs on Plasma Metformin Systemic Exposures Co-Administered Drug Dose of Co-Administered Drug* Dose of Metformin HCl* Geometric Mean Ratio (Ratio With/Without Co-Administered Drug) Reference ID: 5499136 37 No Effect = 1.00 AUC† Cmax No dose adjustments required for the following: Glyburide 5 mg 500 mg‡ 0.98§ 0.99§ Furosemide 40 mg 850 mg 1.09§ 1.22§ Nifedipine 10 mg 850 mg 1.16 1.21 Propranolol 40 mg 850 mg 0.90 0.94 Ibuprofen 400 mg 850 mg 1.05§ 1.07§ Drugs that are eliminated by renal tubular secretion increase the accumulation of metformin [see Warnings and Precautions (5) and Drug Interactions (7)] Cimetidine 400 mg 850 mg 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) and Drug Interactions (7)] Topiramate¶ 100 mg 500 mg 1.25# 1.18 * Single dose unless otherwise noted † AUC = AUC0-∞ ‡ Metformin HCl extended-release tablets 500 mg § Ratio of arithmetic means ¶ Healthy volunteer study at steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours for 7 days. Study conducted to assess pharmacokinetics only # Steady state AUC0-12h. Table 12: Effect of Metformin HCl on Co-Administered Drug Systemic Exposures Co-Administered Drug Dose of Co-Administered Drug* Dose of Metformin HCl* Geometric Mean Ratio (Ratio With/Without Co-Administered Drug) No Effect = 1.00 AUC† Cmax No dose adjustments required for the following: Glyburide 5 mg 500 mg‡ 0.78§ 0.63§ Furosemide 40 mg 850 mg 0.87§ 0.69§ Nifedipine 10 mg 850 mg 1.10‡ 1.08 Propranolol 40 mg 850 mg 1.01‡ 0.94 Ibuprofen 400 mg 850 mg 0.97¶ 1.01¶ Cimetidine 400 mg 850 mg 0.95‡ 1.01 * Single dose unless otherwise noted † AUC = AUC0-∞ ‡ AUC0-24 hr reported § Ratio of arithmetic means, p-value of difference <0.05 ¶ Ratio of arithmetic means. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility INVOKAMET and INVOKAMET XR No animal studies have been conducted with the combined products in INVOKAMET or INVOKAMET XR to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The Reference ID: 5499136 38 following data are based on findings in studies with canagliflozin and metformin HCl individually. Canagliflozin Carcinogenesis Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Sprague-Dawley rats. Canagliflozin did not increase the incidence of tumors in mice dosed at 10, 30, or 100 mg/kg (less than or equal to 14 times exposure from a 300 mg clinical dose). Testicular Leydig cell tumors, considered secondary to increased luteinizing hormone (LH), increased significantly in male rats at all doses tested (10, 30, and 100 mg/kg). In a 12-week clinical trial, LH did not increase in males treated with canagliflozin. Renal tubular adenoma and carcinoma increased significantly in male and female rats dosed at 100 mg/kg, or approximately 12-times exposure from a 300 mg clinical dose. Also, adrenal pheochromocytoma increased significantly in males and numerically in females dosed at 100 mg/kg. Carbohydrate malabsorption associated with high doses of canagliflozin was considered a necessary proximal event in the emergence of renal and adrenal tumors in rats. Clinical trials have not demonstrated carbohydrate malabsorption in humans at canagliflozin doses of up to 2-times the recommended clinical dose of 300 mg. Mutagenesis Canagliflozin was not mutagenic with or without metabolic activation in the Ames assay. Canagliflozin was mutagenic in the in vitro mouse lymphoma assay with but not without metabolic activation. Canagliflozin was not mutagenic or clastogenic in an in vivo oral micronucleus assay in rats and an in vivo oral Comet assay in rats. Metformin HCl Carcinogenesis Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin HCl was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin HCl in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. Mutagenesis There was no evidence of a mutagenic potential of metformin HCl in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Reference ID: 5499136 39 Impairment of Fertility Canagliflozin had no effects on the ability of rats to mate and sire or maintain a litter up to the high dose of 100 mg/kg (approximately 14 times and 18 times the 300 mg clinical dose in males and females, respectively), although there were minor alterations in a number of reproductive parameters (decreased sperm velocity, increased number of abnormal sperm, slightly fewer corpora lutea, fewer implantation sites, and smaller litter sizes) at the highest dosage administered. Fertility of male or female rats was unaffected by metformin HCl when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons. 14 CLINICAL STUDIES 14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus The effectiveness of INVOKAMET and INVOKAMET XR have been established in clinical trials with canagliflozin in combination with metformin HCl alone, metformin HCl and sulfonylurea, metformin HCl and sitagliptin, metformin HCl and a thiazolidinedione (i.e., pioglitazone), and metformin HCl and insulin (with or without other anti-hyperglycemic agents). The efficacy of canagliflozin was compared to a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin), both as add-on combination therapy with metformin HCl and sulfonylurea, and a sulfonylurea (glimepiride), both as add-on combination therapy with metformin HCl. Canagliflozin as Initial Combination Therapy with Metformin HCl Extended-Release A total of 1,186 adult patients with type 2 diabetes inadequately controlled with diet and exercise participated in a 26-week double-blind, active-controlled, parallel-group, 5-arm, multicenter trial to evaluate the efficacy and safety of initial therapy with canagliflozin in combination with metformin HCl extended-release. The median age was 56 years, 48% of patients were male, and the mean baseline eGFR was 87.6 mL/min/1.73 m2. The median duration of diabetes was 1.6 years, and 72% of patients were treatment naïve. After completing a 2-week single-blind placebo run-in period, patients were randomly assigned for a double-blind treatment period of 26 weeks to 1 of 5 treatment groups (Table 13). The metformin HCl extended-release dose was initiated at 500 mg/day for the first week of treatment and then increased to 1,000 mg/day. Metformin HCl extended-release or matching placebo was up-titrated every 2-3 weeks during the next 8 weeks of treatment to a maximum daily dose of 1,500 to 2,000 mg/day, as tolerated; about 90% of patients reached 2,000 mg/day. At the end of treatment, canagliflozin 100 mg and canagliflozin 300 mg in combination with metformin HCl extended-release resulted in a statistically significant greater improvement in HbA1C compared to their respective canagliflozin doses (100 mg and 300 mg) alone or metformin HCl extended-release alone. Reference ID: 5499136 40 Table 13: Results from 26-Week Active-Controlled Clinical Trial of Canagliflozin Alone or Canagliflozin as Initial Combination Therapy with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Metformin HCl extended-release (N=237) Canagliflozin 100 mg (N=237) Canagliflozin 300 mg (N=238) Canagliflozin 100 mg + Metformin HCl extended- release (N=237) Canagliflozin 300 mg + Metformin HCl extended- release (N=237) HbA1C (%) Baseline (mean) 8.81 8.78 8.77 8.83 8.90 Change from baseline (adjusted mean)¶ -1.30 -1.37 -1.42 -1.77 -1.78 Difference from canagliflozin 100 mg (adjusted mean) (95% CI)† -0.40‡ (-0.59, -0.21) Difference from canagliflozin 300 mg (adjusted mean) (95% CI)† -0.36‡ (-0.56, -0.17) Difference from metformin HCl extended- release (adjusted mean) (95% CI)† -0.46‡ (-0.66, -0.27) -0.48‡ (-0.67, -0.28) Percent of patients achieving HbA1C < 7% 38 34 39 47§§ 51§§ * Intent-to-treat population † Least squares mean adjusted for covariates including baseline value and stratification factor ‡ Adjusted p=0.001 §§ Adjusted p<0.05 ¶ There were 121 patients without week 26 efficacy data. Analyses addressing missing data gave consistent results with the results provided in this table. Canagliflozin as Add-on Combination Therapy with Metformin HCl A total of 1,284 adult patients with type 2 diabetes inadequately controlled on metformin HCl monotherapy (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) participated in a 26-week, double-blind, placebo- and active-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl. The mean age was Reference ID: 5499136 41 55 years, 47% of patients were male, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the required metformin HCl dose (N=1,009) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients taking less than the required metformin HCl dose or patients on metformin HCl in combination with another antihyperglycemic agent (N=275) were switched to metformin HCl monotherapy (at doses described above) for at least 8 weeks before entering the 2-week, single-blind, placebo run-in. After the placebo run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, sitagliptin 100 mg, or placebo, administered once daily as add-on therapy to metformin HCl. At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo when added to metformin HCl (see Table 14). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -5.4 mmHg and -6.6 mmHg with canagliflozin 100 mg and 300 mg, respectively. Table 14: Results from 26-Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Metformin HCl (N=183) Canagliflozin 100 mg + Metformin HCl (N=368) Canagliflozin 300 mg + Metformin HCl (N=367) HbA1C (%) Baseline (mean) 7.96 7.94 7.95 Change from baseline (adjusted mean) -0.17 -0.79 -0.94 Difference from placebo (adjusted mean) (95% CI)† -0.62‡ (-0.76, -0.48) -0.77‡ (-0.91, -0.64) Percent of patients achieving HbA1C < 7% 30 46‡ 58‡ Fasting Plasma Glucose (mg/dL) Baseline (mean) 164 169 173 Change from baseline (adjusted mean) 2 -27 -38 Difference from placebo (adjusted mean) (95% CI)† -30‡ (-36, -24) -40‡ (-46, -34) 2-hour Postprandial Glucose (mg/dL) Baseline (mean) 249 258 262 Change from baseline (adjusted mean) -10 -48 -57 Difference from placebo (adjusted mean) (95% CI)† -38‡ (-49, -27) -47‡ (-58, -36) Body Weight Baseline (mean) in kg 86.7 88.7 85.4 % change from baseline (adjusted mean) -1.2 -3.7 -4.2 Difference from placebo (adjusted mean) (95% CI)† -2.5‡ (-3.1, -1.9) -2.9‡ (-3.5, -2.3) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors Reference ID: 5499136 42 ‡ p<0.001 Canagliflozin Compared to Glimepiride, Both as Add-on Combination Therapy with Metformin HCl A total of 1,450 adult patients with type 2 diabetes inadequately controlled on metformin HCl monotherapy (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) participated in a 52-week, double-blind, active-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl. The mean age was 56 years, 52% of patients were male, and the mean baseline eGFR was 90 mL/min/1.73 m2. Patients tolerating maximally required metformin HCl dose (N=928) were randomized after completing a 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin HCl monotherapy (at doses described above) for at least 10 weeks, then completed a 2-week single-blind run-in period. After the 2-week run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride (titration allowed throughout the 52-week trial to 6 or 8 mg), administered once daily as add-on therapy to metformin HCl. As shown in Table 15 and Figure 1, at the end of treatment, canagliflozin 100 mg provided similar reductions in HbA1C from baseline compared to glimepiride when added to metformin HCl therapy. Canagliflozin 300 mg provided a greater reduction from baseline in HbA1C compared to glimepiride, and the relative treatment difference was -0.12% (95% CI: −0.22; −0.02). As shown in Table 15, treatment with canagliflozin 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride. Table 15: Results from 52−Week Clinical Trial Comparing Canagliflozin to Glimepiride in Combination with Metformin HCl in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Canagliflozin 100 mg + Metformin HCl (N=483) Canagliflozin 300 mg + Metformin HCl (N=485) Glimepiride (titrated) + Metformin HCl (N=482) HbA1C (%) Baseline (mean) 7.78 7.79 7.83 Change from baseline (adjusted mean) -0.82 -0.93 -0.81 Difference from glimepiride (adjusted mean) (95% CI)† -0.01‡ (-0.11, 0.09) -0.12‡ (-0.22, -0.02) Percent of patients achieving HbA1C < 7% 54 60 56 Fasting Plasma Glucose (mg/dL) Baseline (mean) 165 164 166 Change from baseline (adjusted mean) -24 -28 -18 Difference from glimepiride (adjusted mean) (95% CI)† -6 (-10, -2) -9 (-13, -5) Body Weight Baseline (mean) in kg 86.8 86.6 86.6 % change from baseline (adjusted mean) -4.2 -4.7 1.0 Reference ID: 5499136 43 12 18 26 36 44 Study Week -- Canagliflozin 1 00 mg ~ -- Canaghflozin 300 mg 52 Wk52 LOCF + - - Glimepiride Difference from glimepiride (adjusted mean) (95% CI)† -5.2§ (-5.7, -4.7) -5.7§ (-6.2, -5.1) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ Canagliflozin + metformin HCl is considered non-inferior to glimepiride + metformin HCl because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%. § p<0.001 Figure 1: Mean HbA1C Change in Adults with Type 2 Diabetes Mellitus Treated with Canagliflozin or Glimepiride in Combination with Metformin HCl at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population) Canagliflozin as Add-on Combination Therapy with Metformin HCl and Sitagliptin A total of 217 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 1,500 mg/day) and sitagliptin 100 mg/day (or equivalent fixed-dose combination) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl and sitagliptin. The mean age was 57 years, 58% of patients were male, 73% of patients were White, 15% were Asian, and 12% were Black or African American. The mean baseline eGFR was 90 mL/min/1.73 m2 and the mean baseline BMI was 32 kg/m2. The mean duration of diabetes was 10 years. Eligible patients entered a 2-week, single-blind, placebo run-in period and were subsequently randomized to canagliflozin 100 mg or placebo, administered once daily as add-on to metformin HCl and sitagliptin. Patients with a baseline eGFR of 70 mL/min/1.73 m2 or greater who were tolerating canagliflozin 100 mg and who required additional glycemic control (fasting finger stick 100 mg/dL or greater at least twice within 2 weeks) were up-titrated to canagliflozin 300 mg. While up-titration occurred as early as Week 4, most (90%) patients randomized to canagliflozin were up-titrated to canagliflozin 300 mg by 6 to 8 weeks. At the end of 26 weeks, canagliflozin once daily resulted in a statistically significant improvement in HbA1C (p<0.001) compared to placebo when added to metformin HCl and sitagliptin (see Table 16). Reference ID: 5499136 44 Table 16: Results from 26−Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl and Sitagliptin in Adults with Type 2 Diabetes Mellitus Efficacy Parameter Placebo + Metformin HCl and Sitagliptin (N=108*) Canagliflozin + Metformin HCl and Sitagliptin (N=109*) HbA1C (%) Baseline (mean) 8.40 8.50 Change from baseline (adjusted mean) -0.03 -0.83 Difference from placebo (adjusted mean) (95% CI)†§ -0.81# (-1.11; -0.51) Percent of patients achieving HbA1C < 7%‡ 9 28 Fasting Plasma Glucose (mg/dL)¶ Baseline (mean) 180 185 Change from baseline (adjusted mean) -3 -28 Difference from placebo (adjusted mean) (95% CI) -25# (-39; -11) * To preserve the integrity of randomization, all randomized patients were included in the analysis. The patient who was randomized once to each arm was analyzed on canagliflozin. † Early treatment discontinuation before week 26, occurred in 11.0% and 24.1% of canagliflozin and placebo patients, respectively. ‡ Patients without week 26 efficacy data were considered as non-responders when estimating the proportion achieving HbA1C < 7%. § Estimated using a multiple imputation method modeling a “wash-out” of the treatment effect for patients having missing data who discontinued treatment. Missing data was imputed only at week 26 and analyzed using ANCOVA. ¶ Estimated using a multiple imputation method modeling a “wash-out” of the treatment effect for patients having missing data who discontinued treatment. A mixed model for repeated measures was used to analyze the imputed data. # p<0.001 Canagliflozin as Add-on Combination Therapy with Metformin HCl and Sulfonylurea A total of 469 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (maximal or near-maximal effective dose) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl and sulfonylurea. The mean age was 57 years, 51% of patients were male, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the protocol-specified doses of metformin HCl and sulfonylurea (N=372) entered a 2-week, single-blind, placebo run-in period. Other patients (N=97) were required to be on a stable protocol-specified dose of metformin HCl and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo administered once daily as add-on to metformin HCl and sulfonylurea. At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl and sulfonylurea. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7.0%, in a significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin HCl and sulfonylurea (see Table 17). Reference ID: 5499136 45 Table 17: Results from 26−Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl and Sulfonylurea in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Metformin HCl and Sulfonylurea (N=156) Canagliflozin 100 mg + Metformin HCl and Sulfonylurea (N=157) Canagliflozin 300 mg + Metformin HCl and Sulfonylurea (N=156) HbA1C (%) Baseline (mean) 8.12 8.13 8.13 Change from baseline (adjusted mean) -0.13 -0.85 -1.06 Difference from placebo (adjusted mean) (95% CI)† -0.71‡ (-0.90, -0.52) -0.92‡ (-1.11, -0.73) Percent of patients achieving HbA1C < 7% 18 43‡ 57‡ Fasting Plasma Glucose (mg/dL) Baseline (mean) 170 173 168 Change from baseline (adjusted mean) 4 -18 -31 Difference from placebo (adjusted mean) (95% CI)† -22‡ (-31, -13) -35‡ (-44, -25) Body Weight Baseline (mean) in kg 90.8 93.5 93.5 % change from baseline (adjusted mean) -0.7 -2.1 -2.6 Difference from placebo (adjusted mean) (95% CI)† -1.4‡ (-2.1, -0.7) -2.0‡ (-2.7, -1.3) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001 Canagliflozin Compared to Sitagliptin, Both as Add-on Combination Therapy with Metformin HCl and Sulfonylurea A total of 755 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (near-maximal or maximal effective dose) participated in a 52 week, double-blind, active-controlled trial to compare the efficacy and safety of canagliflozin 300 mg versus sitagliptin 100 mg in combination with metformin HCl and sulfonylurea. The mean age was 57 years, 56% of patients were male, and the mean baseline eGFR was 88 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin HCl and sulfonylurea (N=716) entered a 2-week single-blind, placebo run-in period. Other patients (N=39) were required to be on a stable protocol-specified dose of metformin HCl and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to canagliflozin 300 mg or sitagliptin 100 mg as add-on to metformin HCl and sulfonylurea. As shown in Table 18 and Figure 2, at the end of treatment, canagliflozin 300 mg provided greater HbA1C reduction compared to sitagliptin 100 mg when added to metformin HCl and sulfonylurea (p<0.05). Canagliflozin 300 mg resulted in a mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. A mean change in systolic blood pressure from baseline of -5.06 mmHg was observed with canagliflozin 300 mg compared to +0.85 mmHg with sitagliptin 100 mg. Reference ID: 5499136 46 w U) 0.0 -0.2 i -0 .4 ID ID C ai= C ID 2 ~ -0.6 0 (0 C E :i ~ -0.8 (()~ _J rS ~ -1 .0 I C -1.2 -1 .4 12 18 26 34 42 52 Study Week canagliflozin 300 mg • - - • Sitagliptin 1 oo mg Wk52 LOCF Table 18: Results from 52−Week Clinical Trial Comparing Canagliflozin to Sitagliptin in Combination with Metformin HCl and Sulfonylurea in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Canagliflozin 300 mg + Metformin HCl and Sulfonylurea (N=377) Sitagliptin 100 mg + Metformin HCl and Sulfonylurea (N=378) HbA1C (%) Baseline (mean) 8.12 8.13 Change from baseline (adjusted mean) -1.03 -0.66 Difference from sitagliptin (adjusted mean) (95% CI)† -0.37‡ (-0.50, -0.25) Percent of patients achieving HbA1C < 7% 48 35 Fasting Plasma Glucose (mg/dL) Baseline (mean) 170 164 Change from baseline (adjusted mean) -30 -6 Difference from sitagliptin (adjusted mean) (95% CI)† -24 (-30, -18) Body Weight Baseline (mean) in kg 87.6 89.6 % change from baseline (adjusted mean) -2.5 0.3 Difference from sitagliptin (adjusted mean) (95% CI)† -2.8§ (-3.3, -2.2) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ Canagliflozin + metformin HCl + sulfonylurea is considered non-inferior to sitagliptin + metformin HCl + sulfonylurea because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%. § p<0.001 Figure 2: Mean HbA1C Change in Adults with Type 2 Diabetes Mellitus Treated with Canagliflozin or Sitagliptin in Combination with Metformin HCl and Sulfonylurea at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population) Canagliflozin as Add-on Combination Therapy with Metformin HCl and Pioglitazone A total of 342 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not Reference ID: 5499136 47 tolerated) and pioglitazone (30 or 45 mg/day) participated in a 26-week, double--blind, placebo- controlled trial to evaluate the efficacy and safety of canagliflozin in combination with metformin HCl and pioglitazone. The mean age was 57 years, 63% of patients were male, and the mean baseline eGFR was 86 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin HCl and pioglitazone (N=163) entered a 2-week, single-blind, placebo run-in period. Other patients (N=181) were required to be on stable protocol-specified doses of metformin HCl and pioglitazone for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo, administered once daily as add-on to metformin HCl and pioglitazone. At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl and pioglitazone. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin HCl and pioglitazone (see Table 19). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -4.1 mmHg and -3.5 mmHg with canagliflozin 100 mg and 300 mg, respectively. Table 19: Results from 26−Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl and Pioglitazone in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Metformin HCl and Pioglitazone (N=115) Canagliflozin 100 mg + Metformin HCl and Pioglitazone (N=113) Canagliflozin 300 mg + Metformin HCl and Pioglitazone (N=114) HbA1C (%) Baseline (mean) 8.00 7.99 7.84 Change from baseline (adjusted mean) -0.26 -0.89 -1.03 Difference from placebo (adjusted mean) (95% CI)† -0.62‡ (-0.81, -0.44) -0.76‡ (-0.95, -0.58) Percent of patients achieving HbA1C < 7% 33 47‡ 64‡ Fasting Plasma Glucose (mg/dL) Baseline (mean) 164 169 164 Change from baseline (adjusted mean) 3 -27 -33 Difference from placebo (adjusted mean) (95% CI)† -29‡ (-37, -22) -36‡ (-43, -28) Body Weight Baseline (mean) in kg 94.0 94.2 94.4 % change from baseline (adjusted mean) -0.1 -2.8 -3.8 Difference from placebo (adjusted mean) (95% CI)† -2.7‡ (-3.6, -1.8) -3.7‡ (-4.6, -2.8) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001 Reference ID: 5499136 48 Canagliflozin as Add-on Combination Therapy with Insulin (With or Without Other Anti-Hyperglycemic Agents, Including Metformin HCl) A total of 1,718 adult patients with type 2 diabetes inadequately controlled on insulin greater than or equal to 30 units/day or insulin in combination with other antihyperglycemic agents participated in an 18-week, double-blind, placebo-controlled subtrial of a cardiovascular trial to evaluate the efficacy and safety of canagliflozin in combination with insulin. Of these patients, a subgroup of 432 patients with inadequate glycemic control received canagliflozin or placebo plus metformin HCl and ≥ 30 units/day of insulin over 18 weeks. In this subgroup, the mean age was 61 years, 67% of patients were male, and the mean baseline eGFR was 81 mL/min/1.73 m2. Patients on metformin HCl in combination with basal, bolus, or basal/bolus insulin for at least 10 weeks entered a 2-week, single-blind, placebo run-in period. Approximately 74% of these patients were on a background of metformin HCl and basal/bolus insulin regimen. After the run-in period, patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo, administered once daily as add-on to metformin HCl and insulin. The mean daily insulin dose at baseline was 93 units, which was similar across treatment groups. At the end of treatment, canagliflozin 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin HCl and insulin. Canagliflozin 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reductions in fasting plasma glucose (FPG), and in percent body weight reductions compared to placebo (see Table 20). Statistically significant (p=0.023 for the 100 mg and p<0.001 for the 300 mg dose) mean change from baseline in systolic blood pressure relative to placebo was –3.5 mmHg and -6 mmHg with canagliflozin 100 mg and 300 mg, respectively. Fewer patients on canagliflozin in combination with metformin HCl and insulin required glycemic rescue therapy: 3.6% of patients receiving canagliflozin 100 mg, 2.7% of patients receiving canagliflozin 300 mg, and 6.2% of patients receiving placebo. An increased incidence of hypoglycemia was observed in this trial, which is consistent with the expected increase of hypoglycemia when an agent not associated with hypoglycemia is added to insulin [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)]. Reference ID: 5499136 49 Table 20: Results from 18−Week Placebo-Controlled Clinical Trial of Canagliflozin in Combination with Metformin HCl and Insulin ≥ 30 Units/Day in Adults with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo + Metformin HCl + Insulin (N=145) Canagliflozin 100 mg + Metformin HCl + Insulin (N=139) Canagliflozin 300 mg + Metformin HCl + Insulin (N=148) HbA1C (%) Baseline (mean) 8.15 8.20 8.22 Change from baseline (adjusted mean) 0.03 -0.64 -0.79 Difference from placebo (adjusted mean) (95% CI)† -0.66‡ (-0.81, -0.51) -0.82‡ (-0.96, -0.67) Percent of patients achieving HbA1C < 7% 9 19§ 29‡ Fasting Plasma Glucose (mg/dL) Baseline 163 168 167 Change from baseline (adjusted mean) 1 -16 -24 Difference from placebo (adjusted mean) (97.5% CI)† -16‡ (-28, -5) -25‡ (-36, -14) Body Weight Baseline (mean) in kg 102.3 99.7 101.1 % change from baseline (adjusted mean) 0.0 -1.7 -2.7 Difference from placebo (adjusted mean) (97.5% CI)† -1.7‡ (-2.4, -1.0) -2.7‡ (-3.4, -2.0) * Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p≤0.001 § p≤0.01 14.2 Glycemic Control Trial in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus Glycemic Control Trial of Canagliflozin in Pediatric Patients Aged 10 years and Older with Type 2 Diabetes Mellitus In a double-blind, placebo-controlled, parallel-group pediatric trial (NCT03170518), 171 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus (HbA1C >6.5% and <11.0%) were randomized to canagliflozin (84 patients) or placebo (87 patients) as add-on to diet and exercise, metformin HCl (>1,000 mg per day or maximally tolerated dosage), insulin, or a combination of metformin HCl and insulin, for a total of 52­ weeks. At Week 13, patients in the canagliflozin arm whose HbA1C was ≥7.0% and eGFR ≥60 mL/min/1.73m2 were re-randomized to either continue on canagliflozin 100 mg orally once daily (n=16) or to up-titrate to 300 mg orally once daily (n=17). At baseline, background therapies included diet and exercise only (14%), insulin monotherapy (11%), metformin HCl and insulin (29%), and metformin HCl monotherapy (46%). The mean HbA1C at baseline was 8.0% and the mean duration of type 2 diabetes mellitus was 2 years. The mean eGFR at baseline was 157.3 mL/min/1.73 m2, and approximately 16% (24/151) of the trial population with measurements had microalbuminuria or macroalbuminuria. Patients with an eGFR less than 60 mL/min/1.73 m2 were not enrolled in the trial; no patients in the trial reached an eGFR < 60 mL/min/1.72m2. The mean age was 14.3 years, 47% were under 15 years of age, Reference ID: 5499136 50 and 68% were female. Approximately 42% were Asian, 42% were White, 11% were Black or African American, 5% were American Indian/Alaska Native, and 36% were of Hispanic or Latino ethnicity. The mean BMI was 30.8 kg/m2 (range 18-57 kg/m2) and the mean BMI Z-score was 1.84. At Week 26, treatment with canagliflozin provided statistically significant improvement in HbA1C from baseline, compared with placebo (see Table 21). The treatment effect with canagliflozin was consistent in the subgroup of patients with metformin with or without insulin as background therapy [adjusted mean change in HbA1C relative to placebo from baseline to Week 26 was –0.74% (95% CI -1.37, -0.11; p = 0.02)]. Table 21: Results at Week 26 in a Placebo-Controlled Trial of Canagliflozin in Combination with Metformin HCl and/or Insulin or as Monotherapy in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus* Efficacy Parameter Placebo (N=87) Canagliflozin (N=84) HbA1C (%) Baseline (mean) 8.3 7.8 Change from baseline†‡ 0.34 -0.38 Difference from placebo 95% CI†‡ -0.73 (-1.26, -0.19)§ FPG (mg/dL) Baseline (mean) 156.5 154.8 Change from baseline†‡ 17.29 -8.22 Difference from placebo 95% CI†‡ -25.51 (-49.55, -1.47) ¶ * Modified intent-to-treat set (All randomized and treated patients with baseline HbA1C measurement). † Multiple imputation using retrieved dropout approach with 1,000 iterations for missing data (canagliflozin N=7 (8.3%), placebo N=7 (8.1%) for HbA1C and canagliflozin N=9 (10.7%), placebo N=7 (8.1%) for FPG). ‡ Least-Square Mean from Analysis of Covariance (ANCOVA) adjusted for baseline value, baseline age stratum (< 15 years vs 15 to < 18 years) and baseline antihyperglycemic agent (AHA) background (i.e., diet and exercise only, metformin monotherapy, insulin monotherapy, or combination of insulin and metformin). § P-value=0.008 (two-sided) ¶ Not evaluated for statistical significance, not part of sequential testing procedure. Glycemic Control Trial of Metformin HCl Immediate-Release in Pediatric Patients Aged 10 to 16 Years with Type 2 Diabetes Mellitus A double-blind, placebo-controlled trial was conducted in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), where patients were treated with metformin HCl immediate-release tablets (up to 2,000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks). The results are displayed in Table 22. Table 22: Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin HCl versus Placebo in Pediatric Patientsa with Type 2 Diabetes Mellitus Metformin HCl Placebo p-value FPG (n=37) (n=36) Baseline 162.4 192.3 Change at Final Visit -42.9 21.4 <0.001 a Pediatric patients mean age 13.8 years (range 10-16 years) Reference ID: 5499136 51 Mean baseline body weight was 205 lbs and 189 lbs in the metformin HCl immediate-release and placebo arms, respectively. Mean change in body weight from baseline to week 16 was ­ 3.3 lbs and -2.0 lbs in the metformin HCl and placebo arms, respectively. 14.3 Canagliflozin Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD). The CANVAS and CANVAS-R trials were multicenter, multi-national, randomized, double-blind parallel group, with similar inclusion and exclusion criteria. Patients eligible for enrollment in both CANVAS and CANVAS-R trials were: 30 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease (66% of the enrolled population) or were 50 years of age or older and had two or more other specified risk factors for cardiovascular disease (34% of the enrolled population). The integrated analysis of the CANVAS and CANVAS-R trials compared the risk of Major Adverse Cardiovascular Event (MACE) between canagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. In CANVAS, patients were randomly assigned 1:1:1 to canagliflozin 100 mg, canagliflozin 300 mg, or matching placebo. In CANVAS-R, patients were randomly assigned 1:1 to canagliflozin 100 mg or matching placebo, and titration to 300 mg was permitted at the investigator’s discretion (based on tolerability and glycemic needs) after Week 13. Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases. A total of 10,134 adult patients were treated (4,327 in CANVAS and 5,807 in CANVAS-R; total of 4,344 randomly assigned to placebo and 5,790 to canagliflozin) for a mean exposure duration of 149 weeks (223 weeks [4.3 years] in CANVAS and 94 weeks [1.8 years] in CANVAS-R). Approximately 78% of the trial population was White, 13% was Asian, and 3% was Black or African American. The mean age was 63 years and approximately 64% were male. The mean HbA1C at baseline was 8.2% and mean duration of diabetes was 13.5 years with 70% of patients having had diabetes for 10 years or more. Approximately 31%, 21% and 17% reported a past history of neuropathy, retinopathy and nephropathy, respectively, and the mean eGFR 76 mL/min/1.73 m2. At baseline, patients were treated with one (19%) or more (80%) antidiabetic medications including metformin HCl (77%), insulin (50%), and sulfonylurea (43%). Reference ID: 5499136 52 At baseline, the mean systolic blood pressure was 137 mmHg, the mean diastolic blood pressure was 78 mmHg, the mean LDL was 89 mg/dL, the mean HDL was 46 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 115 mg/g. At baseline, approximately 80% of patients were treated with renin angiotensin system inhibitors, 53% with beta-blockers, 13% with loop diuretics, 36% with non-loop diuretics, 75% with statins, and 74% with antiplatelet agents (mostly aspirin). During the trial, investigators could modify anti-diabetic and cardiovascular therapies to achieve local standard of care treatment targets with respect to blood glucose, lipid, and blood pressure. More patients receiving canagliflozin compared to placebo initiated anti-thrombotics (5.2% vs 4.2%) and statins (5.8% vs 4.8%) during the trial. For the primary analysis, a stratified Cox proportional hazards model was used to test for non-inferiority against a pre-specified risk margin of 1.3 for the hazard ratio of MACE. In the integrated analysis of CANVAS and CANVAS-R trials, canagliflozin reduced the risk of first occurrence of MACE. The estimated hazard ratio (95% CI) for time to first MACE was 0.86 (0.75, 0.97). Refer to Table 23. Vital status was obtained for 99.6% of patients across the trials. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 3. Reference ID: 5499136 53 24 22 20 18 ~ 16 ~ w 14 12 Subjects Placebo Cana Cana vs. Placebo 0 26 52 4347 4239 4153 5795 5672 5566 HR (95%CI) 0.86 (0.75, 0.97) 78 104 130 4061 2942 1626 5447 4343 2984 l~6~~=bol 156 182 208 234 260 286 312 338 Time (Weeks) 1240 1217 11 87 1156 1120 1095 789 216 2555 2513 2460 2419 2363 2311 1661 448 Table 23: Treatment Effect for the Primary Composite Endpoint, MACE, and its Components in the Integrated Analysis of CANVAS and CANVAS-R Trials in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease* Placebo N=4,347 (%) Canagliflozin N=5,795 (%) Hazard ratio (95% CI)¶ Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)†, ‡, §, 426 (10.4) 585 (9.2) 0.86 (0.75, 0.97) Non-fatal myocardial infarction‡, § 159 (3.9) 215 (3.4) 0.85 (0.69, 1.05) Non-fatal Stroke‡, § 116 (2.8) 158 (2.5) 0.90 (0.71, 1.15) Cardiovascular Death‡, § 185 (4.6) 268 (4.1) 0.87 (0.72, 1.06) * Intent-To-Treat Analysis Set † P-value for superiority (2-sided) = 0.0158 ‡ Number and percentage of first events § Due to pooling of unequal randomization ratios, Cochran-Mantel-Haenszel weights were applied to calculate percentages ¶ Stratified Cox-proportional hazards model with treatment as a factor and stratified by the trial and by prior CV disease Figure 3: Time to First Occurrence of MACE 14.4 Canagliflozin Renal and Cardiovascular Outcomes in Adults with Diabetic Nephropathy and Albuminuria Canagliflozin is indicated to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria ˃ 300 mg/day. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial (CREDENCE) was a multinational, randomized, double-blind, placebo-controlled trial comparing canagliflozin with placebo in adult patients with type 2 diabetes mellitus, an eGFR ≥ 30 to < 90 mL/min/1.73 m2 and albuminuria (urine albumin/creatinine ˃ 300 to ≤ 5,000 mg/g) who were receiving standard of care including a Reference ID: 5499136 54 maximum-tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The primary objective of CREDENCE was to assess the efficacy of canagliflozin relative to placebo in reducing the composite endpoint of end stage kidney disease (ESKD), doubling of serum creatinine, and renal or CV death. Patients were randomized to receive canagliflozin 100 mg (N=2,202) or placebo (N=2,199) and treatment was continued until the initiation of dialysis or renal transplantation. The median follow-up duration for the 4,401 randomized subjects was 137 weeks. Vital status was obtained for 99.9% of subjects. The population was 67% White, 20% Asian, and 5% Black or African American; 32% were of Hispanic or Latino ethnicity. The mean age was 63 years and 66% were male. At randomization, the mean HbA1C was 8.3%, the median urine albumin/creatinine was 927 mg/g, the mean eGFR was 56.2 mL/min/1.73 m2, 50% had prior CV disease, and 15% reported a history of heart failure. The most frequent antihyperglycemic agents (AHA) medications used at baseline were insulin (66%), biguanides (58%), and sulfonylureas (29%). Nearly all subjects (99.9%) were on ACEi or ARB at randomization, approximately 60% were taking an anti-thrombotic agent (including aspirin), and 69% were on a statin. The primary composite endpoint in the CREDENCE trial was the time to first occurrence of ESKD (defined as an eGFR < 15 mL/min/1.73 m2, initiation of chronic dialysis or renal transplant), doubling of serum creatinine, and renal or CV death. Canagliflozin 100 mg significantly reduced the risk of the primary composite endpoint based on a time-to-event analysis [HR: 0.70; 95% CI: 0.59, 0.82; p<0.0001] (see Figure 4). The treatment effect reflected a reduction in progression to ESKD, doubling of serum creatinine and cardiovascular death as shown in Table 24 and Figure 4. There were few renal deaths during the trial. Canagliflozin 100 mg also significantly reduced the risk of hospitalization for heart failure [HR: 0.61; 95% CI: 0.47 to 0.80; p<0.001]. Reference ID: 5499136 55 Table 24: Analysis of Primary Endpoint (including the Individual Components) and Secondary Endpoints from the CREDENCE Trial in Adults with Diabetic Nephropathy and Albuminuria Placebo canagliflozin Endpoint N=2,199 (%) Event Rate* N=2,202 (%) Event Rate* HR† (95% CI) Primary Composite Endpoint (ESKD, doubling of serum creatinine, renal death, or CV death) 340 (15.5) 6.1 245 (11.1) 4.3 0.70 (0.59, 0.82)‡ ESKD 165 (7.5) 2.9 116 (5.3) 2.0 0.68 (0.54, 0.86) Doubling of serum creatinine 188 (8.5) 3.4 118 (5.4) 2.1 0.60 (0.48, 0.76) Renal death 5 (0.2) 0.1 2 (0.1) 0.0 CV death 140 (6.4) 2.4 110 (5.0) 1.9 0.78 (0.61, 1.00) CV death or hospitalization for heart failure 253 (11.5) 4.5 179 (8.1) 3.1 0.69 (0.57, 0.83)§ CV death, non-fatal myocardial infarction or non­ fatal stroke 269 (12.2) 4.9 217 (9.9) 3.9 0.80 (0.67, 0.95)¶ Non-fatal myocardial infarction 87 (4.0) 1.6 71 (3.2) 1.3 0.81 (0.59, 1.10) Non-fatal stroke 66 (3.0) 1.2 53 (2.4) 0.9 0.80 (0.56, 1.15) Hospitalization for heart failure 141 (6.4) 2.5 89 (4.0) 1.6 0.61 (0.47, 0.80)§ ESKD, doubling of serum creatinine or renal death 224 (10.2) 4.0 153 (6.9) 2.7 0.66 (0.53, 0.81)‡ Intent-To-Treat Analysis Set (time to first occurrence) The individual components do not represent a breakdown of the composite outcomes, but rather the total number of subjects experiencing an event during the course of the trial. * Event rate per 100 patient-years. † Hazard ratio (canagliflozin compared to placebo), 95% CI and p-value are estimated using a stratified Cox proportional hazards model including treatment as the explanatory variable and stratified by screening eGFR (≥ 30 to < 45, ≥ 45 to < 60, ≥ 60 to < 90 mL/min/1.73 m2). HR is not presented for renal death due to the small number of events in each group. ‡ P-value <0.0001 § P-value <0.001 ¶ P-value <0.02 The Kaplan-Meier curve (Figure 4) shows time to first occurrence of the primary composite endpoint of ESKD, doubling of serum creatinine, renal death, or CV death. The curves begin to separate by Week 52 and continue to diverge thereafter. Reference ID: 5499136 56 30 28 Cana vs. Placebo 26 24 22 2l 20 C: Q) > 18 w ~ 16 tl 14 Q) E 12 :, (f) °$. 10 8 6 4 2 0 0 26 Subjects at risk Placebo 2199 2178 Cana 2202 2181 HR (95%C I) 0. 70 (0.59, 0.82) 52 78 104 Time (Weeks) 2132 2047 1725 2145 2081 1786 130 1129 1211 , --·­ ·-' 1~ 6~~=bol 156 182 621 170 646 196 Figure 4: CREDENCE: Time to First Occurrence of the Primary Composite Endpoint 16 HOW SUPPLIED/STORAGE AND HANDLING INVOKAMET® tablets are available in bottles of 60 in the strengths listed below: INVOKAMET TABLET STRENGTH canagliflozin/metformin HCl tablets 50 mg/500 mg 50 mg/1,000 mg 150 mg/500 mg 150 mg/1,000 mg Color White Beige Yellow Purple CM CM CM CM Tablet Identification 155 551 215 611 Capsule-shaped, film-coated tablets NDC 50458-540-60 50458-541-60 50458-542-60 50458-543-60 INVOKAMET® XR tablets are available in bottles of 60 in the strengths listed below: INVOKAMET XR TABLET STRENGTH canagliflozin/metformin HCl extended-release tablets 50 mg/500 mg 50 mg/1,000 mg 150 mg/500 mg 150 mg/1,000 mg Color Almost White to Light Orange Pink Orange Reddish Brown Tablet Identification CM1 CM3 CM2 CM4 Oblong, biconvex, film-coated tablets, a thin line on the tablet side may be visible. NDC 50458-940-01 50458-941-01 50458-942-01 50458-943-01 Storage and Handling Keep out of reach of children. Reference ID: 5499136 57 Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30°C (59 °F to 86 °F) [see USP Controlled Room Temperature]. Store and dispense in the original container. Storage in a pill box or pill organizer is allowed for up to 30 days. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-Approved Patient Labeling (Medication Guide). Lactic Acidosis Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in Warnings and Precautions (5.1). Advise patients to discontinue INVOKAMET or INVOKAMET XR immediately and to promptly notify their health care provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Once a patient is stabilized on INVOKAMET or INVOKAMET XR, gastrointestinal symptoms, which are common during initiation of metformin HCl, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Counsel patients against excessive alcohol intake while receiving INVOKAMET or INVOKAMET XR. Inform patients about importance of regular testing of renal function and hematological parameters while receiving INVOKAMET or INVOKAMET XR. Instruct patients to inform their doctor that they are taking INVOKAMET or INVOKAMET XR prior to any surgical or radiological procedure, as temporary discontinuation of INVOKAMET or INVOKAMET XR may be required until renal function has been confirmed to be normal [see Warnings and Precautions (5.1)]. Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis Inform patients that INVOKAMET or INVOKAMET XR can cause potentially fatal ketoacidosis and that type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors. Educate all patients on precipitating factors (such as insulin dose reduction or missed doses, infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform patients that blood glucose may be normal even in the presence of ketoacidosis. Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur, instruct patients to discontinue INVOKAMET or INVOKAMET XR and seek medical attention immediately [see Warnings and Precautions (5.2)]. Reference ID: 5499136 58 Lower Limb Amputation Inform patients that INVOKAMET or INVOKAMET XR is associated with an increased risk of amputations. Counsel patients about the importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop [see Warnings and Precautions (5.3)]. Volume Depletion Inform patients that symptomatic hypotension may occur with INVOKAMET or INVOKAMET XR and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions (5.4)]. Inform patients that dehydration may increase the risk for hypotension and to have adequate fluid intake. Serious Urinary Tract Infections Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.5)]. Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Inform patients that hypoglycemia has been reported when INVOKAMET or INVOKAMET XR is used with insulin or insulin secretagogues. Educate patients or caregivers on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.6)]. Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Inform patients that necrotizing infections of the perineum (Fournier’s gangrene) have occurred with INVOKAMET or INVOKAMET XR. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.7)]. Genital Mycotic Infections in Females (e.g., Vulvovaginitis) Inform female patients that vaginal yeast infection (e.g., vulvovaginitis) may occur and provide them with information on the signs and symptoms of a vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.8)]. Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.8)]. Reference ID: 5499136 59 Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions, such as urticaria, rash, anaphylaxis, and angioedema, have been reported with canagliflozin. Advise patients to report immediately any signs or symptoms suggesting allergic reaction and to discontinue drug until they have consulted prescribing physicians [see Warnings and Precautions (5.9)]. Bone Fracture Inform patients that bone fractures have been reported in adult patients taking canagliflozin. Provide them with information on factors that may contribute to fracture risk [see Warnings and Precautions (5.10)]. Vitamin B12 Deficiency Inform patients about importance of regular hematological parameters while receiving INVOKAMET or INVOKAMET XR [see Warnings and Precautions (5.11)]. Laboratory Tests Inform patients that they will test positive for glucose in their urine while on INVOKAMET or INVOKAMET XR [see Drug Interactions (7)]. Females of Reproductive Age Advise pregnant women, and females of reproductive potential of the potential risk to a fetus with treatment with INVOKAMET or INVOKAMET XR [see Use in Specific Populations (8.1)]. Instruct females of reproductive potential to report pregnancies to their physicians as soon as possible. Inform females that treatment with INVOKAMET or INVOKAMET XR may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)]. Lactation Advise women that breastfeeding is not recommended during treatment with INVOKAMET or INVOKAMET XR [see Use in Specific Populations (8.2)]. Administration Instruct patients to keep INVOKAMET or INVOKAMET XR in the original bottle to protect from moisture. Advise patients that storage in a pill box or pill organizer is allowed for up to 30 days. Instruct patients to take INVOKAMET only as prescribed twice daily with food. If a dose is missed, advise patients not to take two doses of INVOKAMET at the same time. Instruct patients to take INVOKAMET XR only as prescribed once daily with the morning meal. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time Reference ID: 5499136 60 for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take more than two tablets of INVOKAMET XR at the same time. Instruct patients that INVOKAMET XR must be swallowed whole and never crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet. Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA Licensed from Mitsubishi Tanabe Pharma Corporation For patent information: www.janssenpatents.com  Johnson & Johnson and its affiliates 2014 – 2024 Reference ID: 5499136 61 Medication Guide INVOKAMET® (in vok’ a met) (canagliflozin and metformin hydrochloride) tablets, for oral use and INVOKAMET® (in vok’ a met) XR (canagliflozin and metformin hydrochloride) extended-release tablets, for oral use What is the most important information I should know about INVOKAMET or INVOKAMET XR? INVOKAMET and INVOKAMET XR can cause serious side effects, including:  Lactic Acidosis. Metformin, one of the medicines in INVOKAMET and INVOKAMET XR, can cause a rare but serious condition called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital. Stop taking INVOKAMET or INVOKAMET XR and call your healthcare provider right away if you have any of the following symptoms of lactic acidosis: o feel cold in your hands or feet o have a slow or irregular heartbeat o feel very weak or tired o have unusual (not normal) muscle pain o have trouble breathing o have unusual sleepiness or sleep longer than usual o have stomach pains, nausea, or vomiting o feel dizzy or lightheaded Most people who have had lactic acidosis had other conditions that, in combination with metformin use, led to the lactic acidosis. Tell your healthcare provider if you have any of the following, because you have a higher chance for getting lactic acidosis with INVOKAMET or INVOKAMET XR if you: o have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye. o have liver problems. o drink alcohol very often or drink a lot of alcohol in short-term "binge" drinking. o get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids. o have surgery. o have new or worsening symptoms of congestive heart failure such as shortness of breath or increased fluid or swelling of the legs. o have a heart attack, severe infection, or stroke. o are 65 years of age or older. The best way to keep from having a problem with lactic acidosis from metformin is to tell your healthcare provider if you have any of the problems in the list above. Your healthcare provider will decide to stop your INVOKAMET or INVOKAMET XR for a while if you have any of these things.  Diabetic ketoacidosis (increased ketones in your blood or urine) in people with type 1 and other ketoacidosis. INVOKAMET and INVOKAMET XR can cause ketoacidosis that can be life-threatening and may lead to death. Ketoacidosis is a serious condition which needs to be treated in a hospital. People with type 1 diabetes have a high risk of getting ketoacidosis. People with type 2 diabetes or pancreas problems also have an increased risk of getting ketoacidosis. Ketoacidosis can also happen in people who: are sick, cannot eat or drink as usual, skip meals, are on a diet high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount of insulin or miss insulin doses, drink too much alcohol, have a loss of too much fluid from the body (volume depletion), or who have surgery or a procedure that requires not having food for a long time (prolonged fasting). Ketoacidosis can happen even if your blood sugar is less than 250 mg/dL. Your health care provider may ask you to periodically check ketones in your urine or blood.  Stop taking INVOKAMET or INVOKAMET XR and call your health care provider or get medical help right away if you get any of the following. If possible, check for ketones in your urine or blood, even if your blood sugar is less than 250 mg/dL: o nausea o tiredness o vomiting o trouble breathing o stomach-area (abdominal) pain o ketones in your urine or blood  Amputations. INVOKAMET or INVOKAMET XR may increase your risk of lower limb amputations. Amputations mainly involve removal of the toe or part of the foot, however, amputations involving the leg, below and above the knee, have also occurred. Some people had more than one amputation, some on both sides of the body. You may be at a higher risk of lower limb amputation if you: Reference ID: 5499136 1 o have a history of amputation o have heart disease or are at risk for heart disease o have had blocked or narrowed blood vessels, usually in your leg o have damage to the nerves (neuropathy) in your leg o have had diabetic foot ulcers or sores Call your healthcare provider right away if you have new pain or tenderness, any sores, ulcers, or infections in your leg or foot. Your healthcare provider may decide to stop your INVOKAMET or INVOKAMET XR for a while if you have any of these signs or symptoms. Talk to your healthcare provider about proper foot care.  Dehydration. INVOKAMET or INVOKAMET XR can cause some people to become dehydrated (the loss of too much body water). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden worsening of kidney function in people with type 2 diabetes who are taking canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. You may be at higher risk of dehydration if you: o take medicines to lower your blood pressure, including diuretics (water pill) o are on a low sodium (salt) diet o have kidney problems o are 65 years of age or older Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should drink on a daily basis. Call your health care provider right away if you reduce the amount of food or liquid you drink, for example if you cannot eat or you start to lose liquids from your body, for example from vomiting, diarrhea, or being in the sun too long.  Vaginal yeast infection. Women who take INVOKAMET or INVOKAMET XR may get vaginal yeast infections. Yeast infections can be a serious but common side effect of INVOKAMET or INVOKAMET XR. Symptoms of a vaginal yeast infection include: o vaginal odor o white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese) o vaginal itching  Yeast infection of the skin around the penis (balanitis or balanoposthitis). Men who take INVOKAMET or INVOKAMET XR may get a yeast infection of the skin around the penis. Men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include: o redness, itching, or swelling of the penis o rash of the penis o foul smelling discharge from the penis o pain in the skin around the penis Talk to your healthcare provider about what to do if you get symptoms of a yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medication and your symptoms do not go away. INVOKAMET or INVOKAMET XR can have other serious side effects. See “What are the possible side effects of INVOKAMET or INVOKAMET XR?” What is INVOKAMET or INVOKAMET XR?  INVOKAMET contains 2 prescription medicines called canagliflozin (INVOKANA) and metformin hydrochloride (HCl).  INVOKAMET XR contains 2 prescription medicines called canagliflozin (INVOKANA) and metformin HCL extended- release.  INVOKAMET or INVOKAMET XR can be used along with diet and exercise to lower blood sugar (glucose) in adults and children aged 10 years and older with type 2 diabetes. o One of the medicines in INVOKAMET or INVOKAMET XR, canagliflozin (INVOKANA), can also be used in adults with type 2 diabetes who have: o cardiovascular disease and canagliflozin is needed to reduce the risk of major cardiovascular events such as heart attack, stroke, or death. o diabetic kidney disease (nephropathy) with a certain amount of protein in the urine, and canagliflozin is needed to reduce the risk of end stage kidney disease (ESKD), worsening of kidney function, cardiovascular death, and hospitalization for heart failure.  INVOKAMET or INVOKAMET XR is not used to lower blood sugar (glucose) in people with type 1 diabetes.  It is not known if INVOKAMET or INVOKAMET XR is safe and effective in children under 10 years of age. Do not take INVOKAMET or INVOKAMET XR if you: Reference ID: 5499136 2  have severe kidney problems  have a condition called metabolic acidosis, including diabetic ketoacidosis (increased ketones in the blood or urine).  are allergic to canagliflozin, metformin, or any of the ingredients in INVOKAMET or INVOKAMET XR. See the end of this Medication Guide for a list of ingredients in INVOKAMET and INVOKAMET XR. Symptoms of an allergic reaction to INVOKAMET and INVOKAMET XR may include: o rash o raised red patches on your skin (hives) o swelling of the face, lips, mouth, tongue, and throat that may cause difficulty in breathing or swallowing Before taking INVOKAMET or INVOKAMET XR, tell your healthcare provider about all of your medical conditions, including if you:  have type 1 diabetes or have had diabetic ketoacidosis.  have a decrease in your insulin dose.  have a serious infection.  have a history of infection of the vagina or penis.  have a history of amputation.  have had blocked or narrowed blood vessels, usually in your leg.  have damage to the nerves (neuropathy) in your leg.  have had diabetic foot ulcers or sores.  have moderate to severe kidney problems.  have liver problems.  have a history of urinary tract infections or problems with urination.  are on a low sodium (salt) diet. Your healthcare provider may change your diet or your dose of INVOKAMET or INVOKAMET XR.  have ever had an allergic reaction to INVOKAMET or INVOKAMET XR.  are going to get an injection of dye or contrast agents for an x-ray procedure. INVOKAMET or INVOKAMET XR may need to be stopped for a short time. Talk to your healthcare provider about when you should stop INVOKAMET or INVOKAMET XR and when you should start INVOKAMET or INVOKAMET XR again. See "What is the most important information I should know about INVOKAMET or INVOKAMET XR?”  have heart problems, including congestive heart failure.  are going to have surgery or a procedure that requires not having food for a long time (prolonged fasting). Your healthcare provider may stop your INVOKAMET or INVOKAMET XR before you have surgery. Talk to your healthcare provider if you are having surgery about when to stop taking INVOKAMET or INVOKAMET XR and when to start it again.  are eating less or there is a change in your diet.  are dehydrated.  have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.  drink alcohol very often or drink a lot of alcohol in the short-term ("binge" drinking).  have low levels of vitamin B12 or calcium in your blood.  are pregnant or plan to become pregnant. INVOKAMET or INVOKAMET XR may harm your unborn baby. If you become pregnant while taking INVOKAMET or INVOKAMET XR, tell your healthcare provider as soon as possible. Talk with your healthcare provider about the best way to control your blood sugar while you are pregnant.  are premenopausal (before the “change of life”), and do not have periods regularly or at all. INVOKAMET or INVOKAMET XR may increase your chance of becoming pregnant. Talk to your healthcare provider about birth control choices while taking INVOKAMET or INVOKAMET XR, if you are not planning to become pregnant. Tell your healthcare provider right away if you become pregnant while taking INVOKAMET or INVOKAMET XR.  are breastfeeding or plan to breastfeed. INVOKAMET or INVOKAMET XR may pass into your breast milk and may harm your baby. Talk with your healthcare provider about the best way to feed your baby if you are taking INVOKAMET or INVOKAMET XR. Do not breastfeed while taking INVOKAMET or INVOKAMET XR. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. INVOKAMET or INVOKAMET XR may affect the way other medicines work and other medicines may affect how INVOKAMET or INVOKAMET XR works. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. Reference ID: 5499136 3 How should I take INVOKAMET or INVOKAMET XR?  If you are prescribed INVOKAMET, take by mouth 2 times each day with meals exactly as your healthcare provider tells you to take it. Taking INVOKAMET with meals may lower your chance of having an upset stomach.  If you are prescribed INVOKAMET XR, take by mouth 1 time each day with the morning meal exactly as your healthcare provider tells you to take it. Taking INVOKAMET XR with a meal may lower your chance of having an upset stomach.  Swallow INVOKAMET XR whole. Do not crush, cut, or chew.  You may sometimes pass a soft mass in your stools (bowel movement) that looks like INVOKAMET XR tablets. It is normal to see this in your stool.  Your healthcare provider may change your dose if needed.  Your healthcare provider may tell you to take INVOKAMET or INVOKAMET XR along with other diabetes medicines. Low blood sugar can happen more often when INVOKAMET or INVOKAMET XR is taken with certain other diabetes medicines. See “What are the possible side effects of INVOKAMET or INVOKAMET XR?”  Your healthcare provider may tell you to stop taking INVOKAMET or INVOKAMET XR at least 3 days before any surgery or procedure that requires not having food for a long time (prolonged fasting).  If you miss a dose of INVOKAMET, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take 2 tablets of INVOKAMET at the same time. Talk to your healthcare provider if you have questions about a missed dose.  If you miss a dose of INVOKAMET XR, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take more than 2 tablets of INVOKAMET XR at the same time. Talk to your healthcare provider if you have questions about a missed dose.  If you take too much INVOKAMET or INVOKAMET XR, call your healthcare provider or Poison Help line at 1-800-222­ 1222 or go to the nearest hospital emergency room right away.  When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you have any of these conditions and follow your healthcare provider’s instructions.  INVOKAMET and INVOKAMET XR will cause your urine to test positive for glucose.  Your healthcare provider may do certain blood tests before you start INVOKAMET or INVOKAMET XR and during treatment as needed. Your healthcare provider may change your dose of INVOKAMET or INVOKAMET XR based on the results of your blood tests. What should I avoid while taking INVOKAMET or INVOKAMET XR?  Avoid drinking alcohol very often or drinking a lot of alcohol in a short period of time (“binge” drinking). It can increase your chances of getting serious side effects. What are the possible side effects of INVOKAMET or INVOKAMET XR? INVOKAMET or INVOKAMET XR may cause serious side effects including:  See "What is the most important information I should know about INVOKAMET or INVOKAMET XR?”  serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. Tell your healthcare provider if you have any signs or symptoms of a urinary tract infection such as a burning feeling when passing urine, a need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people may also have a fever, back pain, nausea, or vomiting.  low blood sugar (hypoglycemia). If you take INVOKAMET or INVOKAMET XR with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take INVOKAMET or INVOKAMET XR. Signs and symptoms of low blood sugar may include: o headache o drowsiness o weakness o confusion o dizziness o irritability o hunger o fast heartbeat o sweating o shaking or feeling jittery  a rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in people who take canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention Reference ID: 5499136 4 immediately if you have a fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around your anus and genitals: o pain or tenderness o swelling o redness of the skin (erythema)  serious allergic reaction. If you have any symptoms of a serious allergic reaction, stop taking INVOKAMET or INVOKAMET XR and call your healthcare provider right away or go to the nearest hospital emergency room. See “Do not take INVOKAMET or INVOKAMET XR if you:”. Your healthcare provider may give you a medicine for your allergic reaction and prescribe a different medicine for your diabetes.  broken bones (fractures). Bone fractures have been seen in patients taking canagliflozin. Talk to your healthcare provider about factors that may increase your risk of bone fracture.  low vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause a decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 blood levels before. Your healthcare provider may order blood tests to check your vitamin B12 levels. Other common side effects of INVOKAMET or INVOKAMET XR include:  nausea and vomiting  diarrhea  weakness  gas  upset stomach  indigestion  headache  changes in urination, including urgent need to urinate more often, in larger amounts, or at night These are not all the possible side effects of INVOKAMET or INVOKAMET XR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc. at 1-800-526-7736. How should I store INVOKAMET or INVOKAMET XR?  Store INVOKAMET or INVOKAMET XR at room temperature between 68 °F to 77 °F (20 °C to 25 °C).  Store INVOKAMET or INVOKAMET XR in the original container to protect from moisture. Storage in a pill box or pill organizer is allowed for up to 30 days. Keep INVOKAMET and INVOKAMET XR and all medicines out of the reach of children. General information about the safe and effective use of INVOKAMET or INVOKAMET XR. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use INVOKAMET or INVOKAMET XR for a condition for which it was not prescribed. Do not give INVOKAMET or INVOKAMET XR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about INVOKAMET or INVOKAMET XR that is written for health professionals. What are the ingredients in INVOKAMET? Active ingredients: canagliflozin and metformin HCl Inactive ingredients: The tablet core contains croscarmellose sodium (E468), hypromellose, magnesium stearate (E572), and microcrystalline cellulose (E460[i]). The magnesium stearate is vegetable-sourced. In addition, the tablet coating contains Macrogol/PEG3350 (E1521), polyvinyl alcohol (E1203) (partially hydrolyzed), talc (E553b), titanium dioxide (E171), iron oxide yellow (E172) (50 mg/1,000 mg and 150 mg/500 mg tablets only), iron oxide red (E172) (50 mg/1,000 mg, 150 mg/500 mg and 150 mg/1,000 mg tablets only), and iron oxide black (E172) (150 mg/1,000 mg tablets only). What are the ingredients of INVOKAMET XR? Active ingredients: canagliflozin and metformin HCl Inactive ingredients: The tablet core contains croscarmellose sodium (E468), hydroxypropyl cellulose (E463), hypromellose, lactose anhydrous, magnesium stearate (E572) (vegetable-sourced), microcrystalline cellulose (E460[i]), polyethylene oxide, and silicified microcrystalline cellulose (50 mg/500 mg and 50 mg/1,000 mg tablets only). In addition, the tablet coating contains macrogol/PEG3350 (E1521), polyvinyl alcohol (E1203) (partially hydrolyzed), talc (E553b), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172), and iron oxide black (E172) (50 mg/1,000 mg and 150 mg/1,000 mg tablets only). Manufactured for: Janssen Pharmaceuticals, Inc., Titusville, NJ 08560, USA. Licensed from Mitsubishi Tanabe Pharma Corporation. For patent information: www.janssenpatents.com © Johnson & Johnson and its affiliates 2014 - 2024 For more information about INVOKAMET or INVOKAMET XR, call 1-800-526-7736 or visit our websites at www.invokamet.com or www.invokametxr.com. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2024 Reference ID: 5499136 5
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2025-02-12T15:47:54.718216
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0 II HC- D - C: - CH I I C: -= O OMNIPRED® (prednisolone acetate ophthalmic suspension) 1% DESCRIPTION: OMNIPRED® (prednisolone acetate ophthalmic suspension) is an adrenocortical steroid product prepared as sterile ophthalmic suspension for topical ophthalmic use. The active ingredient is represented by the chemical structure: Established name: Prednisolone Acetate Chemical name: Pregna-1,4-diene-3,20-dione, 21-(acetyloxy)-11,17-dihydroxy-,(11β)-. Each mL of OMNIPRED® (prednisolone acetate ophthalmic suspension) 1% contains: Active: prednisolone acetate 1.0%. Preservative: benzalkonium chloride 0.01%. Inactives: citric acid monohydrate (to adjust pH), dibasic sodium phosphate, edetate disodium, glycerin, hypromellose, polysorbate 80, purified water, sodium hydroxide (to adjust pH). CLINICAL PHARMACOLOGY: Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation, such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Corticosteroids are capable of producing a rise in intraocular pressure. INDICATIONS AND USAGE: Steroid responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitides, when the inherent hazard of steroid use is accepted to obtain an advisable diminution in edema and inflammation; corneal injury from chemical, radiation, or thermal burns, or penetration of foreign bodies. CONTRAINDICATIONS: OMNIPRED® (prednisolone acetate ophthalmic suspension) is contraindicated in most viral diseases of the cornea and conjunctiva, including epithelial herpes Reference ID: 5498432 simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. OMNIPRED® (prednisolone acetate ophthalmic suspension) is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation and to other corticosteroids. WARNINGS: FOR TOPICAL OPHTHALMIC USE. Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision, and in posterior subcapsular cataract formation. Prolonged use may also suppress the host immune response and thus increase the hazard of secondary ocular infections. Various ocular diseases and long-term use of topical corticosteroids have been known to cause corneal and scleral thinning. Use of topical corticosteroids in the presence of thin corneal or scleral tissue may lead to perforation. Acute purulent infections of the eye may be masked or activity enhanced by the presence of corticosteroid medication. If this product is used for 10 days or longer, intraocular pressure (IOP) should be routinely monitored even though it may be difficult in children and uncooperative patients. Steroids should be used with caution in the presence of glaucoma. IOP should be checked frequently. The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution; frequent slit lamp microscopy is recommended. Corticosteroids are not effective in mustard gas keratitis and Sjogren's keratoconjunctivitis. PRECAUTIONS: General: The initial prescription and renewal of the medication order should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after two days, the patient should be reevaluated. As fungal infections of the cornea are particularly prone to develop coincidentally with long-term local corticosteroid applications, fungal invasion should be suspected in any persistent corneal ulceration where a corticosteroid has been used or is in use. Fungal cultures should be taken when appropriate. If this product is used for 10 days or longer, IOP should be monitored (see WARNINGS). Information for Patients: If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should be advised to discontinue use of the medication and consult a physician. This product is sterile when packaged. To prevent contamination, care should be taken to avoid touching the bottle tip to eyelids or to any other surface. The use of this bottle by more than one person may spread infection. Keep bottle tightly closed when not in use. Keep out of the reach of children. Carcinogenesis, Mutagenesis, Impairment of Fertility: No studies have been conducted in animals or in humans to evaluate the potential of these effects. Reference ID: 5498432 Pregnancy: Teratogenic effects. Prednisolone has been shown to be teratogenic in mice when given in doses 1-10 times the human dose. Dexamethasone, hydrocortisone and prednisolone were ocularly applied to both eyes of pregnant mice five times per day on Days 10 through 13 of gestation. A significant increase in the incidence of cleft palate was observed in the fetuses of the treated mice. There are no adequate and well controlled studies in pregnant women. OMNIPRED® (prednisolone acetate ophthalmic suspension) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from prednisolone acetate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients. ADVERSE REACTIONS: Adverse reactions include, in decreasing order of frequency, elevation of IOP with possible development of glaucoma and infrequent optic nerve damage, posterior subcapsular cataract formation, and delayed wound healing. Although systemic effects are extremely uncommon, there have been rare occurrences of systemic hypercorticoidism after use of topical steroids. Corticosteroid-containing preparations have also been reported to cause acute anterior uveitis and perforation of the globe. Keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia, loss of accommodation and ptosis have occasionally been reported following local use of corticosteroids. The development of secondary ocular infection (bacterial, fungal and viral) has occurred. Fungal and viral infections of the cornea are particularly prone to develop coincidentally with long-term applications of steroid. The possibility of fungal invasion should be considered in any persistent corneal ulceration where steroid treatment has been used (see WARNINGS). The following additional adverse reactions have been reported with prednisolone use: Cushing’s syndrome and adrenal suppression may occur after very frequent use of ophthalmic prednisolone, particularly in very young children. DOSAGE AND ADMINISTRATION: SHAKE WELL BEFORE USING. Two drops topically in the affected eye(s) four times daily. In cases of bacterial infections, concomitant use of anti-infective agents is mandatory. Care should be taken not to discontinue therapy prematurely. If signs and symptoms fail to improve after two days, the patient should be reevaluated (see PRECAUTIONS). Reference ID: 5498432 The dosing of OMNIPRED® suspension may be reduced, but care should be taken not to discontinue therapy prematurely. In chronic conditions, withdrawal of treatment should be carried out by gradually decreasing the frequency of applications. HOW SUPPLIED: OMNIPRED® (prednisolone acetate ophthalmic suspension) is supplied in a white, round low density polyethylene dispenser with a natural low density polyethylene dispensing plug and pink polypropylene cap. Tamper evidence is provided with a shrink band around the closure and neck area of the package. OMNIPRED® suspension: 5 mL NDC 0065-0638-27 10 mL NDC 0065-0638-25 STORAGE: Store at 8°C to 24°C (46°F to 75°F) in an UPRIGHT position. After opening, OMNIPRED® can be used until the expiration date on the bottle. Distributed by: Sandoz Inc. Princeton, NJ 08540 Reference ID: 5498432
custom-source
2025-02-12T15:47:54.859439
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2024/017469s054lbl.pdf', 'application_number': 17469, 'submission_type': 'SUPPL ', 'submission_number': 54}
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                                                                                                                                      HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use GEMTESA® safely and effectively. See full prescribing information for GEMTESA. GEMTESA (vibegron) tablets, for oral use Initial U.S. Approval: 2020 __________________RECENT MAJOR CHANGES _________________ Indications and Usage, Overactive Bladder in Adult Males with Benign Prostatic Hyperplasia (1.2) 12/2024 Contraindications (4) 10/2024 Warnings and Precautions, Angioedema (5.2) 10/2024 _________________ __________________ INDICATIONS AND USAGE GEMTESA is a beta-3 adrenergic agonist indicated for the treatment of: • overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults. (1.1) • overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adult males on pharmacological therapy for benign prostatic hyperplasia. (BPH) (1.2). ______________ _______________ DOSAGE AND ADMINISTRATION • The recommended dose is one 75 mg tablet orally once daily. (2.1) • Swallow tablet whole with water. (2.1) • Tablet may be crushed and mixed with applesauce. (2.1) _____________ ______________ DOSAGE FORMS AND STRENGTHS Tablets: 75 mg (3) ____________________ ___________________ CONTRAINDICATIONS Do not use if prior hypersensitivity reaction to vibegron or any components of the product. (4) _______________ WARNINGS AND PRECAUTIONS _______________ Urinary Retention: Monitor for urinary retention, especially in patients with bladder outlet obstruction and also in patients taking muscarinic antagonist medications for OAB, in whom the risk of urinary retention may be greater. If urinary retention develops, discontinue GEMTESA. (5.1) Angioedema: Angioedema of the face and/or larynx has been reported with GEMTESA. (5.2) ____________________ADVERSE REACTIONS____________________ Most common adverse reactions (≥2%) reported with GEMTESA were headache, urinary tract infection, nasopharyngitis, diarrhea, nausea, and upper respiratory tract infection. (6.1 To report SUSPECTED ADVERSE REACTIONS, contact Sumitomo Pharma America at 1-833-876-8268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ____________________DRUG INTERACTIONS____________________ Digoxin: Measure serum digoxin concentrations before initiating GEMTESA. Monitor serum digoxin concentrations to titrate digoxin dose to desired clinical effect. (7) _______________ USE IN SPECIFIC POPULATIONS _______________ Pediatric use: Safety and effectiveness in pediatric patients have not been established. (8.4) End-stage Renal Disease with or without Hemodialysis: Not recommended. (8.6) Severe Hepatic Impairment: Not recommended. (8.7) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1. Overactive Bladder in Adults 1.2. Overactive Bladder in Adult Males with Benign Prostatic Hyperplasia (BPH) 2 DOSAGE AND ADMINISTRATION 2.1. Recommended Dosage 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Urinary Retention 5.2 Angioedema 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Overactive Bladder in Adults 14.2 Overactive Bladder in Adult Males with BPH 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 5498572 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Overactive Bladder in Adults GEMTESA® is indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults. 1.2 Overactive Bladder in Adult Males with Benign Prostatic Hyperplasia (BPH) GEMTESA is indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adult males on pharmacological therapy for benign prostatic hyperplasia (BPH). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage of GEMTESA is one 75 mg tablet orally, once daily with or without food. Swallow GEMTESA tablets whole with a glass of water. In adults, GEMTESA tablets also may be crushed, mixed with a tablespoon (approximately 15 mL) of applesauce and taken immediately with a glass of water [see Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS Tablets: 75 mg, oval, light green, film-coated, debossed with V75 on one side and no debossing on the other side. 4 CONTRAINDICATIONS GEMTESA is contraindicated in patients with known hypersensitivity to vibegron or any components of GEMTESA. Hypersensitivity reactions, such as angioedema, have occurred [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Urinary Retention Urinary retention has been reported in patients taking GEMTESA. The risk of urinary retention may be increased in patients with bladder outlet obstruction and also in patients taking muscarinic antagonist medications for the treatment of OAB. Monitor patients for signs and symptoms of urinary retention, particularly in patients with bladder outlet obstruction or patients taking muscarinic antagonist medications for the treatment of OAB. Discontinue GEMTESA in patients who develop urinary retention [see Adverse Reactions (6.1)]. 2 Reference ID: 5498572 5.2 Angioedema Angioedema of the face and/or larynx has been reported with GEMTESA. Angioedema has been reported to occur hours after the first dose or after multiple doses. Angioedema, associated with upper airway swelling, may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, immediately discontinue GEMTESA and provide appropriate therapy and/or measures necessary to ensure a patent airway. GEMTESA is contraindicated in patients with known hypersensitivity to vibegron or any component of GEMTESA [see Contraindications (4) and Adverse Reactions (6.2)]. 6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling:  Urinary retention [see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Overactive Bladder in Adults The safety of GEMTESA was evaluated in a 12-week, double-blind, placebo- and active- controlled study (Study 3003) in patients with OAB [see Clinical Studies (14.1)]. A total of 545 patients received GEMTESA. The majority of the patients were White (78%) and female (85%) with a mean age of 60 years (range 18 to 93 years). Adverse reactions that were reported in Study 3003 at an incidence greater than placebo and in ≥2% of patients treated with GEMTESA are listed in Table 1. Table 1: Adverse Reactions, Exceeding Placebo Rate, Reported in ≥2% of Patients Treated with GEMTESA 75 mg for up to 12 Weeks in Study 3003 GEMTESA 75 mg n (%) Placebo n (%) Number of Patients 545 540 Headache 22 (4.0) 13 (2.4) Nasopharyngitis 15 (2.8) 9 (1.7) Diarrhea 12 (2.2) 6 (1.1) Nausea 12 (2.2) 6 (1.1) Upper respiratory tract infection 11 (2.0) 4 (0.7) Other adverse reactions reported in <2% of patients treated with GEMTESA included: Gastrointestinal disorders: dry mouth, constipation 3 Reference ID: 5498572 Investigations: residual urine volume increased Renal and urinary disorders: urinary retention Vascular disorders: hot flush GEMTESA was also evaluated for long-term safety in an extension study (Study 3004) in 505 patients who completed the 12-week study (Study 3003). Of the 273 patients who received GEMTESA 75 mg once daily in the extension study, 181 patients were treated for a total of one year. Adverse reactions reported in ≥2% of patients treated with GEMTESA 75 mg for up to 52 weeks in the long-term extension study, and not already listed above, were urinary tract infection (6.6%) and bronchitis (2.9%). Overactive Bladder in Adult Males with BPH The safety of GEMTESA was evaluated in a 24-week double-blind, randomized, placebo- controlled study (Study 3005) in male patients with OAB on pharmacological therapy for BPH. A total of 553 patients received GEMTESA [see Clinical Studies (14.2)]. Adverse reactions that were reported in Study 3005 at an incidence greater than placebo and in ≥2% of patients treated with GEMTESA are listed in Table 2 Table 2: Adverse Reactions, Exceeding Placebo Rate, Reported in ≥2% of Patients Treated with GEMTESA 75 mg for up to 12 Weeks in Study 3005 GEMTESA 75 mg n (%) Placebo n (%) Number of Patients 553 551 Hypertension* 50 (9.0) 46 (8.3) Urinary tract infection 14 (2.5) 12 (2.2) *Defined as an average systolic blood pressure (SBP) ≥140mmHg or diastolic BP (DBP) ≥90mmHg on 3 assessments at two consecutive visits, in non-hypertensive patients. *Defined as an average increase of SBP ≥20mmHg or DBP≥10mmHg on 3 assessments at two consecutive visits, or the initiation or increase in dose of antihypertensive medications at any visit, in hypertensive patients. GEMTESA was also evaluated for long-term safety in a 28-week extension study (Study 3006) in 276 patients who completed the 24-week study (Study 3005). Of the 276 patients who received GEMTESA 75 mg once daily in the extension study, 124 patients were treated for a total of one year. There were no additional adverse reactions reported in Study 3006 that are not already included in Section 6.1 above. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of vibegron. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug 4 Reference ID: 5498572 exposure. The following adverse events have been reported in association with vibegron use in worldwide postmarketing experience: Urologic disorders: urinary retention Skin and subcutaneous tissue disorders: angioedema of the face and larynx; hypersensitivity reactions, including urticaria, pruritus, rash and drug eruption; eczema Gastrointestinal disorders: constipation 7 DRUG INTERACTIONS Concomitant use of GEMTESA increases digoxin maximal concentrations (Cmax) and systemic exposure as assessed by area under the concentration-time curve (AUC) [see Clinical Pharmacology (12.3)]. Serum digoxin concentrations should be monitored before initiating and during therapy with GEMTESA and used for titration of the digoxin dose to obtain the desired clinical effect. Continue monitoring digoxin concentrations upon discontinuation of GEMTESA and adjust digoxin dose as needed. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on GEMTESA use in pregnant women to evaluate for a drug- associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, no effects on embryo-fetal development were observed following administration of vibegron during the period of organogenesis at exposures approximately 275­ fold and 285-fold greater than clinical exposure at the recommended daily dose of GEMTESA, in rats and rabbits, respectively. Delayed fetal skeletal ossification was observed in rabbits at approximately 898-fold clinical exposure, in the presence of maternal toxicity. In rats treated with vibegron during pregnancy and lactation, no effects on offspring were observed at 89-fold clinical exposure. Developmental toxicity was observed in offspring at approximately 458-fold clinical exposure, in the presence of maternal toxicity. No effects on offspring were observed at 89-fold clinical exposure (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies carry some risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In an embryo-fetal developmental toxicity study, pregnant rats were treated with daily oral doses of 0, 30, 100, 300, or 1000 mg/kg/day vibegron during the period of organogenesis (Days 6 to 20 5 Reference ID: 5498572 of gestation). These doses were associated with systemic exposures (AUC) 0-, 9-, 89-, 275-, and 1867-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. No embryo-fetal developmental toxicity was observed at doses up to 300 mg/kg/day. Treatment with the high dose of 1000 mg/kg/day was discontinued due to maternal toxicity. In an embryo-fetal developmental toxicity study, pregnant rabbits were treated with daily oral doses of 0, 30, 100, or 300 mg/kg/day vibegron during the period of organogenesis (Days 7 to 20 of gestation). These doses were associated with systemic exposures (AUC) 0-, 86-, 285-, and 898-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. No embryo-fetal developmental toxicity was observed at doses of vibegron up to 100 mg/kg/day. Maternal toxicity (decreased food consumption), reduced fetal body weight, and an increased incidence of delayed skeletal ossification, were observed at 300 mg/kg/day. In a pre- and post-natal developmental toxicity study, pregnant or lactating rats were treated with daily oral doses of 0, 30, 100, or 500 mg/kg/day vibegron from day 6 of gestation through day 20 of lactation. These doses were associated with estimated systemic exposures (AUC) 0-, 9-, 89-, and 458-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. No developmental toxicity was observed in F1 offspring at doses up to 100 mg/kg/day. Maternal toxicity was observed during lactation (decreased body weight gain) at doses ≥100 mg/kg/day and during gestation (decreased body weight gain and food consumption) at 500 mg/kg/day. Developmental toxicity was observed in F1 offspring (increased stillborn index, lethality, reduced viability and weaning indices, decreased body weight and body weight gains, low physical development differentiation indices, and effects on sensory function and reflexes) at 500 mg/kg/day. 8.2 Lactation Risk Summary There are no data on the presence of vibegron in human milk, the effects of the drug on the breastfed infant, or the effects on milk production. When a single oral dose of radiolabeled vibegron was administered to postnatal nursing rats, radioactivity was observed in milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GEMTESA and any potential adverse effects on the breastfed infant from GEMTESA or from the underlying maternal condition. Data Animal Data In a lactational transfer study, lactating rats were treated with a single oral dose of 10 mg/kg radiolabeled [3H] vibegron on postpartum day 10. Levels of radioactivity were determined in milk and plasma collected at 1, 4, 12, and 24 after dosing. The Cmax of total radioactivity in milk and plasma were observed at 9 and 2 hours after dosing, respectively, with a maximum milk-to­ plasma concentration ratio of 2.2 observed at 12 hours after dosing. Vibegron elimination from 6 Reference ID: 5498572 milk showed a similar trend as that from plasma. The radioactivity concentration in milk at 24 hours after administration was approximately 25% of the Cmax. 8.4 Pediatric Use The safety and effectiveness of GEMTESA in pediatric patients have not been established. 8.5 Geriatric Use Of 526 patients who received GEMTESA in the clinical studies for OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency, 242 (46%) were 65 years of age or older, and 75 (14%) were 75 years of age or older [see Clinical Studies (14.1)]. No overall differences in safety or effectiveness of GEMTESA have been observed between patients 65 years of age and older and younger adult patients. Of the total number of GEMTESA-treated patients in clinical studies for OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency in adult males on pharmacological therapy for benign prostatic hyperplasia (BPH), 347 (63%) were 65 years of age and older, while 100 (18%) were 75 years of age and older [see Clinical Studies (14.2)]. No overall differences in safety of GEMTESA have been observed between patients 65 years of age and older and younger adult patients. 8.6 Renal Impairment No dosage adjustment for GEMTESA is recommended for patients with mild, moderate, or severe renal impairment (eGFR 15 to <90 mL/min/1.73 m2). GEMTESA has not been studied in patients with eGFR <15 mL/min/1.73 m2 (with or without hemodialysis) and is not recommended in these patients [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dosage adjustment for GEMTESA is recommended for patients with mild to moderate hepatic impairment (Child-Pugh A and B). GEMTESA has not been studied in patients with severe hepatic impairment (Child-Pugh C) and is not recommended in this patient population [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no experience with inadvertent GEMTESA overdosage. In case of suspected overdose, treatment should be symptomatic and supportive. 11 DESCRIPTION Vibegron is a selective beta-3 adrenergic agonist. The chemical name is (6S)-N-[4-[[(2S,5R)-5­ [(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl]methyl]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2­ a]pyrimidine-6-carboxamide having a molecular formula of C26H28N4O3 and a molecular weight of 444.538 g/mol. The structural formula of vibegron is: 7 Reference ID: 5498572 Vibegron is a crystalline, white to off-white to tan powder. GEMTESA tablets, for oral administration contain 75 mg of vibegron and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, mannitol, and microcrystalline cellulose. The light green film coating contains FD&C Blue No. 2 - aluminum lake, hypromellose, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Vibegron is a selective human beta-3 adrenergic receptor agonist. Activation of the beta-3 adrenergic receptor increases bladder capacity by relaxing the detrusor smooth muscle during bladder filling. 12.2 Pharmacodynamics Vibegron’s exposure-response relationship and the time course of pharmacodynamic response are not fully characterized. Blood Pressure In a 4-week, randomized, placebo-controlled, ambulatory blood pressure study in OAB patients (n=200), daily treatment with GEMTESA 75 mg was not associated with clinically significant changes in blood pressure. Subjects enrolled in this study had a mean age of 59 years and 75% were female. Thirty-five percent of subjects had pre-existing hypertension at baseline and 29% of all subjects were taking at least 1 concomitant antihypertensive medication. Cardiac Electrophysiology GEMTESA does not prolong the QT interval to any clinically relevant extent at a single dose 5.3 times the approved recommended dose. 12.3 Pharmacokinetics Mean vibegron Cmax and AUC increased in a greater than dose-proportional manner up to 600 mg (8 times the approved recommended dosage). Steady state concentrations are achieved within 7 days of once daily dosing. The mean accumulation ratio (Rac) was 1.7 for Cmax and 2.4 for AUC0-24hr. Absorption 8 Reference ID: 5498572 Median vibegron Tmax is approximately 1 to 3 hours. Oral administration of a 75 mg vibegron tablet crushed and mixed with 15 mL of applesauce resulted in no clinically relevant changes in vibegron pharmacokinetics when compared to administration of an intact 75 mg vibegron tablet. Effect of Food No clinically significant differences in vibegron pharmacokinetics were observed following administration of a high-fat meal (53% fat, 869 calories [32.1 g protein, 70.2 g carbohydrate, and 51.1 g fat]). Distribution The mean apparent volume of distribution is 6304 liters. Human plasma protein binding of vibegron is approximately 50%. The average blood-to-plasma concentration ratio is 0.9. Elimination Vibegron has an effective half-life of 30.8 hours across all populations. Metabolism Metabolism plays a minor role in the elimination of vibegron. CYP3A4 is the predominant enzyme responsible for in vitro metabolism. Excretion Following a radiolabeled dose, approximately 59% of the dose (54% as unchanged) was recovered in feces and 20% (19% as unchanged) in urine. Specific Populations No clinically significant differences in the pharmacokinetics of vibegron were observed based on age (18 to 93 years), sex, race/ethnicity (Japanese vs. non-Japanese), mild (eGFR 60 to <90 mL/min/1.73 m2), moderate (eGFR 30 to <60 mL/min/1.73 m2), and severe (eGFR 15 to <30 mL/min/1.73 m2) renal impairment, or moderate (Child-Pugh B) hepatic impairment. The effect of more severe renal impairment (eGFR <15 mL/min/1.73 m2) with or without hemodialysis or severe (Child-Pugh C) hepatic impairment on vibegron pharmacokinetics was not studied. Drug Interaction Studies Clinical Studies Digoxin: Concomitant administration of vibegron increased digoxin Cmax and AUC by 21% and 11%, respectively. Other Drugs: No clinically significant differences in vibegron pharmacokinetics were observed when used concomitantly with ketoconazole (P-gp and strong CYP3A4 inhibitor), diltiazem (P­ gp and moderate CYP3A4 inhibitor), rifampin (strong CYP3A4 inducer), or tolterodine. No clinically significant differences in the pharmacokinetics of the following drugs were observed 9 Reference ID: 5498572 when used concomitantly with vibegron: tolterodine, tolterodine 5-hydroxy metabolite, metoprolol, combined oral contraceptive (ethinyl estradiol, levonorgestrel), or warfarin. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Vibegron is a CYP3A4 substrate. Vibegron did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Vibegron did not induce CYP1A2, CYP2B6, or CYP3A4. Transporter Systems: Vibegron is a P-gp substrate. Vibegron did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2K at clinically relevant concentrations. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity was observed in long-term studies conducted in mice and rats treated with daily oral doses of vibegron for approximately 2 years. In the mouse carcinogenicity study, CD-1 mice were treated with daily oral doses of vibegron up to 90 mg/kg/day in males and up to 150 mg/kg/day in females, corresponding to estimated systemic exposures (AUC) 21- and 55-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. In the rat carcinogenicity study, Sprague Dawley rats were treated with daily oral doses of vibegron up to 30 mg/kg/day in males and up to 180 mg/kg/day in females, corresponding to systemic exposures (AUC) 18- and 117-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. Mutagenesis Vibegron was not mutagenic in in vitro microbial reverse mutation assays, showed no evidence of genotoxic activity in an in vitro human peripheral blood lymphocyte chromosomal aberration assay, and did not increase the frequency of micronucleated polychromatic erythrocytes in an in vivo rat bone marrow micronucleus assay. Impairment of Fertility In fertility/general reproductive toxicity studies conducted in rats, females were treated with daily oral doses of 0, 30, 100, 300, or 1000 mg/kg/day vibegron and males were treated with daily oral doses of 0, 10, 30, or 300 mg/kg/day vibegron. No effects on fertility were observed in female or male rats at doses up to 300 mg/kg/day, associated with systemic exposure (AUC) at least 274-fold higher than in humans treated with the recommended daily dose of GEMTESA. General toxicity, decreased fecundity, and decreased fertility were observed in female rats at 1000 mg/kg/day, associated with estimated systemic exposure 1867-fold higher than in humans treated with the recommended daily dose of GEMTESA. 10 Reference ID: 5498572 14 CLINICAL STUDIES 14.1 Overactive Bladder in Adults The efficacy of GEMTESA was evaluated in a 12-week, double-blind, randomized, placebo- controlled, and active-controlled trial (Study 3003, NCT03492281) in patients with OAB (urge urinary incontinence, urgency, and urinary frequency). Patients were randomized 5:5:4 to receive either GEMTESA 75 mg, placebo, or active control orally, once daily for 12 weeks. For study entry, patients had to have symptoms of OAB for at least 3 months with an average of 8 or more micturitions per day and at least 1 urge urinary incontinence (UUI) per day, or an average of 8 or more micturitions per day and an average of at least 3 urgency episodes per day. Urge urinary incontinence was defined as leakage of urine of any amount because the patient felt an urge or need to urinate immediately. The study population included OAB medication-naïve patients as well as patients who had received prior therapy with OAB medications. The co-primary endpoints were change from baseline in average daily number of micturitions and average daily number of UUI episodes at week 12. Additional endpoints included change from baseline in average daily number of “need to urinate immediately” (urgency) episodes and average volume voided per micturition. A total of 1,515 patients received at least one daily dose of placebo (n=540), GEMTESA 75 mg (n=545), or an active control treatment (n=430). The majority of patients were White (78%) and female (85%) with a mean age of 60 (range 18 to 93) years. Table 3 shows changes from baseline at week 12 for average daily number of micturitions, average daily number of UUI episodes, average daily number of “need to urinate immediately” (urgency) episodes, and average volume voided per micturition. 11 Reference ID: 5498572 Table 3: Mean Baseline and Change from Baseline at Week 12 for Micturition Frequency, Urge Urinary Incontinence Episodes, "Need to Urinate Immediately" (Urgency) Episodes, and Volume Voided per Micturition Parameter GEMTESA 75 mg Placebo Average Daily Number of Micturitions Baseline mean (n) 11.3 (526) 11.8 (520) Change from Baseline* (n) -1.8 (492) -1.3 (475) Difference from Placebo -0.5 95% Confidence Interval -0.8, -0.2 p-value <0.001 Average Daily Number of UUI Episodes Baseline mean (n) 3.4 (403) 3.5 (405) Change from Baseline* (n) -2.0 (383) -1.4 (372) Difference from Placebo -0.6 95% Confidence Interval -0.9, -0.3 p-value <0.0001 Average Daily Number of “Need to Urinate Immediately” (Urgency) Episodes Baseline mean (n) 8.1 (526) 8.1 (520) Change from Baseline* (n) -2.7 (492) -2.0 (475) Difference from Placebo -0.7 95% Confidence Interval -1.1, -0.2 p-value 0.002 Average Volume Voided (mL) per Micturition Baseline mean (n) 155 (524) 148 (514) Change from Baseline* (n) 23 (490) 2 (478) Difference from Placebo 21 95% Confidence Interval 14, 28 p-value <0.0001 * Least squares mean adjusted for treatment, baseline, sex, geographical region, study visit, and study visit by treatment interaction term. Figure 1 and Figure 2 show the mean change from baseline over time in average daily number of micturitions and mean change from baseline over time in average daily number of UUI episodes, respectively. 12 Reference ID: 5498572 0.00 -0.25 -0.50 -0.75 -1.00 -1.25 -1.50 -1.75 -2.00 -2.25 0.00 -0.25 -0.50 -0.75 -1.00 -1.25 -1.50 -1.75 -2.00 -2.25 Baseline 2 Baseline 2 Treatment ----e- Placebo (N=520) -----+- GEMTESA 75 mg(N=526) 4 8 12 Week Treatment ----e- Placebo (N=405) -----+- GEMTESA 75 mg(N=403) 4 8 12 Week Figure 1: Mean (SE) Change from Baseline in the Average Daily Number of Micturitions Figure 2: Mean (SE) Change from Baseline in the Average Daily Number of UUI Episodes LS Mean (SE) Change from Baseline in Patients with At Least 1 Average Daily UUI Episode at Baseline LS Mean (SE) Change from Baseline 13 Reference ID: 5498572 14.2 Overactive Bladder in Adult Males with BPH The safety, tolerability, and efficacy of GEMTESA was evaluated in a multinational 24-week, double-blind, randomized, placebo-controlled trial (Study 3005, NCT03902080) in male patients at least 45 years of age with OAB on pharmacological therapy (i.e., treatment with an alpha blocker, with or without a 5-alpha reductase inhibitor) for BPH. A total of 1105 patients were randomized 1:1 to receive either GEMTESA 75 mg or placebo once daily for 24 weeks. For study entry, patients had symptoms of OAB (an average of 8 or more micturitions per day, 3 or more urgency episodes per day with or without incontinence, and 2 or more nocturia episodes per night) while taking pharmacological therapy for at least 2 months for the treatment of lower urinary tract symptoms due to BPH. Randomization was stratified based on the baseline average number of micturition episodes per day, alpha blocker use with or without 5 alpha reductase inhibitor use, and urinary incontinence. The co-primary endpoints were change from baseline in the average daily number of micturitions and the average daily number of “need to urinate immediately” (urgency) episodes at week 12. Additional endpoints included change from baseline in the average daily number of urge urinary incontinence (UUI) episodes and the average volume voided per micturition. A total of 1104 patients received at least one daily dose of placebo (n=551) or GEMTESA 75 mg (n=553). The majority of patients were White (87%) and enrolled in the U.S. (56%). The mean age was 67 years (range 45 to 97) and at least 63% were ≥ 65 years. Table 4 shows changes from baseline at week 12 for average daily number of micturitions, average daily number of urgency episodes, average daily number of UUI episodes and average volume voided per micturition. 14 Reference ID: 5498572 Table 4: Mean Baseline and Change from Baseline at Week 12 for Micturition Frequency, "Need to Urinate Immediately" (Urgency Episodes), UUI Episodes and Volume Voided per Micturition Parameter GEMTESA 75 mg (N = 538) Placebo (N = 542) Average Daily Number of Micturitions Baseline mean 11.84 11.96 Change from Baseline* -2.04 -1.30 Difference from Placebo -0.74 95% Confidence Interval -1.02, -0.46 Average Daily Number of “Need to Urinate Immediately” (Urgency) Episodes Baseline mean 9.05 9.00 Change from Baseline* -2.88 -1.93 Difference from Placebo -0.95 95% Confidence Interval -1.37, -0.54 Average Daily Number of UUI Episodes N *** 146 151 Baseline mean 3.33 3.23 Change from Baseline* -2.19 -1.39 Difference from Placebo -0.80 95% Confidence Interval -1.33, -0.27 Average Volume Voided (mL) per Micturition Baseline mean 166.37 166.43 Change from Baseline* 25.63 10.56 Difference from Placebo 15.07 95% Confidence Interval 9.13, 21.02 * Least squares mean adjusted for study visit, baseline value, geographical region, interaction of visit by treatment, and stratification factors as randomized (baseline average micturitions per day**, alpha blocker use with or without 5-ARI, baseline urinary incontinence**), geographical region, study visit, and study visit by treatment interaction term. ** Baseline average micturitions per day stratification factor is not included in the model where the continuous value of baseline average micturitions per day is present; baseline urinary incontinence is not included in the model for UUI; *** Only subjects with baseline incontinence have UUI analyzed. 15 Reference ID: 5498572 0.00 -0.25 "' -0.50 Ji ~ "' -0.75 IIl 8 0 <l:I -1.00 "' "" !ii ..c: -1.25 u w' e -150 !ii "' z: u, -1.75 ...l -2.00 -2.25 0.00 -0.25 -0.50 -0.75 -1.00 -1.25 -1.50 -1.75 -2.00 -2.25 -2.50 -2.75 -3.00 -3.25 Baseline 2 Baseline 2 'I- - -1 4 8 Treatment - o - Placebo (N=542) -+- GEMTESA 75 mg(N=538) -- •• --··---I-·· - · · - · · f · · - · · - · --l-· · -· · -· I 12 Week 16 20 24 Treatment ---B--- Placebo (N=542) ---+- GEMTESA 75 mg(N=538) T 4 8 12 Week T 16 20 24 Figure 3 and Figure 4 show the mean change from baseline over time in average daily number of micturitions and mean change from baseline over time in average daily number of urgency episodes, respectively. Figure 3: Mean (SE) Change from Baseline in the Average Daily Number of Micturitions in Male Patients with BPH on Pharmacological Therapy Figure 4: Mean (SE) Change from Baseline in the Average Daily Number of Urgency Episodes in Male Patients with BPH on Pharmacological Therapy LS Mean (SE) Change from Baseline LS Mean (SE) Change from Baseline 16 Reference ID: 5498572 16 HOW SUPPLIED/STORAGE AND HANDLING GEMTESA 75 mg tablets are light green, oval, film-coated tablets, debossed with V75 on one side and no debossing on the other side. GEMTESA is marketed in two packaging configurations: Thirty (30) tablets in a HDPE bottle with a child-resistant cap, NDC 73336-075-30 Ninety (90) tablets in a HDPE bottle with a child-resistant cap, NDC 73336-075-90 Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep this and all medications out of sight and reach of children. Dispose unused medication via a take-back option if available; otherwise follow FDA instructions for disposal in the household trash. See www.fda.gov/drugdisposal for more information. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Urinary Retention Inform patients that GEMTESA has been associated with urinary retention. Inform patients that the risk of urinary retention may be increased in patients taking muscarinic antagonist medications for the treatment of OAB. Instruct patients to contact their healthcare provider if they experience symptoms consistent with urinary retention while taking GEMTESA [see Warnings and Precautions (5.1)]. Angioedema Inform patients that GEMTESA may cause angioedema. Advise patients to immediately discontinue GEMTESA and seek medical attention if angioedema associated with upper airway swelling occurs as this may be life-threatening [see Contraindications (4) and Warnings and Precautions (5.2)]. Administration Instructions Advise patients that GEMTESA tablets can be swallowed whole with a glass of water or may be crushed, mixed with a tablespoon of applesauce and taken immediately with a glass of water [see Dosage and Administration (2.1)]. Manufactured for and Distributed by: Sumitomo Pharma America, Inc. Marlborough, MA 01752 17 Reference ID: 5498572 • • Sumitomo Pharma is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO PHARMA is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO is a registered trademark of Sumitomo Chemical Co., Ltd., used under license. Sumitomo Pharma America, Inc. is a U.S. subsidiary of Sumitomo Pharma Co., Ltd. All other trademarks are the property of their respective owners. 18 Reference ID: 5498572 PATIENT INFORMATION GEMTESA [gem tes' ah] (vibegron) tablets, for oral use What is GEMTESA? GEMTESA is a prescription medicine used to treat the following symptoms due to a condition called overactive bladder in adults, and in adult males taking medicine for benign prostatic hyperplasia (BPH):  urge urinary incontinence: a strong need to urinate with leaking or wetting accidents  urgency: the need to urinate right away  frequency: urinating often It is not known if GEMTESA is safe and effective in children. Do not take GEMTESA if you:  are allergic to vibegron or any of the ingredients in GEMTESA. See the end of this leaflet for a complete list of ingredients in GEMTESA. Before you take GEMTESA, tell your doctor about all of your medical conditions, including if you:  have liver problems.  have kidney problems.  have trouble emptying your bladder or you have a weak urine stream.  take medicines that contain digoxin.  are pregnant or plan to become pregnant. It is not known if GEMTESA will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.  are breastfeeding or plan to breastfeed. It is not known if GEMTESA passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take GEMTESA. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I take GEMTESA?  Take GEMTESA exactly as your doctor tells you to take it.  Take 1 GEMTESA tablet, by mouth, 1 time a day with or without food.  Swallow GEMTESA tablets whole with a glass of water.  You may also crush GEMTESA tablets, mix with 1 tablespoon (about 15 mL) of applesauce, and take right away with a glass of water. What are the possible side effects of GEMTESA? GEMTESA may cause serious side effects, including:  inability to empty your bladder (urinary retention). GEMTESA may increase your chances of not being able to empty your bladder, especially if you have bladder outlet obstruction or take other medicines for treatment of overactive bladder. Tell your doctor right away if you are unable to empty your bladder.  angioedema. GEMTESA may cause an allergic reaction with swelling of the lips, face, tongue, or throat, with or without difficulty breathing and may be life-threatening. Stop using GEMTESA and get emergency medical help right away if you have symptoms of angioedema or trouble breathing. The most common side effects of GEMTESA include:  urinary tract infection  nasal congestion, sore throat or runny nose  nausea  headache  diarrhea  upper respiratory tract infection These are not all the possible side effects of GEMTESA. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store GEMTESA?  Store GEMTESA at room temperature between 68°F to 77°F (20°C to 25°C).  Safely throw away medicine that is no longer needed in your household trash.  You may also dispose of the unused medicine through a take-back option, if available. See www.fda.gov/drugdisposal for more information. Keep GEMTESA and all medicines out of the reach of children. General information about the safe and effective use of GEMTESA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use GEMTESA for a condition for which it was not prescribed. Do not give GEMTESA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about GEMTESA that is written for health professionals. Reference ID: 5498572 • • Sumitomo Pharma What are the ingredients in GEMTESA? Active ingredient: vibegron Inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, mannitol, and microcrystalline cellulose. The light green film coating contains FD&C Blue No. 2 - aluminum lake, hypromellose, iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin. Manufactured for and Distributed by: Sumitomo Pharma America, Inc. Marlborough, MA 01752 is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO PHARMA is a trademark of Sumitomo Pharma Co., Ltd., used under license. SUMITOMO is a registered trademark of Sumitomo Chemical Co., Ltd., used under license. Sumitomo Pharma America, Inc. is a U.S. subsidiary of Sumitomo Pharma Co., Ltd. All other trademarks are the property of their respective owners. For more information, go to www.GEMTESA.com or call 1-833-876-8268. This Patient Information has been approved by the U.S. Food and Drug Administration. Approved: 12/2024 Reference ID: 5498572
custom-source
2025-02-12T15:47:54.901665
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1 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RETEVMO safely and effectively. See full prescribing information for RETEVMO. RETEVMO® (selpercatinib) capsules, for oral use RETEVMO® (selpercatinib) tablets, for oral use Initial U.S. Approval: 2020 --------------------------- RECENT MAJOR CHANGES -------------------------­ Indications and Usage RET-Mutant Medullary Thyroid Cancer (1.2) 09/2024 RET Fusion-Positive Thyroid Cancer (1.3) 06/2024 Other RET Fusion-Positive Solid Tumors (1.4) 05/2024 Dosage and Administration (2.3, 2.5, 2.6, 2.7) 05/2024 Warnings and Precautions (5.11) 05/2024 ---------------------------- INDICATIONS AND USAGE --------------------------­ RETEVMO® is a kinase inhibitor indicated for the treatment of: • Adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test (1.1) • Adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy (1.2) • Adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) (1.3) • Adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options1 (1.4) This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ------------------------DOSAGE AND ADMINISTRATION----------------------­ • Select patients for treatment with RETEVMO based on the presence of a RET gene fusion (NSCLC, thyroid, or other solid tumors) or specific RET gene mutation (MTC). (2.1, 14) • Adult and adolescent patients 12 years of age or older: the recommended dosage is based on weight (2.3): • Less than 50 kg: 120 mg orally twice daily • 50 kg or greater: 160 mg orally twice daily • Pediatric patients 2 to less than 12 years of age: the recommended dosage is based on body surface area (2.3): • 0.33 to 0.65 m2: 40 mg orally three times daily • 0.66 to 1.08 m2: 80 mg orally twice daily • 1.09 to 1.52 m2: 120 mg orally twice daily • ≥1.53 m2: 160 mg orally twice daily • Reduce RETEVMO dose in patients with severe hepatic impairment. (2.7, 8.7) ----------------------DOSAGE FORMS AND STRENGTHS--------------------­ • Capsules: 40 mg, 80 mg. (3) • Tablets: 40 mg, 80 mg, 120 mg, 160 mg. (3) ------------------------------- CONTRAINDICATIONS -----------------------------­ None. (4) ------------------------WARNINGS AND PRECAUTIONS ----------------------­ • Hepatotoxicity: Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. (2.5, 5.1) • Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms. Withhold, reduce the dose or permanently discontinue RETEVMO based on severity. (2.5, 5.2) • Hypertension: Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating RETEVMO. Monitor BP after 1 week, at least monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. (2.5, 5.3) • QT Interval Prolongation: Monitor patients who are at significant risk of developing QTc prolongation. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment. Monitor QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on severity. (2.5, 5.4) • Hemorrhagic Events: Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage. (2.5, 5.5) • Hypersensitivity: Withhold RETEVMO and initiate corticosteroids. Upon resolution, resume at a reduced dose and increase dose by 1 dose level each week until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. (2.5, 5.6) • Tumor Lysis Syndrome: Closely monitor patients at risk and treat as clinically indicated. (5.7) • Risk of Impaired Wound Healing: Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established. (5.8) • Hypothyroidism: Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Withhold until clinically stable or permanently discontinue based on severity. (5.9) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the possible risk to a fetus and to use effective contraception. (5.10, 8.1, 8.3) • Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis (SCFE/SUFE) in Pediatric Patients: Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate (5.11, 6.1) -------------------------------ADVERSE REACTIONS -----------------------------­ The most common adverse reactions (≥25%) include: • Adult patients with solid tumors: edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. (6) • Pediatric patients with solid tumors: musculoskeletal pain, diarrhea, headache, nausea, vomiting, coronavirus infection, abdominal pain, fatigue, pyrexia, and hemorrhage. (6) The most common Grade 3 or 4 laboratory abnormalities (≥5%) include: • Adult patients with solid tumors: decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium. (6) • Pediatric patients with solid tumors: decreased calcium, decreased hemoglobin, and decreased neutrophils. (6) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------- DRUG INTERACTIONS -----------------------------­ • Acid-Reducing Agents: Avoid coadministration. If coadministration cannot be avoided, take RETEVMO with food (with PPI) or modify its administration time (with H2 receptor antagonist or locally-acting antacid). (2.4, 7.1) • Strong and Moderate CYP3A Inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the RETEVMO dose. (2.6, 7.1) • Strong and Moderate CYP3A Inducers: Avoid coadministration. (7.1) Reference ID: 5498247 2 1 • CYP2C8 and CYP3A Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. (7.2) • Certain P-gp and BCRP Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. (7.2) ------------------------USE IN SPECIFIC POPULATIONS----------------------­ • Lactation: Advise not to breastfeed. (8.2) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 RET Fusion-Positive Non-Small Cell Lung Cancer 1.2 RET-Mutant Medullary Thyroid Cancer 1.3 RET Fusion-Positive Thyroid Cancer 1.4 Other RET Fusion-Positive Solid Tumors 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Important Administration Instructions 2.3 Recommended Dosage 2.4 Dosage Modifications for Concomitant Use of Acid- Reducing Agents 2.5 Dosage Modifications for Adverse Reactions 2.6 Dosage Modifications for Concomitant Use of Strong and Moderate CYP3A Inhibitors 2.7 Dosage Modification for Severe Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5.2 Interstitial Lung Disease/Pneumonitis 5.3 Hypertension 5.4 QT Interval Prolongation 5.5 Hemorrhagic Events 5.6 Hypersensitivity 5.7 Tumor Lysis Syndrome 5.8 Risk of Impaired Wound Healing 5.9 Hypothyroidism 5.10 Embryo-Fetal Toxicity 5.11 Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients 6 ADVERSE REACTIONS • Pediatric Use: Monitor open growth plates in pediatric patients. Consider interrupting or discontinuing RETEVMO if abnormalities occur. (8.4) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 12/2024 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on RETEVMO 7.2 Effects of RETEVMO on Other Drugs 7.3 Drugs that Prolong QT Interval 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 RET Fusion-Positive Non-Small Cell Lung Cancer 14.2 RET-Mutant Medullary Thyroid Cancer 14.3 RET Fusion-Positive Thyroid Cancer 14.4 Other RET Fusion-Positive Solid Tumors 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE 1.1 RET Fusion-Positive Non-Small Cell Lung Cancer RETEVMO® is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test. 1.2 RET-Mutant Medullary Thyroid Cancer RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy. 1.3 RET Fusion-Positive Thyroid Cancer RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). 1.4 Other RET Fusion-Positive Solid Tumors Reference ID: 5498247 3 2 RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.4)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients for treatment with RETEVMO based on the presence of a RET gene fusion (NSCLC, thyroid cancer, or other solid tumors) or specific RET gene mutation (MTC) in tumor specimens [see Clinical Studies (14)]. Information on FDA-approved test(s) for the detection of RET gene fusions and RET gene mutations is available at: http://www.fda.gov/CompanionDiagnostics. An FDA-approved companion diagnostic test for the detection of RET gene fusions and RET gene mutations in plasma is not available. 2.2 Important Administration Instructions RETEVMO may be taken with or without food unless coadministered with a proton pump inhibitor (PPI) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. 2.3 Recommended Dosage The recommended dosage of RETEVMO is shown in Table 1: Table 1: Recommended RETEVMO Dosage Population RETEVMO Dosage Adult and adolescent patients 12 years of age or older based on body weight • Less than 50 kg 120 mg twice daily • 50 kg or greater 160 mg twice daily Pediatric patients 2 to less than 12 years of age based on body surface area • 0.33 to 0.65 m2 40 mg three times daily • 0.66 to 1.08 m2 80 mg twice daily • 1.09 to 1.52 m2 120 mg twice daily • ≥1.53 m2 160 mg twice daily Dosing pediatric patients with body surface area less than 0.33 m2 is not recommended Continue treatment with RETEVMO until disease progression or unacceptable toxicity. Swallow the capsules whole. Do not crush or chew the capsules. Do not administer to pediatric patients who are unable to swallow a capsule. Swallow the tablets whole. Do not crush or chew the tablets. Do not take a missed dose unless it is more than 6 hours until next scheduled dose. If vomiting occurs after RETEVMO administration, do not take an additional dose and continue to the next scheduled time for the next dose. 2.4 Dosage Modifications for Concomitant Use of Acid-Reducing Agents Avoid concomitant use of a PPI, a histamine-2 (H2) receptor antagonist, or a locally-acting antacid with RETEVMO [see Drug Interactions (7.1)]. If concomitant use cannot be avoided: • Take RETEVMO with food when coadministered with a PPI. • Take RETEVMO 2 hours before or 10 hours after administration of an H2 receptor antagonist. Reference ID: 5498247 4 • Take RETEVMO 2 hours before or 2 hours after administration of a locally-acting antacid. 2.5 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 2. Table 2: Recommended RETEVMO Dose Reductions for Adverse Reactions Current RETEVMO Dosage Dose Reduction First Second Third 40 mg three times daily 40 mg twice daily 40 mg once daily permanently discontinue 80 mg twice daily 40 mg twice daily 40 mg once daily permanently discontinue 120 mg twice daily 80 mg twice daily 40 mg twice daily 40 mg once daily 160 mg twice daily 120 mg twice daily 80 mg twice daily 40 mg twice daily Permanently discontinue RETEVMO in patients unable to tolerate three dose reductions. The recommended dosage modifications for adverse reactions are provided in Table 3. Table 3: Recommended RETEVMO Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Hepatotoxicity Grade 3 • Withhold RETEVMO and monitor AST/ALT once weekly until resolution to Grade [see Warnings and or 1 or baseline. Precautions (5.1)] Grade 4 • Resume at reduced dose by 2 dose levels and monitor AST and ALT once weekly until 4 weeks after reaching dose taken prior to the onset of Grade 3 or 4 increased AST or ALT. • Increase dose by 1 dose level after a minimum of 2 weeks without recurrence and then increase to dose taken prior to the onset of Grade 3 or 4 increased AST or ALT after a minimum of 4 weeks without recurrence. Interstitial Lung Disease/ Pneumonitis [see Warnings and Precautions (5.2)] Grade 2 • Withhold RETEVMO until resolution. • Resume at a reduced dose. • Discontinue RETEVMO for recurrent ILD/pneumonitis. Grade 3 or Grade 4 • Discontinue RETEVMO for confirmed ILD/pneumonitis. Hypertension [see Warnings and Precautions (5.3)] Grade 3 • Withhold RETEVMO for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled. Grade 4 • Discontinue RETEVMO. QT Interval Prolongation [see Warnings and Precautions (5.4)] Grade 3 • Withhold RETEVMO until recovery to baseline or Grade 0 or 1. • Resume at a reduced dose or permanently discontinue RETEVMO. Grade 4 • Discontinue RETEVMO. Hemorrhagic Grade 3 • Withhold RETEVMO until recovery to baseline or Grade 0 or 1. Events or • Discontinue RETEVMO for severe or life-threatening hemorrhagic events. [see Warnings and Grade 4 Precautions (5.5)] Hypersensitivity All • Withhold RETEVMO until resolution of the event. Initiate corticosteroids. Reactions Grades • Resume at a reduced dose by 3 dose levels while continuing corticosteroids. [see Warnings and • Increase dose by 1 dose level each week until the dose taken prior to the onset Precautions (5.6)] of hypersensitivity is reached, then taper corticosteroids. Reference ID: 5498247 5 Hypothyroidism [see Warnings and Precautions (5.9)] Grade 3 or Grade 4 • Withhold RETEVMO until resolution to Grade 1 or baseline. • Discontinue RETEVMO based on severity. Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 3 or Grade 4 • Withhold RETEVMO until recovery to baseline or Grade 0 or 1. • Resume at a reduced dose. 2.6 Dosage Modifications for Concomitant Use of Strong and Moderate CYP3A Inhibitors Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the RETEVMO dose as recommended in Table 4. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume RETEVMO at the dose taken prior to initiating the CYP3A inhibitor [see Drug Interactions (7.1)]. Table 4: Recommended RETEVMO Dosage for Concomitant Use of Strong and Moderate CYP3A Inhibitors Current RETEVMO Dosage Recommended RETEVMO Dosage Moderate CYP3A Inhibitor Strong CYP3A Inhibitor 40 mg orally three times daily 40 mg orally once daily 40 mg orally once daily 80 mg orally twice daily 40 mg orally twice daily 40 mg orally twice daily 120 mg orally twice daily 80 mg orally twice daily 40 mg orally twice daily 160 mg orally twice daily 120 mg orally twice daily 80 mg orally twice daily 2.7 Dosage Modification for Severe Hepatic Impairment Reduce the recommended dosage of RETEVMO for patients with severe hepatic impairment as recommended in Table 5 [see Use in Specific Populations (8.7)]. Table 5: Recommended RETEVMO Dosage for Severe Hepatic Impairment Current RETEVMO Dosage Recommended RETEVMO Dosage 40 mg orally three times daily 40 mg orally twice daily 80 mg orally twice daily 40 mg orally twice daily 120 mg orally twice daily 80 mg orally twice daily 160 mg orally twice daily 80 mg orally twice daily 3 DOSAGE FORMS AND STRENGTHS Capsules: • 40 mg: gray opaque capsule imprinted with “Lilly”, “3977” and “40 mg” in black ink. • 80 mg: blue opaque capsule imprinted with “Lilly”, “2980” and “80 mg” in black ink. Tablets: • 40 mg: light gray, film coated, round tablet debossed with “Ret 40” on one side and “5340” on the other side. • 80 mg: dark red-purple, film coated, round tablet debossed with “Ret 80” on one side and “6082” on the other side. • 120 mg: light purple, film coated, round tablet debossed with “Ret 120” on one side and “6120” on the other side. • 160 mg: light pink, film coated, round tablet debossed with “Ret 160” on one side and “5562” on the other side. 4 CONTRAINDICATIONS Reference ID: 5498247 6 5 None. WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Serious hepatic adverse reactions occurred in 3% of patients treated with RETEVMO. Increased AST occurred in 59% of patients, including Grade 3 or 4 events in 11% and increased ALT occurred in 55% of patients, including Grade 3 or 4 events in 12% [see Adverse Reactions (6.1)]. The median time to first onset for increased AST was 6 weeks (range: 1 day to 3.4 years) and increased ALT was 5.8 weeks (range: 1 day to 2.5 years). Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)]. 5.2 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with RETEVMO. ILD/pneumonitis occurred in 1.8% of patients who received RETEVMO, including 0.3% with Grade 3 or 4 events, and 0.3% with fatal reactions. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold RETEVMO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce the dose or permanently discontinue RETEVMO based on severity of confirmed ILD [see Dosage and Administration (2.5)]. 5.3 Hypertension Hypertension occurred in 41% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient [see Adverse Reactions (6.1)]. Overall, 6.3% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating RETEVMO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce the dose, or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)]. 5.4 QT Interval Prolongation RETEVMO can cause concentration-dependent QT interval prolongation [see Clinical Pharmacology (12.2)]. An increase in QTcF interval to >500 ms was measured in 7% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 20% of patients [see Adverse Reactions (6.1)]. RETEVMO has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction. Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating RETEVMO and during treatment. Monitor the QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)]. 5.5 Hemorrhagic Events Serious including fatal hemorrhagic events can occur with RETEVMO. Grade ≥3 hemorrhagic events occurred in 3.1% of patients treated with RETEVMO, including 4 (0.5%) patients with fatal hemorrhagic events, including cerebral hemorrhage (n = 2), tracheostomy site hemorrhage (n = 1), and hemoptysis (n=1). Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage [see Dosage and Administration (2.5)]. 5.6 Hypersensitivity Reference ID: 5498247 7 Hypersensitivity occurred in 6% of patients receiving RETEVMO, including Grade 3 hypersensitivity in 1.9%. The median time to onset was 1.9 weeks (range: 5 days to 2 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume RETEVMO at a reduced dose and increase the dose of RETEVMO by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity [see Dosage and Administration (2.5)]. Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity. 5.7 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) occurred in 0.6% of patients with medullary thyroid carcinoma receiving RETEVMO [see Adverse Reactions (6.1)]. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated. 5.8 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, RETEVMO has the potential to adversely affect wound healing. Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established. 5.9 Hypothyroidism RETEVMO can cause hypothyroidism. Hypothyroidism occurred in 13% of patients treated with RETEVMO; all reactions were Grade 1 or 2. Hypothyroidism occurred in 13% of patients (50/373) with thyroid cancer and 13% of patients (53/423) with other solid tumors including NSCLC [see Adverse Reactions (6.1)]. Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold RETEVMO until clinically stable or permanently discontinue RETEVMO based on severity [see Dosage and Administration (2.5)]. 5.10 Embryo-Fetal Toxicity Based on data from animal reproduction studies and its mechanism of action, RETEVMO can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)]. 5.11 Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients Slipped capital femoral epiphysis/slipped upper femoral epiphysis (SCFE/SUFE) occurred in 1 adolescent (3.7% of 27 patients) receiving RETEVMO in LIBRETTO-121 and 1 adolescent (0.5% of 193 patients) receiving RETEVMO in LIBRETTO-531 [see Adverse Reactions (6.1)]. Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate [see Adverse Reactions (6.1)]. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hepatotoxicity [see Warnings and Precautions (5.1)] • Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.2)] • Hypertension [see Warnings and Precautions (5.3)] • QT Interval Prolongation [see Warnings and Precautions (5.4)] • Hemorrhagic Events [see Warnings and Precautions (5.5)] Reference ID: 5498247 6 8 • Hypersensitivity [see Warnings and Precautions (5.6)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.7)] • Risk of Impaired Wound Healing [see Warnings and Precautions (5.8)] • Hypothyroidism [see Warnings and Precautions (5.9)] • Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Adolescent Patients [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in the WARNINGS and PRECAUTIONS and below reflects exposure to RETEVMO as a single agent administered at 160 mg orally twice daily evaluated in 796 patients with advanced solid tumors in LIBRETTO­ 001 [see Clinical Studies (14)]. RET Gene Fusion or Gene Mutation Positive Solid Tumors LIBRETTO-001 Among the 796 patients who received RETEVMO, 84% were exposed for 6 months or longer and 73% were exposed for greater than one year. Among these patients, 96% received at least one dose of RETEVMO at the recommended dosage of 160 mg orally twice daily. The median age was 59 years (range: 15 to 92 years); 0.3% were pediatric patients 12 to 16 years of age; 51% were male; and 69% were White, 23% were Asian, and 3% were Black or African American; and 5% were Hispanic/Latino. The most common tumors were NSCLC (45%), MTC (40%), and non-medullary thyroid carcinoma (7%). Serious adverse reactions occurred in 44% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pneumonia, pleural effusion, abdominal pain, hemorrhage, hypersensitivity, dyspnea, and hyponatremia. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions included sepsis (n = 6), respiratory failure (n = 5), hemorrhage (n = 4), pneumonia (n = 3), pneumonitis (n = 2), cardiac arrest (n=2), sudden death (n = 1), and cardiac failure (n = 1). Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in ≥0.5% of patients included increased ALT (0.6%), fatigue (0.6%), sepsis (0.5%), and increased AST (0.5%). Dosage interruptions due to an adverse reaction occurred in 64% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, increased AST, diarrhea, and hypertension. Dose reductions due to an adverse reaction occurred in 41% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included increased ALT, increased AST, QT prolongation, fatigue, diarrhea, drug hypersensitivity, and edema. The most common adverse reactions (≥25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium. Table 6 summarizes the adverse reactions in LIBRETTO-001. Table 6: Adverse Reactions (≥20%) in Patients Who Received RETEVMO in LIBRETTO-001 Adverse Reaction RETEVMO (n = 796) Grades 1-4# (%) Grades 3-4 (%) General Disorders and Administration Site Conditions Edema1 49 0.8* Fatigue2 46 3.1* Arthralgia 21 0.3* Reference ID: 5498247 9 Gastrointestinal Disorders Diarrhea3 47 5* Dry Mouth 43 0 Abdominal pain4 34 2.5* Constipation 33 0.8* Nausea 31 1.1* Vomiting 22 1.8* Vascular Disorders Hypertension 41 20 Skin and Subcutaneous Tissue Disorders Rash5 33 0.6* Nervous System Disorders Headache6 28 1.4* Respiratory, Thoracic and Mediastinal Disorders Cough7 24 0 Dyspnea8 22 3.1 Blood and Lymphatic System Disorders Hemorrhage9 22 2.6 Investigations Prolonged QT interval 21 4.8* 1 Edema includes edema peripheral, face edema, periorbital edema, eye edema, eyelid edema, orbital edema, localized edema, lymphedema, scrotal edema, peripheral swelling, scrotal swelling, swelling, swelling face, eye swelling, generalized edema, genital edema. 2 Fatigue includes asthenia and malaise. 3 Diarrhea includes defecation urgency, frequent bowel movements, gastrointestinal hypermotility, anal incontinence. 4 Abdominal pain includes abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness, epigastric discomfort, gastrointestinal pain. 5 Rash includes rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, butterfly rash, exfoliative rash, rash follicular, rash generalized, rash vesicular. 6 Headache includes sinus headache, tension headache. 7 Cough includes productive cough, upper airway cough syndrome. 8 Dyspnea includes dyspnea exertional, dyspnea at rest. 9 Hemorrhage includes, epistaxis, hematuria, hemoptysis, contusion, rectal hemorrhage, vaginal hemorrhage, ecchymosis, hematochezia, petechiae, traumatic hematoma, anal hemorrhage, blood blister, blood urine present, cerebral hemorrhage, gastric hemorrhage, hemorrhage intracranial, hemorrhage subcutaneous, spontaneous hematoma, abdominal wall hematoma, angina bullosa hemorrhagica, conjunctival hemorrhage, disseminated intravascular coagulation, diverticulum intestinal hemorrhagic, eye hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hemorrhagic stroke, hemorrhoidal hemorrhage, hepatic hemorrhage, hepatic hematoma, intraabdominal hemorrhage, laryngeal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage, occult blood positive, post procedural hemorrhage, postmenopausal hemorrhage, pelvic hematoma, periorbital hematoma, periorbital hemorrhage, pharyngeal hemorrhage, pulmonary contusion, purpura, retinal hemorrhage, retroperitoneal hematoma, scleral hemorrhage, skin hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, upper gastrointestinal hemorrhage, uterine hemorrhage, vessel puncture site hematoma. * Only includes a grade 3 adverse reaction. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 Clinically relevant adverse reactions in ≤15% of patients who received RETEVMO include hypothyroidism (13%); pneumonia (11%), hypersensitivity (6%); interstitial lung disease/pneumonitis, chylothorax, chylous ascites or tumor lysis syndrome (all < 2%). Table 7 summarizes the laboratory abnormalities in LIBRETTO-001. Reference ID: 5498247 10 1 Table 7: Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-001 Laboratory Abnormality RETEVMO1 Grades 1-4# (%) Grades 3-4 (%) Chemistry Increased AST 59 11 Decreased calcium 59 5.7 Increased ALT 56 12 Decreased albumin 56 2.3 Increased glucose 53 2.8 Increased creatinine 47 2.4 Decreased sodium 42 11 Increased alkaline phosphatase 40 3.4 Increased total cholesterol 35 1.7 Increased potassium 34 2.7 Decreased glucose 34 1.0 Decreased magnesium 33 0.6 Increased bilirubin 30 2.8 Hematology Decreased lymphocytes 52 20 Decreased platelets 37 3.2 Decreased hemoglobin 28 3.5 Decreased neutrophils 25 3.2 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 765 to 791 patients. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 LIBRETTO-121 The safety population described below reflects exposure to RETEVMO as a single agent at 92 mg/m2 orally twice daily evaluated in 27 patients with advanced solid tumors harboring an activating RET alteration in LIBRETTO-121 [see Clinical Studies (14)]. Among the 27 pediatric and adolescent patients who received RETEVMO, 81% were exposed for 6 months or longer and 59% were exposed for greater than one year. The median age was 13 years (range: 2 to 20 years); 22% were pediatric patients 2 to 12 years of age; 59% were male; and 52% were White, 26% were Asian, and 11% were Black or African American; and 19% were Hispanic/Latino. The most common cancers were MTC (52%), and papillary thyroid cancer (37%). Serious adverse reactions occurred in 22% of patients who received RETEVMO. The serious adverse reactions (in 1 patient each) were abdominal infection, abdominal pain, aspiration, constipation, diarrhea, epiphysiolysis, nausea, pneumonia, pneumatosis intestinalis, rhinovirus infection, sepsis, vomiting. Dosage interruptions due to an adverse reaction occurred in 22% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included decreased neutrophils. Dose reductions due to an adverse reaction occurred in 15% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included decreased neutrophils, increased ALT, and increased weight. The most common adverse reactions (≥25%) were musculoskeletal pain, diarrhea, headache, nausea, vomiting, coronavirus infection, abdominal pain, fatigue, pyrexia, and hemorrhage. The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased calcium, decreased hemoglobin, and decreased neutrophils. Reference ID: 5498247 11 Table 8 summarizes the adverse reactions in LIBRETTO-121. Table 8: Adverse Reactions (≥15%) in Patients Who Received RETEVMO in LIBRETTO-121 Adverse Reactions RETEVMO N= 27 Grades 1-4# % Grades 3-4 % Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain1 56 0 Gastrointestinal disorders Diarrhea2 41 0 Nausea 30 3.7* Vomiting 30 7* Abdominal pain3 26 0 Constipation 19 7* Stomatitis4 15 0 Nervous System Disorders Headache 33 0 Infections and Infestations Coronavirus infection 30 0 Upper respiratory tract infection 22 0 General Disorders and Administration Site Conditions Fatigue5 26 0 Pyrexia 26 0 Edema6 19 0 Increased weight 19 7* Blood and Lymphatic System Disorders Hemorrhage7 26 3.7* Respiratory, Thoracic and Mediastinal Disorders Oropharyngeal pain 22 0 Cough 22 0 Endocrine Disorders Hypothyroidism8 19 0 Skin and Subcutaneous Tissue Disorders Rash9 19 0 Renal and Urinary Disorders Proteinuria 15 0 1 Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, non-cardiac chest pain, neck pain, pain in extremity 2 Diarrhea includes anal incontinence 3 Abdominal pain includes abdominal pain upper 4 Stomatitis includes angular cheilitis 5 Fatigue includes asthenia and malaise 6 Edema includes edema peripheral, face edema, localized edema, generalized edema, swelling 7 Hemorrhage includes mouth hemorrhage, epistaxis 8 Hypothyroidism includes blood thyroid stimulating hormone increased, thyroglobulin increased 9 Rash includes rash maculopapular * No Grade 4 events were reported. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Reference ID: 5498247 12 1 Clinically relevant adverse reactions in <15% of patients who received RETEVMO include dizziness (11%), urinary tract infection (11%), decreased appetite (7%), electrocardiogram QT prolonged (7%), hypersensitivity (7%), hypertension (7%), and pneumonia (3.7%). Table 9 summarizes the laboratory abnormalities in LIBRETTO-121. Table 9: Select Laboratory Abnormalities (≥15%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-121 Laboratory Abnormality RETEVMO1 Grades 1-4# (%) Grades 3-4 (%) Chemistry Decreased calcium 59 7 Increased ALT 56 3.7* Increased alkaline phosphatase 52 0 Increased AST 48 3.7* Decreased albumin 44 0 Increased bilirubin 30 0 Increased creatinine 22 0 Decreased potassium 22 3.7 Decreased magnesium 15 3.7 Hematology Decreased neutrophils 44 7* Decreased lymphocytes 24 4.8 Decreased platelets 22 0 Decreased hemoglobin 19 7* Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 21 to 27 patients. * No Grade 4 abnormalities were reported. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5. Treatment-naïve RET Fusion-Positive Non-Small Cell Lung Cancer LIBRETTO-431 The safety population described below reflects exposure to RETEVMO as a single agent administered at 160 mg orally twice daily evaluated in 158 patients with unresectable locally advanced or metastatic RET fusion-positive NSCLC in LIBRETTO-431 [see Clinical Studies (14)]. Among the 158 patients who received RETEVMO, the median duration of exposure was 16.7 months (range: 5 days to 37.9 months); 87% were exposed for 6 months or longer and 70% were exposed for one year or longer. The median age was 61 years (range: 31 to 87 years); 46% were male; and 36% were White, 58% were Asian, 1.3% were Black or African American, 1.3% were American Indian or Alaska Native, and 3.2% were missing. Serious adverse reactions occurred in 35% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pleural effusion, and abnormal hepatic function. Fatal adverse reactions occurred in 4.4% of patients who received RETEVMO; fatal adverse reactions included myocardial infarction (n = 2), respiratory failure (n = 2), cardiac arrest, malnutrition, and sudden death (n = 1, each). Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in ≥1% of patients included increased ALT (1.3%), and myocardial infarction (1.3%). Dosage interruptions due to an adverse reaction occurred in 72% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, hypertension, increased AST, QT prolongation, diarrhea, and COVID-19 infection. Reference ID: 5498247 13 Dose reductions due to an adverse reaction occurred in 51% of patients who received RETEVMO. Adverse reactions requiring dose reductions in ≥5% of patients included increased ALT, increased AST, QT prolongation. The most common adverse reactions (≥25%) in patients who received RETEVMO were hypertension, diarrhea, edema, dry mouth, rash, fatigue, abdominal pain, and musculoskeletal pain. The most common Grade 3 or 4 laboratory abnormalities (≥5%) in patients who received RETEVMO were increased ALT, increased AST, and decreased lymphocytes. Table 10 summarizes the adverse reactions in LIBRETTO-431. Table 10: Adverse Reactions (≥15%) in Patients on Either Arm in LIBRETTO-431 Adverse Reaction RETEVMO (n=158) Chemotherapy with or without pembrolizumab (n=98) Grades 1-4# (%) Grades 3-4 (%) Grades 1-4# (%) Grades 3-4 (%) Vascular disorders Hypertension 48 20* 7 3.1* Gastrointestinal disorders Diarrhea1 44 1.3* 24 2.0* Dry mouth2 39 0 6 0 Abdominal pain3 25 0.6* 19 2.0* Constipation 22 0 40 1.0* Stomatitis4 18 0 16 0 Nausea 13 0 44 1.0* Vomiting5 13 0 23 1.0* General disorders and administration site conditions Edema6 41 2.5* 28 0 Fatigue7 32 3.2* 50 5* Pyrexia 13 0.6* 23 0 Skin and subcutaneous tissue disorders Rash8 33 1.9* 30 1.0* Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain9 25 0 28 0 Investigations Electrocardiogram QT prolonged 20 9* 1.0 0 Infections and infestations COVID-19 infection 19 0.6* 18 0 Metabolism and nutrition disorders Decreased appetite 17 0 34 2.0* 1 Diarrhea includes diarrhea, anal incontinence. 2 Dry mouth includes dry mouth, mucosal dryness. 3 Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, gastrointestinal pain. Reference ID: 5498247 14 4 Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation. 5 Vomiting includes vomiting, retching, regurgitation. 6 Edema includes edema, edema peripheral, face edema, periorbital edema, swelling face, peripheral swelling, localized edema, eyelid edema, orbital edema, eye edema, scrotal edema, penile edema, orbital swelling, periorbital swelling. 7 Fatigue includes fatigue, asthenia, malaise. 8 Rash includes rash, rash maculopapular, skin exfoliation, rash erythematous, rash macular, dermatitis, urticaria, rash papular, dermatitis allergic, rash pustular, rash vesicular, genital rash. 9 Musculoskeletal pain includes musculoskeletal pain, arthralgia, back pain, bone pain, musculoskeletal chest pain, non- cardiac chest pain, neck pain, pain in extremity. * No Grade 4 abnormalities were reported. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Clinically relevant adverse reactions in <15% of patients who received RETEVMO include headache (14%); hemorrhage (13%); urinary tract infections (12%); hypothyroidism (9%); pneumonia (9%); dizziness (8%); interstitial lung disease/pneumonitis (4.4%); hypersensitivity, chylous ascites, and chylothorax (all < 2%). Table 11 summarizes the laboratory abnormalities in LIBRETTO-431. Table 11: Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients on Either Arm in LIBRETTO-431 Laboratory Abnormality1 RETEVMO Chemotherapy with or without pembrolizumab Grades 1-4# (%) Grades 3-4 (%) Grades 1-4# (%) Grades 3-4 (%) Chemistry ALT increased 81 21 63 4.1 AST increased 77 10 46 0 Alkaline phosphatase Increased 35 1.3 22 0 Total bilirubin Increased 52 1.3 9 0 Blood creatinine Increased 23 0 21 0 Magnesium decreased 16 0.6 8 0 Albumin decreased 25 0 5 0 Calcium decreased 53 1.9 24 1.0 Sodium decreased 31 3.2 41 2.1 Potassium decreased 17 1.3 15 1.0 Hematology Platelets decreased 53 3.2 39 5 Lymphocyte count decreased 53 8 64 15 Hemoglobin decreased 21 0 91 5 Neutrophil count decreased 53 2.0 58 11 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available: RETEVMO (range: 154 to 157 patients) and chemotherapy with or without pembrolizumab (range: 96 to 97 patients). # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Increased Creatinine Reference ID: 5498247 1 15 In healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)]. RET-Mutant Medullary Thyroid Cancer LIBRETTO-531 The safety population described below reflects exposure to RETEVMO as a single agent administered at 160 mg (adults) or at 92 mg/m2 (adolescent, not to exceed 160 mg) orally twice daily, in patients with progressive, advanced, kinase inhibitor naïve, RET-mutant medullary thyroid cancer in LIBRETTO-531 [see Clinical Studies (14.2)]. Among the 193 patients who received RETEVMO, the observed median duration of exposure was 14.5 months (range: 25 days to 36 months); 80% were exposed for 6 months or longer and 59% were exposed for one year or longer. The median age was 55 years (range: 12 to 84 years); 63% were male; and 69% were White, 28% were Asian, 2.9% were Black or African American and ethnicity was not routinely collected. Serious adverse reactions occurred in 22% of patients who received RETEVMO. The most frequent serious adverse reactions were pneumonia and pyrexia (n = 3, each) and hypertension and urinary tract infection (n = 2, each). Fatal adverse reactions occurred in 2.1% of patients; fatal adverse reactions included COVID-19, diabetic ketoacidosis, multiple organ dysfunction syndrome, and sudden death (n=1 each). Permanent discontinuation due to an adverse reaction occurred in 4.7% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation were edema, multiple organ dysfunction syndrome, sudden death, AST increased, diabetic ketoacidosis, chronic kidney disease, retinopathy, COVID-19, and somatic symptom disorder (n = 1, each). Dosage interruptions due to an adverse reaction occurred in 49% of patients who received RETEVMO. Adverse reactions requiring dosage omission in ≥5% of patients included ALT increased (9%) and hypertension (7%). Dose reductions due to an adverse reaction occurred in 39% of patients who received RETEVMO. One adverse reaction, increased ALT (7%), required a dose reduction in ≥5% of patients. The most common adverse reactions (≥25%) in patients who received RETEVMO were hypertension, edema, dry mouth, fatigue, and diarrhea. The most common Grade 3 or 4 laboratory abnormalities (≥5%) in patients who received RETEVMO were decreased lymphocytes, increased ALT, decreased neutrophils, increased ALP, increased blood creatinine, decreased calcium, and increased AST. Table 12 summarizes the adverse reactions in LIBRETTO-531. Table 12: Adverse Reactions (≥10%) in Patients Who Received RETEVMO in LIBRETTO-531 Adverse Reaction RETEVMO N = 193 Cabozantinib or Vandetanib N = 97 Grades 1-4# (%) Grades 3-4 (%) Grades 1-4# (%) Grades 3-4 (%) Vascular disorders Hypertension1 43 19* 41 18* General disorders and administration-site conditions Edema2 33 0 5 0 Fatigue3 28 4.1* 47 9* Pyrexia 12 1.0* 2.1 0 Gastrointestinal disorders Dry mouth4 32 0.5* 10 1.0* Diarrhea5 26 3.1* 61 8* Abdominal pain6 18 0.5* 21 2.1* Constipation 16 0 12 0 Reference ID: 5498247 16 Stomatitis7 14 0.5* 42 13* Pyrexia 12 1.0* 2.1 0 Nausea 10 1.0* 32 5* Nervous system disorders Headache8 23 0.5* 21 0 Skin and subcutaneous tissue disorders Rash9 19 1.6* 27 4.1* Reproductive system and breast disorders Erectile dysfunction 16 0 0 0 Investigations Electrocardiogram QT prolonged10 14 4.7* 13 2.1* Metabolism and nutrition disorders Decreased appetite 12 0.5* 28 5* Endocrine disorders Hypothyroidism11 11 0 21 0 1 Hypertension includes hypertension, blood pressure increased. 2 Edema includes edema peripheral, face edema, periorbital edema, swelling face, peripheral swelling, localized edema, eyelid edema, generalized edema, eye swelling, lymphoedema, orbital edema, eye edema, edema, edema genital, swelling, scrotal edema, scrotal swelling, angioedema, skin edema, testicular swelling, vulvovaginal swelling. 3 Fatigue includes fatigue, asthenia, malaise. 4 Dry mouth includes dry mouth, mucosal dryness. 5 Diarrhea includes diarrhea, anal incontinence, defecation urgency, frequent bowel movements, gastrointestinal hypermotility. 6 Abdominal pain included abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, gastrointestinal pain. 7 Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation. 8 Headache includes headache, sinus headache, tension headache. 9 Rash includes rash, rash maculopapular, skin exfoliation, rash erythematous, rash macular, dermatitis, urticaria, rash pruritic, exfoliative rash, rash papular, dermatitis allergic, rash follicular, rash generalized, rash pustular, butterfly rash, rash morbilliform, rash vesicular. 10 Electrocardiogram QT prolongation includes electrocardiogram QT prolonged, electrocardiogram QT interval abnormal. 11 Hypothyroidism includes hypothyroidism, blood thyroid stimulating hormone increased. * Only includes a Grade 3 adverse reaction # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. Clinically relevant adverse reactions in ≤10% of patients who received RETEVMO include dizziness (8%); urinary tract infections (8%); vomiting (8%); pneumonia, interstitial lung disease/pneumonitis, chylous ascites, and hypersensitivity (all < 2%). Table 13 summarizes the laboratory abnormalities in LIBRETTO-531. Table 13: Select Laboratory Abnormalities (≥5%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-531 Laboratory Abnormality RETEVMO1 Cabozantinib or Vandetanib1 Grades 1-4# % Grades 3-4 % Grades 1-4# % Grades 3-4 % Chemistry Calcium decreased 55 5 62 11 ALT increased 53 16 72 7* AST increased 47 5 68 3.2* Alkaline phosphatase increased 37 6 28 5 Reference ID: 5498247 17 Laboratory Abnormality RETEVMO1 Cabozantinib or Vandetanib1 Grades 1-4# % Grades 3-4 % Grades 1-4# % Grades 3-4 % Total bilirubin increased 32 1.1 30 3.2* Blood creatinine increased 27 6 16 8 Sodium decreased 20 3.2* 16 0 Albumin decreased 11 1.1 7 0 Magnesium decreased 9 3.3 26 9 Potassium decreased 8 0 22 4.4* Hematology Lymphocyte count decreased 41 18 36 13 Neutrophil count decreased 33 14 42 19 Platelets decreased 28 1.1 34 1.1* Hemoglobin decreased 18 2.1* 23 2.1* 1 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available: RETEVMO (range: 183 to 191 patients) and chemotherapy with or without cabozantinib or vandetanib (range: 91 to 94 patients). * Only includes a Grade 3 laboratory abnormality # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 Increased Creatinine In healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)]. 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on RETEVMO Acid-Reducing Agents Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce RETEVMO anti-tumor activity. Avoid concomitant use of PPIs, H2 receptor antagonists, and locally-acting antacids with RETEVMO. If coadministration cannot be avoided, take RETEVMO with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid) [see Dosage and Administration (2.4)]. Strong and Moderate CYP3A Inhibitors Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation. Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, reduce the RETEVMO dosage and monitor the QT interval with ECGs more frequently [see Dosage and Administration (2.6), Warning and Precautions (5.4)]. Strong and Moderate CYP3A Inducers Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce RETEVMO anti-tumor activity. Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO. 7.2 Effects of RETEVMO on Other Drugs CYP2C8 and CYP3A Substrates Reference ID: 5498247 18 8 RETEVMO is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling. Certain P-gp and BCRP Substrates RETEVMO is a P-gp and BCRP inhibitor. Concomitant use of RETEVMO with P-gp or BCRP substrates increases their plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp or BCRP substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P­ gp and BCRP substrates provided in their approved product labeling. 7.3 Drugs that Prolong QT Interval RETEVMO is associated with QTc interval prolongation [see Warnings and Precautions (5.4), Clinical Pharmacology (12.2)]. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], RETEVMO can cause fetal harm when administered to a pregnant woman. There are no available data on RETEVMO use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Selpercatinib administration to pregnant rats during the period of organogenesis at oral doses ≥100 mg/kg [approximately 3.6 times the human exposure based on the area under the curve (AUC) at the clinical dose of 160 mg twice daily] resulted in 100% post-implantation loss. At the dose of 50 mg/kg [approximately equal to the human exposure (AUC) at the clinical dose of 160 mg twice daily], 6 of 8 females had 100% early resorptions; the remaining 2 females had high levels of early resorptions with only 3 viable fetuses across the 2 litters. All viable fetuses had decreased fetal body weight and malformations (2 with short tail and one with small snout and localized edema of the neck and thorax). 8.2 Lactation Risk Summary There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with RETEVMO and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Based on animal data, RETEVMO can cause embryolethality and malformations at doses resulting in exposures less than or equal to the human exposure at the clinical dose of 160 mg twice daily [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating RETEVMO [see Use in Specific Populations (8.1)]. Contraception Females Reference ID: 5498247 19 Advise female patients of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Infertility RETEVMO may impair fertility in females and males of reproductive potential [see Use in Specific Populations (8.4), Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of RETEVMO have been established in pediatric patients 2 years of age and older for the treatment of: • advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation who require systemic therapy • advanced or metastatic thyroid cancer with a RET gene fusion who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate) • locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients 2 years of age and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2, 14.3, 14.4)]. The predicted exposures of selpercatinib in pediatric patients at the recommended dosages were within the range of values predicted in patients ≥ 12 years and ≥ 50 kg in body weight receiving the approved recommended dosage of 160 mg twice daily [see Clinical Pharmacology (12.3)]. The safety and effectiveness of RETEVMO have not been established in these indications in patients less than 2 years of age. The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications [see Indications and Usage (1)]. Juvenile Animal Toxicity Data In a juvenile rat toxicity study, animals were dosed daily with selpercatinib from post-natal day 21 to day 70 (approximately equivalent to a human child to late adolescent). Selpercatinib increased physeal thickness of multiple bones, extending into the metaphysis and associated with decreased trabecular bone, which was not reversible at doses approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily. Growth plate changes were associated with impairment of bone modeling, resulting in decreased femur length and with reduction in bone mineral density. Selpercatinib also induced reversible hypocellularity of bone marrow in males at ≥30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily), and reversible alterations of dentin composition at ≥50 mg/kg (approximately 3 times the adult human exposure at the clinical dose of 160 mg twice daily). Irreversible, dose-dependent degeneration of testicular germinal epithelium, with vacuolation of Sertoli cells and corresponding depletion of spermatozoa in the epididymides, was also observed at ≥ 30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily) and affected male reproductive performance at 50 mg/kg (approximately 3 times the adult human exposure at the clinical dose of 160 mg twice daily). Females exhibited delay in attainment of vaginal patency, a marker of sexual maturity, at 125 mg/kg (approximately 4 times the adult human exposure at the clinical dose of 160 mg twice daily); this effect was associated with lower mean body weight. Similar effects in irregular thickening of growth plates in adult rats and minipigs, and tooth dysplasia and malocclusion, resulting in tooth loss in adult rats were observed in repeat dose studies of up to 13-week duration with selpercatinib. Monitor growth plates in pediatric patients with open growth plates. Consider interrupting or discontinuing therapy based on the severity of any growth plate abnormalities and based on an individual risk-benefit assessment. 8.5 Geriatric Use Of 796 patients who received RETEVMO, 34% (268 patients) were ≥65 years of age and 9% (74 patients) were ≥75 years of age. No overall differences were observed in the safety or effectiveness of RETEVMO between patients who were ≥65 years of age and younger patients. Reference ID: 5498247 20 8.6 Renal Impairment No dosage modification is recommended for patients with mild to severe renal impairment [estimated Glomerular Filtration Rate (eGFR) ≥15 to 89 mL/min, estimated by Modification of Diet in Renal Disease (MDRD) equation]. The recommended dosage has not been established for patients with end-stage renal disease (ESRD) [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Reduce the dose when administering RETEVMO to patients with severe [total bilirubin greater than 3 to 10 times upper limit of normal (ULN) and any AST] hepatic impairment [see Dosage and Administration (2.7)]. No dosage modification is recommended for patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) or moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) hepatic impairment. Monitor for RETEVMO-related adverse reactions in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 11 DESCRIPTION RETEVMO contains selpercatinib, a kinase inhibitor. The molecular formula for selpercatinib is C29H31N7O3 and the molecular weight is 525.61 g/mol. The chemical name is 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3­ yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Selpercatinib has the following chemical structure: N N N HO O N OCH3 N N N Selpercatinib is a white to light yellow powder that is slightly hygroscopic. The aqueous solubility of selpercatinib is pH dependent, from sparingly soluble at low pH to practically insoluble at neutral pH. RETEVMO capsules contain either 40 mg or 80 mg of selpercatinib in hard gelatin capsules for oral use. Each capsule contains inactive ingredients of colloidal silicon dioxide and microcrystalline cellulose. The 40 mg capsule shell is composed of gelatin, titanium dioxide, ferric oxide black and black ink. The 80 mg capsule shell is composed of gelatin, titanium dioxide, FD&C blue #1 and black ink. The black ink is composed of shellac, potassium hydroxide and ferric oxide black. RETEVMO tablets contain 40 mg, 80 mg, 120 mg, or 160 mg of selpercatinib as film coated, debossed tablets for oral use. Each tablet contains inactive ingredients of croscarmellose sodium, hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. The tablet film coating material contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Additionally, the film coating of the 40 mg, 80 mg, and 120 mg tablets contains ferrosoferric oxide and the film coating of the 80 mg, 120 mg, and 160 mg tablets contain ferric oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Selpercatinib is a kinase inhibitor. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinib also inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable. In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and 2 and approximately 8-fold lower concentration than VEGFR3. Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T. In addition, selpercatinib showed anti-tumor activity in mice intracranially implanted with a patient-derived RET fusion positive tumor. Reference ID: 5498247 21 12.2 Pharmacodynamics Exposure-Response Relationship Selpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Cardiac Electrophysiology The effect of RETEVMO on the QTc interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state maximum concentration (Cmax) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent. 12.3 Pharmacokinetics The pharmacokinetics of selpercatinib capsules were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. The capsule and tablet dosage forms of selpercatinib are bioequivalent. Steady state selpercatinib AUC and Cmax increased in a slightly greater than dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily [0.06 to 1.5 times the maximum recommended total daily dosage]. Steady-state was reached by approximately 7 days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient of variation (CV%)] Cmax was 2,980 (53%) ng/mL and AUC0-24h was 51,600 (58%) ng*h/mL. Absorption The median tmax of selpercatinib is 2 hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects. Effect of Food For both the capsule and tablet dosage forms no clinically significant differences in selpercatinib AUC or Cmax were observed following administration of a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) in healthy subjects. Distribution The apparent volume of distribution (Vss/F) of selpercatinib is 203 L. Protein binding of selpercatinib is 96% in vitro and is independent of concentration. The blood-to-plasma concentration ratio is 0.7. Elimination The apparent clearance (CL/F) of selpercatinib is 6 L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects. Metabolism Selpercatinib is metabolized predominantly by CYP3A4. Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the radioactive drug components in plasma. Excretion Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% of the administered dose was recovered in feces (14% unchanged) and 24% in urine (12% unchanged). Specific Populations The apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (9.6 kg to 179 kg). No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (2 years to 92 years), sex, or mild, moderate, or severe renal impairment (eGFR ≥15 to 89 mL/min). The effect of ESRD on selpercatinib pharmacokinetics has not been studied. Pediatric patients The exposures of selpercatinib in pediatric patients are predicted to be comparable to those in adult patients administered at the recommended dosages. Patients with Hepatic Impairment Reference ID: 5498247 22 The selpercatinib AUC0-INF increased 1.1-fold in subjects with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST), 1.3-fold in subjects with moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST), and 1.8-fold in subjects with severe (total bilirubin greater than 3 to 10 times ULN and any AST) hepatic impairment, compared to subjects with normal hepatic function. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Proton-Pump Inhibitors (PPI): Coadministration with multiple daily doses of omeprazole (PPI) decreased selpercatinib AUC0-INF and Cmax when RETEVMO was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC0-INF and Cmax when RETEVMO was administered with food (Table 14). Table 14: Change in Selpercatinib Exposure After Coadministration with PPI Selpercatinib AUC0-INF Selpercatinib Cmax RETEVMO fasting Reference Reference RETEVMO fasting + PPI ↓ 69% ↓ 88% RETEVMO with a high-fat meal1 + PPI ↑ 2% ↓ 49% RETEVMO with a low-fat meal2 + PPI No change ↓ 22% 1 High-fat meal: approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively; approximately 800 to 1,000 calories total. 2 Low-fat meal: approximately 390 calories and 10 g of fat. H2 Receptor Antagonists: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after the RETEVMO dose (administered fasting). Strong CYP3A Inhibitors: Coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) increased the selpercatinib AUC0-INF 2.3-fold and Cmax 1.3-fold. Moderate CYP3A Inhibitors: Coadministration of multiple doses of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the selpercatinib AUC 1.6 to 2-fold and Cmax 1.5 to 1.8-fold. Strong CYP3A Inducers: Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the selpercatinib AUC0-INF by 87% and Cmax by 70%. Moderate CYP3A Inducers: Coadministration of multiple doses of bosentan or efavirenz (moderate CYP3A inducers) is predicted to decrease the selpercatinib AUC by 40-70% and Cmax by 34-57%. Weak CYP3A Inducers: Coadministration of multiple doses of modafinil (weak CYP3A inducer) is predicted to decrease the selpercatinib AUC by 33% and Cmax by 26%. CYP2C8 Substrates: Coadministration of RETEVMO with repaglinide (sensitive CYP2C8 substrate) increased the repaglinide AUC0-INF 2.9-fold and Cmax 1.9-fold. CYP3A Substrates: Coadministration of RETEVMO with midazolam (sensitive CYP3A substrate) increased the midazolam AUC0-INF 1.5-fold and Cmax 1.4-fold. P-glycoprotein (P-gp) Substrates: Coadministration of RETEVMO with dabigatran (P-gp substrate) increased the dabigatran AUC0-INF 1.4-fold and Cmax 1.4-fold. BCRP Substrates: Coadministration of RETEVMO with rosuvastatin (BCRP substrate) increased the rosuvastatin AUC0-INF by 1.9-fold and Cmax by 1.7-fold. P-gp Inhibitors: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampin (P-gp inhibitor). MATE1 Substrates: No clinically significant differences in glucose levels were observed when metformin (MATE1 substrate) was coadministered with selpercatinib. In Vitro Studies Reference ID: 5498247 23 CYP Enzymes: Selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Transporter Systems: Selpercatinib inhibits MATE1. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1 [see Adverse Reactions (6.1)]. Selpercatinib does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations. Selpercatinib is a substrate for P-gp and BCRP, but not for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Selpercatinib was not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice when administered by daily oral gavage at doses of up to 60 mg/kg. Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation. Selpercatinib was positive in the in vivo micronucleus assay in rats at concentrations >7 times the Cmax at the human dose of 160 mg twice daily. In general toxicology studies, male rats and minipigs exhibited testicular degeneration which was associated with luminal cell debris and/or reduced luminal sperm in the epididymis at selpercatinib exposures approximately 0.4 (rat) and 0.1 (minipig) times the clinical exposure by AUC at the 160 mg twice daily clinical dose. In a dedicated fertility study in male rats, administration of selpercatinib at doses up to 30 mg/kg/day (approximately twice the clinical exposure by AUC at the 160 twice daily clinical dose) for 28 days prior to cohabitation with untreated females did not affect mating or have clear effects on fertility. Males did, however, display a dose-dependent increase in testicular germ cell depletion and spermatid retention at doses ≥3 mg/kg (~0.2 times the clinical exposure by AUC at the 160 twice daily clinical dose) accompanied by altered sperm morphology at 30 mg/kg. In a dedicated fertility study in female rats treated with selpercatinib for 15 days before mating to Gestational Day 7, there were decreases in the number of estrous cycles at a dose of 75 mg/kg (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). While selpercatinib did not have clear effects on mating performance or ability to become pregnant at any dose level, half of females at the 75 mg/kg dose level had 100% nonviable embryos. At the same dose level in females with some viable embryos there were increases in post-implantation loss. In a 3-month general toxicology study in minipigs, there were findings of decreased or absent corpora lutea at a selpercatinib dose of 15 mg/kg (approximately 0.3 times to the human exposure by AUC at the 160 mg twice daily clinical dose). Corpora luteal cysts were present in the minipig at selpercatinib doses ≥2 mg/kg (approximately 0.07 times the human exposure by AUC at the 160 mg twice daily clinical dose). 14 CLINICAL STUDIES 14.1 RET Fusion-Positive Non-Small Cell Lung Cancer LIBRETTO-001 The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive NSCLC enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). The study enrolled patients with advanced or metastatic RET fusion-positive NSCLC who had progressed on platinum-based chemotherapy and patients with locally advanced (stage III who were not candidates for surgical resection or definitive chemoradiation) or metastatic NSCLC without prior systemic therapy in separate cohorts. Identification of a RET gene alteration was prospectively determined in local laboratories using next generation sequencing (NGS), polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH) or other local testing methods. Adult patients received RETEVMO 160 mg orally twice daily until unacceptable toxicity or disease progression; patients enrolled in the dose escalation phase were permitted to adjust their dose to 160 mg twice daily. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1. RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy Reference ID: 5498247 24 Efficacy was evaluated in 247 patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001. The median age was 61 years (range: 23 to 81); 57% were female; 44% were White, 48% were Asian, 4.9% were Black or African American; and 2.8% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3%) and 97% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1–15); 58% had prior anti-PD1/PD-L1 therapy. RET fusions were detected in 94% of patients using NGS (84.6% tumor samples; 9.3% blood or plasma samples), 4.0% using FISH, 1.6% using PCR and 0.4% by other local testing methods. Efficacy results for previously treated RET fusion-positive NSCLC are summarized in Table 15. Table 15: Efficacy Results in LIBRETTO-001 (RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy) RETEVMO (n = 247) Overall Response Rate1 (95% CI) 61% (55%, 67%) Complete response 7.3% Partial response 54% Duration of Response Median in months (95% CI) 28.6 (20, NE) % with ≥ 12 months2 63% 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable For the 144 patients who received an anti-PD-1 or anti-PD-L1 therapy, either sequentially or concurrently with platinum- based chemotherapy, an exploratory subgroup analysis of ORR was 63% (95% CI: 54%, 70%) and the median DOR was 28.6 months (95% CI: 14.8, NE). Among the 247 patients with previously treated RET fusion-positive NSCLC, 16 had measurable CNS metastases at baseline as assessed by BIRC. One patient received radiation therapy (RT) to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 14 of these 16 patients; 39% of responders had an intracranial DOR of ≥ 12 months. Treatment-naïve RET Fusion-Positive NSCLC Efficacy was evaluated in 69 patients with treatment-naïve RET fusion-positive NSCLC enrolled into a cohort of LIBRETTO-001. The median age was 63 years (range 23 to 92); 62% were female; 70% were White, 19% were Asian, and 6% were Black or African American. ECOG performance status was 0-1 (94%) or 2 (6%) and 99% of patients had metastatic disease. RET fusions were detected in 91% of patients using NGS (60.9% tumor samples; 30.4% in blood), 7.2% using FISH and 1.4% using PCR. Efficacy results for treatment naïve RET fusion-positive NSCLC are summarized in Table 16. Table 16: Efficacy Results in LIBRETTO-001 (Treatment-Naïve RET Fusion-Positive NSCLC) RETEVMO (n =69) Overall Response Rate1 (95% CI) 84% (73%, 92%) Complete response 5.8% Partial response 78% Duration of Response Median in months (95% CI) 20.2 (13, NE) % with ≥ 12 months2 50% Reference ID: 5498247 25 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable Among the 69 patients with treatment-naïve RET fusion-positive NSCLC, 5 had measurable CNS metastases at baseline as assessed by BIRC. Two patients received RT to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 4 of these 5 patients; 38% of responders had an intracranial DOR of ≥ 12 months. LIBRETTO-431 The efficacy of RETEVMO was evaluated in patients with unresectable, locally advanced or metastatic, RET fusion- positive NSCLC enrolled in a multicenter, open-label, active-controlled, randomized trial (LIBRETTO-431, NCT04194944). The trial evaluated RETEVMO compared to platinum-based and pemetrexed chemotherapy with or without pembrolizumab in patients with RET fusion-positive, unresectable locally advanced or metastatic NSCLC with no previous systemic therapy for metastatic disease. Patients (N=261) were randomized to receive either RETEVMO (160 mg orally twice daily) in continuous 21-day cycles or pemetrexed intravenously (IV) (500 mg per square meter of body-surface area) along with the investigator’s choice of platinum therapy (carboplatin IV [AUC 5, maximum dose 750 mg] or cisplatin IV [75 mg per square meter]) with or without pembrolizumab IV (200 mg) every 21 days. Treatment continued until disease progression or unacceptable toxicity. Crossover from the control arm to RETEVMO was permitted following disease progression. Patients were stratified according to geographic region (East Asia vs. elsewhere), brain metastases at baseline (presence vs. absence or unknown), and the investigator’s intent (before randomization) to treat the patient with or without pembrolizumab. Tumor assessments were performed every 6 weeks for two assessments, then every 9 weeks for four assessments, and then every 12 weeks thereafter. The major efficacy outcome measure was progression-free survival (PFS) in patients intended to be treated with chemotherapy in combination with pembrolizumab and in the overall study population as determined by a blinded independent review committee (BIRC) according to RECIST v1.1. Other efficacy outcome measures included overall survival (OS) and overall response rate (ORR). A total of 212 patients were enrolled in LIBRETTO-431 with an intent to treat with pembrolizumab if randomized to the control arm (129 into RETEVMO arm and 83 into chemotherapy with pembrolizumab arm). The median age was 61.5 years (range: 31 to 84 years); 47% were male; 41% White, 55% Asian, and 0.9% Black or African American, 1.4% American Indian or Alaska Native, 1.9% were race not reported; ethnicity was not reported in 96% of patients. ECOG performance status was 0-1 (97%) or 2 (3%), 68% were never smokers, 93% of patients had metastatic disease, and 14% had measurable intracranial metastases at baseline, as determined by a neuroradiologic BIRC. RET fusions were detected in 60% of patients using NGS and 40% using PCR (89% tumor samples; 11% in blood). Efficacy results from the pre-planned interim efficacy analysis are summarized in Table 17. Table 17: Efficacy Results in LIBRETTO-431: RETEVMO versus Chemotherapy with Pembrolizumab RETEVMO (n = 129) Chemotherapy with pembrolizumab (n = 83) Progression-Free Survival Number (%) of patients with an event 49 (38%) 49 (59%) Medians in months (95% CI) 24.8 (16.9, NE) 11.2 (8.8, 16.8) Hazard ratio1 (95% CI) 0.46 (0.31, 0.70) p-value2 0.0002 Overall Response Rate (95% CI) 84% (76, 90) 65% (54, 75) Complete response 7% 6% Partial response 77% 59% Duration of Response Reference ID: 5498247 1.0 0.9 0.8 ~ :c 0.7 nl .c 2 a. nl 0.6 > ·2 Cl Vl 0.5 Ill l!! LL ~ 0.4 _Q 1/l 1/l l!! <:II 2 0.3 a. 0.2 0.1 0.0 # N. Risk RETEVMO Chemotherapy with pembrolizllmab • - ! 1 \ i '-l ___ _ \ ,L ___ : ·-L __ Ll RETE.VMO ----1.....l.... Chemotherapy with _ L .L .1 _ pembroli'zumab 0 3 129 114 83 70 6 9 105 91 55 45 l i, L,_ ____ JJ, t ~ "-, , ___ Ll..J~ 12 15 L _____ L~ L ___ JL __ JL _____ J 18 21 24 Time from Randomization (Months) 72 56 44 27 16 29 21 15 11 6 __ J 27 30 33 36 5 2 0 2 0 0 26 Median in months (95% CI) 24.2 (17.9, NE) 11.5 (9.7, 23.3) % with ≥ 12 months3 60% 30% 1 Based on the stratified Cox proportional hazard model, stratified by geographic location (East Asia versus elsewhere), brain metastases at baseline according to investigator (presence versus absence or unknown). 2 Based on stratified log-rank test, stratified by geographic location (East Asia versus elsewhere), brain metastases at baseline according to investigator (presence versus absence or unknown). 3 Based on observed duration of response. NE = not estimable Figure 1: Kaplan-Meier Curves of Progression-Free Survival in LIBRETTO-431: RETEVMO versus Chemotherapy with Pembrolizumab Among the 212 randomized patients, 29 had measurable CNS metastases at baseline as assessed by BIRC. Responses in intracranial lesions were observed in 14 of 17 patients treated with RETEVMO and 7 of 12 patients treated with chemotherapy with pembrolizumab. Overall survival was immature at the time of the PFS interim analysis. At the time of an updated descriptive analysis of OS (43% of prespecified OS events needed for the final analysis), a total of 49 (31%) and 26 (25%) patients died in the RETEVMO and the control arm, respectively. The OS HR was 1.26 (95% CI: 0.78, 2.04). Overall survival may be affected by the imbalance in post-progression therapies. Of 68 control arm patients who had disease progression, 50 patients (74%) received RETEVMO at progression. Of 71 RETEVMO arm patients who had disease progression, 16 (23%) received chemotherapy and/or immune checkpoint inhibitor therapy, and 44 (62%) continued receiving RETEVMO. 14.2 RET-Mutant Medullary Thyroid Cancer LIBRETTO-001 The efficacy of RETEVMO was evaluated in patients with RET-mutant MTC enrolled in a multicenter, open-label, multi- cohort clinical trial (NCT03157128). The study enrolled patients with advanced or metastatic RET-mutant MTC who had been previously treated with cabozantinib or vandetanib (or both) and patients with advanced or metastatic RET-mutant MTC who were naïve to cabozantinib and vandetanib in separate cohorts. RET-Mutant MTC Previously Treated with Cabozantinib or Vandetanib Reference ID: 5498247 27 Efficacy was evaluated in 55 patients with RET-mutant advanced MTC who had previously treated with cabozantinib or vandetanib enrolled into a cohort of LIBRETTO-001. The median age was 57 years (range: 17 to 84); 66% were male; 89% were White, 7% were Hispanic/Latino, and 1.8% were Black. ECOG performance status was 0-1 (95%) or 2 (5%) and 98% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1 – 8). RET mutation status was detected in 82% of patients using NGS (78% tumor samples; 4% blood or plasma), 16% using PCR, and 2% using an unknown test. The protocol excluded patients with synonymous, frameshift or nonsense RET mutations; the specific mutations used to identify and enroll patients are described in Table 18. Table 18: Mutations used to Identify and Enroll Patients with RET-Mutant MTC in LIBRETTO-001 RET Mutation Type1 Previously Treated (n = 55) Cabozantinib/ Vandetanib Naïve (n = 88) Total (n = 143) M918T 33 49 82 Extracellular cysteine mutation2 7 20 27 V804M or V804L 54 6 11 Other3 10 13 23 1 Somatic or germline mutations; protein change. 2 Extracellular cysteine mutations involving cysteine residues 609, 611, 618, 620, 630, and 634. 3 Other included: K666N (1), D631_L633delinsV (2), D631_L633delinsE (5), D378_G385delinsE (1), D898_E901del (2), A883F (4), E632_L633del (4), L790F (2), T636_V637insCRT(1), D898_E901del + D903_S904delinsEP (1). 4 One patient also had a M918T mutation. Efficacy results for RET-mutant MTC are summarized in Table 19. Table 19: Efficacy Results in LIBRETTO-001 (RET-Mutant MTC Previously Treated with Cabozantinib or Vandetanib) RETEVMO (n = 55) Overall Response Rate1 (95% CI) 76% (63%, 87%) Complete response 18% Partial response 58% Duration of Response Median in months (95% CI) 45.3 (29.9, NE) % with ≥12 months2 76% 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable Cabozantinib and Vandetanib-naïve RET-Mutant MTC Efficacy was evaluated in 88 patients with RET-mutant MTC who were cabozantinib and vandetanib treatment-naïve enrolled into a cohort of LIBRETTO-001. The median age was 58 years (range: 15 to 82) with two patients (2.3%) aged 12 to 16 years; 66% were male; and 86% were White, 4.5% were Asian, and 2.3% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3.4%). All patients (100%) had metastatic disease and 18% had received 1 or 2 prior systemic therapies (including 8% kinase inhibitors, 4.5% chemotherapy, 2.3% anti-PD1/PD-L1 therapy, and 1.1% radioactive iodine). RET mutation status was Reference ID: 5498247 28 detected in 77.3% of patients using NGS (75.0% tumor samples; 2.3% blood samples), 18.2% using PCR, and 4.5% using an unknown test. The mutations used to identify and enroll patients are described in Table 18. Efficacy results for cabozantinib and vandetanib-naïve RET-mutant MTC are summarized in Table 20. Table 20: Efficacy Results in LIBRETTO-001 (Cabozantinib and Vandetanib-naïve RET-Mutant MTC) RETEVMO (n = 88) Overall Response Rate1 (95% CI) 81% (71%, 88%) Complete response 28% Partial response 52% Duration of Response Median in months (95% CI) NR (51.3, NE) % with ≥12 months2 90% 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NR = not reached, NE = not estimable LIBRETTO-531 LIBRETTO-531 was a randomized (2:1), multicenter, open-label study (NCT04211337) in adults and adolescents with advance or metastatic RET-mutant MTC. The study evaluated the efficacy of RETEVMO versus physicians’ choice of cabozantinib or vandetanib in patients with progressive, advanced, kinase inhibitor naïve, RET-mutant medullary thyroid cancer. Patients were randomized to receive either RETEVMO (160 mg twice daily) or physicians’ choice of cabozantinib (140 mg once daily) or vandetanib (300 mg once daily). Patients were stratified based on RET mutation (M918T vs. other) and intended treatment if randomized to the control arm (cabozantinib vs. vandetanib). The primary outcome was progression- free survival (PFS), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1. The median age was 55 years (range: 12 to 84), 63% were male, 58% were White, 23% were Asian, 2.4% were Black or African American, and 17% had unknown race. ECOG performance status was 0-1 (98%) or 2 (1.0%) with 0.7% unknown status. 77% of patients had metastatic disease and 6 patients (2.1%) had received 1 prior systemic therapy. RET mutation status was detected in 90% of patients using NGS (89% tumor samples; 8% blood or plasma), and 10% using PCR. Of patients enrolled in LIBRETTO-531, 63% had M918T RET mutations and 37% had other RET mutations. Efficacy results for LIBRETTO-531 based on the preplanned interim efficacy analysis are provided in Table 21 and Figure 2. At the time of this analysis, overall survival data were immature with 18 deaths observed (14% of pre-specified events). Table 21: Efficacy Results in LIBRETTO-531: RETEVMO versus Cabozantinib or Vandetanib RETEVMO N = 193 Cabozantinib or Vandetanib N = 98 PFS Number (%) of patients with an event 26 (14%) 33 (34%) Median in months (95% CI) NR (NE, NE) 16.8 (12.2, 25.1) Hazard ratio (95% CI)1 0.280 (95% CI: 0.165, 0.475) p-value2 <0.0001 Overall Response Rate ORR (95% CI) 69% (62%, 76%) 39% (29%, 49%) Complete response 12% 4% Partial response 58% 35% Duration of Response Median in months (95% CI) NR (NE, NE) 16.6 (10.4, NE) Reference ID: 5498247 ~ :c (IS .c 0 ... a. iij -~ > ... ::J en QJ QJ ... LL I C .Q 1/) 1/) QJ ... C) 0 0 .9 0.8 0.7 0 .6 0.5 0.4 0 .3 0.2 0 .1 Censored observations --- Se lpe rcatlnlb (N=193) '-\1-1 I ! --: _L L- -\ 71_' ,_ -- -~ i l : _______ JI, lJ, ( _J_ : __ J, iu _____________ L1 : ________ j ___ _ ... a. - - - - - Cabozantlnlb or Vandetanlb (N=98) 0 .0 0 3 6 9 12 15 18 21 24 27 30 Patients At Risk Time from Randomization (Months) Selpercatlnlb 193 159 127 107 84 63 45 35 20 13 7 Cabozantlnlb or Vandetanlb 98 77 55 37 29 21 13 7 7 2 33 36 3 0 0 0 29 Median follow-up time (months) 11.1 12.8 Data from the pre-planned interim efficacy analysis. 1 Based on the stratified Cox proportional hazard model. 2 Based on stratified log-rank test. NR = Not reached; NE = not evaluable Figure 2: Kaplan-Meier Curves of Progression-Free Survival in LIBRETTO-531: RETEVMO versus Cabozantinib or Vandetanib Patient-reported overall side effect impact was evaluated weekly in 222 patients (RETEVMO N = 145; cabozantinib or vandetanib N=77) who received at least one dose of treatment by at least 6 months prior to the data cutoff date and responded to the Functional Assessment of Cancer Therapy item GP5 (FACT GP5). Patient-reported overall side effect impact was derived as a proportion of time on treatment with high side effect bother (defined as response of 3 “Quite a bit” or 4 “Very much”) per FACT GP5. Patient-reported overall side effect impact results for LIBRETTO-531 are provided in Table 22. Table 22. Descriptive Summary of Patient-reported Overall Side Effect Impact While on Treatment in LIBRETTO­ 531 RETEVMO (N=145) Cabozantinib or Vandetanib (N=77) Mean proportion of time with high side effect bother (95% CI) 8% (4.8%, 10%) 24% (17%, 31%) % Patients with high side effect bother 0% of time ≤25% of time 61% 90% 30% 66% Reference ID: 5498247 30 Patient-reported overall side effect impact results were supported by a lower incidence of treatment discontinuation due to adverse reactions for RETEVMO (4.7%) compared to cabozantinib or vandetanib (27%) in patients who received at least one dose of study treatment. The median time on treatment at the data cutoff was 14.5 months in the RETEVMO arm and 8.3 months in the cabozantinib or vandetanib arm in patients who received at least one dose of study treatment. LIBRETTO-121 The efficacy of RETEVMO was evaluated in pediatric and young adult patients with advanced RET-activated solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-121, NCT03899792). Patients received RETEVMO 92 mg/m2 orally twice daily until disease progression, unacceptable toxicity, or other reason for treatment discontinuation. Tumor assessments were performed every 8 weeks for one year, then every 12 weeks; responses were assessed according to RECIST 1.1 per BIRC. Efficacy was evaluated in 14 patients with RET-mutant MTC who were non-responsive to available therapies or had no standard systemic curative therapy available. The median age was 14 years (range 2 to 20); 64% were male; 71% were White, 14% were Black or African American; and 14% were Hispanic/Latino. Patients had metastatic (71%) or locally advanced (29%) disease; 43% had measurable disease at baseline; 21% had received prior systemic therapy. RET- mutant status was detected in 79% of patients using NGS tumor samples and in 21% using PCR. Efficacy results for RET-mutant MTC in pediatric and young adult patients are summarized in Table 23. Table 23: Efficacy Results in LIBRETTO-121 (RET-Mutant MTC) RETEVMO (n = 14) Overall Response Rate1 (95% CI) 43% (18, 71) Complete response 7% Partial response 36% Duration of Response Median in months (95% CI) NR (NE, NE) % with ≥12 months2 100% % with ≥18 months2 67% 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NR = not reached; NE = not estimable 14.3 RET Fusion-Positive Thyroid Cancer LIBRETTO-001 The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive thyroid cancer enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). Efficacy was evaluated in 65 patients with RET fusion-positive thyroid cancer who were radioactive iodine (RAI)-refractory (if RAI was an appropriate treatment option) and were systemic therapy naïve and patients who were previously treated, in separate cohorts. The median age was 59 years (range 20 to 88); 49% were male; 65% were White, 20% were Asian, 4.6% were Black or African American; and 11% were Hispanic/Latino. ECOG performance status was 0-1 (94%) or 2 (6%). All (100%) patients had metastatic disease with primary tumor histologies including papillary thyroid cancer (83%), poorly differentiated thyroid cancer (9%), anaplastic thyroid cancer (6%) and Hurthle cell thyroid cancer (1.5%). Previously treated patients had received a median of 1 prior therapy (range 1–4). RET fusion-positive status was detected in 97% of patients using NGS (89% tumor samples; 8% blood or plasma samples), and 3% using other local testing methods. Efficacy results for RET fusion-positive thyroid cancer are summarized in Table 24. Reference ID: 5498247 31 Table 24: Efficacy Results in LIBRETTO-001 (RET Fusion-Positive Thyroid Cancer) RETEVMO Previously Treated (n = 41) RETEVMO Systemic Therapy Naïve (n = 24) Overall Response Rate1 (95% CI) 85% (71%, 94%) 96% (79%, 100%) Complete response 12% 21% Partial response 73% 75% Duration of Response Median in months (95% CI) 26.7 (12.1, NE) NE (42.8, NE) % with ≥12 months2 54 65 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable Responses were observed in patients with each histology represented, including 3 of 4 patients with anaplastic thyroid cancer (all partial responses) and 6 of 6 patients with poorly differentiated thyroid cancer (1 complete response, 5 partial responses). LIBRETTO-121 The efficacy of RETEVMO was evaluated in pediatric and young adult patients with advanced RET-activated solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-121, NCT03899792) [see Clinical Studies (14.2)]. Efficacy was evaluated in 10 patients with RET fusion-positive thyroid cancer who were non-responsive to available therapies or had no standard systemic curative therapy available. The median age was 13.5 years (range 12 to 20); 60% were male; 40% were White, 50% were Asian; and 30% were Hispanic/Latino. All (100%) patients had metastatic disease and papillary thyroid cancer histology; 40% had measurable disease at baseline; 30% had received prior systemic therapy. RET fusion-positive status was detected in 90% of patients using NGS tumor samples and in 10% using FISH. Efficacy results for RET fusion-positive thyroid cancer in pediatric and young adult patients are summarized in Table 25. Table 25: Efficacy Results in LIBRETTO-121 (RET Fusion-Positive Thyroid Cancer) RETEVMO (n = 10) Overall Response Rate1 (95% CI) 60% (26, 88) Complete response 30% Partial response 30% Duration of Response Median in months (95% CI) NR (NE, NE) % with ≥12 months2 83% % with ≥18 months2 50% 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NR = not reached; NE = not estimable 14.4 Other RET Fusion-Positive Solid Tumors LIBRETTO-001 The efficacy of RETEVMO was evaluated in patients with locally advanced or metastatic RET fusion-positive solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). Efficacy was evaluated in 41 patients with RET fusion-positive tumors other than NSCLC and thyroid cancer with disease progression on or following prior systemic treatment or who had no satisfactory alternative treatment options. Reference ID: 5498247 32 The median age was 50 years (range 21 to 85), 54% were female, 68% were White, 24% were Asian, and 4.9% were Black; and 7% were Hispanic/Latino. ECOG performance status was 0-1 (95%) or 2 (5%) and 95% of patients had metastatic disease. Thirty-seven patients (90%) received prior systemic therapy (median 2 [range 0 – 9]; 32% received 3 or more). The most common cancers were pancreatic adenocarcinoma (27%), colorectal (24%), salivary (10%) and unknown primary (7%). RET fusion-positive status was detected in 97.6% of patients using NGS and 2.4% using FISH. Efficacy results for RET fusion-positive solid tumors other than NSCLC and thyroid cancer are summarized in Table 26 and Table 27. Table 26: Efficacy Results in LIBRETTO-001 (Other RET Fusion-Positive Solid Tumors) RETEVMO (n = 41) Overall Response Rate1 (95% CI) 44% (28, 60) Complete response 4.9% Partial response 39% Duration of Response Median in months (95% CI) 24.5 (9.2, NE) % with ≥6 months2 67% 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable Table 27: Efficacy Results by Tumor Type in LIBRETTO-001 (Other RET Fusion-Positive Solid Tumors) Tumor Type Patients (n = 41) ORR1,2 DOR Range (months) n (%) 95% CI Pancreatic adenocarcinoma 11 6 (55%) (23, 83) 2.5, 38.3+ Colorectal 10 2 (20%) (2.5, 56) 5.6, 13.3 Salivary 4 2 (50%) (7, 93) 5.7, 28.8+ Unknown primary 3 1 (33%) (0.8, 91) 9.2 Breast 2 PR, CR NA 2.3+, 17.3 Sarcoma (soft tissue) 2 PR, SD NA 14.9+ Xanthogranuloma 2 NE, NE NA NA Carcinoid (bronchial) 1 PR NA 24.1+ Carcinoma of the skin 1 NE NA NA Cholangiocarcinoma 1 PR NA 5.6+ Ovarian 1 PR NA 14.5+ Pulmonary carcinosarcoma 1 NE NA NA Rectal neuroendocrine 1 NE NA NA Small intestine 1 CR NA 24.5 + denotes ongoing response. 1 Confirmed overall response rate assessed by BIRC. 2 Best overall response for each patient is presented for tumor types with ≤2 patients. CI = confidence interval, CR = complete response, DOR = duration of response, NA = not applicable, NE = not evaluable, ORR = overall response rate, PR = partial response, SD = stable disease. LIBRETTO-121 Reference ID: 5498247 33 The efficacy of RETEVMO was evaluated in pediatric and young adult patients with advanced RET-activated solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-121, NCT03899792) [see Clinical Studies (14.2)]. Efficacy was evaluated in one patient with locally advanced refractory RET-fusion positive malignant peripheral nerve sheath tumor who did not respond. Responses were observed in patients with RET fusion-positive thyroid cancer [see Clinical Studies (14.3)]. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied RETEVMO capsules are supplied as follows: Capsule Strength Description Package Configuration NDC Number 40 mg Gray opaque, imprinted with “Lilly”, “3977” and “40 mg” in black ink 60 count bottle NDC 0002-3977-60 80 mg Blue opaque, imprinted with “Lilly”, “2980” and “80 mg” in black ink 60 count bottle NDC 0002-2980-60 120 count bottle NDC 0002-2980-26 RETEVMO tablets are supplied in bottles with desiccant in the following configurations: Tablet Strength Description Package Configuration NDC Number 40 mg Light gray, film coated, round tablets debossed with “Ret 40” on one side and “5340” on the other side 60 count bottle NDC 0002-5340-60 80 mg Dark red-purple, film coated, round tablets debossed with “Ret 80” on one side and ”6082” on the other side 60 count bottle NDC 0002-6082-60 120 mg Light purple, film coated, round tablets debossed with “Ret 120” on one side and “6120” on the other side 60 count bottle NDC 0002-6120-60 160 mg Light pink, film coated, round tablets debossed with Ret “160” on one side and “5562” on the other side 60 count bottle NDC 0002-5562-60 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C (59°F to 86°F) are permitted [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Hepatotoxicity Advise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.1)]. Interstitial Lung Disease (ILD)/Pneumonitis Advise patients that ILD/ pneumonitis can occur and to contact their healthcare provider immediately for signs or symptoms of ILD including new or worsening cough or shortness of breath [see Warnings and Precautions (5.2)]. Hypertension Advise patients that they will require regular blood pressure monitoring and to contact their healthcare provider if they experience symptoms of increased blood pressure or elevated readings [see Warnings and Precautions (5.3)]. QT Prolongation Reference ID: 5498247 34 Advise patients that RETEVMO can cause QTc interval prolongation and to inform their healthcare provider if they have any QTc interval prolongation symptoms, such as syncope [see Warnings and Precautions (5.4)]. Hemorrhagic Events Advise patients that RETEVMO may increase the risk for bleeding and to contact their healthcare provider if they experience any signs or symptoms of bleeding [see Warnings and Precautions (5.5)]. Hypersensitivity Reactions Advise patients to monitor for signs and symptoms of hypersensitivity reactions, particularly during the first month of treatment [see Warnings and Precautions (5.6)]. Tumor Lysis Syndrome Advise patients to contact their healthcare provider promptly to report any signs and symptoms of TLS [see Warnings and Precautions (5.7)]. Risk of Impaired Wound Healing Advise patients that RETEVMO may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.8)]. Hypothyroidism Advise patients that RETEVMO can cause hypothyroidism and to immediately contact their healthcare provider for signs or symptoms of hypothyroidism [see Warnings and Precautions (5.9)]. Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis Advise pediatric patients and caregivers to contact their healthcare provider promptly to report any signs and symptoms indicative of slipped capital femoral epiphysis/slipped upper femoral epiphysis [see Warnings and Precautions (5.11)]. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the possible risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during the treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Infertility Advise males and females of reproductive potential that RETEVMO may impair fertility [see Use in Specific Populations (8.4), Nonclinical Toxicology (13.1)]. Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John’s wort, proton pump inhibitors, H2 receptor antagonists, and antacids while taking RETEVMO. If PPIs are required, instruct patients to take RETEVMO with food. If H2 receptor antagonists are required, instruct patients to take RETEVMO 2 hours before or 10 hours after the H2 receptor antagonist. If locally-acting antacids are required, instruct patients to take RETEVMO 2 hours before or 2 hours after the locally-acting antacid [see Drug Interactions (7.1, 7.2)]. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2020, 2024, Eli Lilly and Company. All rights reserved. A1.02-RET-0007-USPI-YYYYMMDD Reference ID: 5498247
custom-source
2025-02-12T15:47:56.225787
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1 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RETEVMO safely and effectively. See full prescribing information for RETEVMO. RETEVMO® (selpercatinib) capsules, for oral use RETEVMO® (selpercatinib) tablets, for oral use Initial U.S. Approval: 2020 --------------------------- RECENT MAJOR CHANGES -------------------------­ Indications and Usage RET-Mutant Medullary Thyroid Cancer (1.2) 09/2024 RET Fusion-Positive Thyroid Cancer (1.3) 06/2024 Other RET Fusion-Positive Solid Tumors (1.4) 05/2024 Dosage and Administration (2.3, 2.5, 2.6, 2.7) 05/2024 Warnings and Precautions (5.11) 05/2024 ---------------------------- INDICATIONS AND USAGE --------------------------­ RETEVMO® is a kinase inhibitor indicated for the treatment of: • Adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test (1.1) • Adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy (1.2) • Adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) (1.3) • Adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options1 (1.4) This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ------------------------DOSAGE AND ADMINISTRATION----------------------­ • Select patients for treatment with RETEVMO based on the presence of a RET gene fusion (NSCLC, thyroid, or other solid tumors) or specific RET gene mutation (MTC). (2.1, 14) • Adult and adolescent patients 12 years of age or older: the recommended dosage is based on weight (2.3): • Less than 50 kg: 120 mg orally twice daily • 50 kg or greater: 160 mg orally twice daily • Pediatric patients 2 to less than 12 years of age: the recommended dosage is based on body surface area (2.3): • 0.33 to 0.65 m2: 40 mg orally three times daily • 0.66 to 1.08 m2: 80 mg orally twice daily • 1.09 to 1.52 m2: 120 mg orally twice daily • ≥1.53 m2: 160 mg orally twice daily • Reduce RETEVMO dose in patients with severe hepatic impairment. (2.7, 8.7) ----------------------DOSAGE FORMS AND STRENGTHS--------------------­ • Capsules: 40 mg, 80 mg. (3) • Tablets: 40 mg, 80 mg, 120 mg, 160 mg. (3) ------------------------------- CONTRAINDICATIONS -----------------------------­ None. (4) ------------------------WARNINGS AND PRECAUTIONS ----------------------­ • Hepatotoxicity: Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. (2.5, 5.1) • Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms. Withhold, reduce the dose or permanently discontinue RETEVMO based on severity. (2.5, 5.2) • Hypertension: Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating RETEVMO. Monitor BP after 1 week, at least monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. (2.5, 5.3) • QT Interval Prolongation: Monitor patients who are at significant risk of developing QTc prolongation. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment. Monitor QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on severity. (2.5, 5.4) • Hemorrhagic Events: Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage. (2.5, 5.5) • Hypersensitivity: Withhold RETEVMO and initiate corticosteroids. Upon resolution, resume at a reduced dose and increase dose by 1 dose level each week until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. (2.5, 5.6) • Tumor Lysis Syndrome: Closely monitor patients at risk and treat as clinically indicated. (5.7) • Risk of Impaired Wound Healing: Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established. (5.8) • Hypothyroidism: Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Withhold until clinically stable or permanently discontinue based on severity. (5.9) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the possible risk to a fetus and to use effective contraception. (5.10, 8.1, 8.3) • Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis (SCFE/SUFE) in Pediatric Patients: Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate (5.11, 6.1) -------------------------------ADVERSE REACTIONS -----------------------------­ The most common adverse reactions (≥25%) include: • Adult patients with solid tumors: edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. (6) • Pediatric patients with solid tumors: musculoskeletal pain, diarrhea, headache, nausea, vomiting, coronavirus infection, abdominal pain, fatigue, pyrexia, and hemorrhage. (6) The most common Grade 3 or 4 laboratory abnormalities (≥5%) include: • Adult patients with solid tumors: decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium. (6) • Pediatric patients with solid tumors: decreased calcium, decreased hemoglobin, and decreased neutrophils. (6) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------- DRUG INTERACTIONS -----------------------------­ • Acid-Reducing Agents: Avoid coadministration. If coadministration cannot be avoided, take RETEVMO with food (with PPI) or modify its administration time (with H2 receptor antagonist or locally-acting antacid). (2.4, 7.1) • Strong and Moderate CYP3A Inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the RETEVMO dose. (2.6, 7.1) • Strong and Moderate CYP3A Inducers: Avoid coadministration. (7.1) Reference ID: 5498246 2 1 • CYP2C8 and CYP3A Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. (7.2) • Certain P-gp and BCRP Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. (7.2) ------------------------USE IN SPECIFIC POPULATIONS----------------------­ • Lactation: Advise not to breastfeed. (8.2) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 RET Fusion-Positive Non-Small Cell Lung Cancer 1.2 RET-Mutant Medullary Thyroid Cancer 1.3 RET Fusion-Positive Thyroid Cancer 1.4 Other RET Fusion-Positive Solid Tumors 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Important Administration Instructions 2.3 Recommended Dosage 2.4 Dosage Modifications for Concomitant Use of Acid- Reducing Agents 2.5 Dosage Modifications for Adverse Reactions 2.6 Dosage Modifications for Concomitant Use of Strong and Moderate CYP3A Inhibitors 2.7 Dosage Modification for Severe Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity 5.2 Interstitial Lung Disease/Pneumonitis 5.3 Hypertension 5.4 QT Interval Prolongation 5.5 Hemorrhagic Events 5.6 Hypersensitivity 5.7 Tumor Lysis Syndrome 5.8 Risk of Impaired Wound Healing 5.9 Hypothyroidism 5.10 Embryo-Fetal Toxicity 5.11 Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients 6 ADVERSE REACTIONS • Pediatric Use: Monitor open growth plates in pediatric patients. Consider interrupting or discontinuing RETEVMO if abnormalities occur. (8.4) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 12/2024 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on RETEVMO 7.2 Effects of RETEVMO on Other Drugs 7.3 Drugs that Prolong QT Interval 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 RET Fusion-Positive Non-Small Cell Lung Cancer 14.2 RET-Mutant Medullary Thyroid Cancer 14.3 RET Fusion-Positive Thyroid Cancer 14.4 Other RET Fusion-Positive Solid Tumors 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE 1.1 RET Fusion-Positive Non-Small Cell Lung Cancer RETEVMO® is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test. 1.2 RET-Mutant Medullary Thyroid Cancer RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy. 1.3 RET Fusion-Positive Thyroid Cancer RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). 1.4 Other RET Fusion-Positive Solid Tumors Reference ID: 5498246 3 2 RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.4)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients for treatment with RETEVMO based on the presence of a RET gene fusion (NSCLC, thyroid cancer, or other solid tumors) or specific RET gene mutation (MTC) in tumor specimens [see Clinical Studies (14)]. Information on FDA-approved test(s) for the detection of RET gene fusions and RET gene mutations is available at: http://www.fda.gov/CompanionDiagnostics. An FDA-approved companion diagnostic test for the detection of RET gene fusions and RET gene mutations in plasma is not available. 2.2 Important Administration Instructions RETEVMO may be taken with or without food unless coadministered with a proton pump inhibitor (PPI) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. 2.3 Recommended Dosage The recommended dosage of RETEVMO is shown in Table 1: Table 1: Recommended RETEVMO Dosage Population RETEVMO Dosage Adult and adolescent patients 12 years of age or older based on body weight • Less than 50 kg 120 mg twice daily • 50 kg or greater 160 mg twice daily Pediatric patients 2 to less than 12 years of age based on body surface area • 0.33 to 0.65 m2 40 mg three times daily • 0.66 to 1.08 m2 80 mg twice daily • 1.09 to 1.52 m2 120 mg twice daily • ≥1.53 m2 160 mg twice daily Dosing pediatric patients with body surface area less than 0.33 m2 is not recommended Continue treatment with RETEVMO until disease progression or unacceptable toxicity. Swallow the capsules whole. Do not crush or chew the capsules. Do not administer to pediatric patients who are unable to swallow a capsule. Swallow the tablets whole. Do not crush or chew the tablets. Do not take a missed dose unless it is more than 6 hours until next scheduled dose. If vomiting occurs after RETEVMO administration, do not take an additional dose and continue to the next scheduled time for the next dose. 2.4 Dosage Modifications for Concomitant Use of Acid-Reducing Agents Avoid concomitant use of a PPI, a histamine-2 (H2) receptor antagonist, or a locally-acting antacid with RETEVMO [see Drug Interactions (7.1)]. If concomitant use cannot be avoided: • Take RETEVMO with food when coadministered with a PPI. • Take RETEVMO 2 hours before or 10 hours after administration of an H2 receptor antagonist. Reference ID: 5498246 4 • Take RETEVMO 2 hours before or 2 hours after administration of a locally-acting antacid. 2.5 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 2. Table 2: Recommended RETEVMO Dose Reductions for Adverse Reactions Current RETEVMO Dosage Dose Reduction First Second Third 40 mg three times daily 40 mg twice daily 40 mg once daily permanently discontinue 80 mg twice daily 40 mg twice daily 40 mg once daily permanently discontinue 120 mg twice daily 80 mg twice daily 40 mg twice daily 40 mg once daily 160 mg twice daily 120 mg twice daily 80 mg twice daily 40 mg twice daily Permanently discontinue RETEVMO in patients unable to tolerate three dose reductions. The recommended dosage modifications for adverse reactions are provided in Table 3. Table 3: Recommended RETEVMO Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Hepatotoxicity Grade 3 • Withhold RETEVMO and monitor AST/ALT once weekly until resolution to Grade [see Warnings and or 1 or baseline. Precautions (5.1)] Grade 4 • Resume at reduced dose by 2 dose levels and monitor AST and ALT once weekly until 4 weeks after reaching dose taken prior to the onset of Grade 3 or 4 increased AST or ALT. • Increase dose by 1 dose level after a minimum of 2 weeks without recurrence and then increase to dose taken prior to the onset of Grade 3 or 4 increased AST or ALT after a minimum of 4 weeks without recurrence. Interstitial Lung Disease/ Pneumonitis [see Warnings and Precautions (5.2)] Grade 2 • Withhold RETEVMO until resolution. • Resume at a reduced dose. • Discontinue RETEVMO for recurrent ILD/pneumonitis. Grade 3 or Grade 4 • Discontinue RETEVMO for confirmed ILD/pneumonitis. Hypertension [see Warnings and Precautions (5.3)] Grade 3 • Withhold RETEVMO for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled. Grade 4 • Discontinue RETEVMO. QT Interval Prolongation [see Warnings and Precautions (5.4)] Grade 3 • Withhold RETEVMO until recovery to baseline or Grade 0 or 1. • Resume at a reduced dose or permanently discontinue RETEVMO. Grade 4 • Discontinue RETEVMO. Hemorrhagic Grade 3 • Withhold RETEVMO until recovery to baseline or Grade 0 or 1. Events or • Discontinue RETEVMO for severe or life-threatening hemorrhagic events. [see Warnings and Grade 4 Precautions (5.5)] Hypersensitivity All • Withhold RETEVMO until resolution of the event. Initiate corticosteroids. Reactions Grades • Resume at a reduced dose by 3 dose levels while continuing corticosteroids. [see Warnings and • Increase dose by 1 dose level each week until the dose taken prior to the onset Precautions (5.6)] of hypersensitivity is reached, then taper corticosteroids. Reference ID: 5498246 5 Hypothyroidism [see Warnings and Precautions (5.9)] Grade 3 or Grade 4 • Withhold RETEVMO until resolution to Grade 1 or baseline. • Discontinue RETEVMO based on severity. Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 3 or Grade 4 • Withhold RETEVMO until recovery to baseline or Grade 0 or 1. • Resume at a reduced dose. 2.6 Dosage Modifications for Concomitant Use of Strong and Moderate CYP3A Inhibitors Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the RETEVMO dose as recommended in Table 4. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume RETEVMO at the dose taken prior to initiating the CYP3A inhibitor [see Drug Interactions (7.1)]. Table 4: Recommended RETEVMO Dosage for Concomitant Use of Strong and Moderate CYP3A Inhibitors Current RETEVMO Dosage Recommended RETEVMO Dosage Moderate CYP3A Inhibitor Strong CYP3A Inhibitor 40 mg orally three times daily 40 mg orally once daily 40 mg orally once daily 80 mg orally twice daily 40 mg orally twice daily 40 mg orally twice daily 120 mg orally twice daily 80 mg orally twice daily 40 mg orally twice daily 160 mg orally twice daily 120 mg orally twice daily 80 mg orally twice daily 2.7 Dosage Modification for Severe Hepatic Impairment Reduce the recommended dosage of RETEVMO for patients with severe hepatic impairment as recommended in Table 5 [see Use in Specific Populations (8.7)]. Table 5: Recommended RETEVMO Dosage for Severe Hepatic Impairment Current RETEVMO Dosage Recommended RETEVMO Dosage 40 mg orally three times daily 40 mg orally twice daily 80 mg orally twice daily 40 mg orally twice daily 120 mg orally twice daily 80 mg orally twice daily 160 mg orally twice daily 80 mg orally twice daily 3 DOSAGE FORMS AND STRENGTHS Capsules: • 40 mg: gray opaque capsule imprinted with “Lilly”, “3977” and “40 mg” in black ink. • 80 mg: blue opaque capsule imprinted with “Lilly”, “2980” and “80 mg” in black ink. Tablets: • 40 mg: light gray, film coated, round tablet debossed with “Ret 40” on one side and “5340” on the other side. • 80 mg: dark red-purple, film coated, round tablet debossed with “Ret 80” on one side and “6082” on the other side. • 120 mg: light purple, film coated, round tablet debossed with “Ret 120” on one side and “6120” on the other side. • 160 mg: light pink, film coated, round tablet debossed with “Ret 160” on one side and “5562” on the other side. 4 CONTRAINDICATIONS Reference ID: 5498246 6 5 None. WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Serious hepatic adverse reactions occurred in 3% of patients treated with RETEVMO. Increased AST occurred in 59% of patients, including Grade 3 or 4 events in 11% and increased ALT occurred in 55% of patients, including Grade 3 or 4 events in 12% [see Adverse Reactions (6.1)]. The median time to first onset for increased AST was 6 weeks (range: 1 day to 3.4 years) and increased ALT was 5.8 weeks (range: 1 day to 2.5 years). Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)]. 5.2 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with RETEVMO. ILD/pneumonitis occurred in 1.8% of patients who received RETEVMO, including 0.3% with Grade 3 or 4 events, and 0.3% with fatal reactions. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold RETEVMO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce the dose or permanently discontinue RETEVMO based on severity of confirmed ILD [see Dosage and Administration (2.5)]. 5.3 Hypertension Hypertension occurred in 41% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient [see Adverse Reactions (6.1)]. Overall, 6.3% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating RETEVMO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce the dose, or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)]. 5.4 QT Interval Prolongation RETEVMO can cause concentration-dependent QT interval prolongation [see Clinical Pharmacology (12.2)]. An increase in QTcF interval to >500 ms was measured in 7% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 20% of patients [see Adverse Reactions (6.1)]. RETEVMO has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction. Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating RETEVMO and during treatment. Monitor the QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration (2.5)]. 5.5 Hemorrhagic Events Serious including fatal hemorrhagic events can occur with RETEVMO. Grade ≥3 hemorrhagic events occurred in 3.1% of patients treated with RETEVMO, including 4 (0.5%) patients with fatal hemorrhagic events, including cerebral hemorrhage (n = 2), tracheostomy site hemorrhage (n = 1), and hemoptysis (n=1). Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage [see Dosage and Administration (2.5)]. 5.6 Hypersensitivity Reference ID: 5498246 7 Hypersensitivity occurred in 6% of patients receiving RETEVMO, including Grade 3 hypersensitivity in 1.9%. The median time to onset was 1.9 weeks (range: 5 days to 2 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume RETEVMO at a reduced dose and increase the dose of RETEVMO by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity [see Dosage and Administration (2.5)]. Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity. 5.7 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) occurred in 0.6% of patients with medullary thyroid carcinoma receiving RETEVMO [see Adverse Reactions (6.1)]. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated. 5.8 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, RETEVMO has the potential to adversely affect wound healing. Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established. 5.9 Hypothyroidism RETEVMO can cause hypothyroidism. Hypothyroidism occurred in 13% of patients treated with RETEVMO; all reactions were Grade 1 or 2. Hypothyroidism occurred in 13% of patients (50/373) with thyroid cancer and 13% of patients (53/423) with other solid tumors including NSCLC [see Adverse Reactions (6.1)]. Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold RETEVMO until clinically stable or permanently discontinue RETEVMO based on severity [see Dosage and Administration (2.5)]. 5.10 Embryo-Fetal Toxicity Based on data from animal reproduction studies and its mechanism of action, RETEVMO can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)]. 5.11 Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients Slipped capital femoral epiphysis/slipped upper femoral epiphysis (SCFE/SUFE) occurred in 1 adolescent (3.7% of 27 patients) receiving RETEVMO in LIBRETTO-121 and 1 adolescent (0.5% of 193 patients) receiving RETEVMO in LIBRETTO-531 [see Adverse Reactions (6.1)]. Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate [see Adverse Reactions (6.1)]. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hepatotoxicity [see Warnings and Precautions (5.1)] • Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.2)] • Hypertension [see Warnings and Precautions (5.3)] • QT Interval Prolongation [see Warnings and Precautions (5.4)] • Hemorrhagic Events [see Warnings and Precautions (5.5)] Reference ID: 5498246 6 8 • Hypersensitivity [see Warnings and Precautions (5.6)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.7)] • Risk of Impaired Wound Healing [see Warnings and Precautions (5.8)] • Hypothyroidism [see Warnings and Precautions (5.9)] • Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Adolescent Patients [see Warnings and Precautions (5.11)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in the WARNINGS and PRECAUTIONS and below reflects exposure to RETEVMO as a single agent administered at 160 mg orally twice daily evaluated in 796 patients with advanced solid tumors in LIBRETTO­ 001 [see Clinical Studies (14)]. RET Gene Fusion or Gene Mutation Positive Solid Tumors LIBRETTO-001 Among the 796 patients who received RETEVMO, 84% were exposed for 6 months or longer and 73% were exposed for greater than one year. Among these patients, 96% received at least one dose of RETEVMO at the recommended dosage of 160 mg orally twice daily. The median age was 59 years (range: 15 to 92 years); 0.3% were pediatric patients 12 to 16 years of age; 51% were male; and 69% were White, 23% were Asian, and 3% were Black or African American; and 5% were Hispanic/Latino. The most common tumors were NSCLC (45%), MTC (40%), and non-medullary thyroid carcinoma (7%). Serious adverse reactions occurred in 44% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pneumonia, pleural effusion, abdominal pain, hemorrhage, hypersensitivity, dyspnea, and hyponatremia. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions included sepsis (n = 6), respiratory failure (n = 5), hemorrhage (n = 4), pneumonia (n = 3), pneumonitis (n = 2), cardiac arrest (n=2), sudden death (n = 1), and cardiac failure (n = 1). Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in ≥0.5% of patients included increased ALT (0.6%), fatigue (0.6%), sepsis (0.5%), and increased AST (0.5%). Dosage interruptions due to an adverse reaction occurred in 64% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, increased AST, diarrhea, and hypertension. Dose reductions due to an adverse reaction occurred in 41% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included increased ALT, increased AST, QT prolongation, fatigue, diarrhea, drug hypersensitivity, and edema. The most common adverse reactions (≥25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium. Table 6 summarizes the adverse reactions in LIBRETTO-001. Table 6: Adverse Reactions (≥20%) in Patients Who Received RETEVMO in LIBRETTO-001 Adverse Reaction RETEVMO (n = 796) Grades 1-4# (%) Grades 3-4 (%) General Disorders and Administration Site Conditions Edema1 49 0.8* Fatigue2 46 3.1* Arthralgia 21 0.3* Reference ID: 5498246 9 Gastrointestinal Disorders Diarrhea3 47 5* Dry Mouth 43 0 Abdominal pain4 34 2.5* Constipation 33 0.8* Nausea 31 1.1* Vomiting 22 1.8* Vascular Disorders Hypertension 41 20 Skin and Subcutaneous Tissue Disorders Rash5 33 0.6* Nervous System Disorders Headache6 28 1.4* Respiratory, Thoracic and Mediastinal Disorders Cough7 24 0 Dyspnea8 22 3.1 Blood and Lymphatic System Disorders Hemorrhage9 22 2.6 Investigations Prolonged QT interval 21 4.8* 1 Edema includes edema peripheral, face edema, periorbital edema, eye edema, eyelid edema, orbital edema, localized edema, lymphedema, scrotal edema, peripheral swelling, scrotal swelling, swelling, swelling face, eye swelling, generalized edema, genital edema. 2 Fatigue includes asthenia and malaise. 3 Diarrhea includes defecation urgency, frequent bowel movements, gastrointestinal hypermotility, anal incontinence. 4 Abdominal pain includes abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness, epigastric discomfort, gastrointestinal pain. 5 Rash includes rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, butterfly rash, exfoliative rash, rash follicular, rash generalized, rash vesicular. 6 Headache includes sinus headache, tension headache. 7 Cough includes productive cough, upper airway cough syndrome. 8 Dyspnea includes dyspnea exertional, dyspnea at rest. 9 Hemorrhage includes, epistaxis, hematuria, hemoptysis, contusion, rectal hemorrhage, vaginal hemorrhage, ecchymosis, hematochezia, petechiae, traumatic hematoma, anal hemorrhage, blood blister, blood urine present, cerebral hemorrhage, gastric hemorrhage, hemorrhage intracranial, hemorrhage subcutaneous, spontaneous hematoma, abdominal wall hematoma, angina bullosa hemorrhagica, conjunctival hemorrhage, disseminated intravascular coagulation, diverticulum intestinal hemorrhagic, eye hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hemorrhagic stroke, hemorrhoidal hemorrhage, hepatic hemorrhage, hepatic hematoma, intraabdominal hemorrhage, laryngeal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage, occult blood positive, post procedural hemorrhage, postmenopausal hemorrhage, pelvic hematoma, periorbital hematoma, periorbital hemorrhage, pharyngeal hemorrhage, pulmonary contusion, purpura, retinal hemorrhage, retroperitoneal hematoma, scleral hemorrhage, skin hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, upper gastrointestinal hemorrhage, uterine hemorrhage, vessel puncture site hematoma. * Only includes a grade 3 adverse reaction. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 Clinically relevant adverse reactions in ≤15% of patients who received RETEVMO include hypothyroidism (13%); pneumonia (11%), hypersensitivity (6%); interstitial lung disease/pneumonitis, chylothorax, chylous ascites or tumor lysis syndrome (all < 2%). Table 7 summarizes the laboratory abnormalities in LIBRETTO-001. Reference ID: 5498246 10 1 Table 7: Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-001 Laboratory Abnormality RETEVMO1 Grades 1-4# (%) Grades 3-4 (%) Chemistry Increased AST 59 11 Decreased calcium 59 5.7 Increased ALT 56 12 Decreased albumin 56 2.3 Increased glucose 53 2.8 Increased creatinine 47 2.4 Decreased sodium 42 11 Increased alkaline phosphatase 40 3.4 Increased total cholesterol 35 1.7 Increased potassium 34 2.7 Decreased glucose 34 1.0 Decreased magnesium 33 0.6 Increased bilirubin 30 2.8 Hematology Decreased lymphocytes 52 20 Decreased platelets 37 3.2 Decreased hemoglobin 28 3.5 Decreased neutrophils 25 3.2 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 765 to 791 patients. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 LIBRETTO-121 The safety population described below reflects exposure to RETEVMO as a single agent at 92 mg/m2 orally twice daily evaluated in 27 patients with advanced solid tumors harboring an activating RET alteration in LIBRETTO-121 [see Clinical Studies (14)]. Among the 27 pediatric and adolescent patients who received RETEVMO, 81% were exposed for 6 months or longer and 59% were exposed for greater than one year. The median age was 13 years (range: 2 to 20 years); 22% were pediatric patients 2 to 12 years of age; 59% were male; and 52% were White, 26% were Asian, and 11% were Black or African American; and 19% were Hispanic/Latino. The most common cancers were MTC (52%), and papillary thyroid cancer (37%). Serious adverse reactions occurred in 22% of patients who received RETEVMO. The serious adverse reactions (in 1 patient each) were abdominal infection, abdominal pain, aspiration, constipation, diarrhea, epiphysiolysis, nausea, pneumonia, pneumatosis intestinalis, rhinovirus infection, sepsis, vomiting. Dosage interruptions due to an adverse reaction occurred in 22% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included decreased neutrophils. Dose reductions due to an adverse reaction occurred in 15% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included decreased neutrophils, increased ALT, and increased weight. The most common adverse reactions (≥25%) were musculoskeletal pain, diarrhea, headache, nausea, vomiting, coronavirus infection, abdominal pain, fatigue, pyrexia, and hemorrhage. The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased calcium, decreased hemoglobin, and decreased neutrophils. Reference ID: 5498246 11 Table 8 summarizes the adverse reactions in LIBRETTO-121. Table 8: Adverse Reactions (≥15%) in Patients Who Received RETEVMO in LIBRETTO-121 Adverse Reactions RETEVMO N= 27 Grades 1-4# % Grades 3-4 % Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain1 56 0 Gastrointestinal disorders Diarrhea2 41 0 Nausea 30 3.7* Vomiting 30 7* Abdominal pain3 26 0 Constipation 19 7* Stomatitis4 15 0 Nervous System Disorders Headache 33 0 Infections and Infestations Coronavirus infection 30 0 Upper respiratory tract infection 22 0 General Disorders and Administration Site Conditions Fatigue5 26 0 Pyrexia 26 0 Edema6 19 0 Increased weight 19 7* Blood and Lymphatic System Disorders Hemorrhage7 26 3.7* Respiratory, Thoracic and Mediastinal Disorders Oropharyngeal pain 22 0 Cough 22 0 Endocrine Disorders Hypothyroidism8 19 0 Skin and Subcutaneous Tissue Disorders Rash9 19 0 Renal and Urinary Disorders Proteinuria 15 0 1 Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, non-cardiac chest pain, neck pain, pain in extremity 2 Diarrhea includes anal incontinence 3 Abdominal pain includes abdominal pain upper 4 Stomatitis includes angular cheilitis 5 Fatigue includes asthenia and malaise 6 Edema includes edema peripheral, face edema, localized edema, generalized edema, swelling 7 Hemorrhage includes mouth hemorrhage, epistaxis 8 Hypothyroidism includes blood thyroid stimulating hormone increased, thyroglobulin increased 9 Rash includes rash maculopapular * No Grade 4 events were reported. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Reference ID: 5498246 12 1 Clinically relevant adverse reactions in <15% of patients who received RETEVMO include dizziness (11%), urinary tract infection (11%), decreased appetite (7%), electrocardiogram QT prolonged (7%), hypersensitivity (7%), hypertension (7%), and pneumonia (3.7%). Table 9 summarizes the laboratory abnormalities in LIBRETTO-121. Table 9: Select Laboratory Abnormalities (≥15%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-121 Laboratory Abnormality RETEVMO1 Grades 1-4# (%) Grades 3-4 (%) Chemistry Decreased calcium 59 7 Increased ALT 56 3.7* Increased alkaline phosphatase 52 0 Increased AST 48 3.7* Decreased albumin 44 0 Increased bilirubin 30 0 Increased creatinine 22 0 Decreased potassium 22 3.7 Decreased magnesium 15 3.7 Hematology Decreased neutrophils 44 7* Decreased lymphocytes 24 4.8 Decreased platelets 22 0 Decreased hemoglobin 19 7* Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 21 to 27 patients. * No Grade 4 abnormalities were reported. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5. Treatment-naïve RET Fusion-Positive Non-Small Cell Lung Cancer LIBRETTO-431 The safety population described below reflects exposure to RETEVMO as a single agent administered at 160 mg orally twice daily evaluated in 158 patients with unresectable locally advanced or metastatic RET fusion-positive NSCLC in LIBRETTO-431 [see Clinical Studies (14)]. Among the 158 patients who received RETEVMO, the median duration of exposure was 16.7 months (range: 5 days to 37.9 months); 87% were exposed for 6 months or longer and 70% were exposed for one year or longer. The median age was 61 years (range: 31 to 87 years); 46% were male; and 36% were White, 58% were Asian, 1.3% were Black or African American, 1.3% were American Indian or Alaska Native, and 3.2% were missing. Serious adverse reactions occurred in 35% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pleural effusion, and abnormal hepatic function. Fatal adverse reactions occurred in 4.4% of patients who received RETEVMO; fatal adverse reactions included myocardial infarction (n = 2), respiratory failure (n = 2), cardiac arrest, malnutrition, and sudden death (n = 1, each). Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in ≥1% of patients included increased ALT (1.3%), and myocardial infarction (1.3%). Dosage interruptions due to an adverse reaction occurred in 72% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, hypertension, increased AST, QT prolongation, diarrhea, and COVID-19 infection. Reference ID: 5498246 13 Dose reductions due to an adverse reaction occurred in 51% of patients who received RETEVMO. Adverse reactions requiring dose reductions in ≥5% of patients included increased ALT, increased AST, QT prolongation. The most common adverse reactions (≥25%) in patients who received RETEVMO were hypertension, diarrhea, edema, dry mouth, rash, fatigue, abdominal pain, and musculoskeletal pain. The most common Grade 3 or 4 laboratory abnormalities (≥5%) in patients who received RETEVMO were increased ALT, increased AST, and decreased lymphocytes. Table 10 summarizes the adverse reactions in LIBRETTO-431. Table 10: Adverse Reactions (≥15%) in Patients on Either Arm in LIBRETTO-431 Adverse Reaction RETEVMO (n=158) Chemotherapy with or without pembrolizumab (n=98) Grades 1-4# (%) Grades 3-4 (%) Grades 1-4# (%) Grades 3-4 (%) Vascular disorders Hypertension 48 20* 7 3.1* Gastrointestinal disorders Diarrhea1 44 1.3* 24 2.0* Dry mouth2 39 0 6 0 Abdominal pain3 25 0.6* 19 2.0* Constipation 22 0 40 1.0* Stomatitis4 18 0 16 0 Nausea 13 0 44 1.0* Vomiting5 13 0 23 1.0* General disorders and administration site conditions Edema6 41 2.5* 28 0 Fatigue7 32 3.2* 50 5* Pyrexia 13 0.6* 23 0 Skin and subcutaneous tissue disorders Rash8 33 1.9* 30 1.0* Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain9 25 0 28 0 Investigations Electrocardiogram QT prolonged 20 9* 1.0 0 Infections and infestations COVID-19 infection 19 0.6* 18 0 Metabolism and nutrition disorders Decreased appetite 17 0 34 2.0* 1 Diarrhea includes diarrhea, anal incontinence. 2 Dry mouth includes dry mouth, mucosal dryness. 3 Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, gastrointestinal pain. Reference ID: 5498246 14 4 Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation. 5 Vomiting includes vomiting, retching, regurgitation. 6 Edema includes edema, edema peripheral, face edema, periorbital edema, swelling face, peripheral swelling, localized edema, eyelid edema, orbital edema, eye edema, scrotal edema, penile edema, orbital swelling, periorbital swelling. 7 Fatigue includes fatigue, asthenia, malaise. 8 Rash includes rash, rash maculopapular, skin exfoliation, rash erythematous, rash macular, dermatitis, urticaria, rash papular, dermatitis allergic, rash pustular, rash vesicular, genital rash. 9 Musculoskeletal pain includes musculoskeletal pain, arthralgia, back pain, bone pain, musculoskeletal chest pain, non- cardiac chest pain, neck pain, pain in extremity. * No Grade 4 abnormalities were reported. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Clinically relevant adverse reactions in <15% of patients who received RETEVMO include headache (14%); hemorrhage (13%); urinary tract infections (12%); hypothyroidism (9%); pneumonia (9%); dizziness (8%); interstitial lung disease/pneumonitis (4.4%); hypersensitivity, chylous ascites, and chylothorax (all < 2%). Table 11 summarizes the laboratory abnormalities in LIBRETTO-431. Table 11: Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients on Either Arm in LIBRETTO-431 Laboratory Abnormality1 RETEVMO Chemotherapy with or without pembrolizumab Grades 1-4# (%) Grades 3-4 (%) Grades 1-4# (%) Grades 3-4 (%) Chemistry ALT increased 81 21 63 4.1 AST increased 77 10 46 0 Alkaline phosphatase Increased 35 1.3 22 0 Total bilirubin Increased 52 1.3 9 0 Blood creatinine Increased 23 0 21 0 Magnesium decreased 16 0.6 8 0 Albumin decreased 25 0 5 0 Calcium decreased 53 1.9 24 1.0 Sodium decreased 31 3.2 41 2.1 Potassium decreased 17 1.3 15 1.0 Hematology Platelets decreased 53 3.2 39 5 Lymphocyte count decreased 53 8 64 15 Hemoglobin decreased 21 0 91 5 Neutrophil count decreased 53 2.0 58 11 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available: RETEVMO (range: 154 to 157 patients) and chemotherapy with or without pembrolizumab (range: 96 to 97 patients). # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Increased Creatinine Reference ID: 5498246 1 15 In healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)]. RET-Mutant Medullary Thyroid Cancer LIBRETTO-531 The safety population described below reflects exposure to RETEVMO as a single agent administered at 160 mg (adults) or at 92 mg/m2 (adolescent, not to exceed 160 mg) orally twice daily, in patients with progressive, advanced, kinase inhibitor naïve, RET-mutant medullary thyroid cancer in LIBRETTO-531 [see Clinical Studies (14.2)]. Among the 193 patients who received RETEVMO, the observed median duration of exposure was 14.5 months (range: 25 days to 36 months); 80% were exposed for 6 months or longer and 59% were exposed for one year or longer. The median age was 55 years (range: 12 to 84 years); 63% were male; and 69% were White, 28% were Asian, 2.9% were Black or African American and ethnicity was not routinely collected. Serious adverse reactions occurred in 22% of patients who received RETEVMO. The most frequent serious adverse reactions were pneumonia and pyrexia (n = 3, each) and hypertension and urinary tract infection (n = 2, each). Fatal adverse reactions occurred in 2.1% of patients; fatal adverse reactions included COVID-19, diabetic ketoacidosis, multiple organ dysfunction syndrome, and sudden death (n=1 each). Permanent discontinuation due to an adverse reaction occurred in 4.7% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation were edema, multiple organ dysfunction syndrome, sudden death, AST increased, diabetic ketoacidosis, chronic kidney disease, retinopathy, COVID-19, and somatic symptom disorder (n = 1, each). Dosage interruptions due to an adverse reaction occurred in 49% of patients who received RETEVMO. Adverse reactions requiring dosage omission in ≥5% of patients included ALT increased (9%) and hypertension (7%). Dose reductions due to an adverse reaction occurred in 39% of patients who received RETEVMO. One adverse reaction, increased ALT (7%), required a dose reduction in ≥5% of patients. The most common adverse reactions (≥25%) in patients who received RETEVMO were hypertension, edema, dry mouth, fatigue, and diarrhea. The most common Grade 3 or 4 laboratory abnormalities (≥5%) in patients who received RETEVMO were decreased lymphocytes, increased ALT, decreased neutrophils, increased ALP, increased blood creatinine, decreased calcium, and increased AST. Table 12 summarizes the adverse reactions in LIBRETTO-531. Table 12: Adverse Reactions (≥10%) in Patients Who Received RETEVMO in LIBRETTO-531 Adverse Reaction RETEVMO N = 193 Cabozantinib or Vandetanib N = 97 Grades 1-4# (%) Grades 3-4 (%) Grades 1-4# (%) Grades 3-4 (%) Vascular disorders Hypertension1 43 19* 41 18* General disorders and administration-site conditions Edema2 33 0 5 0 Fatigue3 28 4.1* 47 9* Pyrexia 12 1.0* 2.1 0 Gastrointestinal disorders Dry mouth4 32 0.5* 10 1.0* Diarrhea5 26 3.1* 61 8* Abdominal pain6 18 0.5* 21 2.1* Constipation 16 0 12 0 Reference ID: 5498246 16 Stomatitis7 14 0.5* 42 13* Pyrexia 12 1.0* 2.1 0 Nausea 10 1.0* 32 5* Nervous system disorders Headache8 23 0.5* 21 0 Skin and subcutaneous tissue disorders Rash9 19 1.6* 27 4.1* Reproductive system and breast disorders Erectile dysfunction 16 0 0 0 Investigations Electrocardiogram QT prolonged10 14 4.7* 13 2.1* Metabolism and nutrition disorders Decreased appetite 12 0.5* 28 5* Endocrine disorders Hypothyroidism11 11 0 21 0 1 Hypertension includes hypertension, blood pressure increased. 2 Edema includes edema peripheral, face edema, periorbital edema, swelling face, peripheral swelling, localized edema, eyelid edema, generalized edema, eye swelling, lymphoedema, orbital edema, eye edema, edema, edema genital, swelling, scrotal edema, scrotal swelling, angioedema, skin edema, testicular swelling, vulvovaginal swelling. 3 Fatigue includes fatigue, asthenia, malaise. 4 Dry mouth includes dry mouth, mucosal dryness. 5 Diarrhea includes diarrhea, anal incontinence, defecation urgency, frequent bowel movements, gastrointestinal hypermotility. 6 Abdominal pain included abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, gastrointestinal pain. 7 Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation. 8 Headache includes headache, sinus headache, tension headache. 9 Rash includes rash, rash maculopapular, skin exfoliation, rash erythematous, rash macular, dermatitis, urticaria, rash pruritic, exfoliative rash, rash papular, dermatitis allergic, rash follicular, rash generalized, rash pustular, butterfly rash, rash morbilliform, rash vesicular. 10 Electrocardiogram QT prolongation includes electrocardiogram QT prolonged, electrocardiogram QT interval abnormal. 11 Hypothyroidism includes hypothyroidism, blood thyroid stimulating hormone increased. * Only includes a Grade 3 adverse reaction # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. Clinically relevant adverse reactions in ≤10% of patients who received RETEVMO include dizziness (8%); urinary tract infections (8%); vomiting (8%); pneumonia, interstitial lung disease/pneumonitis, chylous ascites, and hypersensitivity (all < 2%). Table 13 summarizes the laboratory abnormalities in LIBRETTO-531. Table 13: Select Laboratory Abnormalities (≥5%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-531 Laboratory Abnormality RETEVMO1 Cabozantinib or Vandetanib1 Grades 1-4# % Grades 3-4 % Grades 1-4# % Grades 3-4 % Chemistry Calcium decreased 55 5 62 11 ALT increased 53 16 72 7* AST increased 47 5 68 3.2* Alkaline phosphatase increased 37 6 28 5 Reference ID: 5498246 17 Laboratory Abnormality RETEVMO1 Cabozantinib or Vandetanib1 Grades 1-4# % Grades 3-4 % Grades 1-4# % Grades 3-4 % Total bilirubin increased 32 1.1 30 3.2* Blood creatinine increased 27 6 16 8 Sodium decreased 20 3.2* 16 0 Albumin decreased 11 1.1 7 0 Magnesium decreased 9 3.3 26 9 Potassium decreased 8 0 22 4.4* Hematology Lymphocyte count decreased 41 18 36 13 Neutrophil count decreased 33 14 42 19 Platelets decreased 28 1.1 34 1.1* Hemoglobin decreased 18 2.1* 23 2.1* 1 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available: RETEVMO (range: 183 to 191 patients) and chemotherapy with or without cabozantinib or vandetanib (range: 91 to 94 patients). * Only includes a Grade 3 laboratory abnormality # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 Increased Creatinine In healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)]. 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on RETEVMO Acid-Reducing Agents Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce RETEVMO anti-tumor activity. Avoid concomitant use of PPIs, H2 receptor antagonists, and locally-acting antacids with RETEVMO. If coadministration cannot be avoided, take RETEVMO with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid) [see Dosage and Administration (2.4)]. Strong and Moderate CYP3A Inhibitors Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation. Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, reduce the RETEVMO dosage and monitor the QT interval with ECGs more frequently [see Dosage and Administration (2.6), Warning and Precautions (5.4)]. Strong and Moderate CYP3A Inducers Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce RETEVMO anti-tumor activity. Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO. 7.2 Effects of RETEVMO on Other Drugs CYP2C8 and CYP3A Substrates Reference ID: 5498246 18 8 RETEVMO is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling. Certain P-gp and BCRP Substrates RETEVMO is a P-gp and BCRP inhibitor. Concomitant use of RETEVMO with P-gp or BCRP substrates increases their plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp or BCRP substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P­ gp and BCRP substrates provided in their approved product labeling. 7.3 Drugs that Prolong QT Interval RETEVMO is associated with QTc interval prolongation [see Warnings and Precautions (5.4), Clinical Pharmacology (12.2)]. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], RETEVMO can cause fetal harm when administered to a pregnant woman. There are no available data on RETEVMO use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Selpercatinib administration to pregnant rats during the period of organogenesis at oral doses ≥100 mg/kg [approximately 3.6 times the human exposure based on the area under the curve (AUC) at the clinical dose of 160 mg twice daily] resulted in 100% post-implantation loss. At the dose of 50 mg/kg [approximately equal to the human exposure (AUC) at the clinical dose of 160 mg twice daily], 6 of 8 females had 100% early resorptions; the remaining 2 females had high levels of early resorptions with only 3 viable fetuses across the 2 litters. All viable fetuses had decreased fetal body weight and malformations (2 with short tail and one with small snout and localized edema of the neck and thorax). 8.2 Lactation Risk Summary There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with RETEVMO and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Based on animal data, RETEVMO can cause embryolethality and malformations at doses resulting in exposures less than or equal to the human exposure at the clinical dose of 160 mg twice daily [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating RETEVMO [see Use in Specific Populations (8.1)]. Contraception Females Reference ID: 5498246 19 Advise female patients of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Infertility RETEVMO may impair fertility in females and males of reproductive potential [see Use in Specific Populations (8.4), Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of RETEVMO have been established in pediatric patients 2 years of age and older for the treatment of: • advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation who require systemic therapy • advanced or metastatic thyroid cancer with a RET gene fusion who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate) • locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients 2 years of age and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2, 14.3, 14.4)]. The predicted exposures of selpercatinib in pediatric patients at the recommended dosages were within the range of values predicted in patients ≥ 12 years and ≥ 50 kg in body weight receiving the approved recommended dosage of 160 mg twice daily [see Clinical Pharmacology (12.3)]. The safety and effectiveness of RETEVMO have not been established in these indications in patients less than 2 years of age. The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications [see Indications and Usage (1)]. Juvenile Animal Toxicity Data In a juvenile rat toxicity study, animals were dosed daily with selpercatinib from post-natal day 21 to day 70 (approximately equivalent to a human child to late adolescent). Selpercatinib increased physeal thickness of multiple bones, extending into the metaphysis and associated with decreased trabecular bone, which was not reversible at doses approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily. Growth plate changes were associated with impairment of bone modeling, resulting in decreased femur length and with reduction in bone mineral density. Selpercatinib also induced reversible hypocellularity of bone marrow in males at ≥30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily), and reversible alterations of dentin composition at ≥50 mg/kg (approximately 3 times the adult human exposure at the clinical dose of 160 mg twice daily). Irreversible, dose-dependent degeneration of testicular germinal epithelium, with vacuolation of Sertoli cells and corresponding depletion of spermatozoa in the epididymides, was also observed at ≥ 30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily) and affected male reproductive performance at 50 mg/kg (approximately 3 times the adult human exposure at the clinical dose of 160 mg twice daily). Females exhibited delay in attainment of vaginal patency, a marker of sexual maturity, at 125 mg/kg (approximately 4 times the adult human exposure at the clinical dose of 160 mg twice daily); this effect was associated with lower mean body weight. Similar effects in irregular thickening of growth plates in adult rats and minipigs, and tooth dysplasia and malocclusion, resulting in tooth loss in adult rats were observed in repeat dose studies of up to 13-week duration with selpercatinib. Monitor growth plates in pediatric patients with open growth plates. Consider interrupting or discontinuing therapy based on the severity of any growth plate abnormalities and based on an individual risk-benefit assessment. 8.5 Geriatric Use Of 796 patients who received RETEVMO, 34% (268 patients) were ≥65 years of age and 9% (74 patients) were ≥75 years of age. No overall differences were observed in the safety or effectiveness of RETEVMO between patients who were ≥65 years of age and younger patients. Reference ID: 5498246 20 8.6 Renal Impairment No dosage modification is recommended for patients with mild to severe renal impairment [estimated Glomerular Filtration Rate (eGFR) ≥15 to 89 mL/min, estimated by Modification of Diet in Renal Disease (MDRD) equation]. The recommended dosage has not been established for patients with end-stage renal disease (ESRD) [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Reduce the dose when administering RETEVMO to patients with severe [total bilirubin greater than 3 to 10 times upper limit of normal (ULN) and any AST] hepatic impairment [see Dosage and Administration (2.7)]. No dosage modification is recommended for patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) or moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) hepatic impairment. Monitor for RETEVMO-related adverse reactions in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 11 DESCRIPTION RETEVMO contains selpercatinib, a kinase inhibitor. The molecular formula for selpercatinib is C29H31N7O3 and the molecular weight is 525.61 g/mol. The chemical name is 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3­ yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Selpercatinib has the following chemical structure: N N N HO O N OCH3 N N N Selpercatinib is a white to light yellow powder that is slightly hygroscopic. The aqueous solubility of selpercatinib is pH dependent, from sparingly soluble at low pH to practically insoluble at neutral pH. RETEVMO capsules contain either 40 mg or 80 mg of selpercatinib in hard gelatin capsules for oral use. Each capsule contains inactive ingredients of colloidal silicon dioxide and microcrystalline cellulose. The 40 mg capsule shell is composed of gelatin, titanium dioxide, ferric oxide black and black ink. The 80 mg capsule shell is composed of gelatin, titanium dioxide, FD&C blue #1 and black ink. The black ink is composed of shellac, potassium hydroxide and ferric oxide black. RETEVMO tablets contain 40 mg, 80 mg, 120 mg, or 160 mg of selpercatinib as film coated, debossed tablets for oral use. Each tablet contains inactive ingredients of croscarmellose sodium, hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. The tablet film coating material contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Additionally, the film coating of the 40 mg, 80 mg, and 120 mg tablets contains ferrosoferric oxide and the film coating of the 80 mg, 120 mg, and 160 mg tablets contain ferric oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Selpercatinib is a kinase inhibitor. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinib also inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable. In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and 2 and approximately 8-fold lower concentration than VEGFR3. Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T. In addition, selpercatinib showed anti-tumor activity in mice intracranially implanted with a patient-derived RET fusion positive tumor. Reference ID: 5498246 21 12.2 Pharmacodynamics Exposure-Response Relationship Selpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Cardiac Electrophysiology The effect of RETEVMO on the QTc interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state maximum concentration (Cmax) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent. 12.3 Pharmacokinetics The pharmacokinetics of selpercatinib capsules were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. The capsule and tablet dosage forms of selpercatinib are bioequivalent. Steady state selpercatinib AUC and Cmax increased in a slightly greater than dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily [0.06 to 1.5 times the maximum recommended total daily dosage]. Steady-state was reached by approximately 7 days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient of variation (CV%)] Cmax was 2,980 (53%) ng/mL and AUC0-24h was 51,600 (58%) ng*h/mL. Absorption The median tmax of selpercatinib is 2 hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects. Effect of Food For both the capsule and tablet dosage forms no clinically significant differences in selpercatinib AUC or Cmax were observed following administration of a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) in healthy subjects. Distribution The apparent volume of distribution (Vss/F) of selpercatinib is 203 L. Protein binding of selpercatinib is 96% in vitro and is independent of concentration. The blood-to-plasma concentration ratio is 0.7. Elimination The apparent clearance (CL/F) of selpercatinib is 6 L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects. Metabolism Selpercatinib is metabolized predominantly by CYP3A4. Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the radioactive drug components in plasma. Excretion Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% of the administered dose was recovered in feces (14% unchanged) and 24% in urine (12% unchanged). Specific Populations The apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (9.6 kg to 179 kg). No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (2 years to 92 years), sex, or mild, moderate, or severe renal impairment (eGFR ≥15 to 89 mL/min). The effect of ESRD on selpercatinib pharmacokinetics has not been studied. Pediatric patients The exposures of selpercatinib in pediatric patients are predicted to be comparable to those in adult patients administered at the recommended dosages. Patients with Hepatic Impairment Reference ID: 5498246 22 The selpercatinib AUC0-INF increased 1.1-fold in subjects with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST), 1.3-fold in subjects with moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST), and 1.8-fold in subjects with severe (total bilirubin greater than 3 to 10 times ULN and any AST) hepatic impairment, compared to subjects with normal hepatic function. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Proton-Pump Inhibitors (PPI): Coadministration with multiple daily doses of omeprazole (PPI) decreased selpercatinib AUC0-INF and Cmax when RETEVMO was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC0-INF and Cmax when RETEVMO was administered with food (Table 14). Table 14: Change in Selpercatinib Exposure After Coadministration with PPI Selpercatinib AUC0-INF Selpercatinib Cmax RETEVMO fasting Reference Reference RETEVMO fasting + PPI ↓ 69% ↓ 88% RETEVMO with a high-fat meal1 + PPI ↑ 2% ↓ 49% RETEVMO with a low-fat meal2 + PPI No change ↓ 22% 1 High-fat meal: approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively; approximately 800 to 1,000 calories total. 2 Low-fat meal: approximately 390 calories and 10 g of fat. H2 Receptor Antagonists: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after the RETEVMO dose (administered fasting). Strong CYP3A Inhibitors: Coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) increased the selpercatinib AUC0-INF 2.3-fold and Cmax 1.3-fold. Moderate CYP3A Inhibitors: Coadministration of multiple doses of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the selpercatinib AUC 1.6 to 2-fold and Cmax 1.5 to 1.8-fold. Strong CYP3A Inducers: Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the selpercatinib AUC0-INF by 87% and Cmax by 70%. Moderate CYP3A Inducers: Coadministration of multiple doses of bosentan or efavirenz (moderate CYP3A inducers) is predicted to decrease the selpercatinib AUC by 40-70% and Cmax by 34-57%. Weak CYP3A Inducers: Coadministration of multiple doses of modafinil (weak CYP3A inducer) is predicted to decrease the selpercatinib AUC by 33% and Cmax by 26%. CYP2C8 Substrates: Coadministration of RETEVMO with repaglinide (sensitive CYP2C8 substrate) increased the repaglinide AUC0-INF 2.9-fold and Cmax 1.9-fold. CYP3A Substrates: Coadministration of RETEVMO with midazolam (sensitive CYP3A substrate) increased the midazolam AUC0-INF 1.5-fold and Cmax 1.4-fold. P-glycoprotein (P-gp) Substrates: Coadministration of RETEVMO with dabigatran (P-gp substrate) increased the dabigatran AUC0-INF 1.4-fold and Cmax 1.4-fold. BCRP Substrates: Coadministration of RETEVMO with rosuvastatin (BCRP substrate) increased the rosuvastatin AUC0-INF by 1.9-fold and Cmax by 1.7-fold. P-gp Inhibitors: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampin (P-gp inhibitor). MATE1 Substrates: No clinically significant differences in glucose levels were observed when metformin (MATE1 substrate) was coadministered with selpercatinib. In Vitro Studies Reference ID: 5498246 23 CYP Enzymes: Selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Transporter Systems: Selpercatinib inhibits MATE1. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1 [see Adverse Reactions (6.1)]. Selpercatinib does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations. Selpercatinib is a substrate for P-gp and BCRP, but not for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Selpercatinib was not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice when administered by daily oral gavage at doses of up to 60 mg/kg. Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation. Selpercatinib was positive in the in vivo micronucleus assay in rats at concentrations >7 times the Cmax at the human dose of 160 mg twice daily. In general toxicology studies, male rats and minipigs exhibited testicular degeneration which was associated with luminal cell debris and/or reduced luminal sperm in the epididymis at selpercatinib exposures approximately 0.4 (rat) and 0.1 (minipig) times the clinical exposure by AUC at the 160 mg twice daily clinical dose. In a dedicated fertility study in male rats, administration of selpercatinib at doses up to 30 mg/kg/day (approximately twice the clinical exposure by AUC at the 160 twice daily clinical dose) for 28 days prior to cohabitation with untreated females did not affect mating or have clear effects on fertility. Males did, however, display a dose-dependent increase in testicular germ cell depletion and spermatid retention at doses ≥3 mg/kg (~0.2 times the clinical exposure by AUC at the 160 twice daily clinical dose) accompanied by altered sperm morphology at 30 mg/kg. In a dedicated fertility study in female rats treated with selpercatinib for 15 days before mating to Gestational Day 7, there were decreases in the number of estrous cycles at a dose of 75 mg/kg (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). While selpercatinib did not have clear effects on mating performance or ability to become pregnant at any dose level, half of females at the 75 mg/kg dose level had 100% nonviable embryos. At the same dose level in females with some viable embryos there were increases in post-implantation loss. In a 3-month general toxicology study in minipigs, there were findings of decreased or absent corpora lutea at a selpercatinib dose of 15 mg/kg (approximately 0.3 times to the human exposure by AUC at the 160 mg twice daily clinical dose). Corpora luteal cysts were present in the minipig at selpercatinib doses ≥2 mg/kg (approximately 0.07 times the human exposure by AUC at the 160 mg twice daily clinical dose). 14 CLINICAL STUDIES 14.1 RET Fusion-Positive Non-Small Cell Lung Cancer LIBRETTO-001 The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive NSCLC enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). The study enrolled patients with advanced or metastatic RET fusion-positive NSCLC who had progressed on platinum-based chemotherapy and patients with locally advanced (stage III who were not candidates for surgical resection or definitive chemoradiation) or metastatic NSCLC without prior systemic therapy in separate cohorts. Identification of a RET gene alteration was prospectively determined in local laboratories using next generation sequencing (NGS), polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH) or other local testing methods. Adult patients received RETEVMO 160 mg orally twice daily until unacceptable toxicity or disease progression; patients enrolled in the dose escalation phase were permitted to adjust their dose to 160 mg twice daily. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1. RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy Reference ID: 5498246 24 Efficacy was evaluated in 247 patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001. The median age was 61 years (range: 23 to 81); 57% were female; 44% were White, 48% were Asian, 4.9% were Black or African American; and 2.8% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3%) and 97% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1–15); 58% had prior anti-PD1/PD-L1 therapy. RET fusions were detected in 94% of patients using NGS (84.6% tumor samples; 9.3% blood or plasma samples), 4.0% using FISH, 1.6% using PCR and 0.4% by other local testing methods. Efficacy results for previously treated RET fusion-positive NSCLC are summarized in Table 15. Table 15: Efficacy Results in LIBRETTO-001 (RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy) RETEVMO (n = 247) Overall Response Rate1 (95% CI) 61% (55%, 67%) Complete response 7.3% Partial response 54% Duration of Response Median in months (95% CI) 28.6 (20, NE) % with ≥ 12 months2 63% 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable For the 144 patients who received an anti-PD-1 or anti-PD-L1 therapy, either sequentially or concurrently with platinum- based chemotherapy, an exploratory subgroup analysis of ORR was 63% (95% CI: 54%, 70%) and the median DOR was 28.6 months (95% CI: 14.8, NE). Among the 247 patients with previously treated RET fusion-positive NSCLC, 16 had measurable CNS metastases at baseline as assessed by BIRC. One patient received radiation therapy (RT) to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 14 of these 16 patients; 39% of responders had an intracranial DOR of ≥ 12 months. Treatment-naïve RET Fusion-Positive NSCLC Efficacy was evaluated in 69 patients with treatment-naïve RET fusion-positive NSCLC enrolled into a cohort of LIBRETTO-001. The median age was 63 years (range 23 to 92); 62% were female; 70% were White, 19% were Asian, and 6% were Black or African American. ECOG performance status was 0-1 (94%) or 2 (6%) and 99% of patients had metastatic disease. RET fusions were detected in 91% of patients using NGS (60.9% tumor samples; 30.4% in blood), 7.2% using FISH and 1.4% using PCR. Efficacy results for treatment naïve RET fusion-positive NSCLC are summarized in Table 16. Table 16: Efficacy Results in LIBRETTO-001 (Treatment-Naïve RET Fusion-Positive NSCLC) RETEVMO (n =69) Overall Response Rate1 (95% CI) 84% (73%, 92%) Complete response 5.8% Partial response 78% Duration of Response Median in months (95% CI) 20.2 (13, NE) % with ≥ 12 months2 50% Reference ID: 5498246 25 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable Among the 69 patients with treatment-naïve RET fusion-positive NSCLC, 5 had measurable CNS metastases at baseline as assessed by BIRC. Two patients received RT to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 4 of these 5 patients; 38% of responders had an intracranial DOR of ≥ 12 months. LIBRETTO-431 The efficacy of RETEVMO was evaluated in patients with unresectable, locally advanced or metastatic, RET fusion- positive NSCLC enrolled in a multicenter, open-label, active-controlled, randomized trial (LIBRETTO-431, NCT04194944). The trial evaluated RETEVMO compared to platinum-based and pemetrexed chemotherapy with or without pembrolizumab in patients with RET fusion-positive, unresectable locally advanced or metastatic NSCLC with no previous systemic therapy for metastatic disease. Patients (N=261) were randomized to receive either RETEVMO (160 mg orally twice daily) in continuous 21-day cycles or pemetrexed intravenously (IV) (500 mg per square meter of body-surface area) along with the investigator’s choice of platinum therapy (carboplatin IV [AUC 5, maximum dose 750 mg] or cisplatin IV [75 mg per square meter]) with or without pembrolizumab IV (200 mg) every 21 days. Treatment continued until disease progression or unacceptable toxicity. Crossover from the control arm to RETEVMO was permitted following disease progression. Patients were stratified according to geographic region (East Asia vs. elsewhere), brain metastases at baseline (presence vs. absence or unknown), and the investigator’s intent (before randomization) to treat the patient with or without pembrolizumab. Tumor assessments were performed every 6 weeks for two assessments, then every 9 weeks for four assessments, and then every 12 weeks thereafter. The major efficacy outcome measure was progression-free survival (PFS) in patients intended to be treated with chemotherapy in combination with pembrolizumab and in the overall study population as determined by a blinded independent review committee (BIRC) according to RECIST v1.1. Other efficacy outcome measures included overall survival (OS) and overall response rate (ORR). A total of 212 patients were enrolled in LIBRETTO-431 with an intent to treat with pembrolizumab if randomized to the control arm (129 into RETEVMO arm and 83 into chemotherapy with pembrolizumab arm). The median age was 61.5 years (range: 31 to 84 years); 47% were male; 41% White, 55% Asian, and 0.9% Black or African American, 1.4% American Indian or Alaska Native, 1.9% were race not reported; ethnicity was not reported in 96% of patients. ECOG performance status was 0-1 (97%) or 2 (3%), 68% were never smokers, 93% of patients had metastatic disease, and 14% had measurable intracranial metastases at baseline, as determined by a neuroradiologic BIRC. RET fusions were detected in 60% of patients using NGS and 40% using PCR (89% tumor samples; 11% in blood). Efficacy results from the pre-planned interim efficacy analysis are summarized in Table 17. Table 17: Efficacy Results in LIBRETTO-431: RETEVMO versus Chemotherapy with Pembrolizumab RETEVMO (n = 129) Chemotherapy with pembrolizumab (n = 83) Progression-Free Survival Number (%) of patients with an event 49 (38%) 49 (59%) Medians in months (95% CI) 24.8 (16.9, NE) 11.2 (8.8, 16.8) Hazard ratio1 (95% CI) 0.46 (0.31, 0.70) p-value2 0.0002 Overall Response Rate (95% CI) 84% (76, 90) 65% (54, 75) Complete response 7% 6% Partial response 77% 59% Duration of Response Reference ID: 5498246 1.0 0.9 0.8 ~ :c 0.7 nl .c 2 a. nl 0.6 > ·2 Cl Vl 0.5 Ill l!! LL ~ 0.4 _Q 1/l 1/l l!! <:II 2 0.3 a. 0.2 0.1 0.0 # N. Risk RETEVMO Chemotherapy with pembrolizllmab • - ! 1 \ i '-l ___ _ \ ,L ___ : ·-L __ Ll RETE.VMO ----1.....l.... Chemotherapy with _ L .L .1 _ pembroli'zumab 0 3 129 114 83 70 6 9 105 91 55 45 l i, L,_ ____ JJ, t ~ "-, , ___ Ll..J~ 12 15 L _____ L~ L ___ JL __ JL _____ J 18 21 24 Time from Randomization (Months) 72 56 44 27 16 29 21 15 11 6 __ J 27 30 33 36 5 2 0 2 0 0 26 Median in months (95% CI) 24.2 (17.9, NE) 11.5 (9.7, 23.3) % with ≥ 12 months3 60% 30% 1 Based on the stratified Cox proportional hazard model, stratified by geographic location (East Asia versus elsewhere), brain metastases at baseline according to investigator (presence versus absence or unknown). 2 Based on stratified log-rank test, stratified by geographic location (East Asia versus elsewhere), brain metastases at baseline according to investigator (presence versus absence or unknown). 3 Based on observed duration of response. NE = not estimable Figure 1: Kaplan-Meier Curves of Progression-Free Survival in LIBRETTO-431: RETEVMO versus Chemotherapy with Pembrolizumab Among the 212 randomized patients, 29 had measurable CNS metastases at baseline as assessed by BIRC. Responses in intracranial lesions were observed in 14 of 17 patients treated with RETEVMO and 7 of 12 patients treated with chemotherapy with pembrolizumab. Overall survival was immature at the time of the PFS interim analysis. At the time of an updated descriptive analysis of OS (43% of prespecified OS events needed for the final analysis), a total of 49 (31%) and 26 (25%) patients died in the RETEVMO and the control arm, respectively. The OS HR was 1.26 (95% CI: 0.78, 2.04). Overall survival may be affected by the imbalance in post-progression therapies. Of 68 control arm patients who had disease progression, 50 patients (74%) received RETEVMO at progression. Of 71 RETEVMO arm patients who had disease progression, 16 (23%) received chemotherapy and/or immune checkpoint inhibitor therapy, and 44 (62%) continued receiving RETEVMO. 14.2 RET-Mutant Medullary Thyroid Cancer LIBRETTO-001 The efficacy of RETEVMO was evaluated in patients with RET-mutant MTC enrolled in a multicenter, open-label, multi- cohort clinical trial (NCT03157128). The study enrolled patients with advanced or metastatic RET-mutant MTC who had been previously treated with cabozantinib or vandetanib (or both) and patients with advanced or metastatic RET-mutant MTC who were naïve to cabozantinib and vandetanib in separate cohorts. RET-Mutant MTC Previously Treated with Cabozantinib or Vandetanib Reference ID: 5498246 27 Efficacy was evaluated in 55 patients with RET-mutant advanced MTC who had previously treated with cabozantinib or vandetanib enrolled into a cohort of LIBRETTO-001. The median age was 57 years (range: 17 to 84); 66% were male; 89% were White, 7% were Hispanic/Latino, and 1.8% were Black. ECOG performance status was 0-1 (95%) or 2 (5%) and 98% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1 – 8). RET mutation status was detected in 82% of patients using NGS (78% tumor samples; 4% blood or plasma), 16% using PCR, and 2% using an unknown test. The protocol excluded patients with synonymous, frameshift or nonsense RET mutations; the specific mutations used to identify and enroll patients are described in Table 18. Table 18: Mutations used to Identify and Enroll Patients with RET-Mutant MTC in LIBRETTO-001 RET Mutation Type1 Previously Treated (n = 55) Cabozantinib/ Vandetanib Naïve (n = 88) Total (n = 143) M918T 33 49 82 Extracellular cysteine mutation2 7 20 27 V804M or V804L 54 6 11 Other3 10 13 23 1 Somatic or germline mutations; protein change. 2 Extracellular cysteine mutations involving cysteine residues 609, 611, 618, 620, 630, and 634. 3 Other included: K666N (1), D631_L633delinsV (2), D631_L633delinsE (5), D378_G385delinsE (1), D898_E901del (2), A883F (4), E632_L633del (4), L790F (2), T636_V637insCRT(1), D898_E901del + D903_S904delinsEP (1). 4 One patient also had a M918T mutation. Efficacy results for RET-mutant MTC are summarized in Table 19. Table 19: Efficacy Results in LIBRETTO-001 (RET-Mutant MTC Previously Treated with Cabozantinib or Vandetanib) RETEVMO (n = 55) Overall Response Rate1 (95% CI) 76% (63%, 87%) Complete response 18% Partial response 58% Duration of Response Median in months (95% CI) 45.3 (29.9, NE) % with ≥12 months2 76% 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable Cabozantinib and Vandetanib-naïve RET-Mutant MTC Efficacy was evaluated in 88 patients with RET-mutant MTC who were cabozantinib and vandetanib treatment-naïve enrolled into a cohort of LIBRETTO-001. The median age was 58 years (range: 15 to 82) with two patients (2.3%) aged 12 to 16 years; 66% were male; and 86% were White, 4.5% were Asian, and 2.3% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3.4%). All patients (100%) had metastatic disease and 18% had received 1 or 2 prior systemic therapies (including 8% kinase inhibitors, 4.5% chemotherapy, 2.3% anti-PD1/PD-L1 therapy, and 1.1% radioactive iodine). RET mutation status was Reference ID: 5498246 28 detected in 77.3% of patients using NGS (75.0% tumor samples; 2.3% blood samples), 18.2% using PCR, and 4.5% using an unknown test. The mutations used to identify and enroll patients are described in Table 18. Efficacy results for cabozantinib and vandetanib-naïve RET-mutant MTC are summarized in Table 20. Table 20: Efficacy Results in LIBRETTO-001 (Cabozantinib and Vandetanib-naïve RET-Mutant MTC) RETEVMO (n = 88) Overall Response Rate1 (95% CI) 81% (71%, 88%) Complete response 28% Partial response 52% Duration of Response Median in months (95% CI) NR (51.3, NE) % with ≥12 months2 90% 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NR = not reached, NE = not estimable LIBRETTO-531 LIBRETTO-531 was a randomized (2:1), multicenter, open-label study (NCT04211337) in adults and adolescents with advance or metastatic RET-mutant MTC. The study evaluated the efficacy of RETEVMO versus physicians’ choice of cabozantinib or vandetanib in patients with progressive, advanced, kinase inhibitor naïve, RET-mutant medullary thyroid cancer. Patients were randomized to receive either RETEVMO (160 mg twice daily) or physicians’ choice of cabozantinib (140 mg once daily) or vandetanib (300 mg once daily). Patients were stratified based on RET mutation (M918T vs. other) and intended treatment if randomized to the control arm (cabozantinib vs. vandetanib). The primary outcome was progression- free survival (PFS), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1. The median age was 55 years (range: 12 to 84), 63% were male, 58% were White, 23% were Asian, 2.4% were Black or African American, and 17% had unknown race. ECOG performance status was 0-1 (98%) or 2 (1.0%) with 0.7% unknown status. 77% of patients had metastatic disease and 6 patients (2.1%) had received 1 prior systemic therapy. RET mutation status was detected in 90% of patients using NGS (89% tumor samples; 8% blood or plasma), and 10% using PCR. Of patients enrolled in LIBRETTO-531, 63% had M918T RET mutations and 37% had other RET mutations. Efficacy results for LIBRETTO-531 based on the preplanned interim efficacy analysis are provided in Table 21 and Figure 2. At the time of this analysis, overall survival data were immature with 18 deaths observed (14% of pre-specified events). Table 21: Efficacy Results in LIBRETTO-531: RETEVMO versus Cabozantinib or Vandetanib RETEVMO N = 193 Cabozantinib or Vandetanib N = 98 PFS Number (%) of patients with an event 26 (14%) 33 (34%) Median in months (95% CI) NR (NE, NE) 16.8 (12.2, 25.1) Hazard ratio (95% CI)1 0.280 (95% CI: 0.165, 0.475) p-value2 <0.0001 Overall Response Rate ORR (95% CI) 69% (62%, 76%) 39% (29%, 49%) Complete response 12% 4% Partial response 58% 35% Duration of Response Median in months (95% CI) NR (NE, NE) 16.6 (10.4, NE) Reference ID: 5498246 ~ :c (IS .c 0 ... a. iij -~ > ... ::J en QJ QJ ... LL I C .Q 1/) 1/) QJ ... C) 0 0 .9 0.8 0.7 0 .6 0.5 0.4 0 .3 0.2 0 .1 Censored observations --- Se lpe rcatlnlb (N=193) '-\1-1 I ! --: _L L- -\ 71_' ,_ -- -~ i l : _______ JI, lJ, ( _J_ : __ J, iu _____________ L1 : ________ j ___ _ ... a. - - - - - Cabozantlnlb or Vandetanlb (N=98) 0 .0 0 3 6 9 12 15 18 21 24 27 30 Patients At Risk Time from Randomization (Months) Selpercatlnlb 193 159 127 107 84 63 45 35 20 13 7 Cabozantlnlb or Vandetanlb 98 77 55 37 29 21 13 7 7 2 33 36 3 0 0 0 29 Median follow-up time (months) 11.1 12.8 Data from the pre-planned interim efficacy analysis. 1 Based on the stratified Cox proportional hazard model. 2 Based on stratified log-rank test. NR = Not reached; NE = not evaluable Figure 2: Kaplan-Meier Curves of Progression-Free Survival in LIBRETTO-531: RETEVMO versus Cabozantinib or Vandetanib Patient-reported overall side effect impact was evaluated weekly in 222 patients (RETEVMO N = 145; cabozantinib or vandetanib N=77) who received at least one dose of treatment by at least 6 months prior to the data cutoff date and responded to the Functional Assessment of Cancer Therapy item GP5 (FACT GP5). Patient-reported overall side effect impact was derived as a proportion of time on treatment with high side effect bother (defined as response of 3 “Quite a bit” or 4 “Very much”) per FACT GP5. Patient-reported overall side effect impact results for LIBRETTO-531 are provided in Table 22. Table 22. Descriptive Summary of Patient-reported Overall Side Effect Impact While on Treatment in LIBRETTO­ 531 RETEVMO (N=145) Cabozantinib or Vandetanib (N=77) Mean proportion of time with high side effect bother (95% CI) 8% (4.8%, 10%) 24% (17%, 31%) % Patients with high side effect bother 0% of time ≤25% of time 61% 90% 30% 66% Reference ID: 5498246 30 Patient-reported overall side effect impact results were supported by a lower incidence of treatment discontinuation due to adverse reactions for RETEVMO (4.7%) compared to cabozantinib or vandetanib (27%) in patients who received at least one dose of study treatment. The median time on treatment at the data cutoff was 14.5 months in the RETEVMO arm and 8.3 months in the cabozantinib or vandetanib arm in patients who received at least one dose of study treatment. LIBRETTO-121 The efficacy of RETEVMO was evaluated in pediatric and young adult patients with advanced RET-activated solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-121, NCT03899792). Patients received RETEVMO 92 mg/m2 orally twice daily until disease progression, unacceptable toxicity, or other reason for treatment discontinuation. Tumor assessments were performed every 8 weeks for one year, then every 12 weeks; responses were assessed according to RECIST 1.1 per BIRC. Efficacy was evaluated in 14 patients with RET-mutant MTC who were non-responsive to available therapies or had no standard systemic curative therapy available. The median age was 14 years (range 2 to 20); 64% were male; 71% were White, 14% were Black or African American; and 14% were Hispanic/Latino. Patients had metastatic (71%) or locally advanced (29%) disease; 43% had measurable disease at baseline; 21% had received prior systemic therapy. RET- mutant status was detected in 79% of patients using NGS tumor samples and in 21% using PCR. Efficacy results for RET-mutant MTC in pediatric and young adult patients are summarized in Table 23. Table 23: Efficacy Results in LIBRETTO-121 (RET-Mutant MTC) RETEVMO (n = 14) Overall Response Rate1 (95% CI) 43% (18, 71) Complete response 7% Partial response 36% Duration of Response Median in months (95% CI) NR (NE, NE) % with ≥12 months2 100% % with ≥18 months2 67% 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NR = not reached; NE = not estimable 14.3 RET Fusion-Positive Thyroid Cancer LIBRETTO-001 The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive thyroid cancer enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). Efficacy was evaluated in 65 patients with RET fusion-positive thyroid cancer who were radioactive iodine (RAI)-refractory (if RAI was an appropriate treatment option) and were systemic therapy naïve and patients who were previously treated, in separate cohorts. The median age was 59 years (range 20 to 88); 49% were male; 65% were White, 20% were Asian, 4.6% were Black or African American; and 11% were Hispanic/Latino. ECOG performance status was 0-1 (94%) or 2 (6%). All (100%) patients had metastatic disease with primary tumor histologies including papillary thyroid cancer (83%), poorly differentiated thyroid cancer (9%), anaplastic thyroid cancer (6%) and Hurthle cell thyroid cancer (1.5%). Previously treated patients had received a median of 1 prior therapy (range 1–4). RET fusion-positive status was detected in 97% of patients using NGS (89% tumor samples; 8% blood or plasma samples), and 3% using other local testing methods. Efficacy results for RET fusion-positive thyroid cancer are summarized in Table 24. Reference ID: 5498246 31 Table 24: Efficacy Results in LIBRETTO-001 (RET Fusion-Positive Thyroid Cancer) RETEVMO Previously Treated (n = 41) RETEVMO Systemic Therapy Naïve (n = 24) Overall Response Rate1 (95% CI) 85% (71%, 94%) 96% (79%, 100%) Complete response 12% 21% Partial response 73% 75% Duration of Response Median in months (95% CI) 26.7 (12.1, NE) NE (42.8, NE) % with ≥12 months2 54 65 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable Responses were observed in patients with each histology represented, including 3 of 4 patients with anaplastic thyroid cancer (all partial responses) and 6 of 6 patients with poorly differentiated thyroid cancer (1 complete response, 5 partial responses). LIBRETTO-121 The efficacy of RETEVMO was evaluated in pediatric and young adult patients with advanced RET-activated solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-121, NCT03899792) [see Clinical Studies (14.2)]. Efficacy was evaluated in 10 patients with RET fusion-positive thyroid cancer who were non-responsive to available therapies or had no standard systemic curative therapy available. The median age was 13.5 years (range 12 to 20); 60% were male; 40% were White, 50% were Asian; and 30% were Hispanic/Latino. All (100%) patients had metastatic disease and papillary thyroid cancer histology; 40% had measurable disease at baseline; 30% had received prior systemic therapy. RET fusion-positive status was detected in 90% of patients using NGS tumor samples and in 10% using FISH. Efficacy results for RET fusion-positive thyroid cancer in pediatric and young adult patients are summarized in Table 25. Table 25: Efficacy Results in LIBRETTO-121 (RET Fusion-Positive Thyroid Cancer) RETEVMO (n = 10) Overall Response Rate1 (95% CI) 60% (26, 88) Complete response 30% Partial response 30% Duration of Response Median in months (95% CI) NR (NE, NE) % with ≥12 months2 83% % with ≥18 months2 50% 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NR = not reached; NE = not estimable 14.4 Other RET Fusion-Positive Solid Tumors LIBRETTO-001 The efficacy of RETEVMO was evaluated in patients with locally advanced or metastatic RET fusion-positive solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). Efficacy was evaluated in 41 patients with RET fusion-positive tumors other than NSCLC and thyroid cancer with disease progression on or following prior systemic treatment or who had no satisfactory alternative treatment options. Reference ID: 5498246 32 The median age was 50 years (range 21 to 85), 54% were female, 68% were White, 24% were Asian, and 4.9% were Black; and 7% were Hispanic/Latino. ECOG performance status was 0-1 (95%) or 2 (5%) and 95% of patients had metastatic disease. Thirty-seven patients (90%) received prior systemic therapy (median 2 [range 0 – 9]; 32% received 3 or more). The most common cancers were pancreatic adenocarcinoma (27%), colorectal (24%), salivary (10%) and unknown primary (7%). RET fusion-positive status was detected in 97.6% of patients using NGS and 2.4% using FISH. Efficacy results for RET fusion-positive solid tumors other than NSCLC and thyroid cancer are summarized in Table 26 and Table 27. Table 26: Efficacy Results in LIBRETTO-001 (Other RET Fusion-Positive Solid Tumors) RETEVMO (n = 41) Overall Response Rate1 (95% CI) 44% (28, 60) Complete response 4.9% Partial response 39% Duration of Response Median in months (95% CI) 24.5 (9.2, NE) % with ≥6 months2 67% 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable Table 27: Efficacy Results by Tumor Type in LIBRETTO-001 (Other RET Fusion-Positive Solid Tumors) Tumor Type Patients (n = 41) ORR1,2 DOR Range (months) n (%) 95% CI Pancreatic adenocarcinoma 11 6 (55%) (23, 83) 2.5, 38.3+ Colorectal 10 2 (20%) (2.5, 56) 5.6, 13.3 Salivary 4 2 (50%) (7, 93) 5.7, 28.8+ Unknown primary 3 1 (33%) (0.8, 91) 9.2 Breast 2 PR, CR NA 2.3+, 17.3 Sarcoma (soft tissue) 2 PR, SD NA 14.9+ Xanthogranuloma 2 NE, NE NA NA Carcinoid (bronchial) 1 PR NA 24.1+ Carcinoma of the skin 1 NE NA NA Cholangiocarcinoma 1 PR NA 5.6+ Ovarian 1 PR NA 14.5+ Pulmonary carcinosarcoma 1 NE NA NA Rectal neuroendocrine 1 NE NA NA Small intestine 1 CR NA 24.5 + denotes ongoing response. 1 Confirmed overall response rate assessed by BIRC. 2 Best overall response for each patient is presented for tumor types with ≤2 patients. CI = confidence interval, CR = complete response, DOR = duration of response, NA = not applicable, NE = not evaluable, ORR = overall response rate, PR = partial response, SD = stable disease. LIBRETTO-121 Reference ID: 5498246 33 The efficacy of RETEVMO was evaluated in pediatric and young adult patients with advanced RET-activated solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-121, NCT03899792) [see Clinical Studies (14.2)]. Efficacy was evaluated in one patient with locally advanced refractory RET-fusion positive malignant peripheral nerve sheath tumor who did not respond. Responses were observed in patients with RET fusion-positive thyroid cancer [see Clinical Studies (14.3)]. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied RETEVMO capsules are supplied as follows: Capsule Strength Description Package Configuration NDC Number 40 mg Gray opaque, imprinted with “Lilly”, “3977” and “40 mg” in black ink 60 count bottle NDC 0002-3977-60 80 mg Blue opaque, imprinted with “Lilly”, “2980” and “80 mg” in black ink 60 count bottle NDC 0002-2980-60 120 count bottle NDC 0002-2980-26 RETEVMO tablets are supplied in bottles with desiccant in the following configurations: Tablet Strength Description Package Configuration NDC Number 40 mg Light gray, film coated, round tablets debossed with “Ret 40” on one side and “5340” on the other side 60 count bottle NDC 0002-5340-60 80 mg Dark red-purple, film coated, round tablets debossed with “Ret 80” on one side and ”6082” on the other side 60 count bottle NDC 0002-6082-60 120 mg Light purple, film coated, round tablets debossed with “Ret 120” on one side and “6120” on the other side 60 count bottle NDC 0002-6120-60 160 mg Light pink, film coated, round tablets debossed with Ret “160” on one side and “5562” on the other side 60 count bottle NDC 0002-5562-60 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C (59°F to 86°F) are permitted [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Hepatotoxicity Advise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.1)]. Interstitial Lung Disease (ILD)/Pneumonitis Advise patients that ILD/ pneumonitis can occur and to contact their healthcare provider immediately for signs or symptoms of ILD including new or worsening cough or shortness of breath [see Warnings and Precautions (5.2)]. Hypertension Advise patients that they will require regular blood pressure monitoring and to contact their healthcare provider if they experience symptoms of increased blood pressure or elevated readings [see Warnings and Precautions (5.3)]. QT Prolongation Reference ID: 5498246 34 Advise patients that RETEVMO can cause QTc interval prolongation and to inform their healthcare provider if they have any QTc interval prolongation symptoms, such as syncope [see Warnings and Precautions (5.4)]. Hemorrhagic Events Advise patients that RETEVMO may increase the risk for bleeding and to contact their healthcare provider if they experience any signs or symptoms of bleeding [see Warnings and Precautions (5.5)]. Hypersensitivity Reactions Advise patients to monitor for signs and symptoms of hypersensitivity reactions, particularly during the first month of treatment [see Warnings and Precautions (5.6)]. Tumor Lysis Syndrome Advise patients to contact their healthcare provider promptly to report any signs and symptoms of TLS [see Warnings and Precautions (5.7)]. Risk of Impaired Wound Healing Advise patients that RETEVMO may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.8)]. Hypothyroidism Advise patients that RETEVMO can cause hypothyroidism and to immediately contact their healthcare provider for signs or symptoms of hypothyroidism [see Warnings and Precautions (5.9)]. Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis Advise pediatric patients and caregivers to contact their healthcare provider promptly to report any signs and symptoms indicative of slipped capital femoral epiphysis/slipped upper femoral epiphysis [see Warnings and Precautions (5.11)]. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the possible risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during the treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Infertility Advise males and females of reproductive potential that RETEVMO may impair fertility [see Use in Specific Populations (8.4), Nonclinical Toxicology (13.1)]. Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John’s wort, proton pump inhibitors, H2 receptor antagonists, and antacids while taking RETEVMO. If PPIs are required, instruct patients to take RETEVMO with food. If H2 receptor antagonists are required, instruct patients to take RETEVMO 2 hours before or 10 hours after the H2 receptor antagonist. If locally-acting antacids are required, instruct patients to take RETEVMO 2 hours before or 2 hours after the locally-acting antacid [see Drug Interactions (7.1, 7.2)]. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2020, 2024, Eli Lilly and Company. All rights reserved. A1.02-RET-0007-USPI-YYYYMMDD Reference ID: 5498246
custom-source
2025-02-12T15:47:56.261613
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CEFAZOLIN FOR INJECTION safely and effectively. See full prescribing information for CEFAZOLIN FOR INJECTION. CEFAZOLIN for injection, for intravenous use Initial U.S. Approval: 1973 --------------------------RECENT MAJOR CHANGES------------------------­ Dosage and Administration (2.1, 2.2, 2.3, 2.6) 12/2024 --------------------------INDICATIONS AND USAGE-------------------------- Cefazolin for Injection is a cephalosporin antibacterial indicated for: • Treatment of the following infections caused by susceptible isolates of the designated microorganisms in adult and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved: o Respiratory tract infections (1.1) o Urinary tract infections (1.2) o Skin and skin structure infections (1.3) o Biliary tract infections (1.4) o Bone and joint infections (1.5) o Genital infections (1.6) o Septicemia (1.7) o Endocarditis (1.8) • Perioperative prophylaxis in adult patients (1.9) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefazolin for Injection and other antibacterial drugs, Cefazolin for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria (1.10) ------------------------DOSAGE AND ADMINISTRATION---------------------- Cefazolin for Injection, 2 grams/vial: • For intravenous infusion (2.1) • For intravenous bolus injection (2.1) • Not for intramuscular administration (2.1) Cefazolin for Injection, 3 grams/vial: • For intravenous infusion only (2.1) • Not for intravenous bolus injection administration or intramuscular administration (2.1) Recommended Dosage in Adult Patients with CLcr that is greater than or equal to 55 mL/min (2.2) Type of Infection Dose Frequency Moderate to severe infections 500 mg to 1 gram every 6 to 8 hours Mild infections caused by susceptible gram-positive cocci 250 mg to 500 mg every 8 hours Acute, uncomplicated urinary tract infections 1 gram every 12 hours Pneumococcal pneumonia 500 mg every 12 hours Severe, life-threatening infections (e.g., endocarditis, septicemia)* 1 gram to 1.5 grams every 6 hours 1 gram to 2 grams ½ to 1 hour prior to start of surgery Perioperative prophylaxis 500 mg to 1 gram during surgery for lengthy procedures (e.g., 2 hours or more) 500 mg to 1 gram every 6 to 8 hours for 24 hours postoperatively Recommended Dosage in Pediatric Patients with CLcr that is greater than or equal to 70 mL/min (2.3) Type of Infection Dose Frequency Mild to moderately severe infections 25 mg per kg to 50 mg per kg divided into 3 or 4 equal doses Severe infections May increase to 100 mg per kg divided into 3 or 4 equal doses • Dosage adjustment is required for adult patients with CLcr that is less than 55 mL/min and pediatric patients with CLcr that is less than 70 mL/min (2.4) • See full prescribing information for preparation and administration instructions (2.6) ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ For Injection: 2 grams or 3 grams of cefazolin as a powder in single-dose vial for reconstitution (3) -------------------------------CONTRAINDICATIONS-----------------------------­ Hypersensitivity to cefazolin or other cephalosporin class antibacterial drugs, penicillins, or other beta-lactams (4) ------------------------WARNINGS AND PRECAUTIONS----------------------­ • Hypersensitivity Reactions: Cross-hypersensitivity may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction occurs, discontinue the drug (5.1) • Clostridioides difficile-Associated Diarrhea (CDAD): May range in severity from mild to fatal colitis. Evaluate if diarrhea occurs. (5.3) • Prothrombin Activity: May be associated with a fall in prothrombin activity. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated (5.5) -------------------------------ADVERSE REACTIONS------------------------­ Adult and Pediatric Patients: Most common adverse reactions are gastrointestinal (nausea, vomiting, diarrhea), and allergic reactions (anaphylaxis, skin rash) (6) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689, or the FDA at 1-800-FDA­ 1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------- Probenecid: The renal excretion of cefazolin is inhibited by probenecid. Co- administration of probenecid with Cefazolin for Injection is not recommended (7) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/2024 * In rare instances, doses of up to 12 grams of cefazolin per day have been used. Confidential Reference ID: 5498547 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Respiratory Tract Infections 1.2 Urinary Tract Infections 1.3 Skin and Skin Structure Infections 1.4 Biliary Tract Infections 1.5 Bone and Joint Infections 1.6 Genital Infections 1.7 Septicemia 1.8 Endocarditis 1.9 Perioperative Prophylaxis 1.10 Usage 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions 2.2 Recommended Dosage for the Treatment of Infections 2.3 Recommended Dosage for Perioperative Prophylactic Use in Adults 2.4 Recommended Dosage in Adult and Pediatric Patients with Renal Impairment 2.5 Pediatric Dosage Preparation Guide 2.6 Preparation of Cefazolin for Injection 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions to Cefazolin, Cephalosporins, Penicillins, or Other Beta-lactams 5.2 Seizures in Patients with Renal Impairment 5.3 Clostridioides difficile–Associated Diarrhea 5.4 Risk of Development of Drug-resistant Bacteria 5.5 Prothrombin Activity 5.6 Drug/Laboratory Test Interactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 6.3 Cephalosporin-class Adverse Reactions 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Respiratory Tract Infections Cefazolin for Injection is indicated for the treatment of respiratory tract infections due to Streptococcus pneumoniae, Klebsiella species, Hemophilus influenzae, Staphylococcus aureus (methicillin-susceptible), and Group A beta-hemolytic streptococci in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1, 2.2, 2.4 and 2.5)]. Limitations of Use Injectable benzathine penicillin is considered to be the drug of choice in treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cefazolin for Injection is indicated for the eradication of streptococci from the nasopharynx; however, data establishing the efficacy of Cefazolin for Injection in the subsequent prevention of rheumatic fever are not available at present. 1.2 Urinary Tract Infections Cefazolin for Injection is indicated for the treatment of urinary tract infections due to Escherichia coli, Proteus mirabilis, and Klebsiella species (spp.) in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1, 2.2, 2.4 and 2.5)]. Confidential Reference ID: 5498547 --- 1.3 Skin and Skin Structure Infections Cefazolin for Injection is indicated for the treatment of skin and skin structure infections due to S. aureus (methicillin-susceptible), Group A beta-hemolytic streptococci, and Streptococcus species (spp.) in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1, 2.2, 2.4 and 2.5)]. 1.4 Biliary Tract Infections Cefazolin for Injection is indicated for the treatment of biliary tract infections due to E. coli, various isolates of Streptococcus spp., P. mirabilis, Klebsiella spp., and S. aureus (methicillin-susceptible) in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1, 2.2, 2.4 and 2.5)]. 1.5 Bone and Joint Infections Cefazolin for Injection is indicated for the treatment of bone and joint infections due to S. aureus in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1, 2.2, 2.4 and 2.5)]. 1.6 Genital Infections Cefazolin for Injection is indicated for the treatment of genital infections (i.e., prostatitis, epididymitis) due to E. coli, P. mirabilis, and Klebsiella species in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1, 2.2, 2.4 and 2.5)]. 1.7 Septicemia Cefazolin for Injection is indicated for the treatment of septicemia due to S. pneumoniae, S. aureus (methicillin-susceptible), P. mirabilis, E. coli, and Klebsiella species in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1, 2.2, 2.4 and 2.5)]. 1.8 Endocarditis Cefazolin for Injection is indicated for the treatment of endocarditis due to S. aureus (methicillin-susceptible) and Group A beta-hemolytic streptococci in adults and pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Dosage and Administration (2.1, 2.2, 2.4 and 2.5)]. Confidential Reference ID: 5498547 1.9 Perioperative Prophylaxis Cefazolin for Injection is indicated for perioperative prophylaxis in adults. The prophylactic administration of Cefazolin for Injection preoperatively, intraoperatively and postoperatively may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures which are classified as contaminated or potentially contaminated (e.g., vaginal hysterectomy, and cholecystectomy in high-risk patients such as those older than 70 years, with acute cholecystitis, obstructive jaundice, or common duct bile stones). The perioperative use of Cefazolin for Injection is indicated in surgical patients in whom infection at the operative site would present a serious risk (e.g., during open-heart surgery and prosthetic arthroplasty). The prophylactic administration of Cefazolin for Injection should usually be discontinued within a 24-hour period after the surgical procedure. In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of Cefazolin for Injection may be continued for 3 to 5 days following the completion of surgery. If there are signs of infection, specimens for cultures should be obtained for the identification of the causative organism so that appropriate therapy may be instituted [see Dosage and Administration (2.3)]. 1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefazolin for Injection and other antibacterial drugs, Cefazolin for Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Important Administration Instructions • Cefazolin for Injection, 2 grams/vial: Cefazolin for Injection, 2 grams/vial, is for intravenous infusion or intravenous bolus injection in adult and pediatric patients [see Dosage and Administration (2.2 2.3, and 2.6)]. Not for intramuscular administration. • Cefazolin for Injection, 3 grams/vial: Cefazolin for Injection, 3 grams/vial, is for intravenous infusion only in adult and pediatric patients [see Dosage and Administration (2.2, 2.3, 2.5, and 2.6)]. Cefazolin for Injection, 3 grams/vial is not for intravenous bolus injection or intramuscular administration [see Dosage and Administration (2.5, 2.6)]. Confidential Reference ID: 5498547 2.2 Recommended Dosage for the Treatment of Infections Recommended Dosage for the Treatment of Infections in Adults with Creatinine Clearance (CLcr) Equal to 55 mL/min or Greater The recommended adult dosages of Cefazolin for Injection for the treatment of infections [see Indications and Usage (1.1 to 1.8)] are outlined in Table 1 below. Administration instructions are as follows: • Cefazolin for Injection, 2 grams/vial is for intravenous infusion or intravenous bolus injection in adult patients [see Dosage and Administration (2.6)]. • Cefazolin for Injection, 3 grams/vial is only for intravenous infusion in adult patients. • Cefazolin for Injection, 3 grams/vial is not for intravenous bolus injection in adult patients [see Dosage and Administration (2.6)]. • Cefazolin for Injection 2 grams/vial and 3 grams/vial are not for intramuscular injection. Table 1: Recommended Dosage in Adult Patients with CLcr Equal to 55 mL/min or Greater Site and Type of Infection Dose Frequency Moderate to severe infections 500 mg to 1 gram every 6 to 8 hours Mild infections caused by susceptible gram–positive cocci 250 mg to 500 mg every 8 hours Acute, uncomplicated urinary tract infections 1 gram every 12 hours Pneumococcal pneumonia 500 mg every 12 hours Severe, life-threatening infections (e.g., endocarditis, septicemia)* 1 gram to 1.5 grams every 6 hours *In rare instances, doses of up to 12 grams of Cefazolin for Injection per day have been used. Recommended Dosage for the Treatment of Infections in Pediatric Patients 1 Month of Age and Older with CLcr Equal to 70 mL/min or Greater The recommended pediatric dosages for the treatment of infections [see Indications and Usage (1.1 to 1.8)] are outlined in Table 2 below. Administration instructions are as follows: • Cefazolin for Injection, 2 grams/vial is for intravenous infusion or intravenous bolus injection in pediatric patients [see Dosage and Administration (2.5, 2.6)]. • Cefazolin for Injection, 3 grams/vial is only for intravenous infusion in pediatric patients. • Cefazolin for Injection, 3 grams/vial is not for intravenous bolus injection in pediatric patients [see Dosage and Administration (2.6)]. • Cefazolin for Injection 2 grams/vial and 3 grams/vial are not for intramuscular injection. Confidential Reference ID: 5498547 Table 2: Recommended Dosage in Pediatric Patients 1 Month of Age and Older with CLcr 70 mL/min or Greater for Treatment of Infections [see Indications and Usage (1.1 to 1.8)] Type of Severity Recommended Total Daily Dosage Mild to moderately severe infections 25 mg/kg to 50 mg/kg, divided into 3 or 4 equal doses Severe infections May increase to 100 mg/kg, divided into 3 or 4 equal doses 2.3 Recommended Dosage for Perioperative Prophylactic Use in Adults Recommended Dosage for Perioperative Prophylaxis in Adults with CLcr Equal to 55 mL/min or Greater To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended dosages are described in Table 3 below. Administration instructions are as follows: • Cefazolin for Injection, 2 grams/vial is for intravenous infusion or intravenous bolus injection in adult patients [see Dosage and Administration (2.4, 2.6)]. • Cefazolin for Injection, 3 grams/vial is only for intravenous infusion in adult patients. • Cefazolin for Injection, 3 grams/vial is not for intravenous bolus injection in adult patients [see Dosage and Administration (2.4, 2.6)]. • Cefazolin for Injection 2 grams/vial and 3 grams/vial are not for intramuscular injection. Table 3: Recommended Dosage for Perioperative Prophylaxis in Adults with CLcr of 55 mL/min or Greater Dose administered ½ hour to 1 hour prior to the start of surgery Additional dose during lengthy operative procedures (e.g., 2 hours or more) Dose for 24 hours post-operatively 1 gram to 2 grams 500 mg to 1 gram 500 mg to 1 gram every 6 hours to 8 hours It is important that (1) the preoperative dose be given just (1/2 hour to 1 hour) prior to the start of surgery so that adequate antibacterial levels are present in the serum and tissues at the time of initial surgical incision; and (2) Cefazolin for Injection be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibacterial drug at the anticipated moments of greatest exposure to infective organisms. The perioperative prophylactic administration of cefazolin should usually be discontinued within a 24-hour period after the surgical procedure. In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of Cefazolin for Injection may be continued for Confidential Reference ID: 5498547 3 to 5 days following the completion of surgery. 2.4 Recommended Dosage in Adult and Pediatric Patients with Renal Impairment Recommended Dosage in Adult Patients with CLcr less than 55 mL/min The recommended dosage of Cefazolin for Injection in adult patients with renal impairment (CLcr less than 55 mL/min) is outlined in Table 4 below. Table 4: Recommended Dosage in Adult Patients with CLcr Less than 55 mL/min Creatinine Clearance Dose Frequency 35 to 54 mL/min Recommended dose every 8 hours or longer 11 to 34 mL/min Half of recommended dose every 12 hours 10 mL/min or less Half of recommended dose every 18 to 24 hours *All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Recommended Dosage in Pediatric Patients 1 Month of Age and Older with CLcr less than 70 mL/min The recommended dosage of Cefazolin for Injection in pediatric patients 1 month of age and older with renal impairment (CLcr less than 70 mL/min) is outlined in Table 5 below. Table 5: Recommended Dosage in Pediatric Patients 1 Month of Age and Older with CLcr Less than 70 mL/min Creatinine Clearance Recommended Dosage 40 to 70 mL/min 60% of the normal daily dose given in equally divided doses every 12 hours 20 to 40 mL/min 25% of the normal daily dose given in equally divided doses every 12 hours 5 to 20 mL/min 10% of the normal daily dose every 24 hours *All dosage recommendations apply after an initial loading dose. 2.5 Pediatric Dosage Preparation Guide Table 6: Pediatric Dosage Guide 25 mg/kg/day Divided into 3 Doses Weight 25 mg/kg/day Divided into 3 Doses Kg Approximate Single Dose mg/every 8 hours Volume (mL) needed with dilution of 136 mg/mL Dose (mL) from final concentration 40 mg/mL Dose (mL) from final concentration 30 mg/mL Dose (mL) from final concentration 20 mg/mL 4.5 40 mg 0.29 mL 1 1.3 2 Confidential Reference ID: 5498547 9 75 mg 0.55 mL 1.9 2.5 3.8 13.6 115 mg 0.85 mL 2.9 3.8 5.8 18.1 150 mg 1.1 mL 3.8 5 7.5 22.7 190 mg 1.4 mL 4.8 6.3 9.5 Table 7: Pediatric Dosage Guide 25 mg/kg/day Divided into 4 Doses Weight 25 mg/kg/day Divided into 4 Doses Kg Approximate Single Dose mg/every 6 hours Volume (mL) needed with dilution of 136 mg/mL Dose (mL) from final concentration 40 mg/mL Dose (mL) from final concentration 30 mg/mL Dose (mL) from final concentration 20 mg/mL 4.5 30 mg 0.22 mL 0.8 1 1.5 9 55 mg 0.40 mL 1.4 1.8 2.8 13.6 85 mg 0.63 mL 2.1 2.8 4.3 18.1 115 mg 0.85 mL 2.9 3.8 5.8 22.7 140 mg 1.03 mL 3.5 4.7 7 Table 8: Pediatric Dosage Guide 50 mg/kg/day Divided into 3 Doses Weight 50 mg/kg/day Divided into 3 Doses Kg Approximate Single Dose mg/every 8 hours Volume (mL) needed with dilution of 136 mg/mL Dose (mL) from final concentration 40 mg/mL Dose (mL) from final concentration 30 mg/mL Dose (mL) from final concentration 20 mg/mL 4.5 75 mg 0.55 mL 1.8 2.5 3.7 9 150 mg 1.10 mL 3.7 5 7.5 13.6 225 mg 1.65 mL 5.6 7.5 11.2 18.1 300 mg 2.21 mL 7.5 10 15 22.7 375 mg 2.76 mL 9.3 12.5 18.7 Table 9: Pediatric Dosage Guide 50 mg/kg/day Divided into 4 Doses Weight 50 mg/kg/day Divided into 4 Doses Kg Approximate Single Dose mg/every 6 hours Volume (mL) needed with dilution of 136 mg/mL Dose (mL) from final concentration 40 mg/mL Dose (mL) from final concentration 30 mg/mL Dose (mL) from final concentration 20 mg/mL 4.5 55 mg 0.40 mL 1.4 1.8 2.8 9 110 mg 0.81 mL 2.8 3.7 5.5 13.6 170 mg 1.25 mL 4.3 5.7 8.5 18.1 225 mg 1.65 mL 5.6 7.5 11.3 22.7 285 mg 2.10 mL 7.1 9.5 14.3 2.6 Preparation of Cefazolin for Injection Parenteral drug products should be inspected visually for particulate matter and discoloration Confidential Reference ID: 5498547 prior to administration, whenever solution and container permit. If particulate matter is evident in reconstituted fluids, the drug solutions should be discarded. Reconstituted solutions may range in color from pale yellow to yellow. Reconstitution and Dilution Intravenous Bolus Injection Administration (2g Vial only) For preparation of intravenous bolus injection (2 grams/vial only) use the following steps: • Reconstitute Cefazolin for Injection, 2 grams/vial single-dose vials with Sterile Water for Injection according to Table 10 below. Shake well until dissolved. • Further dilute vials with an additional 11 mL Sterile Water for Injection and shake well. • Inject the solution intravenously slowly, directly, or through tubing for patients receiving parenteral fluids as follows: o For 1 g dose, inject the solution intravenously slowly over 3 to 5 minutes and o For 2 g dose, inject the solution intravenously slowly over 7 to 11 minutes Table 10: Volume and Concentration for Intravenous Bolus Injection Reconstitution (2 g vial only) Cefazolin for Injection Vial Contents Amount of Sterile Water for Injection for Reconstitution Approximate Reconstituted Concentration Approximate Available Volume 2 grams 5.5 mL 333 mg/mL 6.6 mL Pain associated with intravenous bolus administration has been reported with Cefazolin for Injection. Intermittent or Continuous Intravenous Infusion For intermittent or continuous intravenous infusion, reconstitute Cefazolin for Injection single-dose vials with Sterile Water for Injection according to Table 11 below and shake well. After reconstitution further dilute according to Table 11 using the following diluents: For intermittent or continuous intravenous infusion: Dilute reconstituted Cefazolin for Injection in one of the following solutions: • Sodium Chloride Injection, USP • 5% Dextrose Injection, USP Discard unused portion. Confidential Reference ID: 5498547 Table 11: Volumes for Reconstitution and Dilution and Final Concentrations for Intermittent or Continuous Intravenous Infusion Cefazolin for Injection Vial Contents Amount of Sterile Water for Injection for Reconstitution Approximate Reconstituted Concentrations Recommended Diluent Volume Approximate Final Concentrations 2 grams 15 mL 136 mg/mL 50 mL or 100 mL 40 mg/mL or 20 mg/mL 3 grams 15 mL 196 mg/mL 100 mL 30 mg/mL Storage of Reconstituted and Diluted Solutions When reconstituted or diluted according to the instructions above, Cefazolin for Injection is stable for 24 hours at room temperature or for 7 days if stored under refrigeration at 2°C to 8°C (36°F to 46°F). 3 DOSAGE FORMS AND STRENGTHS Cefazolin for Injection is available as 2 grams or 3 grams of cefazolin as a white to off-white crystalline powder in single-dose vial for reconstitution. 4 CONTRAINDICATIONS Cefazolin for Injection is contraindicated in patients who have a history of immediate hypersensitivity reactions (e.g., anaphylaxis, serious skin reactions) to cefazolin or the cephalosporin class of antibacterial drugs, penicillins, or other beta-lactams [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions to Cefazolin, Cephalosporins, Penicillins, or Other Beta-lactams Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with Cefazolin for Injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefazolin, cephalosporins, penicillins, or carbapenems. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibacterial drugs has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Cefazolin for Injection occurs, discontinue the drug. 5.2 Seizures in Patients with Renal Impairment Seizures may occur with the administration of Cefazolin for Injection, particularly in patients with renal impairment when the dosage is not reduced appropriately. Discontinue Confidential Reference ID: 5498547 Cefazolin for Injection if seizures occur or make appropriate dosage adjustments in patients with renal impairment [see Dosage and Administration (2.4)]. Anticonvulsant therapy should be continued in patients with known seizure disorders. 5.3 Clostridioides difficile-Associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefazolin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.4 Risk of Development of Drug-resistant Bacteria Prescribing Cefazolin for Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Prolonged use of Cefazolin for Injection may result in the overgrowth of nonsusceptible organisms. Careful clinical observation of the patient is essential. 5.5 Prothrombin Activity Cefazolin for Injection may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. 5.6 Drug/Laboratory Test Interactions Urinary Glucose A false positive reaction for glucose in the urine may occur with Benedict’s solution, Fehling’s solution or with CLINITEST® tablets, but not with enzyme-based tests such as CLINISTIX®. Coombs Test Positive direct and indirect antiglobulin (Coombs) tests have occurred; these may also occur in neonates whose mothers received cephalosporins before delivery. Confidential Reference ID: 5498547 6 ADVERSE REACTIONS The following clinically significant adverse reactions to cefazolin for injection are described below and elsewhere in the labeling: • Hypersensitivity reactions to Cefazolin, Cephalosporins, Penicillins, or Other Beta­ lactams [see Warnings and Precautions (5.1)] • Seizures in Patients with Renal Impairment [see Warnings and Precautions (5.2)] • Clostridioides difficile-associated Diarrhea [see Warnings and Precautions (5.3)] • Prothrombin Activity [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following reactions have been reported: Gastrointestinal: Diarrhea, oral candidiasis (oral thrush), vomiting, nausea, stomach cramps, anorexia and Clostridioides difficile colitis. Onset of Clostridioides difficile colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.3)]. Allergic: Anaphylaxis, eosinophilia, itching, drug fever, skin rash, Stevens-Johnson syndrome. Hematologic: Neutropenia, leukopenia, thrombocytopenia, thrombocythemia. Hepatic: Transient rise in serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and alkaline phosphatase levels has been observed. Reports of hepatitis have been received. Renal: Reports of increased BUN and creatinine levels, as well as renal failure, have been received. Local Reactions: Instances of phlebitis have been reported at site of injection. Some induration has occurred. Other Reactions: Pruritus (including genital, vulvar and anal pruritus, genital moniliasis, and vaginitis). 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of cefazolin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Serum sickness-like reaction Renal and urinary disorders: Acute tubulointerstitial nephritis (ATIN) Skin and subcutaneous tissue disorders: Acute generalized exanthematous pustulosis (AGEP) 6.3 Cephalosporin-class Adverse Reactions In addition to the adverse reactions listed above that have been observed in patients treated with cefazolin, the following adverse reactions and altered laboratory tests have been Confidential Reference ID: 5498547 reported for cephalosporin-class antibacterials: Erythema multiforme, toxic epidermal necrolysis, renal impairment, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, a fall in prothrombin activity, hepatic impairment including cholestasis, and pancytopenia. 7 DRUG INTERACTIONS The renal excretion of cefazolin is inhibited by probenecid. Co-administration of probenecid with Cefazolin for Injection is not recommended. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published prospective cohort studies, case series and case reports over several decades with cefazolin use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. These studies have methodologic limitations, including small sample size, retrospective study design, and inconsistent comparator groups. Cefazolin crosses the placenta. Animal reproduction studies performed in rats, mice and rabbits administered cefazolin during organogenesis at doses 1 to 3 times the maximum recommended human dose (MRHD) did not demonstrate adverse developmental outcomes. In rats subcutaneously administered cefazolin prior to delivery and throughout lactation, there were no adverse effects on offspring at a dose approximately 2 times the MRHD (see Data) The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Reproduction studies have been performed in rats, mice and rabbits administered cefazolin subcutaneously during organogenesis at doses of 2000, 2400 and 240 mg/kg/day (approximately 1 to 3 times the maximum recommended human dose on a body surface area comparison). There was no evidence of any adverse effects on embryofetal development due to cefazolin. In a peri-postnatal study in rats, cefazolin administered subcutaneously up to 1200 mg/kg/day (approximately 2 times the MRHD based on body surface area comparison) to pregnant dams prior to delivery and through lactation caused no adverse effects on offspring. Confidential Reference ID: 5498547 8.2 Lactation Risk Summary Data from published literature report that cefazolin is present in human milk but is not expected to accumulate in a breastfed infant. There are no data on the effects of cefazolin on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Cefazolin for Injection and any potential adverse effects on the breastfed child from Cefazolin for Injection or from the underlying maternal condition. 8.4 Pediatric Use Cefazolin for Injection is indicated for the treatment of respiratory tract infections, urinary tract infections, skin and skin structure infections, biliary tract infections, bone and joint infections, genital infections, septicemia, and endocarditis in pediatric patients 1 month of age and older for whom appropriate dosing with this formulation can be achieved [see Indications and Usage (1.1 to 1.8) and Dosage and Administration (2.2)]. Safety and effectiveness of Cefazolin for Injection in premature infants and neonates have not been established. 8.5 Geriatric Use Of the 920 subjects who received cefazolin for injection in clinical studies, 313 (34%) were 65 years and over, while 138 (15%) were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)]. 8.6 Renal Impairment When Cefazolin for Injection is administered to patients with low urinary output because of impaired renal function, lower daily dosage is required [see Dosage and Administration (2.4)]. 10 OVERDOSAGE Accidental overdosage resulting in seizures may occur in patients with renal impairment who receive doses greater than the recommended dosage of Cefazolin for Injection [see Warnings and Precautions (5.2)]. If seizures associated with accidental overdosage occur, discontinue Cefazolin for Injection and give supportive treatment. 11 DESCRIPTION Cefazolin for Injection contains cefazolin sodium, a semi-synthetic cephalosporin. It is the Confidential Reference ID: 5498547 sodium salt of 3-{[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-methyl}-8-oxo-7-[2-(1H-tetrazol-1­ yl) acetamido]-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid. The molecular formula is C14H13N8NaO4S3 and molecular weight is 476.49. Structural Formula: Cefazolin for Injection is supplied as a sterile powder in single-dose vials. The 2 g/vial Cefazolin for Injection contains 2 grams of cefazolin (equivalent to 2.097 g of cefazolin sodium). The 3 g/vial Cefazolin for Injection contains 3 grams of cefazolin (equivalent to 3.144 grams of cefazolin sodium). The 2 g/vial Cefazolin for Injection contains 96 mg of sodium. The 3 g/vial Cefazolin for Injection contains 144 mg of sodium. After reconstitution with sterile water for injection, the drug product solution has a pH of 4.0 to 6.0. Cefazolin for Injection, 2 grams/vial, is intended for intravenous infusion or intravenous bolus injection. Cefazolin for Injection, 2 grams/vial is not for intramuscular administration. Cefazolin for Injection, 3 grams/vial, is intended for intravenous infusion only. Cefazolin for Injection, 3 grams/vial is not for intravenous bolus injection or intramuscular administration in adult or pediatric patients [see Dosage and Administration (2.1, 2.2,2.3)]. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Cefazolin is an antibacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics The pharmacokinetic/pharmacodynamic relationship for cefazolin has not been evaluated in patients. 12.3 Pharmacokinetics Studies have shown that following intravenous administration of cefazolin for injection to normal volunteers, mean serum concentrations peaked at approximately 185 mcg/mL and were approximately 4 mcg/mL at 8 hours for a 1-gram dose. In a study (using normal volunteers) of constant intravenous infusion with dosages of 3.5 mg/kg for 1 hour (approximately 250 mg) and 1.5 mg/kg the next 2 hours (approximately 100 mg), cefazolin for injection produced a steady serum level at the third hour of approximately 28 mcg/mL. Studies in patients hospitalized with infections indicate that cefazolin for injection produces Confidential Reference ID: 5498547 mean peak serum levels approximately equivalent to those seen in normal volunteers. Distribution Bile levels in patients without obstructive biliary disease can reach or exceed serum levels by up to five times; however, in patients with obstructive biliary disease, bile levels of cefazolin for injection are considerably lower than serum levels (< 1 mcg/mL). In synovial fluid, the level of cefazolin for injection becomes comparable to that reached in serum at about 4 hours after drug administration. Studies of cord blood show prompt transfer of cefazolin for injection across the placenta. Cefazolin for injection is present in very low concentrations in the milk of nursing mothers. Elimination The serum half-life for cefazolin for injection is approximately 1.8 hours following IV administration. Excretion Cefazolin for injection is excreted unchanged in the urine. In the first 6 hours approximately 60% of the drug is excreted in the urine and this increases to 70% to 80% within 24 hours. Specific Populations Patients with Renal Impairment In patients undergoing peritoneal dialysis (2 L/hr.), cefazolin for injection produced mean serum levels of approximately 10 and 30 mcg/mL after 24 hours’ instillation of a dialyzing solution containing 50 mg/L and 150 mg/L, respectively. Mean peak levels were 29 mcg/mL (range 13 to 44 mcg/mL) with 50 mg/L (3 patients), and 72 mcg/mL (range 26 to 142 mcg/mL) with 150 mg/L (6 patients). 12.4 Microbiology Mechanism of Action Cefazolin is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Resistance Predominant mechanisms of bacterial resistance to cephalosporins include the presence of extended-spectrum beta-lactamases and enzymatic hydrolysis. Methicillin-resistant staphylococci are uniformly resistant to cefazolin. Most isolates of indole positive Proteus (Proteus vulgaris), Enterobacter spp. (including Klebsiella aerogenes), Morganella morganii, Providencia rettgeri, Serratia spp., and Pseudomonas spp. are resistant to cefazolin. Antimicrobial Activity Cefazolin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]: Aerobic bacteria Confidential Reference ID: 5498547 Gram-positive bacteria Staphylococcus aureus (methicillin susceptible) Staphylococcus epidermidis (methicillin susceptible) Group A beta-hemolytic streptococci Streptococcus pneumoniae Streptococcus species Gram-negative bacteria Escherichia coli Hemophilus influenzae Klebsiella species Proteus mirabilis Susceptibility Test Methods For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity and Mutagenesis Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of Cefazolin for Injection have not been performed. Impairment of Fertility Fertility studies conducted in rats subcutaneously administered cefazolin at doses of 2000 mg/kg/day (approximately 3 times the maximum recommended human dose based on body surface area comparison) showed no impairment of mating and fertility. 16 HOW SUPPLIED/STORAGE AND HANDLING Cefazolin for Injection is available as 2 grams or 3 grams of cefazolin as a white to off- white crystalline powder in single-dose vial for reconstitution. Cefazolin for Injection, USP Packaged NDC No. 2 grams/vial Carton of 25 vials 0143-9139-25 3 grams/vial Carton of 25 vials 0143-9140-25 Before reconstitution protect from light and store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Storage conditions for reconstituted and diluted solutions of Cefazolin for Injection are described in another section of labeling [see Dosage and Administration (2.6)]. Confidential Reference ID: 5498547 17 PATIENT COUNSELING INFORMATION Serious Allergic Reactions Advise patients that allergic reactions, including serious allergic reactions could occur and that serious reactions require immediate treatment and discontinuation of Cefazolin for Injection. Patients should report to their health care provider any previous allergic reactions to cefazolin, cephalosporins, penicillins, or other similar antibacterials [see Warnings and Precautions (5.1)]. Seizures Advise patients that seizures could occur with Cefazolin for Injection. Instruct patients to inform a healthcare provider at once of any signs and symptoms of seizures, for immediate treatment, dosage adjustment, or discontinuation of Cefazolin for Injection [see Warnings and Precautions (5.2)]. Diarrhea Advise patients that diarrhea is a common problem caused by antibacterials, which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterials. If this occurs, patients should contact a physician as soon as possible [see Warnings and Precautions (5.3)]. Antibacterial Resistance Patients should be counseled that antibacterial drugs including Cefazolin for Injection, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefazolin for Injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefazolin for Injection or other antibacterial drugs in the future [see Warnings and Precautions (5.4)]. Manufactured by HIKMA FARMACÊUTICA (PORTUGAL), S.A. Estrada do Rio da Mó, 8, 8A e 8B – Fervença – 2705-906 Terrugem SNT, PORTUGAL Distributed by Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 CLINITEST is a registered trademark of Miles, Inc. CLINISTIX is a registered trademark of Bayer Corporation. PIN609-WES/3 Confidential Reference ID: 5498547
custom-source
2025-02-12T15:47:56.501901
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use IDHIFA safely and effectively. See full prescribing information for IDHIFA. IDHIFA® (enasidenib) tablets, for oral use Initial U.S. Approval: 2017 WARNING: DIFFERENTIATION SYNDROME See full prescribing information for complete boxed warning. Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution (5.1, 6.1). ---------------------------INDICATIONS AND USAGE---------------------------­ IDHIFA is an isocitrate dehydrogenase-2 inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA- approved test (1.1). -----------------------DOSAGE AND ADMINISTRATION----------------------­ 100 mg orally once daily until disease progression or unacceptable toxicity (2.2). ----------------------DOSAGE FORMS AND STRENGTHS--------------------­ Tablets: 50 mg or 100 mg (3). -------------------------------CONTRAINDICATIONS-----------------------------­ None (4). -----------------------WARNINGS AND PRECAUTIONS----------------------­ Embryo-Fetal Toxicity: IDHIFA can cause fetal harm. Advise patients of the potential risk to a fetus and use effective contraception (5.2, 8.1, 8.3). -------------------------------ADVERSE REACTIONS-----------------------------­ The most common adverse reactions (≥20%) are nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Bristol Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS-----------------------------­ • Certain CYP1A2 and CYP2C19 Substrates: Avoid concomitant use unless otherwise recommended in the Prescribing Information (7.1). • Certain CYP3A Substrates: Avoid concomitant use unless otherwise recommended in the Prescribing Information (7.1). • Certain OATP1B1, OATP1B3, and BCRP Substrates: Avoid concomitant use unless otherwise recommended in the Prescribing Information (7.1). --------------------------USE IN SPECIFIC POPULATIONS--------------------­ Lactation: Advise not to breastfeed (8.2). See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: DIFFERENTIATION SYNDROME 1 INDICATIONS AND USAGE 1.1 Acute Myeloid Leukemia 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Recommended Dosage 2.3 Monitoring and Dosage Modifications for Toxicities 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Differentiation Syndrome 5.2 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effect of IDHIFA on Other Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Acute Myeloid Leukemia 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID: 5498174 FULL PRESCRIBING INFORMATION WARNING: DIFFERENTIATION SYNDROME Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, and hepatic, renal, or multi- organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. 1 INDICATIONS AND USAGE 1.1 Acute Myeloid Leukemia IDHIFA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA- approved test. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients for the treatment of AML with IDHIFA based on the presence of IDH2 mutations in the blood or bone marrow [see Indications and Usage (1.1) and Clinical Studies (14.1)]. Information on FDA-approved tests for the detection of IDH2 mutations in AML is available at http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage The recommended dosage of IDHIFA is 100 mg taken orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response. Swallow tablets whole. Do not chew, split, or crush IDHIFA tablets. Administer IDHIFA tablets orally about the same time each day. If a dose of IDHIFA is vomited, missed, or not taken at the usual time, administer the dose as soon as possible on the same day, and return to the normal schedule the following day. 2.3 Monitoring and Dosage Modifications for Toxicities Assess blood counts and blood chemistries for leukocytosis and tumor lysis syndrome prior to the initiation of IDHIFA and monitor at a minimum of every 2 weeks for at least the first 3 months during treatment. Manage any abnormalities promptly [see Adverse Reactions (6.1)]. Interrupt dosing or reduce dose for toxicities. See Table 1 for dosage modification guidelines. 1 Reference ID: 5498174 Table 1: Dosage Modifications for IDHIFA-Related Toxicities Adverse Reaction Recommended Action • Differentiation syndrome • If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring [see Warnings and Precautions (5.1)]. • Interrupt IDHIFA if severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids [see Warnings and Precautions (5.1)]. • Resume IDHIFA when signs and symptoms improve to Grade 2* or lower. • Noninfectious leukocytosis (white blood cell • Initiate treatment with hydroxyurea, as per [WBC] count greater than 30 x 109/L) standard institutional practices. • Interrupt IDHIFA if leukocytosis is not improved with hydroxyurea, and then resume IDHIFA at 100 mg daily when WBC is less than 30 x 109/L. • Elevation of bilirubin greater than 3 times the upper limit of normal (ULN) sustained for ≥2 weeks without elevated transaminases or other hepatic disorders • Reduce IDHIFA dose to 50 mg daily. • Resume IDHIFA at 100 mg daily if bilirubin elevation resolves to less than 2 x ULN. • Other Grade 3* or higher toxicity considered • Interrupt IDHIFA until toxicity resolves to Grade related to treatment including tumor lysis syndrome 2* or lower. • Resume IDHIFA at 50 mg daily; may increase to 100 mg daily if toxicities resolve to Grade 1* or lower. • If Grade 3* or higher toxicity recurs, discontinue IDHIFA. *Grade 1 is mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening. 3 DOSAGE FORMS AND STRENGTHS IDHIFA is available in the following tablet strengths: • 50 mg enasidenib tablet: Pale yellow to yellow oval-shaped film-coated tablet debossed “ENA” on one side and “50” on the other side. • 100 mg enasidenib tablet: Pale yellow to yellow capsule-shaped film-coated tablet debossed “ENA” on one side and “100” on the other side. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Differentiation Syndrome In the clinical trial, 14% of patients treated with IDHIFA experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. While there is no diagnostic test for differentiation syndrome, symptoms in patients treated with IDHIFA included acute respiratory 2 Reference ID: 5498174 distress represented by dyspnea and/or hypoxia (68%) and need for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever (36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid weight gain (21%); and pericardial effusion (18%). Hepatic, renal, and multi-organ dysfunction have also been observed. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, in as early as 1 day and up to 5 months after IDHIFA initiation. If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt IDHIFA until signs and symptoms are no longer severe [see Dosage and Administration (2.3)]. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended. 5.2 Embryo-Fetal Toxicity Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. In animal embryo-fetal toxicity studies, enasidenib caused embryo-fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area under the concentration-time curve (AUC) at the recommended human dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with IDHIFA and for 2 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for 2 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Differentiation Syndrome [see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety evaluation of single-agent IDHIFA is based on 214 patients with relapsed or refractory AML who were assigned to receive 100 mg daily [see Clinical Studies (14.1)]. The median duration of exposure to IDHIFA was 4.3 months (range 0.3 to 23.6). The 30-day and 60-day mortality rates observed with IDHIFA were 4.2% (9/214) and 11.7% (25/214), respectively. Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation 3 Reference ID: 5498174 syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure. Overall, 92 of 214 patients (43%) required a dose interruption due to an adverse reaction; the most frequent adverse reactions leading to dose interruption were differentiation syndrome (4%) and leukocytosis (3%). Ten of 214 patients (5%) required a dose reduction due to an adverse reaction; no adverse reaction required dose reduction in more than 2 patients. Thirty-six of 214 patients (17%) permanently discontinued IDHIFA due to an adverse reaction; the most frequent adverse reaction leading to permanent discontinuation was leukocytosis (1%). The most common adverse reactions (≥20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin and decreased appetite. Adverse reactions reported in the trial are shown in Table 2. Table 2: Adverse Reactions Reported in ≥10% (Any Grade) or ≥3% (Grade 3-5) of Patients with Relapsed or Refractory AML IDHIFA (100 mg daily) N=214 Body System Adverse Reaction All Grades N=214 n (%) ≥Grade 3 N=214 n (%) Gastrointestinal Disordersa Nausea 107 (50) 11 (5) Diarrhea 91 (43) 17 (8) Vomiting 73 (34) 4 (2) Metabolism and Nutrition Disorders Decreased appetite 73 (34) 9 (4) Tumor lysis syndromeb 13 (6) 12 (6) Blood and Lymphatic System Disorders Differentiation syndromec 29 (14) 15 (7) Noninfectious leukocytosis 26 (12) 12 (6) Nervous System Disorders Dysgeusia 25 (12) 0 (0) a Gastrointestinal disorders observed with IDHIFA treatment can be associated with other commonly reported events such as abdominal pain, and weight decreased. b Tumor lysis syndrome observed with IDHIFA treatment can be associated with commonly reported uric acid increased. c Differentiation syndrome can be associated with other commonly reported events such as respiratory failure, dyspnea, hypoxia, pyrexia, peripheral edema, rash, or renal insufficiency. Other clinically significant adverse reactions occurring in <10% of patients included: • Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary edema, acute respiratory distress syndrome 4 Reference ID: 5498174 Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in Table 3. Table 3: Most Common (≥20%) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AML IDHIFA (100 mg daily) N=214 Parametera All Grades (%) Grade ≥3 (%) Total bilirubin increased 81 15 Calcium decreased 74 8 Potassium decreased 41 15 Phosphorus decreased 27 8 a Includes abnormalities occurring up to 28 days after last IDHIFA dose, if new or worsened by at least one grade from baseline, or if baseline was unknown. The denominator varies based on data collected for each parameter (N=213 except phosphorous N=209). Elevated Bilirubin IDHIFA may interfere with bilirubin metabolism through inhibition of UGT1A1 [see Clinical Pharmacology (12.3)]. Thirty-seven percent of patients (80/214) experienced total bilirubin elevations ≥2 x ULN at least one time. Of those patients who experienced total bilirubin elevations ≥2 x ULN, 35% had elevations within the first month of treatment, and 89% had no concomitant elevation of transaminases or other severe adverse events related to liver disorders. No patients required a dose reduction for hyperbilirubinemia; treatment was interrupted in 3.7% of patients, for a median of 6 days. Three patients (1.4%) discontinued IDHIFA permanently due to hyperbilirubinemia. Noninfectious Leukocytosis IDHIFA can induce myeloid proliferation resulting in a rapid increase in white blood cell count. Tumor Lysis Syndrome IDHIFA can induce myeloid proliferation resulting in a rapid reduction in tumor cells which may pose a risk for tumor lysis syndrome. Other Clinical Trials Experience The following adverse reactions occurred in other clinical trials of IDHIFA at the recommended dosage: neutropenia, thrombocytopenia, anemia, stomatitis, renal failure, fatigue, dyspnea, and QT prolongation. 5 Reference ID: 5498174 7 DRUG INTERACTIONS 7.1 Effect of IDHIFA on Other Drugs Certain CYP1A2 Substrates Avoid concomitant use with IDHIFA unless otherwise recommended in the Prescribing Information for CYP1A2 substrates where minimal concentration changes may lead to serious adverse reactions. Consider reducing the frequency of caffeine intake from various food and beverages in a 24 hour period while taking IDHIFA because IDHIFA may increase the effect of caffeine in patients who are sensitive to it. Enasidenib is a CYP1A2 inhibitor. Concomitant use of IDHIFA increases the exposure of CYP1A2 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to the substrates. Certain CYP2C19 substrates Avoid concomitant use with IDHIFA unless otherwise recommended in the Prescribing Information for CYP2C19 substrates where minimal concentration changes may lead to serious adverse reactions. Enasidenib is a CYP2C19 inhibitor. Concomitant use of IDHIFA increases the exposure of CYP2C19 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. Certain CYP3A substrates Avoid concomitant use with IDHIFA unless otherwise recommended in the Prescribing Information for CYP3A substrates where minimal concentration changes may lead to reduced efficacy. Do not administer IDHIFA with anti-fungal agents that are substrates of CYP3A due to expected loss of antifungal efficacy. Co-administration of IDHIFA may decrease the concentrations of hormonal contraceptives. Consider alternative methods of contraception in patients receiving IDHIFA [See use in Specific Population (8.1, 8.3)]. Enasidenib is a CYP3A inducer. Concomitant use of IDHIFA decreases the exposure of CYP3A substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of the substrates. Certain OATP1B1, OATP1B3, and BCRP Substrates Avoid coadministration of IDHIFA with OATP1B1, OATP1B3, and BCRP substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the OATP1B1, OATP1B3, and BCRP substrates dosage(s) in accordance with the respective Prescribing Information. Enasidenib is an OATP1B1, OATP1B3, and BCRP transporter inhibitor. Concomitant use of IDHIFA increases the exposure of OATP1B1, OATP1B3, and BCRP substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates. 6 Reference ID: 5498174 Certain P-glycoprotein (P-gp) Substrates When coadministered with IDHIFA, follow recommended P-gp substrates Prescribing Information and monitor more frequently for adverse reactions related to these substrates. Enasidenib is a P-gp transporter inhibitor. Concomitant use of IDHIFA increases the exposure of P-gp substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to the substrates. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on animal embryo-fetal toxicity studies, IDHIFA can cause fetal harm when administered to a pregnant woman. There are no available data on IDHIFA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of enasidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 0.1 times the steady state clinical exposure based on the AUC at the recommended human dose (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data Enasidenib administered to pregnant rats at a dose of 30 mg/kg twice daily during organogenesis (gestation days 6-17) was associated with maternal toxicity and adverse embryo-fetal effects including post-implantation loss, resorptions, decreased viable fetuses, lower fetal birth weights, and skeletal variations. These effects occurred in rats at approximately 1.6 times the clinical exposure at the recommended human daily dose of 100 mg/day. In pregnant rabbits treated during organogenesis (gestation days 7-19), enasidenib was maternally toxic at doses equal to 5 mg/kg/day or higher (exposure approximately 0.1 to 0.6 times the steady state clinical exposure at the recommended daily dose) and caused spontaneous abortions at 5 mg/kg/day (exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose). 8.2 Lactation Risk Summary There are no data on the presence of enasidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with IDHIFA and for 2 months after the last dose. 7 Reference ID: 5498174 8.3 Females and Males of Reproductive Potential Based on animal embryo-fetal toxicity studies, IDHIFA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to starting IDHIFA. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with IDHIFA and for 2 months after the last dose. Coadministration of IDHIFA may decrease the concentrations of combined hormonal contraceptives. Advise patients using hormonal contraceptives to use an effective non-hormonal contraceptive method during treatment with IDHIFA and for 2 months after the last dose [see Drug Interactions (7.1)]. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for 2 months after the last dose of IDHIFA. Infertility Based on findings in animals, IDHIFA may impair fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness of IDHIFA in pediatric patients have not been established. 8.5 Geriatric Use No dosage adjustment is required for IDHIFA based on age. In the clinical study, 61% of 214 patients were aged 65 years or older, while 24% were older than 75 years. No overall differences in effectiveness or safety were observed between patients aged 65 years or older and younger patients. 11 DESCRIPTION Enasidenib is an inhibitor of isocitrate dehydrogenase-2 (IDH2) enzyme. Enasidenib is available as the mesylate salt with the chemical name: 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4­ yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate. Or 2-Propanol, 2-methyl-1-[[4-[6-(trifluoromethyl)-2-pyridinyl]-6-[[2-(trifluoromethyl)-4­ pyridinyl]amino-1,3,5-triazin-2-yl]amino]-, methanesulfonate (1:1). The chemical structure is: 8 Reference ID: 5498174 CF3 N CF3 CH3SO3H N N N N N N OH H H The empirical formula is C19H17F6N7O • CH3SO3H (C20H21F6N7O4S), and the molecular weight is 569.48 g/mol. Enasidenib is practically insoluble (solubility ≤74 mcg/mL) in aqueous solutions across physiological pH range (pH 1.2 and 7.4). IDHIFA (enasidenib) is available as a 50 mg tablet (equivalent to 60 mg enasidenib mesylate) and a 100 mg tablet (equivalent to 120 mg enasidenib mesylate) for oral administration. Each tablet contains inactive ingredients of colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose acetate succinate, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, sodium starch glycolate, talc, and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Enasidenib is a small molecule inhibitor of the isocitrate dehydrogenase 2 (IDH2) enzyme. Enasidenib targets the mutant IDH2 variants R140Q, R172S, and R172K at approximately 40-fold lower concentrations than the wild-type enzyme in vitro. Inhibition of the mutant IDH2 enzyme by enasidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH2 mutated AML. In blood samples from patients with AML with mutated IDH2, enasidenib decreased 2-HG levels, reduced blast counts and increased percentages of mature myeloid cells. 12.2 Pharmacodynamics Cardiac Electrophysiology The potential for QTc prolongation with enasidenib was evaluated in an open-label study in patients with advanced hematologic malignancies with an IDH2 mutation. No large mean changes in the QTc interval (>20 ms) were observed following treatment with enasidenib. 12.3 Pharmacokinetics The peak plasma concentration (Cmax) is 1.4 mcg/mL [coefficient of variation (CV%) 50%] after a single dose of 100 mg, and 13.1 mcg/mL (CV% 45%) at steady state for 100 mg daily. The area under concentration time curve (AUC) of enasidenib increases in an approximately dose proportional manner from 50 mg (0.5 times approved recommended dosage) to 450 mg (4.5 times approved recommended dosage) daily dose. Steady-state plasma levels are reached within 29 days of once-daily dosing. Accumulation is approximately 10-fold when administered once daily. 9 Reference ID: 5498174 Absorption The absolute bioavailability after 100 mg oral dose of enasidenib is approximately 57%. After a single oral dose, the median time to Cmax (Tmax) is 4 hours. Distribution The mean volume of distribution (Vd) of enasidenib is 55.8 L (CV% 29). Human plasma protein binding of enasidenib is 98.5% and of its metabolite AGI-16903 is 96.6% in vitro. Elimination Enasidenib has a terminal half-life of 7.9 days and a mean total body clearance (CL/F) of 0.70 L/hour (CV% 62.5). Metabolism Enasidenib accounted for 89% of the radioactivity in circulation and AGI-16903, the N-dealkylated metabolite, represented 10% of the circulating radioactivity. Metabolism of enasidenib is mediated by multiple cytochrome P450 (CYP) enzymes (e.g., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and by multiple UDP glucuronosyl transferases (UGTs) (e.g., UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15) in vitro. Further metabolism of the metabolite AGI-16903 is also mediated by multiple enzymes (e.g., CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9) in vitro. Excretion Eighty-nine percent (89%) of enasidenib is eliminated in feces and 11% in the urine. Excretion of unchanged enasidenib accounts for 34% of the radiolabeled drug in the feces and 0.4% in the urine. Specific Populations No clinically meaningful effect on the pharmacokinetics of enasidenib was observed for the following covariates: age (19 years to 100 years), race (White, Black, or Asian), mild hepatic impairment [defined as total bilirubin ≤ upper limit of normal (ULN) and aspartate transaminase (AST) >ULN or total bilirubin 1 to 1.5 times ULN and any AST], renal impairment (defined as creatinine clearance ≥30 mL/min by Cockcroft-Gault formula), sex, body weight (39 kg to 136 kg), and body surface area. Drug Interaction Studies Clinical Studies CYP1A2 Substrates: Caffeine (a sensitive CYP1A2 substrate) AUC0-INF and Cmax increased by 655% and 18%, respectively, following concomitant use of multiple doses of IDHIFA 100 mg with a single oral dose of 100 mg caffeine. CYP2C19 substrates: Omeprazole (a sensitive CYP2C19 substrate) AUC0-INF and Cmax increased by 86% and 47%, respectively, following concomitant use of multiple doses of IDHIFA 100 mg with a single oral dose of omeprazole 40 mg. 10 Reference ID: 5498174 CYP2D6 substrates: Dextromethorphan (a sensitive CYP2D6 substrate) AUC0-INF and Cmax increased by 37% and 24% respectively, following concomitant use of multiple doses of IDHIFA 100 mg with a single oral dose of dextromethorphan 30 mg. CYP3A substrates: Midazolam (a sensitive CYP3A substrate) AUC0-INF and Cmax decreased by 43% and 23%, respectively, following concomitant use of multiple doses of IDHIFA 100 mg with a single intravenous dose of midazolam 0.03 mg/kg. The decrease in midazolam exposure following oral administration of midazolam is expected to be larger than that following intravenous administration of midazolam. This is due to induction of CYP3A4 first pass metabolism by enasidenib and the reduced bioavailability of the midazolam oral formulation compared to the midazolam intravenous formulation. CYP2C9 and CYP2C8 substrates: Coadministration of multiple doses of IDHIFA 100 mg did not have clinically significant effect on the exposure of flurbiprofen (a CYP2C9 substrate) or pioglitazone (a CYP2C8 substrate). OATP1B1, OATP1B3, and BCRP Substrates: Rosuvastatin (an OATP1B1, OATP1B3, and BCRP substrate) AUC0-INF and Cmax increased by 244% and 366%, respectively, following concomitant use of multiple doses of IDHIFA 100 mg with a single oral dose of rosuvastatin 10 mg. P-gp Substrates: Digoxin (a P-gp Substrate) AUC0-30h and Cmax increased by 20% and 26%, respectively, following concomitant use of multiple doses of IDHIFA 100 mg with a single oral dose of digoxin 0.25 mg. In Vitro Studies CYP and UGT Enzymes: Enasidenib inhibits CYP2B6 and UGT1A1. The metabolite AGI-16903 inhibits CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Enasidenib induces CYP2B6. Transporter Systems: Enasidenib is not a substrate for P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). AGI-16903 is a substrate of both P-gp and BCRP. Enasidenib and AGI-16903 are not substrates of multidrug resistance-associated protein 2 (MRP2), organic anion transporter 1 (OAT1), OAT3, organic anion transporter family member 1B1 (OATP1B1), OATP1B3, and organic cation transporter 2 (OCT2). Enasidenib inhibits OAT1 and OCT2, but not MRP2 or OAT3. AGI-16903 inhibits BCRP, OAT1, OAT3, OATP1B1, and OCT2, but not P-gp, MRP2, or OATP1B3. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with enasidenib. Enasidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Enasidenib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay, or in an in vivo rat bone marrow micronucleus assay. 11 Reference ID: 5498174 Fertility studies in animals have not been conducted with enasidenib. In repeat-dose toxicity studies with twice daily oral administration of enasidenib in rats up to 90-days in duration, changes were reported in male and female reproductive organs including seminiferous tubular degeneration, hypospermia, atrophy of the seminal vesicle and prostate, decreased corpora lutea and increased atretic follicles in the ovaries, and atrophy in the uterus. 14 CLINICAL STUDIES 14.1 Acute Myeloid Leukemia The efficacy of IDHIFA was evaluated in an open-label, single-arm, multicenter, two-cohort clinical trial (Study AG221-C-001, NCT01915498) of 199 adult patients with relapsed or refractory AML and an IDH2 mutation, who were assigned to receive 100 mg daily dose. Cohort 1 included 101 patients and Cohort 2 included 98 patients. IDH2 mutations were identified by a local diagnostic test and retrospectively confirmed by the Abbott RealTime IDH2 assay, or prospectively identified by the Abbott RealTime IDH2 assay, which is the FDA-approved test for selection of patients with AML for treatment with IDHIFA. IDHIFA was given orally at starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage adverse events. The baseline demographic and disease characteristics are shown in Table 4. The baseline demographics and disease characteristics were similar in both study cohorts. Table 4: Baseline Demographic and Disease Characteristics in Patients with Relapsed or Refractory AML Demographic and Disease Characteristics IDHIFA (100 mg daily) N=199 Demographics Age (Years) Median (Min, Max) 68 (19, 100) Age Categories, n (%) <65 years ≥65 years to <75 years ≥75 years 76 (38) 74 (37) 49 (25) Sex, n (%) Male Female 103 (52) 96 (48) Race, n (%) White Black Asian Native Hawaiian/Other Pacific Islander Other / Not Provided 153 (77) 10 (5) 1 (1) 1 (1) 34 (17) Disease Characteristics, n (%) ECOG PSa, n (%) 0 1 2 46 (23) 124 (62) 28 (14) 12 Reference ID: 5498174 Relapsed AML, n (%) Refractory AML, n (%) 95 (48) 104 (52) IDH2 Mutationb, n (%) R140 R172 155 (78) 44 (22) Time from Initial AML Diagnosis (months) Median (min, max) (172 patients) 11.3 (1.2, 129.1) Cytogenetic Risk Status, n (%) Intermediate Poor Missing /Failure 98 (49) 54 (27) 47 (24) Prior Stem Cell Transplantation for AML, n (%) 25 (13) Transfusion Dependent at Baselinec, n (%) 157 (79) Number of Prior Anticancer Regimens, n (%)d 1 2 ≥3 Median number of prior therapies (min, max) 89 (45) 64 (32) 46 (23) 2 (1, 6) ECOG PS: Eastern Cooperative Oncology Group Performance Status. a 1 patient had missing baseline ECOG PS. b For 3 patients with different mutations detected in bone marrow compared to blood, the result of blood is reported. c Patients were defined as transfusion dependent at baseline if they received any red blood cell or platelet transfusions within the 8-week baseline period. d Includes intensive and/or nonintensive therapies. Efficacy was established on the basis of the rate of complete response (CR)/complete response with partial hematologic recovery (CRh), the duration of CR/CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in Table 5 and were similar in both cohorts. The median follow-up was 6.6 months (range, 0.4 to 27.7 months). Similar CR/CRh rates were observed in patients with either R140 or R172 mutation. Table 5: Efficacy Results in Patients with Relapsed or Refractory AML Endpoint IDHIFA (100 mg daily) N=199 CRa n (%) 95% CI Median DORb (months) 95% CI 37 (19) (13, 25) 8.2 (4.7, 19.4) CRhc n (%) 95% CI Median DOR (months) 95% CI 9 (4) (2, 8) 9.6 (0.7, NA) CR/CRh n (%) 95% CI Median DOR (months) 95% CI 46 (23) (18, 30) 8.2 (4.3, 19.4) CI: confidence interval, NA: not available. 13 Reference ID: 5498174 a CR (complete remission) was defined as <5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets >100,000/microliter and absolute neutrophil counts [ANC] >1,000/microliter). b DOR (duration of response) was defined as time since first response of CR or CRh to relapse or death, whichever is earlier. c CRh (complete remission with partial hematological recovery) was defined as <5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter). For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, 0.5 to 7.5 months) and the median time to best response of CR/CRh was 3.7 months (range, 0.6 to 11.2 months). Of the 46 patients who achieved a best response of CR/CRh, 39 (85%) did so within 6 months of initiating IDHIFA. Among the 157 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 53 (34%) became independent of RBC and platelet transfusions during any 56-day post baseline period. Of the 42 patients who were independent of both RBC and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post baseline period. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied 50 mg tablet: Pale yellow to yellow oval-shaped film-coated tablet debossed “ENA” on one side and “50” on the other side. • 30-count bottles of 50 mg tablets with a desiccant canister (NDC 59572-705-30) 100 mg tablet: Pale yellow to yellow capsule-shaped film-coated tablet debossed “ENA” on one side and “100” on the other side. • 30-count bottles of 100 mg tablets with a desiccant canister (NDC 59572-710-30) Storage Store at 20°C-25°C (68°F-77°F); excursions permitted between 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Keep the bottle tightly closed. Store and dispense in the original bottle (with a desiccant canister) to protect from moisture. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Differentiation Syndrome Advise patients on the risks of developing differentiation syndrome as early as 1 day and during the first 5 months on treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, bone pain, rapid weight gain or swelling of their arms or legs, to their healthcare provider for further evaluation [see Boxed Warning and Warnings and Precautions (5.1)]. 14 Reference ID: 5498174 Tumor Lysis Syndrome Advise patients on the risks of developing tumor lysis syndrome. Advise patients on the importance of maintaining high fluid intake and the need for frequent monitoring of blood chemistry values [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. Gastrointestinal Adverse Reactions Advise patients on risk of experiencing gastrointestinal reactions, such as diarrhea, nausea, vomiting, decreased appetite, and changes in their sense of taste. Ask patients to report these reactions to their healthcare provider, and advise patients how to manage them [see Adverse Reactions (6.1)]. Elevated Blood Bilirubin Inform patients that taking IDHIFA may cause elevated blood bilirubin, which is due to its mechanism of action, and not due to liver damage. Advise patients to report any changes to the color of their skin or the whites of their eyes to their healthcare provider for further evaluation [see Adverse Reactions (6.1)]. Embryo-Fetal Toxicity Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to notify their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.2), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use an effective non-hormonal contraceptive method during treatment with IDHIFA and for 2 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for 2 months after the last dose. Coadministration of IDHIFA may decrease the concentrations of combined hormonal contraceptives. [see Drug Interactions (7.1) and Use in Specific Populations (8.3)]. Lactation Advise women not to breastfeed during treatment with IDHIFA and for 2 months after the last dose [see Use in Specific Populations (8.2)]. Drug Interactions Advise patients to inform their healthcare providers of all concomitant products, including over­ the-counter products and supplements [see Drug Interactions (7.1)]. Dosing and Storage Instructions • Advise patients not to chew, split, or crush the tablets but swallow whole with a cup of water. • Instruct patients that if they miss a dose or vomit after a dose of IDHIFA, to take it as soon as possible on the same day and return to normal schedule the following day. Advise patients not to take 2 doses to make up for the missed dose [see Dosage and Administration (2.2)]. • Keep IDHIFA in the original container. Keep the container tightly closed with desiccant canister inside to protect the tablets from moisture [see How Supplied/Storage and Handling (16)]. 15 Reference ID: 5498174 Marketed by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA Licensed from: Servier Pharmaceuticals LLC Boston, MA 02210 Trademarks are the property of their respective owners. IDHIFA® is a trademark of Celgene Corporation, a Bristol Myers Squibb company. Pat. https://www.bms.com/patient-and-caregivers/our-medicines.html IDHPI.007/MG.006 16 Reference ID: 5498174
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2025-02-12T15:47:56.530650
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TRYNGOLZA safely and effectively. See full prescribing information for TRYNGOLZA. TRYNGOLZA (olezarsen) injection, for subcutaneous use Initial U.S. Approval: 2024 -----------------------------INDICATIONS AND USAGE-------------------­ TRYNGOLZA is an APOC-III-directed antisense oligonucleotide (ASO) indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). (1) ------------------------DOSAGE AND ADMINISTRATION--------------­ • The recommended dosage of TRYNGOLZA is 80 mg administered subcutaneously once monthly. (2.1) • Administer TRYNGOLZA into the abdomen or front of the thigh. The back of the upper arm can also be used as an injection site if a healthcare provider or caregiver administers the injection. (2.2) ---------------------DOSAGE FORMS AND STRENGTHS---------------­ Injection: 80 mg/0.8 mL in a single-dose autoinjector. (3) -------------------------------CONTRAINDICATIONS----------------------­ History of serious hypersensitivity reactions to olezarsen or any of the excipients in TRYNGOLZA. (4) ------------------------WARNINGS AND PRECAUTIONS----------------­ Hypersensitivity reactions have been reported in patients treated with olezarsen. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur. (5.1) -------------------------------ADVERSE REACTIONS----------------------­ Most common adverse reactions (incidence >5% of TRYNGOLZA- treated patients and >3% higher frequency than placebo) were injection site reactions, decreased platelet count, and arthralgia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Ionis Pharmaceuticals Inc. at toll free number 1-833-644-6647 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5500028 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE TRYNGOLZA is indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage of TRYNGOLZA is 80 mg administered subcutaneously once monthly [see Dosage and Administration (2.2)]. 2.2 Administration Instructions Prior to initiation, train patients and/or caregivers on proper preparation and administration of TRYNGOLZA [see Instructions for Use]. Remove the single-dose autoinjector from the refrigerator 30 minutes prior to the injection and allow to warm to room temperature. Do not use other warming methods. Inspect TRYNGOLZA visually for particulate matter prior to administration. The solution should be clear and colorless to yellow. Do not use if cloudiness, particulate matter, or discoloration is observed prior to administration. Maintain a low-fat diet (≤20g fat per day) in conjunction with TRYNGOLZA. Inject TRYNGOLZA subcutaneously into the abdomen or front of the thigh. The back of the upper arm can also be used as an injection site if a healthcare provider or caregiver administers the injection. Administer TRYNGOLZA as soon as possible after a missed dose. Resume dosing at monthly intervals from the date of the most recently administered dose. 3 DOSAGE FORMS AND STRENGTHS Injection: 80 mg/0.8 mL of olezarsen as a clear, colorless to yellow solution in a single-dose autoinjector. 4 CONTRAINDICATIONS TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to olezarsen or any of the excipients in TRYNGOLZA. Hypersensitivity reactions, including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgias, requiring medical treatment have occurred [see Warnings and Precautions (5.1)] Reference ID: 5500028 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgias) have been reported in patients treated with TRYNGOLZA [see Adverse Reactions (6.1)]. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of TRYNGOLZA cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of TRYNGOLZA was evaluated in 66 patients with FCS enrolled in Trial 1 (NCT #04568434) [see Clinical Studies (14)]. In this trial, 43 patients received at least one dose of TRYNGOLZA, 50 mg (N=21) or 80 mg (N=22) and 23 patients received placebo. TRYNGOLZA 50 mg is not an approved dosing regimen for FCS [see Dosage and Administration (2.1)]. Across treatment groups, the mean age was 45 years and 42% of patients were male. Eighty-five percent (85%) of patients were White, 9% were Asian and 6% were reported as other races; 11% identified as Hispanic or Latino ethnicity. Forty-three (43) patients were exposed to TRYNGOLZA for a median of 52 weeks; 22 patients were treated with TRYNGOLZA 80 mg every 4 weeks for a median of 52 weeks. Adverse reactions led to discontinuation of treatment in 7% of TRYNGOLZA-treated patients and 0% of placebo-treated patients. The most common reasons for TRYNGOLZA treatment discontinuation were hypersensitivity reactions. Adverse reactions (>5% of patients treated with TRYNGOLZA and at >3% higher frequency than placebo) are presented in Table 1. Table 1: Adverse Reactions That Occurred in >5% of Patients Treated with TRYNGOLZA and at >3% Higher Frequency than Placebo (Trial 1) Adverse Reactiona Total TRYNGOLZA (N = 43) Placebo (N = 23) Injection site reactions 8 (19%) 2 (9%) Decreased platelet count 5 (12%) 1 (4%) Arthralgia 4 (9%) 0 a Grouped terms composed of several similar terms Reference ID: 5500028 Laboratory Tests Decrease in Platelet Count: TRYNGOLZA can cause reductions in platelet count. In Trial 1, the mean platelet count in the TRYNGOLZA 80 mg group was 188,000 mm3 at baseline, and the mean percent change in platelet count was -10% at Week 53. In comparison, the mean platelet count in the placebo group was 215,000/mm3 at baseline, and the mean percent change in platelet count was 22% at Week 53. No TRYNGOLZA-treated patient with FCS had a platelet count <50,000/mm3. There were no major bleeding events associated with a low platelet count. Overall, the proportion of patients experiencing a bleeding adverse event was similar across the TRYNGOLZA and placebo treatment groups. Increase in Glucose: Small increases in average values in fasting glucose (≤17 mg/dL) and HbA1c (<0.2 percentage points) were observed over time with TRYNGOLZA treatment in the FCS population in Trial 1. The incidence of hyperglycemia (defined as adverse events, new antidiabetic medication, or laboratory values) was higher in olezarsen-treated patients without a medical history of diabetes at baseline (52%) compared to placebo-treated patients (35%). Increase in Liver Enzymes: Increases from baseline in liver enzymes within the normal range were observed with olezarsen treatment in the FCS population. These increases occurred within the first 3 months of treatment and stabilized. Liver enzymes returned towards baseline with discontinuation of olezarsen. Increase in LDL-cholesterol: Increases in low-density lipoprotein cholesterol (LDL-C) and total apolipoprotein B (apoB) were observed in the FCS population treated with TRYNGOLZA compared to those treated with placebo [see Clinical Studies (14)]. Despite increases in LDL-C, the maximum LDL­ C value remained low for most patients (i.e., <70 mg/dL for 74% of patients treated with TRYNGOLZA). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on TRYNGOLZA use in pregnant women to inform drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Patients with FCS are at risk for pancreatitis during pregnancy because of defects in lipid metabolism and increased triglyceride levels (see Clinical Considerations). In animal reproduction studies conducted with the unconjugated antisense oligonucleotide (lacking GalNAc) in rabbits and mice, no adverse effects on development or pregnancy were observed at doses 21 times or 20 times, respectively, the maximum recommended clinical dose. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively. Reference ID: 5500028 Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk During pregnancy, triglyceride levels increase during the third trimester of pregnancy. In patients with underlying defects in lipid metabolism, such as FCS, severe gestational hypertriglyceridemia may occur, increasing the risk of acute pancreatitis during pregnancy. Data Animal Data Olezarsen was not evaluated for potential effects on embryofetal development (EFD). However, effects of the administration of the unconjugated antisense oligonucleotide (ASO), which shares the same nucleotide sequence but lacks the N-acetyl galactosamine [GalNAc] moiety [see Description (11)], were evaluated. In a combined fertility and embryo-fetal development study in mice, the unconjugated ASO was administered to male and female mice by subcutaneous injection at doses of 10.5, 35, and 87.5 mg/kg/week prior to mating and through to the completion of organogenesis (gestation day 15). No adverse developmental outcomes occurred at doses up to 87.5 mg/kg/week (approximately 21-times the monthly maximum recommended human dose (MRHD) based on a body surface area (BSA) comparison of the unconjugated ASO). In an embryo-fetal development study in pregnant rabbits, the unconjugated ASO was administered by subcutaneous injection at doses of 10.5, 21, and 52.5 mg/kg/week during the period of organogenesis (gestation days 6 to 18). No adverse developmental effects were observed at doses up to 21 mg/kg/week (approximately 20-times the monthly MRHD based on a BSA comparison of the unconjugated ASO). In a pre-/postnatal toxicity study in mice, the unconjugated ASO was administered at 10.5, 35, or 87.5 mg/kg/week during the period of organogenesis and continuing until weaning (gestation day 6 through lactation day 21). Offspring body weights at 87.5 mg/kg/week (21-times the monthly MRHD based on BSA) were lower throughout their lives and were associated with slight delays in the attainment of morphological and developmental landmarks. No adverse effects on offspring were observed at 35 mg/kg/week (approximately 9-times the monthly MRHD based on a BSA comparison of the unconjugated ASO). 8.2 Lactation Risk Summary There are no data on the presence of olezarsen in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. However, the unconjugated antisense ASO, which shares the same nucleotide sequence but lacks GalNAc, was present in the milk of lactating mice at low levels. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Oligonucleotide-based products typically have poor oral bioavailability; therefore, it is considered unlikely that low levels present in milk will lead to clinically relevant levels in breastfed infants. The Reference ID: 5500028 developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRYNGOLZA and any potential adverse effects on the breast-fed infant from TRYNGOLZA or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of TRYNGOLZA in pediatric patients have not been established. 8.5 Geriatric Use No dose adjustment is recommended in patients aged 65 years and older [see Clinical Pharmacology (12.3)]. In clinical studies, 111 (38%) patients treated with TRYNGOLZA were ≥65 years of age. No overall differences in safety or effectiveness of TRYNGOLZA have been observed between patients 65 years of age and older and younger adult patients. 8.6 Renal Impairment No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to <90 mL/min) [see Clinical Pharmacology (12.3)]. TRYNGOLZA has not been studied in patients with severe renal impairment or end-stage renal disease. 8.7 Hepatic Impairment No dose adjustment is recommended in patients with mild hepatic impairment [see Clinical Pharmacology (12.3)]. TRYNGOLZA has not been studied in patients with moderate or severe hepatic impairment. 11 DESCRIPTION Olezarsen is an ASO directed inhibitor of Apolipoprotein C-III (apoC-III) mRNA, conjugated to a ligand containing three N-acetyl galactosamine (GalNAc) residues to enable delivery of the ASO to hepatocytes. TRYNGOLZA contains olezarsen sodium as the active ingredient. Olezarsen sodium is a white to yellow solid and it is freely soluble in water and in phosphate buffer. The molecular formula of olezarsen sodium is C296H419N71O154P20S19Na20 and the molecular weight is 9124.48 daltons. The chemical name of olezarsen sodium is DNA, d(P-thio) ([2′-O-(2-methoxyethyl)] rA-[2′-O-(2­ methoxyethyl)] rG-[2′-O-(2-methoxyethyl)] m5rC-[2′-O-(2-methoxyethyl)] m5rU-[2′-O-(2­ methoxyethyl)] m5rU-m5C-T-T-G-T-m5C-m5C-A-G-m5C-[2′-O-(2-methoxyethyl)] m5rU-[2′-O-(2­ methoxyethyl)] m5rU-[2′-O-(2-methoxyethyl)] m5rU-[2′-O-(2-methoxyethyl)] rA-[2′-O-(2­ methoxyethyl)]m5rU), 5′-[26-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-14,14-bis[[3-[[6-[[2­ (acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]hexyl]amino]-3-oxopropoxy]methyl]-8,12,19-trioxo­ 16-oxa-7,13,20-triazahexacos-1-yl hydrogen phosphate], sodium salt (1:20). The structure of olezarsen sodium is presented below: Reference ID: 5500028 O NH2 NH2 HO O O P O Na+ O P O O P O O O O O O O O O O O O O O O O O O R P NH O O O O O NH NH O O NH O O HN O O O HO HO HO HO HO HO HO OH O H N NH O O O O O O O O Na+ - O O O R P O P O O Na+ - S O Na+ - S O O Na+ - S O P O O O O O O Na+ - S O P P O Na+ - S O Na+ - S O P P O Na+ - S O P Na+ - S O P Na+ - S O P Na+ - S O - S P Na+ - S O O Na+ - S O P Na+ S O O R R O O O O R - P Na+ - S O P Na+ - S O P Na+ - S O P R = OCH2CH2OCH3 O O O O O O O O R O R O R Na+ - S O O R OH R O O O N N N N N N N NH2 N N N N NH2 N NH N N O NH2 N NH N N O NH2 N NH N N O NH2 N N NH2 O N N NH2 O N N NH2 O N N NH2 O N N O N NH O O N NH O O N NH O O N NH O N NH O O N NH O O N NH O O N NH O O N NH O N Na+ - S NH O O TRYNGOLZA is a sterile, preservative-free solution for subcutaneous injection. Each single-dose autoinjector contains 80 mg olezarsen (equivalent to 84 mg of olezarsen sodium) in 0.8 mL of solution. The solution also contains the following inactive ingredients: disodium hydrogen phosphate, sodium chloride, sodium dihydrogen phosphate to maintain pH and provide tonicity, and water for injection. The solution may include hydrochloric acid and/or sodium hydroxide for pH adjustment between 6.9 to 7.9. Each dose of TRYNGOLZA injection contains 6 mg of phosphorous and 5 mg of sodium. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Olezarsen is an ASO-GalNAc3 conjugate that binds to apoC-III mRNA leading to mRNA degradation and resulting in a reduction of serum apoC-III protein. Reduction of apoC-III protein leads to increased clearance of plasma TG and VLDL. 12.2 Pharmacodynamics Fasting apoC-III Olezarsen decreased fasting apoC-III following administration of TRYNGOLZA 80 mg dosage every 4 weeks to patients with FCS [See Clinical Studies (14)]. The placebo-corrected percent change in fasting apoC-III from baseline was -57% at 1 month, -69% at 3 months, -72% at 6 months, and -80% at 12 months. Reference ID: 5500028 Cardiac Electrophysiology At a dose 1.5-times the maximum approved recommended dosage, TRYNGOLZA does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Olezarsen steady state mean (SD) maximum concentrations (Cmax) is 883 (662) ng/mL and area under the curve (AUCτ) is 7440 (3880) ng*h/mL at the approved recommended dosage in patients with FCS. Olezarsen Cmax and AUC increase dose-proportionally following single subcutaneous doses ranging from 10 to 120 mg (i.e., 0.13- to 1.5-times the approved recommended dose) in healthy volunteers. No olezarsen accumulation occurs with repeat dosing. Absorption Olezarsen time to Cmax (Tmax) is approximately 2 hours following subcutaneous administration. Distribution The population estimates for the apparent central volume of distribution is 91.9 L and the apparent peripheral volume of distribution is 2960 L for olezarsen. Olezarsen is greater than 99% bound to plasma proteins, in vitro. Olezarsen distributes primarily to the liver and kidney after subcutaneous dosing. Elimination Olezarsen terminal elimination half-life is approximately 4 weeks. Metabolism Olezarsen is metabolized by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver. Excretion Less than 1% of olezarsen administered dose is eliminated unchanged in urine within 24 hours. Specific Populations No clinically significant differences in the pharmacokinetics of olezarsen were observed based on age (< 65 to ≥ 75 years), body weight, sex, race (White, Black or African American, Asian, Japanese, American Indian or Alaska Native, Native Hawaiian or Pacific Islander), mild-to-moderate renal impairment (eGFR ≥30 to <90 mL/min) [CKD-EPI], or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN; , or total bilirubin >1 to 1.5 x ULN and any AST, National Cancer Institute Organ Dysfunction Working Group criteria). The effect of severe renal impairment (eGFR < 30 mL/min), end- Reference ID: 5500028 stage renal disease, moderate or severe hepatic impairment (total bilirubin > 1.5 x ULN with any AST) on olezarsen pharmacokinetics is unknown. Drug Interaction Studies In Vitro Studies CYP450 Enzymes: Olezarsen is not an inhibitor or inducer of CYP450 enzymes. Transporter Systems: Olezarsen is not a substrate or inhibitor of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, P-gp, and BSEP. Protein Binding: Olezarsen does not displace warfarin and ibuprofen from plasma protein binding sites. 12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the study described below with the incidence of anti-drug antibodies in other studies, including those of olezarsen. In Trial 1, with duration of treatment up to 53 weeks, 18 out of 43 (42%) patients treated with TRYNGOLZA developed treatment-emergent ADAs. The presence of ADAs did not affect olezarsen plasma Cmax, but increased Ctrough. Although ADA development was not found to affect the pharmacodynamics, safety, or efficacy of TRYNGOLZA in these patients, the available data are limited to make definitive conclusions. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No long-term carcinogenicity studies were conducted with olezarsen in animals. However, the unconjugated antisense oligonucleotide (ASO) lacking GalNAc was administered weekly in mice and rats at subcutaneous doses of 0, 6, 25, 40 mg/kg/week (along with a mouse-specific surrogate ASO at 25 mg/kg/week) and 0, 0.2, 1, 5 mg/kg/week, respectively, for 2 years. In male mice, there were statistically significant increases in the incidences of hepatocellular adenomas and carcinomas at ≥25 mg/kg/week and hemangiomas and hemangiosarcomas at all doses. In female mice, there were statistically significant increases in the incidences of histiocytic sarcomas at all doses (including the mouse-specific surrogate) and pituitary gland adenomas at 25 mg/kg/week. In rats, the incidence of malignant fibrous histiocytoma at the injection site was increased in both sexes at doses ≥1 mg/kg/week. These tumors are considered a response to chronic tissue irritation and inflammation caused by repeated subcutaneous injection. The clinical significance of these findings is uncertain. Mutagenesis Reference ID: 5500028 Olezarsen was negative for genotoxicity in vitro (bacterial reverse mutation assay and chromosome aberration assay in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus assay). Impairment of Fertility Olezarsen was administered at doses of 0, 5, 10, or 20 mg/kg given every other week to male and female mice prior to mating, followed by every other day dosing after mating and until gestation day 6 in females. There was no effect on fertility in mice administered olezarsen at doses up to 20 mg/kg (approximately 2-times the monthly maximum recommended human dose based on body surface area). 14 CLINICAL STUDIES The efficacy of TRYNGOLZA was demonstrated in a randomized, placebo-controlled, double-blind clinical trial in adult patients with genetically identified FCS and fasting triglyceride (TG) levels ≥880 mg/dL (Trial 1; NCT04568434). After a ≥4-week run-in period where patients continued to follow a low-fat diet with ≤20 grams fat per day, patients were randomly assigned to receive doses every 4 weeks of TRYNGOLZA 80 mg (n=22) or matching volume of placebo (n=23) via subcutaneous injection over a 53 week treatment period. Patient demographic and baseline characteristics were generally similar across the treatment groups [see Adverse Reactions (6.1)]. The proportion of patients with diabetes at enrollment was 32% in the TRYNGOLZA 80 mg group compared with 26% in the placebo group. Patients in the TRYNGOLZA 80 mg and placebo groups were treated with statins (27%), omega-3 fatty acids (42%), fibrates (49%), or other lipid lowering therapies (13%) at study entry. Seventy-one percent (71%) of patients in the TRYNGOLZA 80 mg and placebo groups combined had a history of documented acute pancreatitis in the prior 10 years. Mean (SD) and median fasting TG levels at baseline were 2,604 (1,364) mg/dL and 2,303 mg/dL, respectively (range of 334 to 6,898 mg/dL). The primary endpoint was percent change in fasting triglycerides from baseline to Month 6 (average of Weeks 23, 25, and 27) compared to placebo. The difference between TRYNGOLZA 80 mg group and the placebo group in percent change in fasting triglycerides from baseline to Month 6 was -42.5% (95% CI: -74.1%, -10.9%; p=0.0084). For additional results see Table 2. Reference ID: 5500028 3 "' ' "' w " "' ~ " " 00 "' u ,1j +i ·~ " w w 0 0 >, " ,-< w "' ~ ·• 'H " 0 E-< " "' " " ·• ·• " "' 00 w " :,: 0. -~ Pl acebo TRYNGOLZA 80 MG 1 0 0 - 1 0 -20 - 3 0 -40 -so Base l i ne 23 22 Mon t h 23 22 1 - ------- --- --- ___ _ Mon t h 3 Mon t h 6 Visit - - ---- - - - Month 9 - -II - Placeb o -------- TRYNGOL ZA 80 MG 23 22 23 22 23 22 - - - --- Month 1 2 23 22 Table 2. Mean Baseline (BL) and Mean Percent (%) Changes from Baseline in Lipid/ Lipoprotein Parameters in Patients with FCS at Month 6 in Trial 1 Parameter TRYNGOLZA 80 mg N = 22 Placebo N = 23 TRYNGOLZA 80 mg vs. Placebo (mg/dL) BL % change Month 6 BL % change Month 6 Treatment Difference % change (95% CI) at Month 6 Triglycerides 2613.1 -30 2595.7 +12 -42.5a (-74.1, -10.9) Non-HDL-C 262.9 -18 271.3 +5.7 -23.4 (-45.3, -1.5) LDL-C 22.8 +64 16.7 +9 +55.0b (0.7, 109.4) Total ApoB 58.4 +20 59.7 +9 +11.7 (-12.6, 35.9) ApoB-48 11.6 -51 14.2 +25 -75.9 (-149.8, -2.0) Abbreviations: apoB = apolipoprotein B; non-HDL-C = non high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol. Note: Analyses results were based on an analysis of covariance model with treatment, the two randomization stratification factors, prior history of pancreatitis within 10 years prior to Screening (yes vs. no), previous treatment with the unconjugated ASO (yes vs. no) as the fixed effects and log-transformed Baseline value as a covariate. Missing data was imputed using placebo washout imputation. The 95% CIs of treatment differences were calculated using a robust variance estimator. For triglycerides and non-HDL, a test of residual normality did not indicate significant departure from normal distribution. a Reached statistical significance (p value < 0.05). b Mean LDL-C levels increased but remained within normal range (i.e., <70 mg/dL for 74% of patients treated with TRYNGOLZA). Median percent change from baseline (Figure 2) and median absolute TG values (Figure 3) over time demonstrated a consistent lowering effect during the 12-month treatment period. Figure 2. Percent Change in Fasting Triglyceride (mg/dL) Over Time Reference ID: 5500028 3 0,"' A ' .,, ~ +' - 00 "' 00 µ. w '< "' 0 -~ A w 0 "' -~ >, "' rl w 0, ~ -~ E-< Placebo TRYNGOLZA 80 MG 3500 3000 2500 ._ --- 2000 1500 1000 Basel in e 23 22 --- --- -.- Month 23 22 1 .. _ - - Month 3 Month 6 Vi s i t Month 9 - .. - Placebo - TRYNG0LZA 80 MG 23 22 23 22 23 22 _ ... Month 12 23 22 Figure 3. Fasting Triglyceride (mg/dL) Over Time Over the 12-month treatment period, the numerical incidence of acute pancreatitis in patients treated with TRYNGOLZA 80 mg was lower compared with placebo [1 (5%) patient in the TRYNGOLZA 80 mg group compared with 7 (30%) patients in the placebo group]; all of these patients had a prior history of pancreatitis within 10 years prior to screening. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied TRYNGOLZA injection is a sterile, preservative-free, clear, colorless to yellow solution supplied in a single-dose autoinjector. Each autoinjector of TRYNGOLZA is filled to deliver 0.8 mL of solution containing 80 mg of olezarsen. TRYNGOLZA is available in cartons containing one 80 mg single-dose autoinjector each. (NDC 71860-101-01). 16.2 Storage and Handling Store the TRYNGOLZA autoinjector in the refrigerator between 2°C and 8°C (36°F and 46°F) in the original carton. Once taken out of the refrigerator, the TRYNGOLZA autoinjector can be stored at room temperature between 15°C and 30°C (59°F and 86°F) in the original carton for up to 6 weeks. If not used within the 6 weeks stored at room temperature, discard TRYNGOLZA. Do not freeze. Do not expose to heat. Protect from light. 17 PATIENT COUNSELING INFORMATION Reference ID: 5500028 Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Hypersensitivity Inform patients that serious hypersensitivity reactions, including bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgia, have been reported in patients treated with TRYNGOLZA. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct them to stop taking TRYNGOLZA and seek medical advice promptly if such symptoms occur. [see Warnings and Precautions (5.1)]. Adherence to Diet Advise patients with FCS that use of lipid-regulating agents does not reduce the importance of adhering to a low-fat diet [see Dosage and Administration (2)]. Missed Dose Instruct patients to take TRYNGOLZA as prescribed. If a dose is missed, instruct patients to take it as soon as they remember. Resume dosing at monthly intervals from the date of the most recently administered dose [see Dosage and Administration (2.1)]. Distributed by: Ionis Pharmaceuticals Inc., Carlsbad, CA 92010 TRYNGOLZA is a trademark of Ionis Pharmaceuticals Inc. All other trademarks are the property of their respective owners. © 2024 IONIS Pharmaceuticals Inc. Reference ID: 5500028 PATIENT INFORMATION TRYNGOLZA™ [trin-GOLE-zah] (olezarsen) injection, for subcutaneous use What is TRYNGOLZA? TRYNGOLZA is a prescription medicine used along with diet to reduce triglycerides (fat in the blood) in the treatment of adults with a condition that keeps the body from breaking down fats called familial chylomicronemia syndrome (FCS). It is not known if TRYNGOLZA is safe and effective in children. Do not use TRYNGOLZA if: • you have had a serious allergic reaction to olezarsen or any of the ingredients in TRYNGOLZA. See the end of this Patient Information for a complete list of ingredients. Before using TRYNGOLZA, tell your healthcare provider about all of your medical conditions, including if you: • are pregnant or plan to become pregnant. It is not known if TRYNGOLZA can harm your unborn baby. Tell your healthcare provider if you become pregnant while using TRYNGOLZA. • are breastfeeding or plan to breastfeed. It is not known if TRYNGOLZA passes into your breast milk and if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby while using TRYNGOLZA. Tell your healthcare provider about all the medicines you take, including prescription and over-the­ counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use TRYNGOLZA? • Read the detailed Instructions for Use that comes with your TRYNGOLZA single-dose autoinjector. • Your healthcare provider will show you and/or your caregiver how to inject TRYNGOLZA the first time. • TRYNGOLZA is injected under your skin (subcutaneous use) in your stomach area (abdomen) or the front of your upper legs (thighs). Only a healthcare provider or caregiver may give you an injection in the back of your upper arm. • TRYNGOLZA should be injected 1 time each month. • If you miss a dose, take the missed dose as soon as possible. Then inject TRYNGOLZA 1 month from the date of your last dose to get back on a monthly dosing schedule. If you have questions about your dosing schedule, ask your healthcare provider. • Stay on your low-fat diet (less than 20 grams of fat each day) while using TRYNGOLZA. What are the possible side effects of TRYNGOLZA? • Allergic reactions: TRYNGOLZA can cause side effects including allergic reactions that may be serious. Allergic reactions can include redness of the skin, red itchy bumps (hives), swelling of the face, chills or trouble breathing. Stop taking TRYNGOLZA and call your healthcare provider or get emergency help right away if you have any of these symptoms. The most common side effects of TRYNGOLZA include: • injection site reactions (such as redness or pain at the injection site) • decreased platelet count (blood cells that help to clot blood) • joint pain or stiffness These are not all the possible side effects of TRYNGOLZA. Tell your healthcare provider if you have any side effect that bothers you or that does not go away while taking TRYNGOLZA. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. How should I store TRYNGOLZA? • Store TRYNGOLZA autoinjector in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton. • TRYNGOLZA can also be stored at room temperature between 59°F to 86°F (15°C to 30°C) in the original carton for up to 6 weeks. Reference ID: 5500028 • Do not let TRYNGOLZA reach temperatures above 86°F (30°C). • Throw away the TRYNGOLZA autoinjector if kept at room temperature longer than 6 weeks. • Do not freeze. • Do not expose TRYNGOLZA autoinjector to heat. • Protect from light. • Keep the TRYNGOLZA autoinjector in the carton until ready to use. • Do not store the autoinjector with the clear cap removed. Keep TRYNGOLZA and all medicines out of the reach of children. General information about the safe and effective use of TRYNGOLZA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use TRYNGOLZA for a condition for which it was not prescribed. Do not give TRYNGOLZA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TRYNGOLZA that is written for health professionals. What are the ingredients in TRYNGOLZA? Active ingredient: olezarsen sodium. Inactive ingredients: disodium hydrogen phosphate, sodium chloride, sodium dihydrogen phosphate to maintain pH and provide tonicity and water for injection. The solution may include hydrochloric acid and/or sodium hydroxide for pH adjustment. Distributed by: Ionis Pharmaceuticals Inc. Carlsbad, CA 92010 TRYNGOLZA is a trademark of Ionis Pharmaceuticals Inc. All other trademarks are the property of their respective owners. For more information, go to www.TRYNGOLZA.com or call 1-833-644-6647. If you still have questions, contact your healthcare provider. This Patient Information has been approved by the U.S. Food and Drug Administration Approved: 12/2024 Reference ID: 5500028 ent Doc-ID: AZDoc0037512 Template Version Number: 1 - INSTRUCTIONS FOR USE TRYNGOLZA™ [trin-GOLE-zah] (olezarsen) injection, for subcutaneous use Single-dose autoinjector 80 mg/0.8 mL This Instructions for Use contains information on how to inject TRYNGOLZA™ using the autoinjector. Read this Instructions for Use before you start using your TRYNGOLZA autoinjector and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Your healthcare provider should show you or your caregiver how to use the TRYNGOLZA autoinjector the right way. If you or your caregiver have any questions, talk to your healthcare provider. Important information: • TRYNGOLZA is injected under the skin (subcutaneous use) only. • Each autoinjector contains 1 single-dose and can only be used 1 time. • Do not remove the clear cap until you are ready to inject TRYNGOLZA (See Step 5). • Do not share your autoinjector with anyone. • Do not use if the autoinjector appears damaged. Storage information: • Store the autoinjector in the refrigerator between 36°F to 46°F (2°C to 8°C) in the original carton. • TRYNGOLZA can also be stored at room temperature between 59°F to 86°F (15°C to 30°C) in the original carton for up to 6 weeks. • Do not let TRYNGOLZA reach temperatures above 86°F (30°C). • Throw away the TRYNGOLZA autoinjector if kept at room temperature longer than 6 weeks. • Do not freeze. • Do not expose the autoinjector to heat. • Protect from light. • Keep the autoinjector in the carton until ready to use. • Do not store the autoinjector with the clear cap removed. Keep TRYNGOLZA and all medicine out of the reach of children. Parts of your TRYNGOLZA autoinjector 1 Reference ID: 5500028 ent Doc-ID: AZDoc0037512 Template Version Number: 1 □ (..______.:::~) II Wait ...,_______.___ ~ bf @ I minutes , , Check , ' , ' , ' • 9 1 I EXP MM!YYYY Single-dose autoinjector Other supplies (not included) Alcohol wipe Cotton ball or gauze Plunger Viewing window Medicine Clear cap Orange needle shield Sharps container Small bandage Preparing to inject TRYNGOLZA Step 1 Remove from the refrigerator a) Remove the autoinjector from the refrigerator. b) Keep the autoinjector in the original carton and let the autoinjector come to room temperature for 30 minutes before injecting. Do not try to speed up the warming process using other heat sources, such as a microwave or hot water. Step 2 Check the medicine a) Check the expiration (EXP) date. b) Check the medicine through the viewing window. The TRYNGOLZA medicine should be clear and colorless to yellow. There should be no particles. It is normal to see air bubbles in the solution. 2 Reference ID: 5500028 ent Doc-ID: AZDoc0037512 Template Version Number: 1 Orarnge Clear needle cap shield ' ' ' \ ' ' ... Do not use the autoinjector if the: • clear cap is missing or not attached. • expiration (EXP) date has passed. • medicine looks cloudy, discolored, or has particles. • autoinjector appears damaged. For healthcare Step 3 Choose the injection site For all providers or a) Choose an injection site on the stomach or the front of the thigh. b) Only your healthcare provider or caregivers may choose the back of upper arm. Do not inject: • within 2 inches (5 cm) of the belly button (navel). • into skin that is bruised, tender, red, or hard. • into scars or damaged skin. Step 4 Wash hands and clean the injection site a) Wash your hands with soap and water. b) Clean the injection site with an alcohol wipe in a circular motion. Let the skin air dry. Do not touch the cleaned skin before injecting. Injecting TRYNGOLZA Step 5 Remove and throw away the clear cap a) Hold the autoinjector by the middle with the clear cap facing away from you. b) Remove the clear cap by pulling it straight off. Do not twist it off. The needle is inside the orange needle shield. c) Throw away the clear cap in the trash or sharps container. • Do not remove the clear cap until right before you inject. • Do not recap the autoinjector. • Do not push the orange needle shield against the hand or finger. caregivers only back of the upper arm stomach thigh 3 Reference ID: 5500028 ent Doc-ID: AZDoc0037512 Template Version Number: 1 a) Pl.ace b} Push ~- _ Orange t -- ---plunger rod c}Hod Step 6 Begin injection a) Hold the autoinjector in 1 hand. Place the orange needle shield at a 90-degree angle against your skin. Make sure you can see the viewing window. b) Push firmly and hold the autoinjector straight against the skin. You will hear a click as the injection starts. You may hear a second click. This is normal. The procedure is not finished. c) Hold the autoinjector against the skin for 10 seconds to make sure the full dose has been given. Do not move, turn, or change the angle of the autoinjector during the injection. Step 7 Finish injection a) Check that the orange plunger rod has moved down to fill the entire viewing window. • If the orange plunger rod does not fill the viewing window, you may not have received the full dose. • If this happens or if you have other concerns, contact your healthcare provider. b) Remove the autoinjector by lifting it straight up. After removal from the skin, the orange needle shield locks into place and covers the needle. c) There may be a small amount of blood or liquid where you injected. This is normal. If needed, press a cotton ball or gauze on the area and apply a small bandage. Do not reuse the autoinjector. Throwing away TRYNGOLZA 4 Reference ID: 5500028 ent Doc-ID: AZDoc0037512 Template Version Number: 1 r '-E ""V 4 Ste p 8 T hr ow away autoinjector a) Put the used autoinjector in a sharps container right away after use. Do not throw away the autoinjector in your household trash. Do not recycl e your us ed s harps disposal container. Do not reuse the autoi njector or c lear cap. If y ou do not have an FDA-cleared sharps container, you may use a hous ehold container that is: • made of a heavy-duty plastic, • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, • upright and stable during use, • leak-resistant, and • properly labelled to warn of hazardous waste inside the container. When your sharps dispos al c ontainer is almost ful l, you will need to follow y our c ommunity guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away us ed autoinjectors. For more information about safe sharps dis posal, and specific information about sharps dispos al in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. Do not throw away your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. For more information, go to https://www.TRYNG OLZA.com or call 1-833-644-6647. If you s till have questions, contact your healthc are prov ider. Dis tributed by: Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010 This Instructions for Use has been approved by the U.S. Food and Drug Administration Issued: 12/2024 5 Reference ID: 5500028
custom-source
2025-02-12T15:47:57.557921
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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZEPBOUND safely and effectively. See full prescribing information for ZEPBOUND. ZEPBOUND® (tirzepatide) Injection, for subcutaneous use Initial U.S. Approval: 2022 WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • In rats, tirzepatide causes thyroid C-cell tumors. It is unknown whether ZEPBOUND causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined (5.1, 13.1). • ZEPBOUND is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors (4, 5.1). --------------------------- RECENT MAJOR CHANGES -------------------------- Indications and Usage (1) 12/2024 Dosage and Administration (2.2) 12/2024 Warnings and Precautions Pulmonary Aspiration During General Anesthesia or Deep Sedation (5.10) 10/2024 ---------------------------- INDICATIONS AND USAGE --------------------------- ZEPBOUND® is a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist indicated in combination with a reduced-calorie diet and increased physical activity: • to reduce excess body weight and maintain weight reduction long term in adults with obesity or adults with overweight in the presence of at least one weight-related comorbid condition. (1) • to treat moderate to severe obstructive sleep apnea (OSA) in adults with obesity. (1) Limitations of Use: Coadministration with other tirzepatide-containing products or with any GLP-1 receptor agonist is not recommended. (1) ------------------------ DOSAGE AND ADMINISTRATION ----------------------- Recommended Dose Escalation Schedule • The recommended starting dosage is 2.5 mg injected subcutaneously once weekly for 4 weeks. Increase the dosage in 2.5 mg increments after at least 4 weeks until recommended maintenance dosage is achieved. (2.1) • Consider treatment response and tolerability when selecting the maintenance dosage. (2.1) Recommended Maintenance and Maximum Dosage • Weight Reduction and Long-Term Maintenance: 5 mg, 10 mg, or 15 mg injected subcutaneously once weekly. (2.2) • Obstructive Sleep Apnea: 10 mg or 15 mg injected subcutaneously once weekly. (2.2) Maximum Recommended Dosage: 15 mg injected subcutaneously once weekly. (2.2) Administration Instructions See full prescribing information for administration instructions. (2.4) ----------------------DOSAGE FORMS AND STRENGTHS --------------------- Injection: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg per 0.5 mL in single-dose pen or single-dose vial (3) ------------------------------- CONTRAINDICATIONS ------------------------------ • Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (4) • Known serious hypersensitivity to tirzepatide or any of the excipients in ZEPBOUND (4) ------------------------ WARNINGS AND PRECAUTIONS ----------------------- • Severe Gastrointestinal Adverse Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. Has not been studied in patients with severe gastrointestinal disease and is not recommended in these patients. (5.2) • Acute Kidney Injury: Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. (5.3) • Acute Gallbladder Disease: Has been reported in clinical trials. If cholecystitis is suspected, gallbladder studies and clinical follow-up are indicated. (5.4) • Acute Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. (5.5) • Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported postmarketing with tirzepatide. If suspected, advise patients to promptly seek medical attention and discontinue ZEPBOUND. (5.6) • Hypoglycemia: Concomitant use with insulin or an insulin secretagogue may increase the risk of hypoglycemia, including severe hypoglycemia. Reducing dose of insulin or insulin secretagogue may be necessary. Inform all patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. (5.7) • Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus: Has not been studied in patients with non- proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Monitor patients with a history of diabetic retinopathy for progression. (5.8) • Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts. Discontinue ZEPBOUND if symptoms develop. (5.9) • Pulmonary Aspiration During General Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. (5.10) ------------------------------- ADVERSE REACTIONS ------------------------------ The most common adverse reactions, reported in ≥5% of patients treated with ZEPBOUND are: nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection site reactions, fatigue, hypersensitivity reactions, eructation, hair loss, gastroesophageal reflux disease. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------- DRUG INTERACTIONS ------------------------------ ZEPBOUND delays gastric emptying and has the potential to impact the absorption of concomitantly administered oral medications. (7.2) ------------------------ USE IN SPECIFIC POPULATIONS ----------------------- • Pregnancy: May cause fetal harm. When pregnancy is recognized, discontinue ZEPBOUND. (8.1) • Females of Reproductive Potential: Advise females using oral contraceptives to switch to a non-oral contraceptive method or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved Medication Guide. Revised: 12/2024 Reference ID: 5501094 2 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF THYROID C-CELL TUMORS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose Escalation Schedule 2.2 Recommended Maintenance and Maximum Dosage 2.3 Recommendations Regarding Missed Dose 2.4 Important Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors 5.2 Severe Gastrointestinal Adverse Reactions 5.3 Acute Kidney Injury 5.4 Acute Gallbladder Disease 5.5 Acute Pancreatitis 5.6 Hypersensitivity Reactions 5.7 Hypoglycemia 5.8 Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus 5.9 Suicidal Behavior and Ideation 5.10 Pulmonary Aspiration During General Anesthesia or Deep Sedation 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Concomitant Use with Insulin or an Insulin Secretagogue (e.g., Sulfonylurea) 7.2 Oral Medications 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Weight Reduction and Long-Term Maintenance Studies in Adults with Obesity or Overweight 14.2 Obstructive Sleep Apnea Studies in Adults with Obesity 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5501094 3 FULL PRESCRIBING INFORMATION WARNING: RISK OF THYROID C-CELL TUMORS • In rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether ZEPBOUND causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)]. • ZEPBOUND is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Contraindications (4)]. Counsel patients regarding the potential risk for MTC with the use of ZEPBOUND and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with ZEPBOUND [see Contraindications (4) and Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE ZEPBOUND® is indicated in combination with a reduced-calorie diet and increased physical activity: • to reduce excess body weight and maintain weight reduction long term in adults with obesity or adults with overweight in the presence of at least one weight-related comorbid condition. • to treat moderate to severe obstructive sleep apnea (OSA) in adults with obesity. Limitations of Use ZEPBOUND contains tirzepatide. Coadministration with other tirzepatide-containing products or with any glucagon-like peptide-1 (GLP-1) receptor agonist is not recommended. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose Escalation Schedule • The recommended starting dosage of ZEPBOUND for all indications is 2.5 mg injected subcutaneously once weekly for 4 weeks. • The 2.5 mg dosage is for treatment initiation and is not approved as a maintenance dosage. • Follow the dosage escalation below for all indications to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. • After 4 weeks, increase the dosage to 5 mg injected subcutaneously once weekly. The dosage may be increased in 2.5 mg increments, after at least 4 weeks on the current dose [see Dosage and Administration (2.2)]. • Consider treatment response and tolerability when selecting the maintenance dosage. If patients do not tolerate a maintenance dosage, consider a lower maintenance dosage. 2.2 Recommended Maintenance and Maximum Dosage Recommended Maintenance Dosage Weight Reduction and Long-Term Maintenance The recommended maintenance dosage is 5 mg, 10 mg, or 15 mg, injected subcutaneously once weekly. OSA The recommended maintenance dosage is 10 mg or 15 mg injected subcutaneously once weekly. Maximum Recommended Dosage The maximum dosage of ZEPBOUND for all indications is 15 mg injected subcutaneously once weekly. 2.3 Recommendations Regarding Missed Dose • If a dose is missed, instruct patients to administer ZEPBOUND as soon as possible within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule. Reference ID: 5501094 4 • The day of weekly administration can be changed, if necessary, as long as the time between the two doses is at least 3 days (72 hours). 2.4 Important Administration Instructions • Prior to initiation of ZEPBOUND, train patients and caregivers on proper injection technique. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations. • Instruct patients using the single-dose vial to use a syringe appropriate for dose administration (e.g., a 1 mL syringe capable of measuring a 0.5 mL dose). • Inspect ZEPBOUND visually before use. It should appear clear and colorless to slightly yellow. Do not use ZEPBOUND if particulate matter or discoloration is seen. • Administer ZEPBOUND in combination with a reduced-calorie diet and increased physical activity. • Administer ZEPBOUND once weekly at any time of day, with or without meals. • Inject ZEPBOUND subcutaneously in the abdomen, thigh, or upper arm. • Rotate injection sites with each dose. 3 DOSAGE FORMS AND STRENGTHS Injection: Clear, colorless to slightly yellow solution in pre-filled single-dose pens or single-dose vials, each available in the following strengths: • 2.5 mg/0.5 mL • 5 mg/0.5 mL • 7.5 mg/0.5 mL • 10 mg/0.5 mL • 12.5 mg/0.5 mL • 15 mg/0.5 mL 4 CONTRAINDICATIONS ZEPBOUND is contraindicated in patients with: • A personal or family history of MTC or in patients with MEN 2 [see Warnings and Precautions (5.1)]. • Known serious hypersensitivity to tirzepatide or any of the excipients in ZEPBOUND. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with tirzepatide [see Warnings and Precautions (5.6) and Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-Cell Tumors In rats, tirzepatide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) in a 2-year study at clinically relevant plasma exposures [see Nonclinical Toxicology (13.1)]. It is unknown whether ZEPBOUND causes thyroid C-cell tumors, including MTC, in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined. ZEPBOUND is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of ZEPBOUND and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with ZEPBOUND. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Severe Gastrointestinal Adverse Reactions Use of ZEPBOUND has been associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions (6.1)]. In a pool of two ZEPBOUND clinical trials for weight reduction (Studies 1 and 2), severe gastrointestinal Reference ID: 5501094 5 adverse reactions were reported more frequently among patients receiving ZEPBOUND (5 mg 1.7%, 10 mg 2.5%, 15 mg 3.1%) than placebo (1%). Similar rates of severe gastrointestinal adverse reactions were observed in ZEPBOUND clinical trials for weight reduction and in ZEPBOUND clinical trials for OSA. ZEPBOUND has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients. 5.3 Acute Kidney Injury Use of ZEPBOUND has been associated with acute kidney injury, which can result from dehydration due to gastrointestinal adverse reactions to ZEPBOUND, including nausea, vomiting, and diarrhea [see Adverse Reactions (6.1)]. In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function in patients reporting adverse reactions to ZEPBOUND that could lead to volume depletion. 5.4 Acute Gallbladder Disease Treatment with ZEPBOUND and GLP-1 receptor agonists is associated with an increased occurrence of acute gallbladder disease. In a pool of two ZEPBOUND clinical trials for weight reduction (Studies 1 and 2), cholelithiasis was reported in 1.1% of ZEPBOUND-treated patients and 1% of placebo-treated patients, cholecystitis was reported in 0.7% of ZEPBOUND- treated patients and 0.2% of placebo-treated patients, and cholecystectomy was reported in 0.2% of ZEPBOUND-treated patients and no placebo-treated patients. Acute gallbladder events were associated with weight reduction. Similar rates of cholelithiasis were reported in ZEPBOUND clinical trials for weight reduction and in ZEPBOUND trials for OSA. If cholecystitis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. 5.5 Acute Pancreatitis Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists or tirzepatide. In clinical trials of tirzepatide for a different indication, 14 events of acute pancreatitis were confirmed by adjudication in 13 tirzepatide-treated patients (0.23 patients per 100 years of exposure) versus 3 events in 3 comparator-treated patients (0.11 patients per 100 years of exposure). In a pool of two ZEPBOUND clinical trials for weight reduction (Studies 1 and 2), 0.2% of ZEPBOUND-treated patients had acute pancreatitis confirmed by adjudication (0.14 patients per 100 years of exposure) versus 0.2% of placebo-treated patients (0.15 patients per 100 years of exposure). The exposure-adjusted incidence rate for treatment-emergent adjudication-confirmed pancreatitis in the pooled clinical studies for OSA (Studies 5 and 6) was 0.84 patients per 100 years for ZEPBOUND and 0 for placebo-treated patients. After initiation of ZEPBOUND, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting). If pancreatitis is suspected, discontinue ZEPBOUND and initiate appropriate management. Continuation of ZEPBOUND after a confirmed diagnosis of pancreatitis should be individually determined in the clinical judgment of a patient’s health care provider. 5.6 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) in patients treated with tirzepatide. In a pool of two ZEPBOUND clinical studies for weight reduction (Studies 1 and 2), 0.1% of ZEPBOUND-treated patients had severe hypersensitivity reactions compared to no placebo-treated patients. Similar rates of severe hypersensitivity reactions were observed in ZEPBOUND clinical trials for weight reduction and in ZEPBOUND trials for OSA. If hypersensitivity reactions occur, advise patients to promptly seek medical attention and discontinue use of ZEPBOUND. Do not use in patients with a previous serious hypersensitivity reaction to tirzepatide or any of the excipients in ZEPBOUND [see Contraindications (4) and Adverse Reactions (6.2)]. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with GLP-1 receptor agonists. Use caution in patients with a history of angioedema or anaphylaxis with a GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with ZEPBOUND. Reference ID: 5501094 6 5.7 Hypoglycemia ZEPBOUND lowers blood glucose and can cause hypoglycemia. In a trial of patients with type 2 diabetes mellitus and BMI ≥27 kg/m2 (Study 2), hypoglycemia (plasma glucose <54 mg/dL) was reported in 4.2% of ZEPBOUND-treated patients versus 1.3% of placebo-treated patients. In this trial, patients taking ZEPBOUND in combination with an insulin secretagogue (e.g., sulfonylurea) had increased risk of hypoglycemia (10.3%) compared to ZEPBOUND-treated patients not taking a sulfonylurea (2.1%). There is also increased risk of hypoglycemia in patients treated with tirzepatide in combination with insulin [see Drug Interactions (7.1)]. Hypoglycemia has also been associated with ZEPBOUND and GLP-1 receptor agonists in adults without type 2 diabetes mellitus [see Adverse Reactions (6.1)]. Inform patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. In patients with diabetes mellitus, monitor blood glucose prior to starting ZEPBOUND and during ZEPBOUND treatment. The risk of hypoglycemia may be lowered by a reduction in the dose of insulin or sulfonylurea (or other concomitantly administered insulin secretagogue). 5.8 Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Tirzepatide has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy. 5.9 Suicidal Behavior and Ideation Suicidal behavior and ideation have been reported in clinical trials with other weight management products. Monitor patients treated with ZEPBOUND for the emergence or worsening of depression, suicidal thoughts or behaviors, and/or any unusual changes in mood or behavior. Discontinue ZEPBOUND in patients who experience suicidal thoughts or behaviors. Avoid ZEPBOUND in patients with a history of suicidal attempts or active suicidal ideation. 5.10 Pulmonary Aspiration During General Anesthesia or Deep Sedation ZEPBOUND delays gastric emptying [see Clinical Pharmacology (12.2)]. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking ZEPBOUND, including whether modifying preoperative fasting recommendations or temporarily discontinuing ZEPBOUND could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking ZEPBOUND. 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2)] • Acute Kidney Injury [see Warnings and Precautions (5.3)] • Acute Gallbladder Disease [see Warnings and Precautions (5.4)] • Acute Pancreatitis [see Warnings and Precautions (5.5)] • Hypersensitivity Reactions [see Warnings and Precautions (5.6)] • Hypoglycemia [see Warnings and Precautions (5.7)] • Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus [see Warnings and Precautions (5.8)] • Suicidal Behavior and Ideation [see Warnings and Precautions (5.9)] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions (5.10)] Reference ID: 5501094 7 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Patients for Weight Reduction and Long-Term Maintenance Pool of Placebo-Controlled Weight Reduction Trials in Adults with Obesity or Overweight, with or without Type 2 Diabetes (Study 1 and Study 2) ZEPBOUND was evaluated for safety in a pool of two randomized, double-blind, placebo-controlled trials that included 2,519 adult patients with obesity or overweight treated with ZEPBOUND for up to 72 weeks and a 4-week off drug follow- up period (Study 1 and Study 2) [see Clinical Studies (14.1)]. The mean age of patients was 47 years and 37% were male. The population was 72% White, 12% Asian, 8% Black or African American, and 7% American Indian or Alaska Native; 51% identified as Hispanic or Latino ethnicity. Baseline characteristics included an average BMI of 37.4 kg/m2, 29% with a BMI ≥40 kg/m2, 41% with hypertension, 37% with dyslipidemia, 25% with type 2 diabetes mellitus, 7% with obstructive sleep apnea, and 4% with cardiovascular disease. Across both trials, 4.8%, 6.3%, and 6.7% of patients treated with 5 mg, 10 mg, and 15 mg of ZEPBOUND, respectively, permanently discontinued treatment as a result of adverse reactions compared to 3.4% of patients treated with placebo. The majority of patients who discontinued ZEPBOUND due to adverse reactions did so during the first few months of treatment due to gastrointestinal adverse reactions. Common Adverse Reactions Table 1 shows common adverse reactions associated with the use of ZEPBOUND in the pool of two placebo-controlled trials for weight reduction (Study 1 and Study 2). These adverse reactions occurred more commonly with ZEPBOUND than with placebo and occurred in at least 2% of patients treated with ZEPBOUND. Table 1: Adverse Reactions (≥2% and Greater than Placebo) in ZEPBOUND-Treated Adults with Obesity or Overweight in Weight Reduction and Long-term Maintenance Trials (Study 1 and Study 2) Adverse Reaction Placebo (N=958) % ZEPBOUND 5 mg (N=630) % ZEPBOUND 10 mg (N=948) % ZEPBOUND 15 mg (N=941) % Nausea 8 25 29 28 Diarrheaa 8 19 21 23 Vomiting 2 8 11 13 Constipationb 5 17 14 11 Abdominal Painc 5 9 9 10 Dyspepsia 4 9 9 10 Injection Site Reactionsd 2 6 8 8 Fatiguee 3 5 6 7 Hypersensitivity Reactions 3 5 5 5 Eructation 1 4 5 5 Hair Loss 1 5 4 5 Gastroesophageal Reflux Disease 2 4 4 5 Flatulence 2 3 3 4 Abdominal Distension 2 3 3 4 Dizziness 2 4 5 4 Hypotensionf 0 1 1 2 a Includes diarrhea, frequent bowel movements. b Includes constipation, feces hard. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness. Reference ID: 5501094 8 d Includes multiple related adverse event terms, such as injection site bruising, injection site erythema, injection site pruritus, injection site pain, injection site rash, injection site reaction. e Includes asthenia, fatigue, lethargy, malaise. f Includes blood pressure decreased, hypotension, orthostatic hypotension. In a clinical trial for weight reduction that included an intensive lifestyle intervention lead-in period (Study 3), 287 patients were treated with ZEPBOUND for up to 72 weeks. In a randomized withdrawal trial (Study 4), 783 patients were treated with ZEPBOUND for up to 36 weeks, and 335 of these patients were treated for up to 88 weeks [see Clinical Studies (14.1)]. In Study 3, 10% of ZEPBOUND-treated patients and 2% of placebo-treated patients discontinued drug due to adverse reactions. In Study 4, 7% of patients discontinued ZEPBOUND treatment before randomized withdrawal at Week 36 due to adverse reactions. In Study 3 and Study 4, adverse reactions were similar to those reported in the two pooled ZEPBOUND clinical trials (Study 1 and Study 2). Gastrointestinal Adverse Reactions In a pool of Study 1 and 2, gastrointestinal adverse reactions occurred more frequently among patients receiving ZEPBOUND (5 mg 56%, 10 mg 56%, 15 mg 56%) than placebo (30%). More patients receiving ZEPBOUND 5 mg (1.9%), ZEPBOUND 10 mg (3.3%), and ZEPBOUND 15 mg (4.3%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.5%). The majority of nausea, vomiting, and/or diarrhea events occurred during dose escalation and decreased over time. Hypotension In a pool of Study 1 and 2, hypotension occurred more frequently among patients taking ZEPBOUND (1.6%) than patients taking placebo (0.1%). Hypotension was more frequently seen in ZEPBOUND-treated patients on concomitant antihypertensive therapy (2.2%) compared to ZEPBOUND-treated patients not on antihypertensive therapy (1.2%). Hypotension also occurred in association with gastrointestinal adverse events and dehydration. Hypersensitivity Reactions In a pool of Study 1 and 2, immediate hypersensitivity reactions (within one day after drug administration) occurred in 2.1% of ZEPBOUND-treated patients compared to 0.4% of placebo-treated patients, while non-immediate hypersensitivity reactions occurred in 3.5% of ZEPBOUND-treated patients compared to 2.7% of placebo-treated patients. Among ZEPBOUND-treated patients, hypersensitivity reactions were more frequent in those with anti-tirzepatide antibodies (6.2%) compared to those who did not develop anti-tirzepatide antibodies (3%) [see Clinical Pharmacology (12.6)]. The majority of the hypersensitivity reactions in trials were skin reactions (e.g., rash, itching). Injection Site Reactions In ZEPBOUND-treated patients in a pool of Study 1 and 2, injection site reactions were more frequent in those with anti- tirzepatide antibodies (11.3%) compared to those who did not develop anti-tirzepatide antibodies (1%) [see Clinical Pharmacology (12.6)]. Hair Loss Hair loss adverse reactions in ZEPBOUND-treated patients were associated with weight reduction. In a pool of Study 1 and 2, hair loss was reported more frequently in female than male patients in the ZEPBOUND (7.1% female versus 0.5% male) and placebo (1.3% female versus 0% male) treatment groups. No ZEPBOUND-treated patients and one placebo- treated patient discontinued study treatment due to hair loss. Other Adverse Reactions Acute Kidney Injury In a pool of Study 1 and 2, acute kidney injury was reported in 0.5% of ZEPBOUND-treated patients compared to 0.2% of placebo-treated patients. Acute Gallbladder Disease In a pool of Study 1 and 2, cholelithiasis was reported in 1.1% of ZEPBOUND-treated patients and 1% of placebo-treated patients, cholecystitis was reported in 0.7% of ZEPBOUND-treated patients and 0.2% of placebo-treated patients, and cholecystectomy was reported in 0.2% of ZEPBOUND-treated patients and no placebo-treated patients. Hypoglycemia In Study 2, a trial of patients with type 2 diabetes mellitus and BMI ≥27 kg/m2, hypoglycemia (plasma glucose <54 mg/dL) was reported in 4.2% of ZEPBOUND-treated patients versus 1.3% of placebo-treated patients. In Study 1, a trial of ZEPBOUND in adults with obesity/overweight without type 2 diabetes mellitus, there was no systematic capturing of hypoglycemia, but plasma glucose <54 mg/dL was reported in 0.3% of ZEPBOUND-treated patients versus no placebo-treated patients. Reference ID: 5501094 9 Heart Rate Increase In a pool of Study 1 and 2, treatment with ZEPBOUND resulted in a mean increase in heart rate of 1 to 3 beats per minute compared to no increase in placebo-treated patients. Dysesthesia In a pool of Study 1 and 2, dysesthesia occurred more frequently among patients receiving ZEPBOUND (5 mg 0.2%, 10 mg 0.2%, 15 mg 0.4%) than placebo (0.1%). Dysgeusia In a pool of Study 1 and 2, dysgeusia was reported by 0.4% of ZEPBOUND-treated patients and no placebo-treated patients. Dry Mouth In a pool of Study 1 and 2, dry mouth or dry throat was reported by 1% of ZEPBOUND-treated patients and 0.1% of placebo-treated patients. Laboratory Abnormalities Amylase and Lipase Increase In a pool of Study 1 and 2, treatment with ZEPBOUND resulted in mean increases from baseline in serum pancreatic amylase concentrations of 20% to 25% and serum lipase concentrations of 28% to 35%, compared to mean increases from baseline in pancreatic amylase of 2.1% and serum lipase of 5.8% in placebo-treated patients. The clinical significance of elevations in amylase or lipase with ZEPBOUND is unknown in the absence of other signs and symptoms of pancreatitis. Adverse Reactions in Patients with Obstructive Sleep Apnea ZEPBOUND was evaluated in 2 randomized, double-blind, placebo-controlled trials (Study 5 and Study 6) that included a total of 467 adult patients with moderate to severe OSA and obesity [see Clinical Studies (14.2)]. Study 5 enrolled 234 patients who were unable or unwilling to use Positive Airway Pressure (PAP) therapy and Study 6 enrolled 235 patients who were on PAP therapy. The adverse reactions observed with ZEPBOUND 10 mg or 15 mg administered subcutaneously once weekly were similar to those reported in the two pooled placebo controlled clinical trials for weight reduction (Study 1 and Study 2). 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of tirzepatide, the active ingredient in ZEPBOUND. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. Hypersensitivity: anaphylaxis, angioedema Gastrointestinal: ileus Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation. 7 DRUG INTERACTIONS 7.1 Concomitant Use with Insulin or an Insulin Secretagogue (e.g., Sulfonylurea) ZEPBOUND lowers blood glucose. When initiating ZEPBOUND, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (e.g., sulfonylureas) to reduce the risk of hypoglycemia [see Warnings and Precautions (5.7)]. 7.2 Oral Medications ZEPBOUND delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with ZEPBOUND. Monitor patients on oral medications dependent on threshold concentrations for efficacy and those with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with ZEPBOUND. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception, for 4 weeks after initiation with ZEPBOUND and for 4 weeks after each dose escalation. Hormonal Reference ID: 5501094 10 contraceptives that are not administered orally should not be affected [see Use in Specific Populations (8.3) and Clinical Pharmacology (12.2, 12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZEPBOUND (tirzepatide) during pregnancy. Pregnant patients exposed to ZEPBOUND and healthcare providers are encouraged to contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979). Risk Summary Weight loss offers no benefit to a pregnant patient and may cause fetal harm. Advise pregnant patients that weight loss is not recommended during pregnancy and to discontinue ZEPBOUND when a pregnancy is recognized (see Clinical Considerations). Available data with tirzepatide in pregnant patients are insufficient to evaluate for a drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Based on animal reproduction studies, there may be risks to the fetus from exposure to tirzepatide during pregnancy. In pregnant rats administered tirzepatide during organogenesis, fetal growth reductions and fetal abnormalities occurred at clinical exposure in maternal rats based on AUC. In rabbits administered tirzepatide during organogenesis, fetal growth reductions were observed at clinically relevant exposures based on AUC. These adverse embryo/fetal effects in animals coincided with pharmacological effects on maternal weight and food consumption (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is increased when compared to the general population. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those with obesity or overweight, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. Data Animal Data In pregnant rats given twice weekly subcutaneous doses of 0.02, 0.1, and 0.5 mg/kg tirzepatide [0.03-, 0.07-, and 0.5-fold the maximum recommended human dose (MRHD) of 15 mg once weekly based on AUC] during organogenesis, increased incidences of external, visceral, and skeletal malformations, increased incidences of visceral and skeletal developmental variations, and decreased fetal weights coincided with pharmacologically-mediated reductions in maternal body weights and food consumption at 0.5 mg/kg. In pregnant rabbits given once weekly subcutaneous doses of 0.01, 0.03, or 0.1 mg/kg tirzepatide (0.01-, 0.06-, and 0.2-fold the MRHD) during organogenesis, pharmacologically mediated effects on the gastrointestinal system resulting in maternal mortality or abortion in a few rabbits occurred at all dose levels. Reduced fetal weights associated with decreased maternal food consumption and body weights were observed at 0.1 mg/kg. In a pre- and post-natal study in rats administered subcutaneous doses of 0.02, 0.10, or 0.25 mg/kg tirzepatide twice weekly from implantation through lactation, F1 pups from F0 maternal rats given 0.25 mg/kg tirzepatide had statistically significant lower mean body weight when compared to controls from post-natal day 7 through post-natal day 126 for males and post-natal day 56 for females. 8.2 Lactation Risk Summary There are no data on the presence of tirzepatide or its metabolites in animal or human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZEPBOUND and any potential adverse effects on the breastfed infant from ZEPBOUND or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Use of ZEPBOUND may reduce the efficacy of oral hormonal contraceptives due to delayed gastric emptying. This delay is largest after the first dose and diminishes over time. Advise patients using oral hormonal contraceptives to switch to a Reference ID: 5501094 11 non-oral contraceptive method, or add a barrier method of contraception, for 4 weeks after initiation with ZEPBOUND and for 4 weeks after each dose escalation [see Drug Interactions (7.2) and Clinical Pharmacology (12.2, 12.3)]. 8.4 Pediatric Use The safety and effectiveness of ZEPBOUND have not been established in pediatric patients. 8.5 Geriatric Use In a pool of two fixed dose ZEPBOUND clinical studies for weight reduction (Study 1 and Study 2), 226 (9%) ZEPBOUND- treated patients were 65 years of age or older, and 13 (0.5%) ZEPBOUND-treated patients were 75 years of age or older at baseline. No overall differences in safety or effectiveness of ZEPBOUND have been observed between patients 65 years of age and older and younger adult patients. ZEPBOUND clinical studies in OSA (Study 5 and Study 6) did not include sufficient numbers of patients age 65 years or older to determine whether they respond differently from younger adult patients. Other reported clinical experience with tirzepatide has not identified differences in responses between the elderly and younger patients. 8.6 Renal Impairment No dosage adjustment of ZEPBOUND is recommended for patients with renal impairment. In subjects with renal impairment including end-stage renal disease (ESRD), no change in tirzepatide pharmacokinetics (PK) was observed [see Clinical Pharmacology (12.3)]. Monitor renal function in patients reporting adverse reactions to ZEPBOUND that could lead to volume depletion [see Warnings and Precautions (5.3)]. 8.7 Hepatic Impairment No dosage adjustment of ZEPBOUND is recommended for patients with hepatic impairment. In a clinical pharmacology study in subjects with varying degrees of hepatic impairment, no change in tirzepatide PK was observed [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In the event of an overdosage, contact the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. A period of observation and treatment for these symptoms may be necessary, taking into account the half-life of tirzepatide of approximately 5 days. 11 DESCRIPTION ZEPBOUND (tirzepatide) injection, for subcutaneous use, contains tirzepatide, a GIP receptor and GLP-1 receptor agonist. Tirzepatide is based on the GIP sequence and contains aminoisobutyric acid (Aib) in positions 2 and 13, a C-terminal amide, and Lys residue at position 20 that is attached to 1,20-eicosanedioic acid via a linker. The molecular weight is 4813.53 Da and the empirical formula is C225H348N48O68. Structural formula: ZEPBOUND is a clear, colorless to slightly yellow, sterile solution for subcutaneous use. Each single-dose pen or single- dose vial contains preservative-free 0.5 mL solution of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg of tirzepatide and the following excipients: sodium chloride (4.1 mg), sodium phosphate dibasic heptahydrate (0.7 mg), and water for injection. Hydrochloric acid solution and/or sodium hydroxide solution may have been added to adjust the pH. ZEPBOUND has a pH of 6.5 – 7.5. Reference ID: 5501094 12 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tirzepatide is a GIP receptor and GLP-1 receptor agonist. It contains a C20 fatty diacid that enables albumin binding and prolongs the half-life. Tirzepatide selectively binds to and activates both the GIP and GLP-1 receptors, the targets for native GIP and GLP-1. GLP-1 is a physiological regulator of appetite and caloric intake. Nonclinical studies suggest the addition of GIP may further contribute to the regulation of food intake. Both GIP receptors and GLP-1 receptors are found in areas of the brain involved in appetite regulation. Animal studies show that tirzepatide distributes to and activates neurons in brain regions involved in regulation of appetite and food intake. 12.2 Pharmacodynamics Tirzepatide lowers body weight with greater fat mass loss than lean mass loss. Tirzepatide decreases calorie intake. The effects are likely mediated by affecting appetite. Tirzepatide stimulates insulin secretion in a glucose-dependent manner and reduces glucagon secretion. Tirzepatide increases insulin sensitivity, as demonstrated in a hyperinsulinemic euglycemic clamp study in patients with type 2 diabetes mellitus after 28 weeks of treatment. These effects can lead to a reduction of blood glucose. Tirzepatide delays gastric emptying. The delay is largest after the first dose and this effect diminishes over time. 12.3 Pharmacokinetics The pharmacokinetics of tirzepatide is similar between healthy subjects, patients with overweight or obesity, and patients with OSA and obesity. Steady-state plasma tirzepatide concentrations were achieved following 4 weeks of once weekly administration. Tirzepatide exposure increases in a dose-proportional manner. Absorption Following subcutaneous administration, the median time (range) to maximum plasma concentration of tirzepatide is 24 hours (8 to 72 hours). The mean absolute bioavailability of tirzepatide following subcutaneous administration is 80%. Similar exposure was achieved with subcutaneous administration of tirzepatide in the abdomen, thigh, or upper arm. Distribution The mean [coefficient of variation (CV)%] apparent steady-state volumes of distribution of tirzepatide following subcutaneous administration in patients with overweight or obesity and patients with OSA and obesity are approximately 9.7 L (29%) and 11.8 L (37%), respectively. Tirzepatide is highly bound to plasma albumin (99%). Elimination The apparent population mean clearance of tirzepatide in patients with overweight or obesity and patients with OSA and obesity is approximately 0.06 L/h (CV% ~ 20%). The elimination half-life is approximately 5-6 days in patients with overweight or obesity, and in patients with OSA and obesity. Metabolism Tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid, and amide hydrolysis. Excretion The primary excretion routes of tirzepatide metabolites are via urine and feces. Intact tirzepatide is not observed in urine or feces. Specific Populations The intrinsic factors of age (18 to 84 years), sex, race (71% White, 11% Asian, 9% American Indian or Alaska Native, and 8% Black or African American), ethnicity, or body weight do not have a clinically relevant effect on the PK of tirzepatide. Patients with Renal Impairment Renal impairment does not impact the pharmacokinetics of tirzepatide. The pharmacokinetics of tirzepatide after a single 5 mg dose were evaluated in patients with different degrees of renal impairment (mild, moderate, severe, ESRD) compared with subjects with normal renal function. Data from clinical studies have also shown that renal impairment in patients with overweight or obesity does not impact the pharmacokinetics of tirzepatide [see Use in Specific Populations (8.6)]. Reference ID: 5501094 13 Patients with Hepatic Impairment Hepatic impairment does not impact the pharmacokinetics of tirzepatide. The pharmacokinetics of tirzepatide after a single 5 mg dose were evaluated in patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function [see Use in Specific Populations (8.7)]. Drug Interaction Studies Potential for Tirzepatide to Influence the Pharmacokinetics of Other Drugs In vitro studies have shown low potential for tirzepatide to inhibit or induce CYP enzymes, and to inhibit drug transporters. ZEPBOUND delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications [see Drug Interactions (7.2)]. The impact of tirzepatide on gastric emptying was greatest after a single dose of 5 mg and diminished after subsequent doses. Following a first dose of tirzepatide 5 mg, acetaminophen maximum concentration (Cmax) was reduced by 55%, and the median peak plasma concentration (tmax) occurred 1 hour later. After coadministration at Week 6 with tirzepatide 15 mg, there was no meaningful impact on acetaminophen Cmax and tmax. Overall acetaminophen exposure (AUC0-24hr) was not influenced. Following administration of a combined oral contraceptive (0.035 mg ethinyl estradiol and 0.25 mg norgestimate) in the presence of a single dose of tirzepatide 5 mg, mean Cmax of ethinyl estradiol, norgestimate, and norelgestromin was reduced by 59%, 66%, and 55%, while mean AUC was reduced by 20%, 21%, and 23%, respectively. A delay in tmax of 2.5 to 4.5 hours was observed. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies. The incidence of anti-drug antibodies (ADA) to ZEPBOUND was evaluated in adult patients with overweight or obesity or with OSA and obesity in clinical studies lasting 52 weeks or longer. Anti-tirzepatide antibodies were detected in 64.5% (1591/2467) of ZEPBOUND-treated patients in weight reduction clinical studies 1 and 2, and 60.6% (137/226) of ZEPBOUND-treated patients in OSA clinical studies [see Clinical Studies (14)]. Of the ZEPBOUND-treated patients in weight reduction clinical studies 40% and 16.5% of patients developed antibodies that were cross-reactive to native GIP or native GLP-1, respectively. Of the ZEPBOUND-treated patients in OSA clinical studies, 37.2% and 19.5% of patients developed antibodies that were cross reactive to native GIP and native GLP-1, respectively. Neutralizing antibodies against tirzepatide activity on the GIP or GLP-1 receptors and against native GIP or GLP-1 were detected in 2.8% and 2.7% and 0.8% and 0.1% respectively, of ZEPBOUND-treated patients in weight reduction clinical studies. No ZEPBOUND-treated patients in OSA studies developed neutralizing antibodies against tirzepatide activity on the GIP or GLP-1 receptors or against native GIP or native GLP-1. No clinically significant effect of anti-tirzepatide antibodies on pharmacokinetics or effectiveness of ZEPBOUND has been identified. More ZEPBOUND-treated patients who developed anti-tirzepatide antibodies experienced hypersensitivity reactions or injection site reactions than those who did not develop these antibodies [see Adverse Reactions (6.1)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year carcinogenicity study was conducted with tirzepatide in male and female rats at doses of 0.15, 0.50, and 1.5 mg/kg (0.1-, 0.4-, and 1-fold the MRHD of 15 mg once weekly based on AUC) administered by subcutaneous injection twice weekly. A statistically significant increase in thyroid C-cell adenomas was observed in male rats (≥0.5 mg/kg) and female rats (≥0.15 mg/kg), and a statistically significant increase in thyroid C-cell adenomas and carcinomas combined was observed in male and female rats at all doses examined. In a 6-month carcinogenicity study in rasH2 transgenic mice, tirzepatide at doses of 1, 3, and 10 mg/kg administered by subcutaneous injection twice weekly was not tumorigenic. Tirzepatide was not genotoxic in a rat bone marrow micronucleus assay. Reference ID: 5501094 14 In fertility and early embryonic development studies, male and female rats were administered twice weekly subcutaneous doses of 0.5, 1.5, or 3 mg/kg (0.3-, 1-, and 2-fold and 0.3-, 0.9-, and 2-fold, respectively, the MRHD of 15 mg once weekly based on AUC). No effects of tirzepatide were observed on sperm morphology, mating, fertility, and conception. In female rats, an increase in the number of females with prolonged diestrus and a decrease in the mean number of corpora lutea resulting in a decrease in the mean number of implantation sites and viable embryos was observed at all dose levels. These effects were considered secondary to the pharmacological effects of tirzepatide on food consumption and body weight. 14 CLINICAL STUDIES 14.1 Weight Reduction and Long-Term Maintenance Studies in Adults with Obesity or Overweight Weight Reduction in Adults with Obesity or Overweight, with or without Type 2 Diabetes Mellitus (Study 1 and Study 2) Overview of Study 1 and Study 2 The efficacy of ZEPBOUND for weight reduction in conjunction with a reduced-calorie diet and increased physical activity was studied in two randomized, double-blind, placebo-controlled fixed-dosage trials (Study 1 and Study 2) in adults aged 18 years and older. In Studies 1 and 2, all patients received a standard lifestyle intervention which included instruction on a reduced-calorie diet (approximately 500 kcal/day deficit) and increased physical activity counseling (recommended minimum of 150 min/week) that began with the first dose of study medication or placebo and continued throughout the trial. Patients also received counseling on behavior modification strategies to adhere to diet and exercise recommendations. In both trials, weight reduction was assessed after 72 weeks of treatment (at least 52 weeks at maintenance dose). Study 1 (NCT04184622) was a 72-week trial that enrolled 2,539 adult patients with obesity (BMI ≥30 kg/m2), or with overweight (BMI 27 to <30 kg/m2) and at least one weight-related comorbid condition, such as dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease; patients with type 2 diabetes mellitus were excluded. Patients were randomized in a 1:1:1:1 ratio to once weekly fixed dosage of ZEPBOUND 5 mg, ZEPBOUND 10 mg, ZEPBOUND 15 mg, or placebo, with an escalation period of up to 20 weeks followed by the maintenance period. At baseline, mean age was 45 years (range 18-84 years), 68% were female, 71% were White, 11% were Asian, 9% were American Indian/Alaska Native, and 8% were Black or African American. A total of 48% were Hispanic or Latino ethnicity. Mean baseline body weight was 104.8 kg and mean BMI was 38 kg/m2. Baseline characteristics included 32% with hypertension, 30% with dyslipidemia, 8% with obstructive sleep apnea, and 3% with cardiovascular disease. Study 2 (NCT04657003) was a 72-week trial that enrolled 938 adult patients with BMI ≥27 kg/m2 and type 2 diabetes mellitus. Patients included in the trial had HbA1c 7-10% and were treated with either diet and exercise alone, or any oral anti-hyperglycemic agent except dipeptidyl peptidase-4 (DPP-4) inhibitors or GLP-1 receptor agonists. Patients who were taking insulin or injectable GLP-1 receptor agonists for type 2 diabetes mellitus were excluded. Patients were randomized in a 1:1:1 ratio to once weekly fixed dosage of ZEPBOUND 10 mg, ZEPBOUND 15 mg, or placebo with an escalation period of up to 20 weeks followed by the maintenance period. At baseline, mean age was 54 years (range 18-85 years), 51% were female, 76% were White, 13% were Asian, and 8% were Black or African American. A total of 60% were Hispanic or Latino ethnicity. Mean baseline body weight was 100.7 kg and mean BMI was 36.1 kg/m2. Baseline characteristics included 66% with hypertension, 61% with dyslipidemia, 8% with obstructive sleep apnea, and 10% with cardiovascular disease. Results for Study 1 and Study 2 The proportions of patients who discontinued study drug in Study 1 were 14.3%, 16.4%, and 15.1% for the 5 mg, 10 mg, and 15 mg ZEPBOUND-treated groups, respectively, and 26.4% for the placebo-treated group. The proportions of patients who discontinued study drug in Study 2 were 9.3% and 13.8% for the 10 mg and 15 mg ZEPBOUND-treated groups, respectively, and 14.9% for the placebo-treated group. For Studies 1 and 2, weight reduction was assessed after 72 weeks of treatment (at least 52 weeks at maintenance dose). In both studies, the primary efficacy parameters were mean percent change in body weight and the percentage of patients achieving ≥5% weight reduction from baseline to Week 72 (see Table 2). After 72 weeks of treatment, ZEPBOUND resulted in a statistically significant reduction in body weight compared with placebo, and greater proportions of patients treated with ZEPBOUND 5 mg, 10 mg, and 15 mg achieved at least 5% weight reduction compared to placebo. Among patients treated with ZEPBOUND 10 mg and 15 mg, greater proportions of patients achieved at least 10%, 15%, and 20% weight reduction compared to placebo (see Table 2). A reduction in body weight was observed with ZEPBOUND irrespective of age, sex, race, ethnicity, baseline BMI, and glycemic status. Reference ID: 5501094 15 Table 2: Changes in Body Weight at Week 72 in Studies 1 and 2 in Patients with Obesity or Overweight Study 1 Study 2 Intention-to-Treat (ITT) Populationa Placebo N = 643 ZEPBOUND 5 mg N = 630 ZEPBOUND 10 mg N = 636 ZEPBOUND 15 mg N = 630 Placebo N = 315 ZEPBOUND 10 mg N = 312 ZEPBOUND 15 mg N = 311 Body Weight Baseline mean (kg) 104.8 102.9 105.8 105.6 101.7 100.9 99.6 % Change from baselineb -3.1 -15.0 -19.5 -20.9 -3.2 -12.8 -14.7 % Difference from placebob (95% CI) -11.9 (-13.4, _10.4)d -16.4 (_17.9, -14.8)d -17.8 (_19.3, -16.3)d -9.6 (-11.1, -8.1)d -11.6 (-13.0, -10.1)d % of Patients losing ≥5% body weight 34.5 85.1 88.9 90.9 32.5 79.2 82.8 % Difference from placebo (95% CI) 50.3 (44.3, 56.2)c,d 54.6 (49.1, 60.0)c,d 56.4 (50.9, 62.0)c,d 46.8 (39.5, 54.1)c,d 50.4 (43.1, 57.8)c,d % of Patients losing ≥10% body weight 18.8 68.5 78.1 83.5 9.5 60.5 64.8 % Difference from placebo (95% CI) 49.3 (43.6, 54.9)c,e 59.5 (54.2, 64.9)c,d 64.8 (59.6, 70.1)c,d 51.0 (44.4, 57.7)c,d 55.3 (48.6, 62.0)c,d % of Patients losing ≥15% body weight 8.8 48.0 66.6 70.6 2.7 39.7 48.0 % Difference from placebo (95% CI) 38.7 (33.6, 43.7)c,e 58.1 (53.2, 63.0)c,d 62.0 (57.2, 66.8)c,d 37.0 (31.1, 42.9)c,d 45.4 (39.4, 51.4)c,d % of Patients losing ≥20% body weight 3.1 30.0 50.1 56.7 1.0 21.5 30.8 % Difference from placebo (95% CI) 26.6 (22.4, 30.7)c,e 47.3 (42.7, 51.9)c,d 53.8 (49.3, 58.3)c,d 20.5 (15.7, 25.4)c,d 29.7 (24.3, 35.0)c,d Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; N = number of patients randomly assigned to study drug. a The intention-to-treat population includes all randomly assigned patients. For Study 1 at Week 72, body weight was missing for 21.6%, 10.2%, 10.5%, and 9.4% of patients randomly assigned to placebo, ZEPBOUND 5 mg, 10 mg, and 15 mg, respectively. For Study 2 at Week 72, body weight was missing for 11.1%, 4.8%, and 8.4% of patients randomly assigned to placebo, ZEPBOUND 10 mg, and 15 mg, respectively. The missing values were imputed by a hybrid approach using retrieved dropouts from the same treatment group (if missing not due to COVID-19) or using all non-missing data assuming missing at random (for missing solely due to COVID-19). b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. c Analyzed using logistic regression adjusted for baseline value. d p-value<0.001 (unadjusted 2-sided) for superiority, controlled for type I error rate. e Not controlled for type I error rate. The cumulative frequency distributions of change in body weight are shown in Figure 1 for Study 1 and Figure 2 for Study 2. One way to interpret this figure is to select a change in body weight of interest on the horizontal axis and note the corresponding proportions of patients (vertical axis) in each treatment group who achieved at least that degree of weight reduction. For example, note that the vertical line arising from -10% in Figure 1 intersects the ZEPBOUND 15 mg and placebo curves at approximately 83.5%, and 18.8%, respectively, which correspond to the values shown in Table 2. Reference ID: 5501094 16 Figure 1: Changes in Body Weight (%) from Baseline to Week 72 in Study 1 in Patients with Obesity or Overweight (without Type 2 Diabetes) Note: Based on average percent weight change of each randomized patient within each specific treatment arm from 100 imputed datasets including observed data and imputed data using hybrid approach for missing values. Reference ID: 5501094 17 Figure 2: Changes in Body Weight (%) from Baseline to Week 72 in Study 2 in Patients with Obesity or Overweight and Type 2 Diabetes Note: Based on average percent weight change of each randomized patient within each specific treatment arm from 100 imputed datasets including observed data and imputed data using hybrid approach for missing values. The time courses of weight reduction with ZEPBOUND and placebo from baseline through Week 72 are depicted in Figure 3 for Study 1 and Figure 4 for Study 2. Reference ID: 5501094 18 Figure 3: Change from Baseline (%) in Body Weight in Study 1 in Patients with Obesity or Overweight (without Type 2 Diabetes) Note: Displayed results are from the Intent-to-Treat Population. (1) Observed mean value from Week 0 to Week 72, and (2) least-squares mean ± standard error at Week 72 hybrid imputation (HI). Reference ID: 5501094 19 Figure 4: Change from Baseline (%) in Body Weight in Study 2 in Patients with Obesity or Overweight and Type 2 Diabetes Note: Displayed results are from the Intent-to-Treat Population. (1) Observed mean value from Week 0 to Week 72, and (2) least squares mean ± standard error at Week 72 hybrid imputation (HI). Changes in waist circumference and cardiometabolic parameters with ZEPBOUND are shown in Table 3 for Study 1 and Study 2. Table 3: Changes in Anthropometry and Cardiometabolic Parameters at Week 72 in Studies 1 and 2 in Patients with Obesity or Overweight Study 1 Study 2 Intention-to-Treat (ITT) Populationa Placebo N = 643 ZEPBOUND 5 mg N = 630 ZEPBOUND 10 mg N = 636 ZEPBOUND 15 mg N = 630 Placebo N = 315 ZEPBOUND 10 mg N = 312 ZEPBOUND 15 mg N = 311 Waist Circumference (cm) Baseline mean 114.0 113.2 114.8 114.4 116.0 114.2 114.6 Change from baselineb -4.0 -14.0 -17.7 -18.5 -3.3 -10.8 -13.1 Difference from placebob (95% CI) -10.1 (-11.6, -8.6)e -13.8 (-15.2, -12.3)d -14.5 (-15.9, -13.0)d -7.4 (-9.0, -5.9)d -9.8 (-11.2, -8.3)d Systolic Blood Pressure (mmHg) Baseline mean 122.9 123.6 123.8 123.0 131.0 130.6 130.0 Change from baselineb -1.0 -6.6 -7.7 -7.4 -1.2 -5.6 -7.1 Difference from placebob (95% CI) -5.6 (-7.2, -3.9)e -6.7 (-8.4, -5.0)e -6.4 (-8.0, -4.8)e -4.4 (-6.7, -2.1)e -5.9 (-8.3, -3.6)e Reference ID: 5501094 20 Diastolic Blood Pressure (mmHg) Baseline mean 79.6 79.3 79.9 79.3 79.4 80.2 79.7 Change from baselineb -0.8 -4.9 -5.0 -4.5 -0.3 -2.1 -2.9 Difference from placebob (95% CI) -4.1 (-5.2, -3.0)e -4.2 (-5.3, -3.0)e -3.7 (-4.8, -2.7)e -1.8 (-3.3, -0.4)e -2.7 (-4.2, -1.2)e Pulse Rate (beats per minute) Baseline mean 72.9 72.4 71.8 72.4 74.8 75.9 75.6 Change from baselinef 0.1 0.6 2.3 2.6 -0.5 0.6 1.0 Difference from placebof (95% CI) 0.5 (-0.5, 1.5)e 2.2 (1.2, 3.2)e 2.5 (1.5, 3.4)e 1.2 (-0.1, 2.5)e 1.5 (0.2, 2.8)e Total Cholesterol (mg/dL) Baseline meang 187.5 187.1 190.6 187.5 174.9 173.9 167.0 % change from baselineb -1.8 -3.8 -4.4 -6.3 2.8 -2.8 -1.0 Relative difference from placebob (95% CI) -2.1 (-4.5, 0.4)c,e -2.7 (-5.1, -0.2)c,e -4.6 (-6.8, -2.2)c,e -5.5 (-8.7, -2.2)c,e -3.8 (-7.1, -0.3)c,e LDL Cholesterol (mg/dL) Baseline meang 109.4 108.7 112.3 109.3 92.4 90.5 85.7 % change from baselineb -1.7 -4.6 -5.6 -7.1 7.4 1.8 4.1 Relative difference from placebob (95% CI) -2.9 (-6.6, 0.9)c,e -4.0 (-7.5, -0.5)c,e -5.5 (-8.9, -2.0)c,e -5.2 (-10.1, 0.1)c,e -3.0 (-8.4, 2.6)c,e HDL Cholesterol (mg/dL) Baseline meang 46.6 47.6 47.6 47.6 42.7 43.8 42.2 % change from baselineb -0.7 6.9 9.2 8.0 0.2 8.2 9.7 Relative difference from placebob (95% CI) 7.7 (4.6, 10.8)c,e 9.9 (6.7, 13.2)c,e 8.7 (5.7, 11.8)c,e 8.0 (4.2, 11.8)c,e 9.5 (5.6, 13.5)c,e Non-HDL Cholesterol (mg/dL) Baseline meang 138.3 137.0 140.4 137.5 129.6 127.2 121.9 % change from baselineb -2.3 -8.0 -9.4 -11.7 3.7 -6.6 -5.2 Relative difference from placebob (95% CI) -5.8 (-8.9, -2.6)c,e -7.2 (-10.3, -4.1)c,e -9.6 (-12.4, -6.6)c,e -9.9 (-14.1, -5.6)c,e -8.5 (-12.9, -4.0)c,e Triglycerides (mg/dL) Baseline meang 130.8 128.7 125.7 128.1 165.0 158.8 158.5 % change from baselineb -5.6 -21.2 -23.8 -29.1 -3.3 -27.1 -27.3 Relative difference from placebob (95% CI) -16.5 (-21.2, -11.4)c,e -19.3 (-23.9, -14.4)c,e -24.9 (-29.1, -20.4)c,e -24.6 (-30.0, -18.7)c,e -24.8 (-30.3, -18.9)c,e HbA1c (%) Baseline mean 5.6 5.6 5.5 5.6 8.0 8.0 8.1 Change from baselineb -0.1 -0.4 -0.4 -0.4 -0.5 -2.1 -2.1 Difference from placebob (95% CI) -0.3 (-0.3, -0.2)e -0.4 (-0.4, -0.3)e -0.4 (-0.4, -0.3)e -1.6 (-1.7, -1.4)d -1.6 (-1.8, -1.4)d Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; N = number of patients randomly assigned to study drug. a The intention-to-treat population includes all randomly assigned patients. The missing values were imputed by a hybrid approach using retrieved dropouts from the same treatment group (if missing not due to COVID-19) or using all non-missing data assuming missing at random (for missing solely due to COVID-19). b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. c Analyzed using log-transformed data. Reference ID: 5501094 21 d p-value<0.001 (unadjusted 2-sided) for superiority, controlled for type I error rate. e Not controlled for type I error rate. f Least-squares mean from mixed model for repeated measures adjusted for baseline value and other stratification factors. g Baseline value is the geometric mean. Weight Reduction Following Intensive Lifestyle Intervention in Adults with Obesity or Overweight (Study 3) Overview of Study 3 Study 3 (NCT04657016) was an 84-week trial with a 12-week intensive lifestyle intervention lead-in period (Week -12 to Week 0), followed by a 72-week randomized treatment period of ZEPBOUND versus placebo (Week 0 to Week 72) with a standard lifestyle intervention. Only patients who lost ≥5% body weight during the 12-week intensive lifestyle lead-in period entered the 72-week randomized treatment period. The trial initially enrolled 806 adult patients (aged 18 years and older) with obesity (BMI ≥30 kg/m2), or with overweight (BMI 27 to <30 kg/m2) and at least one weight-related comorbid condition, such as dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease; patients with type 2 diabetes mellitus were excluded. During the intensive lifestyle intervention lead-in period, lifestyle instruction was delivered 8 times over 12 weeks by a dietician or dietician-equivalent, with all patients receiving instruction to exercise for at least 150 minutes per week and to reduce their caloric intake to approximately 1,200 kcal/day (females) or 1,500 kcal/day (males). Patients also received counseling on behavior modification strategies to adhere to diet and exercise recommendations. At the end of the 12-week intensive lifestyle intervention lead-in period, 579 patients who achieved ≥5% weight reduction were randomized in a 1:1 ratio to ZEPBOUND or placebo for 72 weeks. ZEPBOUND dosages were escalated over a period of up to 20 weeks to a maximum tolerated dosage (MTD) of 10 mg or 15 mg subcutaneous once weekly. During the randomized treatment period, patients received a standard lifestyle instruction every 12 weeks on reduced-calorie diet (approximately 500 kcal/day deficit) and increased physical activity (recommended minimum of 150 min/week) that began with the first dose of ZEPBOUND or placebo and continued throughout the 72-week treatment period; behavior modification strategies were recommended as needed. Weight reduction was assessed after 72 weeks of treatment (at least 52 weeks at maintenance dose). For the 579 patients who were randomized, mean body weight at enrollment prior to entering the 12-week lifestyle lead-in period (Week -12) was 109.5 kg and mean BMI was 38.6 kg/m2. At randomization (Week 0), after the 12-week intensive lifestyle lead-in period, mean body weight was 101.9 kg and mean BMI was 35.9 kg/m2. The mean age of patients randomized to treatment was 46 years (range 18-77 years), 63% were female, 86% were White, 11% were Black or African American, and 1% were Asian. A total of 54% were Hispanic or Latino ethnicity. Baseline characteristics for the 579 randomized patients included 34% with hypertension, 26% with dyslipidemia, 10% with obstructive sleep apnea, and 2% with cardiovascular disease. Results for Study 3 At the end of the 12-week intensive lifestyle intervention lead-in, for patients who subsequently entered the randomized treatment period (n=579), the average body weight loss due to lifestyle was 6.9% (Week -12 to Week 0). Eighty-six percent (86%) of ZEPBOUND-treated patients had a maximum tolerated dosage of 15 mg weekly based on their final dose during the double-blind treatment period. The time course of weight reduction during the lead-in and from Week 0 to Week 72 with ZEPBOUND and placebo are depicted in Figure 5. Reference ID: 5501094 22 Figure 5: Change in Body Weight (%) After 12-Week Intensive Lifestyle Intervention Lead-In Followed by Randomized Treatment and a Standard Lifestyle Intervention (Study 3) in Patients with Obesity or Overweight Note: Displayed results are from the randomized Population. (1) Observed mean value from Week -12 to Week 72, and (2) least squares mean ± standard error at Week 72 hybrid imputation (HI). Change from Week -12 is not a primary endpoint in Study 3. The proportions of patients who discontinued study drug after randomization were 21.3% for the ZEPBOUND-treated group and 30.5% for the placebo-treated group. For Study 3, the primary efficacy parameters were mean percent change in body weight from randomization (Week 0) to Week 72 and the percentage of patients achieving ≥5% weight reduction from randomization (Week 0) to Week 72. Amongst randomized patients who already lost ≥5% body weight during the 12-week intensive lifestyle lead-in period, subsequent treatment with ZEPBOUND resulted in a statistically significant reduction in body weight compared to placebo from randomization (Week 0) to Week 72. A greater proportion of patients treated with ZEPBOUND achieved at least 5%, 10%, 15%, and 20% weight reduction from Week 0 to Week 72 compared to placebo (see Table 4). Table 4: Changes in Body Weight After 12-Week Intensive Lifestyle Intervention Lead-In Followed by Randomized Treatment and a Standard Lifestyle Intervention (Study 3) in Patients with Obesity or Overweight Study 3 N = 579a Body weight Mean (kg) at Week -12 109.5 Intention-to-Treat (ITT) Populationa,b Placebo N = 292 ZEPBOUND MTD (10 mg or 15 mg) N = 287 Body Weight Mean (kg) at Week 0 101.3 102.5 Reference ID: 5501094 23 % Change from randomization at Week 72c 2.5 -18.4 % Difference from placebo, at Week 72c (95% CI) -20.8 (-23.2, -18.5)e % of Patients losing ≥5% body weight 16.5 87.5 % Difference from placebo (95% CI) 71.1 (63.6, 78.5)d,e % of Patients losing ≥10% body weight 8.9 76.7 % Difference from placebo (95% CI) 67.9 (60.7, 75.1)d,e % of Patients losing ≥15% body weight 4.2 65.4 % Difference from placebo (95% CI) 61.3 (54.5, 68.1)d,e % of Patients losing ≥20% body weight 2.2 44.7 % Difference from placebo (95% CI) 42.6 (36.0, 49.1)d,e Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; MTD = maximum tolerated dose; N = number of patients randomly assigned to study drug. a The intent-to-treat population included only randomized patients with ≥5% weight loss at Week 0 after 12 weeks of intensive lifestyle intervention. During the 12-week lead-in period, 227 of 806 patients (28.2%) discontinued from the study. Of these 141 (17.5%) discontinued due to not achieving the randomization criteria of ≥5% weight reduction. b The intent-to-treat population includes all randomly assigned patients. For Study 3 at Week 72, body weight was missing for 23.6% and 8.7% of patients randomly assigned to placebo and ZEPBOUND MTD (10 or 15 mg). The missing values were imputed by a hybrid approach using retrieved dropouts from the same treatment group (if missing not due to COVID-19) or using all non-missing data assuming missing at random (for missing solely due to COVID-19). c Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. d Analyzed using logistic regression adjusted for baseline value. e p-value<0.001 (unadjusted 2-sided) for superiority, controlled for type I error rate. Changes in waist circumference and cardiometabolic parameters are shown in Table 5. Table 5: Changes in Anthropometry and Cardiometabolic Parameters After 12-Week Intensive Lifestyle Intervention Lead-In Followed by Randomized Treatment and a Standard Lifestyle Intervention (Study 3) in Patients with Obesity or Overweight Intention-to- Treat (ITT) Populationa All Randomized Patients N=579 Placebo N=292 ZEPBOUND MTD (10 mg or 15 mg) N=287 Baseline (Week -12) Change from Week -12 to Week 0 Randomization (Week 0) Change from Week 0 to Week 72 Randomization (Week 0) Change from Week 0 to Week 72 Difference from placebo, Week 0 to Week 72 (95% CI) Waist circumference (cm)h 116.1 -6.7 109.6 0.2b 109.3 -14.6b -14.8b (-17.2, -12.5)d Systolic Blood Pressure (mmHg)h 126.2 -5.0 120.8 3.5b 121.7 -5.1b -8.6b (-11.3, -6.0)e Diastolic Blood Pressure (mmHg)h 81.7 -2.9 78.3 2.1b 79.3 -3.2b -5.3b (-6.9, -3.7)e Pulse Rate (beats per minute)h 73.0 -1.6 70.7 0.9f 72.2 2.7f 1.8f (0.3, 3.4)e HbA1c (%)h 5.5 -0.1 5.4 0.0b 5.3 -0.4b -0.4b (-0.5, -0.3)e Reference ID: 5501094 24 Total Cholesterol (mg/dL)g,h 190.2 -8.6 181.6 4.3 181.7 -2.4 -6.4b (-9.0, -3.6)c,e LDL Cholesterol (mg/dL)g,h 111.6 -3.5 107.5 4.4 108.0 -5.6 -9.6b (-13.7, -5.4)c,e HDL Cholesterol (mg/dL)g,h 48.4 -1.2 47.8 5.4 46.9 15.2 9.3b (4.5, 14.2)c,e Non-HDL Cholesterol (mg/dL)g,h 139.2 -7.4 131.5 4.4 132.4 -8.8 -12.6b (-15.9, -9.3)c,e Triglycerides (mg/dL)g,h 123.1 -19.8 108.8 2.1 111.7 -23.5 -25.1b (-30.9, -18.9)c,e Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; N = number of patients randomly assigned to study drug. a The intent-to-treat population included all randomly assigned patients. The missing values were imputed by a hybrid approach using retrieved dropouts from the same treatment group (if missing not due to COVID-19) or using all non-missing data assuming missing at random (for missing solely due to COVID-19). b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. c Analyzed using log-transformed data. d p-value<0.001 (unadjusted 2-sided) for superiority, controlled for type I error rate. e Not controlled for type I error rate. f Least-squares mean from mixed model for repeated measures adjusted for baseline value and other stratification factors. g Baseline and randomization values are the geometric mean. h Observed means are shown for change from Week -12 to Week 0. Least-square means are shown for change from Week 0 to Week 72. Weight Reduction Following Randomized Withdrawal in Adults with Obesity or Overweight (Study 4) Overview of Study 4 Study 4 (NCT04660643) was an 88-week randomized withdrawal trial in which all patients received open-label ZEPBOUND during a 36-week lead-in period, followed by randomization to either continue ZEPBOUND or switch to placebo for 52 weeks. The trial enrolled 783 adult patients (aged 18 years and older) with obesity (BMI ≥30 kg/m2), or with overweight (BMI 27 to <30 kg/m2) and at least one weight-related comorbid condition, such as dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease; patients with type 2 diabetes mellitus were excluded. All patients received a standard lifestyle intervention which included instruction on a reduced-calorie diet (approximately 500 kcal/day deficit) and increased physical activity counseling (recommended minimum of 150 min/week) that began with the first dose of ZEPBOUND, during the lead-in period, and continued throughout the trial. During the 36-week open-label ZEPBOUND lead-in period, ZEPBOUND dosages were escalated over a period of up to 20 weeks to an MTD of 10 mg or 15 mg subcutaneous once weekly. After the lead-in period, patients were randomized at Week 36 to continue ZEPBOUND or switch to placebo for 52 weeks. Of the 783 patients who started ZEPBOUND at Week 0, 14.4% discontinued treatment before randomization at Week 36, and adverse events were the most common reason for discontinuation (6.8%). At Week 36, a total of 670 patients were randomized in a 1:1 ratio to ZEPBOUND MTD or placebo for 52 weeks. For the 670 randomized patients, at study entry (Week 0) mean body weight was 107.3 kg and mean BMI was 38.4 kg/m2, and at randomization (Week 36, after the open-label ZEPBOUND lead-in period) mean body weight was 85.2 kg and mean BMI was 30.5 kg/m2. Among the randomized patients, the mean age was 49 years (range 19-81 years), 71% were female, 80% were White, 11% were Black or African American, and 7% were Asian. A total of 44% were Hispanic or Latino ethnicity. Baseline characteristics for the 670 randomized patients included 35% with hypertension, 32% with dyslipidemia, 12% with obstructive sleep apnea, and 6% with cardiovascular disease. Results for Study 4 At the end of the 36-week open-label ZEPBOUND lead-in period, of the 670 randomized patients, 93% were on ZEPBOUND MTD of 15 mg weekly and 7% were on MTD of 10 mg weekly. After open-label ZEPBOUND treatment, randomized patients (n=670) had an average body weight loss of 20.9% (Week 0 to Week 36). The time course of weight reduction from Week 0 through Week 88 is depicted in Figure 6. Reference ID: 5501094 25 Figure 6: Change in Body Weight (%) After 36-Week Open-Label Treatment Followed by Randomized Withdrawal (Study 4) in Patients with Obesity or Overweight Note: Displayed results are from the randomized population. (1) Displayed results are observed mean value from Week 0 to Week 88 and (2) least squares mean ± standard error at Week 88 hybrid imputation (HI). Change from Week 0 was not a primary endpoint in Study 4. The proportions of patients who discontinued study drug after randomization at Week 36 were 10.4% for the ZEPBOUND- treated group and 17.9% for the placebo-treated group. For Study 4, the primary efficacy parameter was mean percent change in body weight from randomization (Week 36) to Week 88. After weight loss with ZEPBOUND treatment during the open-label lead-in period (Week 0 to Week 36), continued treatment with ZEPBOUND from randomization (Week 36) to Week 88 resulted in a statistically significant reduction in body weight compared with placebo (see Table 6). Table 6: Changes in Body Weight After 36-Week Open-Label Treatment Followed by Randomized Withdrawal (Study 4) in Patients with Obesity or Overweight Study 4 N=670a Body weight Mean at Week 0 (kg) 107.3 Intention-to-Treat (ITT) Populationa Placebo N=335 ZEPBOUND (MTD 10 mg or 15 mg) N=335 Body Weight Mean at Week 36 (kg) 85.8 84.6 Reference ID: 5501094 26 % change from Week 36 at Week 88b 14.0 -5.5 % difference from placebo at Week 88 (95% CI)b -19.4 (-21.2, -17.7)d Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; MTD = maximum tolerated dose; N = number of patients randomly assigned to study drug. a The intent-to-treat population included all randomly assigned patients and did not include 113 patients who were enrolled but not randomized. At Week 88, body weight was missing for 13.7% and 7.5% of patients randomly assigned to placebo and ZEPBOUND MTD (10 or 15 mg), respectively. The missing values were imputed by a hybrid approach using retrieved dropouts from the same treatment group (if missing not due to COVID-19) or using all non-missing data assuming missing at random (for missing solely due to COVID-19). b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. c Analyzed using logistic regression adjusted for baseline value. d p-value<0.001 (unadjusted 2-sided) for superiority, controlled for type I error rate. Changes in waist circumference and cardiometabolic parameters in Study 4 are shown in Table 7. Table 7: Mean Changes in Anthropometry and Cardiometabolic Parameters After 36-Week Open-Label Treatment Followed by Randomized Withdrawal (Study 4) in Patients with Obesity or Overweight Intention-to- Treat (ITT) Populationa All Randomized Patients N=670 Placebo N=335 ZEPBOUND MTD (10 mg or 15 mg) N=335 Baseline (Week 0) Change from Week 0 to Week 36 Randomization (Week 36) Change from Week 36 to Week 88 Randomization (Week 36) Change from Week 36 to Week 88 Difference from placebo, Week 36 to Week 88 (95% CI) Waist circumference (cm)h 115.2 -17.8 98.2 7.8b 96.8 -4.3b -12.1b (-13.5, -10.6)d Systolic Blood Pressure (mmHg)h 126.1 -11.2 114.8 8.2b 115.0 2.0b -6.2b (-8.2, -4.3)e Diastolic Blood Pressure (mmHg)h 80.9 -5.1 76.2 3.2b 75.4 -0.7b -3.8b (-5.2, -2.4)e Pulse Rate (beats per minute)h 72.5 5.0 77.8 -5.2f 77.1 -2.1f 3.1f (1.9, 4.3)e HbA1c (%)h 5.5 -0.5 5.0 0.3b 5.1 -0.0b -0.3b (-0.3, -0.2)e Total Cholesterol (mg/dL)g,h 188.3 -12.4 176.1 8.0 175.9 2.7 -4.9b (-7.4, -2.4)c,e LDL Cholesterol (mg/dL)g,h 108.6 -1.9 107.6 3.2 105.9 -3.5 -6.5b (-10.0, -2.9)c,e HDL Cholesterol (mg/dL)g,h 49.9 -2.7 47.3 14.8 47.7 18.7 3.4b (0.2, 6.6)c,e Non-HDL Cholesterol (mg/dL)g,h 135.8 -9.8 126.3 5.1 126.0 -3.4 -8.1b (-11.3, -4.8)c,e Triglycerides (mg/dL)g,h 121.4 -40.4 85.5 13.5 90.9 -4.8 -16.1b (-21.7, -10.0)c,e Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; N = number of patients randomly assigned to study drug. a The intent-to-treat population included all randomly assigned patients. The missing values were imputed by a hybrid approach using retrieved dropouts from the same treatment group (if missing not due to COVID-19) or using all non-missing data assuming missing at random (for missing solely due to COVID-19). b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. c Analyzed using log-transformed data. d p-value<0.001 (unadjusted 2-sided) for superiority, controlled for type I error rate. e Not controlled for type I error rate. Reference ID: 5501094 27 f Least-squares mean from mixed model for repeated measures adjusted for baseline value and other stratification factors. g Baseline and randomization values are the geometric mean. h Observed means are shown for change from Week 0 to Week 36. Least-square means are shown for change from Week 36 to Week 88. 14.2 Obstructive Sleep Apnea Studies in Adults with Obesity Overview of Study 5 and Study 6 The efficacy of ZEPBOUND for moderate to severe obstructive sleep apnea (OSA) (apnea-hypopnea index [AHI] ≥15) in patients with obesity (BMI ≥30 kg/m2) was evaluated in a master protocol clinical trial (NCT05412004) that included two randomized, double-blind, placebo-controlled trials (Study 5 and Study 6) of 52 weeks duration. The two trials enrolled a total of 469 adult patients. In Studies 5 and 6, patients were randomized in a 1:1 ratio to receive ZEPBOUND or placebo for 52 weeks. ZEPBOUND dosages were escalated over a period of up to 20 weeks to maximum tolerated dosage (MTD) of 10 mg or 15 mg subcutaneous once weekly [see Dosage and Administration (2.1, 2.2)]. Patients with type 2 diabetes mellitus were excluded and all patients received instruction on a reduced-calorie diet and increased physical activity counseling throughout the study. Study 5 enrolled 234 adult patients with moderate to severe OSA and obesity who were unable or unwilling to use Positive Airway Pressure (PAP) therapy. Patients had a mean age of 48 years (range: 20 to 76 years), 67% were male, 66% were White, 20% were Asian, 8% were American Indian/Alaska Native, and 6% were Black or African American. A total of 42% were Hispanic or Latino ethnicity. Study 6 enrolled 235 adult patients with moderate to severe OSA and obesity who were on PAP therapy. Patients had a mean age of 52 years (range: 26 to 79 years), 72% were male, 73% were White, 14% were Asian, 8% were American Indian/Alaska Native, and 5% were Black or African American. A total of 32% were Hispanic or Latino ethnicity. Table 8 describes the baseline disease characteristics of patients in Studies 5 and 6. Table 8: Baseline Disease Characteristics of Patients with OSA and Obesity in Study 5 and Study 6 Study 5 (N=234) Study 6 (N=235) Baseline AHI (events/hour), mean (SD) 51.5 (31) 49.5 (26.7) Moderate OSA, %a 35.2 30.9 Severe OSA, %b 63.1 68.2 ESS Total, mean (SD) 10.5 (5.2) 10 (4.6) Total Hypoxic Burden (% min/hour), mean (SD) 208.4 (189.1) 193 (174.6) BMI (kg/m2), mean (SD) 39.1 (7) 38.7 (6) Pre-diabetes, % 65 56.6 Hypertension, % 75.6 77.4 Cardiac disorders, % 10.3 11.1 Dyslipidemia, % 80.8 83.8 Abbreviations: AHI = Apnea-Hypopnea Index; BMI = body-mass index; ESS = Epworth Sleepiness Score; OSA = obstructive sleep apnea; SD = standard deviation. a Moderate OSA was defined as an AHI ≥15 – 30 events/hour on polysomnogram at baseline. b Severe OSA was defined as an AHI ≥30 events/hour on polysomnogram at baseline. Results for Study 5 and Study 6 The primary endpoint for Studies 5 and 6 was the change from baseline in the apnea-hypopnea index (AHI) at Week 52. Patients in Study 5 were unable or unwilling to use PAP therapy, and patients in Study 6 were on PAP therapy and instructed to suspend PAP for 7 days prior to assessment of the primary endpoint. The clinical studies for OSA did not evaluate the timing or appropriateness of PAP discontinuation in patients who were previously compliant with PAP therapy. In Studies 5 and 6, treatment with ZEPBOUND for 52 weeks resulted in a statistically significant reduction in AHI compared with placebo, and greater proportions of patients treated with ZEPBOUND achieved remission or mild non- Reference ID: 5501094 28 symptomatic OSA compared to placebo. Table 9 provides the efficacy results for Studies 5 and 6. A reduction in AHI was observed with ZEPBOUND irrespective of age, sex, ethnicity, baseline BMI, or baseline OSA severity. In both Studies 5 and 6, patients treated with ZEPBOUND achieved a greater reduction in systolic blood pressure and high-sensitivity C- reactive protein levels compared to placebo. Table 9: Changes in Apnea-Hypopnea Index (AHI), Hypoxic Burden, and Body Weight at Week 52 in Study 5 and Study 6 Modified Intent-to-Treat (mITT) Populationa Study 5 Study 6 Placebo N = 120 ZEPBOUND MTD (10 mg or 15 mg) N = 114 Placebo N = 114 ZEPBOUND MTD (10 mg or 15 mg) N = 119 AHI (events/hr) Baseline mean 50.1 52.9 53.1 46.1 Change from baselineb -5.3 -25.3 -5.5 -29.3 Difference from placebob (95% CI) -20 (-25.8, -14.2)e -23.8 (-29.6, -17.9)e % change in AHI % change from baselineb -3 -50.7 -2.5 -58.7 % difference from placebob (95% CI) -47.7 (-65.8, -29.6)e -56.2 (-73.7, -38.7)e % of patients with ≥50% reduction in AHId 19 61.2 23.3 72.4 % difference from placebo (95% CI) 42.8 (30.8, 54.8)e 48.6 (36.6, 60.7)e Remission or mild non-symptomatic OSA % of Patients with AHI <5 or AHI 5-14 and ESS≤10d 15.9 42.2 14.3 50.2 % difference from placebo (95% CI) 28.7 (18.3, 39.2)e 33.2 (22.1, 44.3)e Sleep apnea-specific hypoxic burden (% min/h) Baseline meanf 137.8 153.6 142.1 132.2 Change from baselineb -25.1 -95.2 -41.7 -103 Difference from placebob (95% CI) -70.1 (-90.9, -49.3)c,e -61.3 (-84.7, -37.9)c,e Body weight (kg) Baseline mean 112.8 116.7 115.1 115.8 % change from baselineb -1.6 -17.7 -2.3 -19.6 % difference from placebob (95% CI) -16.1 (-18, -14.2)e -17.3 (-19.3, -15.3)e Abbreviations: AHI = Apnea-Hypopnea Index; ANCOVA = analysis of covariance; CI = confidence interval; ESS = Epworth Sleepiness Scale; h = hour; MTD = maximum tolerated dose; N = number of participants randomly assigned and received at least 1 dose of study drug. a Analyses were based on the modified intent-to-treat population which was defined as randomly assigned participants who were exposed to at least 1 dose of study intervention; two participants in Study 6 were randomized but did not receive study drug. b Least-squares mean from ANCOVA adjusted for baseline values and stratification factors, with multiple imputation for missing data at Week 52. c Analyzed using log transformed data. d Calculated by combining proportion of participants achieving target in imputed datasets. e p-value <0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. f Baseline value is the geometric mean. The time course of change in AHI with ZEPBOUND and placebo from baseline through Week 52 are shown in Figure 7 for Study 5. Similar results were demonstrated for Study 6. Reference ID: 5501094 29 Figure 7: Change from Baseline in Apnea-Hypopnea Index (AHI) Through Week 52 (Study 5) Abbreviations: AHI = Apnea-Hypopnea Index; ANCOVA = analysis of covariance; MI = multiple imputation; MTD = maximum tolerated dose. Note: Displayed results are from modified Intent-to-Treat Population. (1) Observed mean value from Week 0 through Week 52, and (2) least squares mean ± standard error at Week 52 from ANCOVA adjusted for baseline values and stratification factors, with multiple imputation of missing data. Sleep-Related Impairment In OSA clinical studies (Study 5 and Study 6), ZEPBOUND-treated patients showed improvement in sleep-related impairment compared to those who received placebo. Sleep-related impairment was assessed using the Patient-Reported Outcomes Measurement Information System® (PROMIS) Short Form Sleep-Related Impairment 8a. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ZEPBOUND (tirzepatide) is a clear, colorless to slightly yellow solution available in cartons containing 4 pre-filled single- dose pens or 1 single-dose vial as follows: Total Strength per Total Volume Pen NDC Vial NDC 2.5 mg/0.5 mL 0002-2506-80 0002-0152-01 5 mg/0.5 mL 0002-2495-80 0002-0243-01 7.5 mg/0.5 mL 0002-2484-80 0002-1214-01 10 mg/0.5 mL 0002-2471-80 0002-1340-01 12.5 mg/0.5 mL 0002-2460-80 0002-1423-01 15 mg/0.5 mL 0002-2457-80 0002-2002-01 Reference ID: 5501094 30 16.2 Storage and Handling • Store ZEPBOUND in a refrigerator at 2°C to 8°C (36°F to 46°F). • If needed, each single-dose pen or single-dose vial can be stored unrefrigerated at temperatures not to exceed 30°C (86°F) for up to 21 days. If ZEPBOUND is stored at room temperature, it should not be returned to the refrigerator. • Discard if not used within 21 days after removing from the refrigerator. • Do not freeze ZEPBOUND. Do not use ZEPBOUND if frozen. • Store ZEPBOUND in the original carton to protect from light. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Risk of Thyroid C-Cell Tumors Inform patients that ZEPBOUND causes thyroid C-cell tumors in rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, persistent hoarseness, dysphagia, or dyspnea) to their healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)]. Severe Gastrointestinal Adverse Reactions Inform patients of the potential risk of severe gastrointestinal adverse reactions. Instruct patients to contact their healthcare provider if they have severe or persistent gastrointestinal symptoms [see Warnings and Precautions (5.2)]. Acute Kidney Injury Advise patients treated with ZEPBOUND of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function and explain the associated signs and symptoms of renal impairment, as well as the possibility of dialysis as a medical intervention if renal failure occurs [see Warnings and Precautions (5.3)]. Acute Gallbladder Disease Inform patients of the risk of acute gallbladder disease. Instruct patients to contact their healthcare provider for appropriate clinical follow-up if gallbladder disease is suspected [see Warnings and Precautions (5.4)]. Acute Pancreatitis Inform patients of the potential risk for pancreatitis. Instruct patients to discontinue ZEPBOUND promptly and contact their healthcare provider if pancreatitis is suspected (severe abdominal pain that may radiate to the back, and which may or may not be accompanied by vomiting) [see Warnings and Precautions (5.5)]. Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions have been reported with use of tirzepatide. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking ZEPBOUND and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.6)]. Hypoglycemia Inform patients of the risk of hypoglycemia and educate patients on the signs and symptoms of hypoglycemia. Advise patients on insulin or insulin secretagogue therapy that they may have an increased risk of hypoglycemia when using ZEPBOUND and to report signs and/or symptoms of hypoglycemia to their healthcare provider [see Warnings and Precautions (5.7)]. Diabetic Retinopathy Complications Inform patients with type 2 diabetes mellitus to contact their healthcare provider if changes in vision are experienced during treatment with ZEPBOUND [see Warnings and Precautions (5.8)]. Suicidal Behavior and Ideation Advise patients to report emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Inform patients that if they experience suicidal thoughts or behaviors, they should stop taking ZEPBOUND [see Warnings and Precautions (5.9)]. Reference ID: 5501094 31 Pulmonary Aspiration During General Anesthesia or Deep Sedation Inform patients that ZEPBOUND may cause their stomach to empty more slowly which may lead to complications with anesthesia or deep sedation during planned surgeries or procedures. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking ZEPBOUND [see Warnings and Precautions (5.10)]. Pregnancy Advise a pregnant patient of the potential risk to a fetus. Advise patients to inform their healthcare provider if they are pregnant or intend to become pregnant during treatment with ZEPBOUND. Advise patients that there will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZEPBOUND during pregnancy [see Use in Specific Populations (8.1)]. Contraception Use of ZEPBOUND may reduce the efficacy of oral hormonal contraceptives. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method or add a barrier method of contraception for 4 weeks after initiation with ZEPBOUND and for 4 weeks after each dose escalation [see Drug Interactions (7.2), Use in Specific Populations (8.3), and Clinical Pharmacology (12.3)]. Administration Instruct patients how to prepare and administer the correct dose of ZEPBOUND and assess their ability to inject subcutaneously to ensure the proper administration of ZEPBOUND. Instruct patients using the single-dose vial to use a syringe appropriate for dose administration (e.g., a 1 mL syringe capable of measuring a 0.5 mL dose) [see Dosage and Administration (2.4)]. Missed Doses Inform patients if a dose is missed, it should be administered as soon as possible within 4 days after the missed dose. If more than 4 days have passed, the missed dose should be skipped and the next dose should be administered on the regularly scheduled day. In each case, inform patients to resume their regular once weekly dosing schedule [see Dosage and Administration (2.3)]. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2023, YYYY, Eli Lilly and Company. All rights reserved. B4.0-NL-ZEP-0004-USPI-YYYYMMDD Reference ID: 5501094 1 Medication Guide ZEPBOUND® (ZEHP-bownd) (tirzepatide) injection, for subcutaneous use What is the most important information I should know about ZEPBOUND? ZEPBOUND may cause serious side effects, including: • Possible thyroid tumors, including cancer. Tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer. In studies with rats, ZEPBOUND and medicines that work like ZEPBOUND caused thyroid tumors, including thyroid cancer. It is not known if ZEPBOUND will cause thyroid tumors, or a type of thyroid cancer called medullary thyroid carcinoma (MTC) in people. • Do not use ZEPBOUND if you or any of your family have ever had a type of thyroid cancer called MTC, or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). What is ZEPBOUND? • ZEPBOUND is an injectable prescription medicine that may help adults with: • obesity, or some adults with overweight who also have weight-related medical problems, to lose excess body weight and keep the weight off. • moderate to severe obstructive sleep apnea (OSA) and obesity to improve their OSA. • ZEPBOUND should be used with a reduced-calorie diet and increased physical activity. • ZEPBOUND contains tirzepatide and should not be used with other tirzepatide-containing products or any GLP-1 receptor agonist medicines. • It is not known if ZEPBOUND is safe and effective for use in children. Do not use ZEPBOUND if: • you or any of your family have ever had a type of thyroid cancer called MTC or if you have an endocrine system condition called MEN 2. • you have had a serious allergic reaction to tirzepatide or any of the ingredients in ZEPBOUND. See the end of this Medication Guide for a complete list of ingredients in ZEPBOUND. Before using ZEPBOUND, tell your healthcare provider about all of your medical conditions, including if you: • have or have had problems with your pancreas or kidneys. • have severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems with digesting food. • have a history of diabetic retinopathy. • are scheduled to have surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). • are pregnant or plan to become pregnant. ZEPBOUND may harm your unborn baby. Tell your healthcare provider if you become pregnant while using ZEPBOUND. ◦ Pregnancy Exposure Registry: There will be a pregnancy exposure registry for women who have taken ZEPBOUND during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry, or you may contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979). ◦ Birth control pills by mouth may not work as well while using ZEPBOUND. If you take birth control pills by mouth, your healthcare provider may recommend another type of birth control for 4 weeks after you start ZEPBOUND and for 4 weeks after each increase in your dose of ZEPBOUND. Talk to your healthcare provider about birth control methods that may be right for you while using ZEPBOUND. • are breastfeeding or plan to breastfeed. It is not known if ZEPBOUND passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while using ZEPBOUND. Reference ID: 5501094 2 Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ZEPBOUND may affect the way some medicines work, and some medicines may affect the way ZEPBOUND works. Before using ZEPBOUND, tell your healthcare provider if you are taking medicines to treat diabetes including an insulin or sulfonylurea which could increase your risk of low blood sugar. Talk to your healthcare provider about low blood sugar levels and how to manage them. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use ZEPBOUND? • Read the Instructions for Use that comes with ZEPBOUND. • Use ZEPBOUND exactly as your healthcare provider tells you to. A healthcare provider should show you how to prepare to inject your dose of ZEPBOUND before injecting the first time. • Use ZEPBOUND with a reduced-calorie diet and increased physical activity. • ZEPBOUND is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm. • Use ZEPBOUND 1 time each week, at any time of the day. • You may change the day of the week you use ZEPBOUND as long as the time between the 2 doses is at least 3 days (72 hours). • If you miss a dose of ZEPBOUND, take the missed dose as soon as possible within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip the missed dose and take your next dose on the regularly scheduled day. Do not take 2 doses of ZEPBOUND within 3 days (72 hours) of each other. • ZEPBOUND may be taken with or without food. • Change (rotate) your injection site with each weekly injection. You may use the same area of your body but be sure to choose a different injection site in that area. Do not use the same site for each injection. • In case of overdose, get medical help or contact a Poison Center expert right away at 1-800-222-1222. Advice is also available online at poisonhelp.org. What are the possible side effects of ZEPBOUND? ZEPBOUND may cause serious side effects, including: • See “What is the most important information I should know about ZEPBOUND?” • severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use ZEPBOUND. Tell your healthcare provider if you have stomach problems that are severe or will not go away. • kidney problems (kidney failure). Diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems. It is important for you to drink fluids to help reduce your chance of dehydration. • gallbladder problems. Gallbladder problems have happened in some people who use ZEPBOUND. Tell your healthcare provider right away if you get symptoms of gallbladder problems which may include: ◦ pain in your upper stomach (abdomen) ◦ yellowing of skin or eyes (jaundice) ◦ fever ◦ clay-colored stools • inflammation of your pancreas (pancreatitis). Stop using ZEPBOUND and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back. • serious allergic reactions. Stop using ZEPBOUND and get medical help right away if you have any symptoms of a serious allergic reaction including: ◦ swelling of your face, lips, tongue or throat ◦ fainting or feeling dizzy ◦ problems breathing or swallowing ◦ very rapid heartbeat ◦ severe rash or itching • low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use ZEPBOUND with medicines that can cause low blood sugar, such as an insulin or sulfonylurea. Signs and symptoms of low blood sugar may include: ◦ dizziness or light-headedness ◦ blurred vision ◦ anxiety, irritability, or mood changes ◦ sweating ◦ slurred speech ◦ hunger ◦ confusion or drowsiness ◦ shakiness ◦ weakness ◦ headache ◦ fast heartbeat ◦ feeling jittery Reference ID: 5501094 3 • changes in vision in patients with type 2 diabetes. Tell your healthcare provider if you have changes in vision during treatment with ZEPBOUND. • depression or thoughts of suicide. You should pay attention to any changes in your mood, behaviors, feelings, or thoughts. Call your healthcare provider right away if you have any changes to your mental health that are new, worse, or worry you. • food or liquid getting into the lungs during surgery or other procedures that use anesthesia or deep sleepiness (deep sedation). ZEPBOUND may increase the chance of food getting into your lungs during surgery or other procedures. Tell all your healthcare providers that you are taking ZEPBOUND before you are scheduled to have surgery or other procedures. The most common side effects of ZEPBOUND include: • nausea • stomach (abdominal) pain • allergic reactions • diarrhea • indigestion • belching • vomiting • injection site reactions • hair loss • constipation • feeling tired • heartburn Talk to your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of ZEPBOUND. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ZEPBOUND? • Store ZEPBOUND in the refrigerator between 36°F to 46°F (2°C to 8°C). Store ZEPBOUND in the original carton until use to protect it from light. • If needed, each single-dose pen or single-dose vial can be stored at room temperature up to 86°F (30°C) for up to 21 days. If ZEPBOUND is stored at room temperature, it should not be returned to the refrigerator. • Discard if not used within 21 days after removing from the refrigerator. • Do not freeze ZEPBOUND. Do not use ZEPBOUND if frozen. Keep ZEPBOUND and all medicines out of the reach of children. General information about the safe and effective use of ZEPBOUND. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ZEPBOUND for a condition for which it was not prescribed. Do not give ZEPBOUND to other people, even if they have the same condition you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ZEPBOUND that is written for health professionals. What are the ingredients in ZEPBOUND? Active ingredient: tirzepatide Inactive ingredients: sodium chloride, sodium phosphate dibasic heptahydrate, and water for injection. Hydrochloric acid solution and/or sodium hydroxide solution may have been added to adjust the pH. ZEPBOUND® is a registered trademark of Eli Lilly and Company. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2023, YYYY, Eli Lilly and Company. All rights reserved. For more information, go to www.zepbound.com or call 1-800-545-5979. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2024 B2.0-NL-ZEP-0003-MG-YYYYMMDD Reference ID: 5501094 INSTRUCTIONS FOR USE ZEPBOUND™ (ZEHP-bownd) (tirzepatide) injection, for subcutaneous use 2.5 mg/0.5 mL single-dose pen 5 mg/0.5 mL single-dose pen 7.5 mg/0.5 mL single-dose pen 10 mg/0.5 mL single-dose pen 12.5 mg/0.5 mL single-dose pen 15 mg/0.5 mL single-dose pen use 1 time each week Important information you need to know before injecting ZEPBOUND Read this Instructions for Use and the Medication Guide before using your ZEPBOUND pen and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk to your healthcare provider about how to inject ZEPBOUND the right way. • ZEPBOUND is a single-dose prefilled pen. • ZEPBOUND is used 1 time each week. • Inject under the skin (subcutaneously) only. • You or another person can inject into your stomach (abdomen) or thigh. • Another person can inject into the back of your upper arm. Reference ID: 5501094 Guide to parts Preparing to inject ZEPBOUND Remove the pen from the refrigerator. Leave the gray base cap on until you are ready to inject. Check the pen label to make sure you have the right medicine and dose, and that it has not expired. Inspect the pen to make sure that it is not damaged. Make sure the medicine: • is not frozen • is not cloudy • is colorless to slightly yellow • does not have particles Wash your hands. Expiration Date Purple Injection Button Lock Ring Indicator Lock or Unlock Medicine Clear Base Gray Base Cap Bottom and Needle End Top Reference ID: 5501094 Step 1 Choose your injection site Your healthcare provider can help you choose the injection site that is best for you. You or another person can inject the medicine in your stomach (abdomen) or thigh. Another person should give you the injection in the back of your upper arm. Change (rotate) your injection site each week. You may use the same area of your body but be sure to choose a different injection site in that area. Step 2 Pull off the gray base cap Make sure the pen is locked. Do not unlock the pen until you place the clear base on your skin and are ready to inject. Pull the gray base cap straight off and throw it away in your household trash. Do not put the gray base cap back on – this could damage the needle. Do not touch the needle. Step 3 Place clear base on skin, then unlock Place the clear base flat against your skin at the injection site. Clear Base Gray Base Cap Reference ID: 5501094 Unlock by turning the lock ring. Step 4 Press and hold up to 10 seconds Press and hold the purple injection button for up to 10 seconds. Listen for: • First click = injection started • Second click = injection completed You will know your injection is complete when the gray plunger is visible. After your injection, place the used pen in a sharps container. See Disposing of your used pen. Disposing of your used pen • Put your used pen in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) pens in your household trash. • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: - made of a heavy-duty plastic, - can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, - upright and stable during use, - leak-resistant, and - properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not recycle your used sharps disposal container. Gray Plunger Reference ID: 5501094 Storage and handling • Store your pen in the refrigerator between 36°F to 46°F (2°C to 8°C). • You may store your pen at room temperature up to 86°F (30°C) for up to 21 days. If you store the pen at room temperature, do not return the pen to the refrigerator. • Discard the pen if not used within 21 days after removing from the refrigerator. • Do not freeze your pen. If the pen has been frozen, throw the pen away and use a new pen. • Store your pen in the original carton to protect your pen from light. • The pen has glass parts. Handle it carefully. If you drop the pen on a hard surface, do not use it. Use a new pen for your injection. • Keep your ZEPBOUND pen and all medicines out of the reach of children. Commonly asked questions What if I see air bubbles in my pen? Air bubbles are normal. What if my pen is not at room temperature? It is not necessary to warm the pen to room temperature. What if I unlock the pen and press the purple injection button before pulling off the gray base cap? Do not remove the gray base cap. Throw away the pen and get a new pen. What if there is a drop of liquid on the tip of the needle when I remove the gray base cap? A drop of liquid on the tip of the needle is normal. Do not touch the needle. Do I need to hold the injection button down until the injection is complete? This is not necessary, but it may help you keep the pen steady against your skin. I heard more than 2 clicks during my injection—2 loud clicks and 1 soft one. Did I get my complete injection? Some people may hear a soft click right before the second loud click. That is the normal operation of the pen. Do not remove the pen from your skin until you hear the second loud click. I am not sure if my pen worked the right way. Check to see if you have received your dose. Your dose was delivered the right way if the gray plunger is visible. Also, see Step 4 of the instructions. If you do not see the gray plunger, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) for further instructions. Until then, store your pen safely to avoid an accidental needle stick. What if there is a drop of liquid or blood on my skin after my injection? This is normal. Press a cotton ball or gauze over the injection site. Do not rub the injection site. Other information • If you have vision problems, do not use your pen without help from a person trained to use the ZEPBOUND pen. Where to learn more • If you have questions or problems with your ZEPBOUND pen, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider. • For more information about the ZEPBOUND pen, visit our website at www.zepbound.com. Gray Plunger Reference ID: 5501094 Scan this code to launch www.zepbound.com Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA ZEPBOUND is a trademark of Eli Lilly and Company. Copyright © 2023, Eli Lilly and Company. All rights reserved. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: November 2023 ZEP-0002-PEN-IFU-20231109 Reference ID: 5501094 INSTRUCTIONS FOR USE ZEPBOUND® [ZEHP-bownd] (tirzepatide) injection, for subcutaneous use 2.5 mg/0.5 mL single-dose vial 5 mg/0.5 mL single-dose vial 7.5 mg/0.5 mL single-dose vial 10 mg/0.5 mL single-dose vial 12.5 mg/0.5 mL single-dose vial 15 mg/0.5 mL single-dose vial Important information you need to know before injecting ZEPBOUND Read this Instructions for Use before you start taking ZEPBOUND and each time you get a new vial. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Do not share your needles or syringes with other people. You may give other people a serious infection or get a serious infection from them. Talk to your healthcare provider about how to inject ZEPBOUND the right way. • ZEPBOUND is a single-dose vial. • ZEPBOUND is used 1 time each week. • Inject under the skin (subcutaneously) only. • You or another person may inject into your stomach (abdomen) or thigh. • Another person can inject into the back of your upper arm. Gather supplies needed to give your injection • 1 single-dose ZEPBOUND vial • 1 syringe and 1 needle, supplied separately (for example, use a 1 mL syringe and needle as recommended by your healthcare provider) • 1 alcohol swab • gauze • 1 sharps container for throwing away used needles and syringes. See “Disposing of used needles and syringes” at the end of these instructions. Reference ID: 5501094 Guide to parts Vial Needle and Syringe (not included) Needle Shield Needle Plunger Tip Plunger Note: The needle and syringe are not included. The needle and syringe recommended by your healthcare provider may look different than the needle and syringe in this Instructions for Use. Preparing to inject ZEPBOUND Remove the vial from the refrigerator. Check the vial label to make sure you have the right medicine and dose, and that it has not expired. Make sure the medicine: • is not frozen • is colorless to slightly yellow • is not cloudy • does not have particles Always use a new syringe and needle for each injection to prevent infections and blocked needles. Do not reuse or share your syringes or needles with other people. You may give other people a serious infection or get a serious infection from them. Wash your hands with soap and water. Step 1: Pull off the plastic protective cap. Do not remove the rubber stopper. Step 2: Wipe the rubber stopper with an alcohol swab. Protective Cap Rubber Stopper (under Cap) Syringe Body Reference ID: 5501094 Step 3: Remove the outer wrapping from the syringe. Step 4: Remove the outer wrapping from the needle. The syringe that your healthcare provider recommended may have a pre-attached needle. If the needle is attached, skip to step 6. Step 5: Place the needle on top of the syringe and turn until it is tight and firmly attached. Step 6: Remove the needle shield by pulling straight off. Step 7: Hold the syringe in one hand with the needle pointing up. With the other hand pull down on the plunger until the plunger tip reaches the line on the syringe indicating that 0.5 mL of air has been drawn into the syringe. Step 8: Push the needle through the rubber stopper of the vial. Step 9: Push the plunger all the way in. This puts air into the vial and makes it easier to pull the solution from the vial. Reference ID: 5501094 Step 10: Turn the vial and syringe upside down. Make sure that the tip of the needle is in the liquid and slowly pull the plunger down until the plunger tip is past the 0.5 mL line. If there are air bubbles, tap the syringe gently a few times to let any air bubbles rise to the top. Step 11: Slowly push the plunger up until the plunger tip reaches the 0.5 mL line. Step 12: Pull the syringe out of the rubber stopper of the vial. Injecting ZEPBOUND • Inject exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you should pinch the skin before injecting. • Change (rotate) your injection site within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. • Do not inject where the skin has pits, is thickened, or has lumps. • Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. • Do not mix ZEPBOUND with any other medicine. • Do not inject ZEPBOUND in the same injection site used for other medicines. Reference ID: 5501094 Step 13: Choose your injection site. You can inject ZEPBOUND under the skin (subcutaneously) of your stomach area (abdomen) or thighs. Someone else can inject in your stomach area, thighs, or the back of the upper arms. Step 14: Insert the needle into your skin. Step 15: Push down on the plunger to inject your dose. The needle should stay in your skin for at least 5 seconds to make sure you have injected all of your dose. Step 16: Pull the needle out of your skin. • If you see blood after you take the needle out of your skin, press the injection site with a piece of gauze or an alcohol swab. Do not rub the area. • Do not recap the needle. Recapping the needle can lead to a needle stick injury. Disposing of used needles and syringes • Put your used needle and syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. • If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: - made of a heavy-duty plastic, - can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, - upright and stable during use, - leak-resistant, and - properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you Reference ID: 5501094 should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal. • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Storing ZEPBOUND • Store all unopened vials in the refrigerator at 36°F to 46°F (2°C to 8°C). • You may store the unopened vial at room temperature up to 86°F (30°C) for up to 21 days. • Do not freeze. Do not use if ZEPBOUND has been frozen. • Store the vial in the original carton to protect from light. • Throw away all opened vials after use, even if there is medicine left in the vial. Keep ZEPBOUND vials, syringes, needles, and all medicines out of the reach of children. If you have any questions or problems with your ZEPBOUND, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA ZEPBOUND is a registered trademark of Eli Lilly and Company. Copyright © 2024, Eli Lilly and Company. All rights reserved. ZEP-0001-VL-IFU-20240328 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: March 2024 Reference ID: 5501094
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2025-02-12T15:47:58.820097
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Alhemo safely and effectively. See full prescribing information for Alhemo. Alhemo® (concizumab-mtci) injection, for subcutaneous use Initial U.S. Approval: 2024 --------------------------INDICATIONS AND USAGE--------------------------- Alhemo is a tissue factor pathway inhibitor (TFPI) antagonist indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with:  hemophilia A (congenital factor VIII deficiency) with FVIII inhibitors  hemophilia B (congenital factor IX deficiency) with FIX inhibitors (1) ----------------------DOSAGE AND ADMINISTRATION----------------------- Administer Alhemo by subcutaneous injection to the abdomen or thigh with daily rotation of injection sites. (2.2) Recommended dosing regimen: o Day 1: Loading dose of 1 mg/kg o Day 2: Once-daily dose of 0.2 mg/kg until individualization of maintenance dose (see below)  4 weeks after initiation of treatment: For dose optimization, measure concizumab-mtci plasma concentration by Concizumab Enzyme-Linked Immunosorbent Assay (ELISA) prior to administration of next scheduled dose. An FDA-authorized test for the measurement of concizumab-mtci concentration in plasma is not currently available. o Once the concizumab-mtci concentration result is available, individualize the maintenance dose of Alhemo no later than 8 weeks after initiation of treatment, based on the following concizumab-mtci plasma concentrations:  Less than 200 ng/mL: adjust to a once-daily dose of 0.25 mg/kg (2.1)  200 to 4,000 ng/mL: continue once-daily dose of 0.2 mg/kg (2.1)  Greater than 4,000 ng/mL: adjust to a once-daily dose of 0.15 mg/kg (2.1)  See full Prescribing Information for important preparation and administration instructions. (2.3, 2.4) --------------------DOSAGE FORMS AND STRENGTHS---------------------- Injection:  60 mg/1.5 mL (40 mg/mL) in a single-patient-use prefilled pen (3)  150 mg/1.5 mL (100 mg/mL) in a single-patient-use prefilled pen (3)  300 mg/3 mL (100 mg/mL) in a single-patient-use prefilled pen (3) -------------------------------CONTRAINDICATIONS------------------------------ Alhemo is contraindicated in patients with a history of known serious hypersensitivity to Alhemo or its components or the inactive ingredients. (4) -----------------------WARNINGS AND PRECAUTIONS------------------------  Thromboembolic Events: Inform patients of the signs and symptoms of thromboembolic events. Monitor patients for thromboembolic events. Advise patients to report these signs and symptoms, and if they occur discontinue prophylaxis. (5.1)  Hypersensitivity Reactions: In the event of a severe hypersensitivity reaction, discontinue Alhemo. (5.2)  Increased Laboratory Values of Fibrin D dimer and Prothrombin Fragment 1+2. Alhemo increases values of fibrin D dimer and prothrombin fragment 1+2. (5.3) ------------------------------ADVERSE REACTIONS------------------------------- The most frequently reported adverse reactions (incidence ≥5%) were injection site reactions and urticaria. (6.1) ------------------------------DRUG INTERACTIONS------------------------------- While treatment with all bypassing agents (e.g., rFVIIa or aPCC) can be used for breakthrough bleeds, high and/or frequent doses of bypassing agents with Alhemo increases the risk of thromboembolism. (7.1) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 12/2024 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Changing to Alhemo from Other Hemostatic Products 2.3 Instructions and Dosage Modification for Bypassing Agents for Breakthrough Bleeding 2.4 Administration and Use Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Thromboembolic Events 5.2 Hypersensitivity Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Bypassing agents 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Increased Body Weight 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.6 Immunogenicity 12.7 Interference of Concizumab-mtci with Laboratory Tests 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Hemophilia A and B with Inhibitors - Adults and Adolescents 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. Reference ID: 5501236 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Alhemo is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with:  hemophilia A (congenital factor VIII deficiency) with FVIII inhibitors  hemophilia B (congenital factor IX deficiency) with FIX inhibitors 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage For subcutaneous use only. Alhemo should be administered once-daily. Avoid missed doses. Recommended dosing regimen:  Day 1: Loading dose of 1 mg/kg  Day 2: Once-daily dose of 0.2 mg/kg until individualization of maintenance dose (see below) o 4 weeks after initiation of treatment: For dose optimization measure concizumab-mtci plasma concentration by Concizumab Enzyme-Linked Immunosorbent Assay (ELISA) prior to administration of next scheduled dose. An FDA-authorized test for the measurement of concizumab-mtci concentration in plasma is not currently available.  Once the concizumab-mtci concentration result is available, individualize the maintenance dose of Alhemo. no later than 8 weeks after initiation of treatment, based on the following concizumab-mtci- plasma concentrations: o Less than 200 ng/mL: adjust to a once-daily dose of 0.25 mg/kg o 200 to 4,000 ng/mL: continue once-daily dose of 0.2 mg/kg o Greater than 4,000 ng/mL: adjust to a once-daily dose of 0.15 mg/kg The calculated dose is rounded off to the nearest injectable dose as follows:  60 mg/1.5 mL (40 mg/mL) in increments of 0.4 mg (brown label)  150 mg/1.5 mL (100 mg/mL) in increments of 1 mg (gold label)  300 mg/3 mL (100 mg/mL) in increments of 1 mg (white label) Additional measurements of concizumab-mtci plasma concentration should be taken at routine clinical follow-ups provided the patient has been on the same maintenance dose for 8 weeks of treatment to ensure steady-state plasma concentration. Maintenance of concizumab plasma concentration above 200 ng/mL is important to decrease the risk of bleeding episodes. If concizumab-mtci plasma concentration remains below 200 ng/mL at two consecutive measurements, the benefits of continued Alhemo treatment should be evaluated versus the potential risk of bleeding events, and alternative therapies if available should be considered. As Alhemo is dosed by body weight (mg/kg), it is important to recalculate the dose when patients experience body weight changes. Missed Dose Adherence to daily dosing of Alhemo is important to maintain protection against bleeding. This is especially important during the initial 4 weeks of treatment to ensure a correct maintenance dose is established. Patients who miss a dose during the initial 4-week period should inform their healthcare professional and resume once-daily dosing at the initial 0.2 mg/kg dose level. Missed Doses Once the Maintenance Dose Has Been Established The following dosing guidelines should apply ONLY when a patient has forgotten to or neglected to take their once-daily maintenance dose:  1 missed dose: Resume once-daily treatment at the maintenance dose level  2 to 6 missed doses: Resume treatment with a double dose followed by once-daily treatment at the maintenance dose level  7 or more missed doses: Physician should be contacted, and a new loading dose should be considered [see Recommended Dosage (2.1)] Management of Breakthrough Bleeds No dose adjustment of Alhemo is required in the case of breakthrough bleeds. Reference ID: 5501236 Management in the Perioperative Setting No dose adjustment of Alhemo is required in the case of minor surgeries. As there is limited experience in the perioperative setting, it is generally recommended to pause Alhemo at least 4 days prior to major surgery. Alhemo therapy can be resumed 10–14 days after surgery on the same maintenance dose without a new loading dose, considering the overall clinical picture of the patient. If necessary, consult a physician experienced in surgery of patients with bleeding disorders. Immune Tolerance Induction The safety and efficacy of concomitant use of Alhemo in patients receiving ongoing Immune Tolerance Induction (ITI), a desensitization strategy for the eradication of inhibitors, have not been established, and no data are available. Careful assessment of the potential benefits and risks should be performed if continuation or initiation of Alhemo during ITI is considered. 2.2 Changing to Alhemo from Other Hemostatic Products  Discontinue treatment with rFVIIa at least 12 hours before starting Alhemo.  Discontinue treatment with activated prothrombin complex concentrate (aPCC) at least 48 hours before starting Alhemo.  Discontinue prophylactic use of standard half-life factor VIII (FVIII) or factor IX (FIX) at least 24 hours before starting Alhemo.  When changing from other products to Alhemo, the half-life of the previous product should be considered. Healthcare providers should discuss with patients receiving Alhemo and/or their caregivers the dose and schedule of bypassing agents or FVIII or FIX, if required, while receiving Alhemo prophylaxis. 2.3 Instructions and Dosage Modification for Bypassing Agents for Breakthrough Bleeding Treatment with all bypassing agents (e.g., rFVIIa or aPCC) can be used for breakthrough bleeds, and the dose and duration will depend on the location and severity of the bleed. For mild and moderate bleeds that require additional treatment with bypassing agents (e.g., rFVIIa or aPCC), the lowest-approved dose and the dose interval in the approved product labeling is recommended. For aPCC, a maximum dose of 100 units/kg body weight within 24 hours is recommended. For severe bleeds, follow the dosing instructions provided in the approved labeling for the specific product based on clinical judgement. 2.4 Administration and Use Instructions Treatment is intended for use under the guidance of a healthcare provider. Treatment should be initiated in a non-bleeding state. Alhemo may be self-administered or administered by a caregiver after appropriate training and reading the Instructions for Use, if a healthcare provider determines that is appropriate. Administer Alhemo by subcutaneous injection to the abdomen or thigh with rotation of injection site every day. Subcutaneous injections should not be given in areas where the skin is tender, bruised, red or hard, or areas where there are moles, scars, or stretch marks. Children and lean patients should be instructed to use injection techniques that minimize risk of intramuscular injection, e.g. injecting into a pinched fold of skin. Always use a new needle for each injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Alhemo is a clear to slightly opalescent and colorless to slightly yellow solution that may contain translucent to white particles. Do not use if the solution is discolored. Each Alhemo prefilled pen is for use by a single patient. An Alhemo pen must not be shared between patients, even if the needle is changed. Alhemo is recommended to be used with NovoFine® or NovoFine® Plus needles with a gauge of 32 and a length of 4 mm. If needles longer than 4 mm are used, injection techniques that minimize the risk of intramuscular injection should be used. Instructions for delivering the dosage are provided in the Instructions for Use leaflet enclosed with each Alhemo single-patient-use prefilled pen. Reference ID: 5501236 3 DOSAGE FORMS AND STRENGTHS Alhemo injection is a clear to slightly opalescent and colorless to slightly yellow solution that may contain translucent to white particles, available in the following presentations:  60 mg/1.5 mL (40 mg/mL) in a single-patient-use prefilled pen  150 mg/1.5 mL (100 mg/mL) in a single-patient-use prefilled pen  300 mg/3 mL (100 mg/mL) in a single-patient use-prefilled pen 4 CONTRAINDICATIONS Alhemo is contraindicated in patients with a history of known serious hypersensitivity to Alhemo or its components or the inactive ingredients [see Warnings and Precautions (5.1) and Description (11)]. 5 WARNINGS AND PRECAUTIONS 5.1 Thromboembolic Events Venous and arterial thromboembolic events were reported in 1.3% of patients (4/320) in Alhemo clinical trials. These cases occurred in patients with multiple risk factors for thromboembolism, including the use of high doses or prolonged treatment with factor product or bypassing agent (2 of 4 events). Risk factors for thromboembolism may include the use of high and/or frequent doses of breakthrough bleed treatments (factor products or bypassing agents) or conditions in which tissue factor is overexpressed (e.g., atherosclerotic disease, crush injury, cancer, disseminated intravascular coagulation, thrombotic microangiopathy, or septicemia). Inform Alhemo treated patients of signs and symptoms of thromboembolic events. Monitor patients for thromboembolic events. In case of suspicion of thromboembolic events, discontinue Alhemo and initiate further investigations and management strategies. 5.2 Hypersensitivity Reactions Alhemo is contraindicated in patients with a history of known serious hypersensitivity to Alhemo or its components or the inactive ingredients. Hypersensitivity reactions including erythema, rash, pruritus, and abdominal pain have occurred in Alhemo treated patients. One patient (less than 1% of patients treated in the clinical studies) experienced anaphylaxis which resolved after treatment with antihistamines and corticosteroids. Instruct patients of the signs of acute hypersensitivity reactions. Instruct patients to contact their healthcare provider for mild reactions and to seek urgent medical attention for moderate to severe reactions. Discontinue Alhemo if severe hypersensitivity symptoms occur, and initiate medical management. 5.3 Increased Laboratory Values of Fibrin D-dimer and Prothrombin Fragment 1+2 Increased levels of fibrin D-dimer and increased levels of prothrombin fragment 1.2 were seen in 29 (9.1%) and 18 (5.6%) of patients, respectively. The plasma concentration of concizumab-mtci is positively correlated with fibrin D-dimer and prothrombin fragments 1.2 indicating a hemostatic effect of concizumab-mtci. For patients taking Alhemo, these coagulation biomarkers may not be reliable predictive markers for clinical decision-making with suspicion of thrombosis such as deep vein thrombosis (DVT) and pulmonary embolism (PE). 6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:  Thromboembolic Events [see Warnings and Precautions (5.1)]  Hypersensitivity Reactions [see Warnings and Precautions (5.2)]  Increased Laboratory Values of Fibrin D-dimer and Prothrombin Fragment 1+2 [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. Reference ID: 5501236 The data in the WARNINGS AND PRECAUTIONS reflect exposure to Alhemo based on pooled data from clinical trials explorer3 (phase 1b), explorer4 (phase 2), explorer5 (phase 2), explorer7 (phase 3) and explorer8 (phase 3), in which a total of 320 male patients with hemophilia A with and without inhibitors and hemophilia B with and without inhibitors received at least one dose of Alhemo as routine prophylaxis. The patients were exposed for a total of 475 exposure years. Patients with HAwI (hemophilia A with inhibitors) and HBwI (hemophilia B with inhibitors) The data described below reflect exposure of 52 patients with HAwI and HBwI who were previously treated on-demand therapy and who were randomized in explorer7 to arm 1 to receive on- demand treatment with bypassing agents (n = 19) or arm 2 to receive Alhemo prophylaxis (n = 33) at the recommended dosing regimen [see Clinical Studies (14)]. The median duration of treatment was 31.1 weeks (range 3.9, 72.9 weeks) in arm 1 (on- demand arm) and 40.1 weeks (range 3.1, 56.3 weeks) in arm 2 (Alhemo prophylaxis). Serious adverse reactions were reported in 6.1% of patients who received Alhemo. These serious adverse reactions were renal infarct and hypersensitivity reaction. Permanent discontinuation of Alhemo due to an adverse reaction occurred in 1 patient due to a renal infarct. Dosage interruptions of Alhemo due to an adverse reaction occurred in 1 patient (3%) and was a hypersensitivity reaction. The most common adverse reactions (≥5%) were injection site reactions and urticaria (see Table 1). Table 1. Adverse Reactions Reported in ≥5% HAwI and HBwI Patients Randomized to Alhemo in Explorer7 Adverse Reaction Alhemo Prophylaxis N=33 (%) On-demand Treatment N=19 (%) Injection site reactions 18% 0% Urticaria 6% 0% Injection site reactions included: Injection site bruising, Injection site erythema, Injection site hematoma, Injection site hemorrhage, Injection site reaction and Injection site urticaria. Urticaria included: Urticaria and Injection site urticaria. 7 DRUG INTERACTIONS 7.1 Bypassing Agents Take appropriate precautions when treating break-through bleeding events in hemophilia patients receiving Alhemo prophylaxis and a bypassing agent [see Dosage and Administration (2.1)]. For mild and moderate bleeds that require additional treatment with bypassing agents (e.g., rFVIIa or aPCC), the lowest-approved dose in the approved product labeling is recommended. For aPCC, a maximum dose of 100 units/kg body weight within 24 hours is recommended. For severe bleeds, follow the dosing instructions provided in the approved labeling for the specific product based on clinical judgement. Additive and sometimes synergistic increase in thrombin peak as quantified in the thrombin generation assay has been observed in plasma from hemophilia patients who were on prophylactic treatment with concizumab-mtci with concomitant presence of rFVIII, rFIX or bypassing agents including rFVIIa and aPCC [see Clinical Pharmacology (12.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, Alhemo may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on Alhemo use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with Alhemo. Although there are no data on concizumab-mtci, monoclonal antibodies can be actively transported across the placenta, and concizumab-mtci may cause fetal harm. It is unknown whether Alhemo can affect reproductive capacity. Alhemo should only be used during pregnancy if the potential benefit for the mother outweighs the potential risk to the fetus. The estimated background risk of birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Reference ID: 5501236 8.2 Lactation Risk Summary There is no information regarding the presence of Alhemo in either human or animal milk, the effect on the breastfed child, or the effects on milk production. Clinical Considerations Human IgGs are known to be excreted in breast milk during the first few days after birth, decreasing to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. Afterwards, Alhemo could be used during breast-feeding if clinically needed. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential. Contraception Women of childbearing potential should use a highly effective form of contraception during treatment with Alhemo and for 7 weeks after ending treatment. The benefits and thromboembolic risks of the type of contraceptives used should be evaluated by the treating physician. 8.4 Pediatric Use The safety and effectiveness of Alhemo for hemophilia A and B with inhibitors have been established in pediatric patients aged 12 years and older. Use of Alhemo for this indication is supported by evidence from adequate and well-controlled studies in adult and pediatric patients aged 12 years and older [see Adverse Reactions (6.1) and Clinical Studies (14)]. The safety and effectiveness of Alhemo for hemophilia A and B with inhibitors have not been established in pediatric patients younger than 12 years of age. 8.5 Geriatric Use Clinical studies of Alhemo did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. 8.6 Increased Body Weight The apparent clearance and volume of distribution of concizumab-mtci decreased with increasing body weight [see Clinical Pharmacology (12.3)]. However, patients should receive the approved recommended Alhemo dosage titration and concizumab-mtci plasma concentration monitoring regardless of body weight [see Dosage and Administration (2.1)]. 11 DESCRIPTION Concizumab-mtci, is a humanized IgG4 monoclonal antibody produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells with an approximate molecular weight of 149 kDa. Alhemo (concizumab-mtci) injection is a clear to slightly opalescent, and colorless to slightly yellow solution that may contain translucent to white particles. Alhemo is supplied as a single-patient-use prefilled pen for subcutaneous injection. Each 1 mL of Alhemo single-patient-use prefilled pen (60 mg/1.5 mL) contains 40 mg active ingredient concizumab-mtci. Each 1 mL of Alhemo single-patient-use prefilled pen (150 mg/1.5 mL) contains 100 mg active ingredient concizumab-mtci. Each 1 mL of Alhemo single-patient-use prefilled pen (300 mg/3 mL) contains 100 mg active ingredient concizumab-mtci. Each 1 mL of Alhemo single-patient-use prefilled pen contains the following excipients: arginine hydrochloride (5.27 mg), histidine (5.12 mg), phenol (3.5 mg), polysorbate 80 (0.25 mg), sodium chloride (1.46 mg), sucrose (51.3 mg), and water for injection. Hydrochloric acid and sodium hydroxide may be added to adjust the pH to 6.0. Reference ID: 5501236 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Concizumab-mtci is a monoclonal antibody antagonist of endogenous Tissue Factor Pathway Inhibitor (TFPI). Through the inhibition of TFPI, concizumab-mtci acts to enhance FXa production during the initiation phase of coagulation which leads to improved thrombin generation and clot formation with the goal of achieving hemostasis in patients with Hemophilia A or B with inhibitors. The effect of concizumab-mtci is not influenced by the presence of inhibitory antibodies to FVIII or FIX. There is no structural relationship or sequence homology between concizumab-mtci and FVIII or FIX and, as such, treatment with concizumab-mtci does not induce or enhance the development of direct inhibitors to FVIII or FIX. 12.2 Pharmacodynamics Increasing concizumab-mtci dose levels resulted in decreased levels of free TFPI (plasma TFPI not bound to concizumab-mtci) and increased duration of free TFPI suppression. Free TFPI plasma levels pre-dose decreased from a geometric mean (CV%) of 88.3 (20%) ng/mL at baseline to 10.7 (105%) ng/mL at week 24 in patients on Alhemo prophylaxis, while the geometric mean (CV%) was 76.0 (18%) ng/mL at week 24 for patients on no Alhemo prophylaxis. Mean thrombin peak within the range of normal plasma reflected that concizumab-mtci re‐established thrombin generation capacity. Drug Interaction In vitro studies Additive and sometimes synergistic increase in thrombin peak as quantified in the thrombin generation assay has been observed in plasma from hemophilia patients who were on prophylactic treatment with concizumab-mtci with concomitant presence of rFVIII, rFIX or bypassing agents including rFVIIa and aPCC. Depending on concentrations of concizumab-mtci and hemostatic agents, the impact on thrombin peak ranged from being additive with all hemostatic agents to an extra 40% effect with rFVIIa, an extra 33% effect with aPCC, an extra 22% with rFVIII and less than 13% with rFIX. 12.3 Pharmacokinetics Peak and trough geometric mean plasma concizumab-mtci concentrations at steady state are shown in Table 2. Following a single Alhemo loading dose of 1 mg/kg, the steady state concentrations were reached around Day 4 and remained within a stable exposure range with daily maintenance doses. Concizumab-mtci AUC and Cmax increased with increasing dose in a greater than dose- proportional manner following subcutaneous administration. Table 2 Steady state concizumab-mtci concentrations during 24-hour dosing interval at week 24 Parameters HAwI and HBwI All maintenance doses N=99a Cmax,ss (ng/mL), geometric mean (CV%) 1167.1 (128%) Ctrough,ss (ng/mL), geometric mean (CV%) 665.4 (221%) Cmax / Ctrough ratio, mean (SD) 2.2 (5.2) Abbreviations: Cmax,ss, maximum plasma concentration at steady state; Ctrough,ss, trough plasma concentration at steady state; HAwI, hemophilia a with inhibitors; HBwI, hemophilia B with inhibitors. aOn concizumab-mtci dosing regimen. Absorption Concizumab-mtci time to maximum plasma concentration ranged from 8 hours to 99 hours (4.1 days) following a single Alhemo subcutaneous dose of 0.05 to 3 mg/kg in healthy and hemophilia subjects. Distribution Concizumab-mtci volume of distribution for a typical 70 kg patient is about 3 L. Reference ID: 5501236 Elimination Concizumab-mtci is cleared via linear and non-linear mechanisms. Concizumab-mtci exhibited non-linear pharmacokinetics due to target-mediated drug disposition (TMDD) which occurs when it forms concizumab-mtci/TFPI complex. Once the target becomes saturated, linear pathway (i.e., catabolism) dominates. Based on population pharmacokinetic analysis, 90% of concizumab-mtci is expected to be eliminated by the end of approximately 4 days after the last dose (time for 50% of drug to be eliminated is approximately 1 day). Metabolism Concizumab-mtci is expected to be metabolized into small peptides by catabolic pathways. Specific Populations No clinically significant differences in the pharmacokinetics of concizumab-mtci were observed based on age (12 year to 79 years), race (White 62.9%, Asian 25.0%, Black 6.0%), hemophilia type (A vs B). No dedicated studies have been conducted to evaluate the impact of renal or hepatic impairment. As concizumab-mtci is a monoclonal antibody, there is no expectation for concizumab-mtci exposures to be different in patients with renal or hepatic impairment. Body weight The apparent clearance and volume of distribution of concizumab-mtci increased with increasing body weight (27 kg to 130.7 kg) [see Use in Specific Populations (8.6)]. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and the specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described below with the incidence of ADA in other studies, including those of concizumab-mtci or of other concizumab products. During the treatment period in 4 trials with a duration of 11 weeks, ≥76 weeks, ≥76 weeks, and ≥32 weeks, 47 out of the 185 treated patients (25.4%) developed anti-concizumab-mtci antibodies. Among the 47 patients who tested positive for ADA, 12 patients (25.5%) developed neutralizing antibodies (NAbs) against concizumab-mtci. In 1 patient who developed NAb against concizumab- mtci, free TFPI levels were restored to baseline indicative of effectiveness likely being compromised. In the remaining 46 patients, there was no identified clinically significant effect of the antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of concizumab-mtci. 12.7 Interference of Concizumab-mtci with Laboratory Tests In vitro studies No clinically significant interference with standard prothrombin and activated partial thromboplastin time assays or FVIII or FIX activity measurement using clot and chromogenic assays was observed with concizumab-mtci. Further, no clinically relevant interference with assays for inhibitory antibodies to FVIII or FIX (Bethesda assay) was observed with concizumab-mtci. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been conducted to evaluate the carcinogenic potential of concizumab-mtci nor have studies been performed to determine the effects of concizumab-mtci on genotoxicity. In a 26-week toxicity study in sexually mature male and female cynomolgus monkeys with subcutaneous doses up to 9 mg/kg/day (corresponding to 3400-fold the human exposure, based on AUC0 to 24h), concizumab-mtci did not affect fertility (testicular size, sperm functionality or menstrual cycle duration) and did not cause any changes in the male or female reproductive organs. 13.2 Animal Toxicology and/or Pharmacology Pharmacology mediated formation of thrombi manifested in cynomolgus monkeys dosed subcutaneously during toxicology studies of 13-weeks (≥ 10 mg/kg/day), 26-weeks (≥ 3 mg/kg/day) and 52-weeks (≥ 1 mg/kg/day) in duration corresponding to ≥ 3732-fold, ≥ 955- fold and ≥ 308-fold, respectively, the human clinical exposure based on AUC0 to 24h in patients with Hemophilia A or B at the MRHD. Reference ID: 5501236 In a 28-day drug-drug interaction toxicity study in cynomolgus monkey with daily dosing of 1 mg/kg concizumab-mtci to achieve steady state, three consecutive intravenous doses of up to 1 mg/kg rFVIIa were administered with 2-hour intervals to the concizumab-mtci dosed animals. No adverse findings were observed at a concizumab-mtci exposure corresponding to 205-fold the human exposure, based on AUC0 to 24h. 14 CLINICAL STUDIES Hemophilia A and B with Inhibitors in Patients ≥12 Years of Age (explorer7) The efficacy of Alhemo in patients with hemophilia A and B with inhibitors was evaluated in the explorer7 trial (NCT04083781), a multi-national, multi-center, open-label, phase 3 trial that investigated the safety and efficacy of Alhemo for routine prophylaxis in 91 adults (58 HAwI and 33 HBwI) and 42 adolescents (22 HAwI and 20 HBwI) male patients with hemophilia A or B with inhibitors who have been prescribed, or are in need of, treatment with bypassing agents. Eptacog alfa was the rFVIIa used in explorer7. Patients were excluded if they had a history, current signs or symptoms, or at high risk of thromboembolic events, ongoing or planned immune tolerance induction treatment, in addition to patients with planned major surgery. Among the 133 patients treated with Alhemo in the trial the mean age was 29 years (range: 12 to 79); 42 patients were 12 to <18 years of age, 89 patients were 18 to 64 years of age, and 2 patients were ≥65 years of age, and all were male. Seventy-eight (78) patients were White, 37 patients were Asian, 9 patients were Black or African American, 6 patients had race information unreported, and 3 patients were American Indian or Alaska Native; 6 patients identified as Hispanic or Latino, 122 patients identified as not Hispanic or Latino and 5 patients had ethnicity information unreported. The trial was comprised of 4 arms, two randomized arms and two non-randomized arms:  Arms 1 and 2: 52 patients (27 HAwI, and 25 HBwI), previously treated on-demand, were randomized 1:2 to no prophylaxis (arm 1: on demand treatment with bypassing agents) or Alhemo prophylaxis (arm 2), with stratification by hemophilia type (HAwI, HBwI) and prior 24-week bleeding rate (< 9 or ≥9)  Arms 3 and 4: 81 additional patients (53 HAwI and 28 HBwI) treated with Alhemo prophylaxis Treatment with Alhemo included a loading dose of 1 mg/kg on the first day and a once-daily dose of 0.20 mg/kg starting on the second day. The dose was individualized to 0.25 mg/kg or 0.15 mg/kg if Alhemo plasma concentration measured once after 4 weeks of treatment was <200 ng/mL or >4000 ng/mL, respectively. Measurement of concizumab-mtci plasma concentration after 4 weeks was used to optimize the daily maintenance dose. In the trial, a total of 108 patients received their individualized dose, 1 patient on 0.15 mg/kg, 79 patients on 0.20 mg/kg and 28 patients on 0.25 mg/kg. Efficacy was evaluated in hemophilia A and B patients with inhibitors when all patients in arms 1 and 2 had completed at least 24 or at least 32 weeks, respectively), by comparing the number of treated bleeding episodes between Alhemo prophylaxis (arm 2) and no prophylaxis (arm 1). Using a negative binomial model, a ratio of the annualized bleeding rates (ABR) was estimated to 0.14 (p<0.001), corresponding to a reduction in ABR of 86% for subjects on Alhemo prophylaxis compared to no prophylaxis. The estimated mean ABR was 1.7 [95%CI: 1.01; 2.87] for patients on Alhemo prophylaxis (arm 2) and 11.8 [95%CI: 7.03; 19.86] for patients on no prophylaxis (arm 1). 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Alhemo (concizumab-mtci) injection is a clear to slightly opalescent, colorless to slightly yellow liquid, that may contain translucent to white particles. Alhemo is available as one single-patient-use prefilled pen per carton in the following presentations (see Table 3): Table 3 Alhemo Presentations Presentation Label NDC Number 60 mg/1.5 mL (40 mg/mL) Brown 0169-2084-15 150 mg/1.5 mL (100 mg/mL) Gold 0169-2080-15 300 mg/3 mL (100 mg/mL) White 0169-2081-03 Reference ID: 5501236 Storage and Handling Before first use: Store in a refrigerator at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. Do not freeze. After first use: Store in a refrigerator at 36℉ to 46˚F (2℃ to 8˚C) or at room temperature below 86˚F (30˚C) for up to 28 days. Write the date of first use in the space provided on the carton. Discard the unused portion of the pen 28 days after first opening. Store Alhemo with the cap on and in the original carton to protect from light. Alhemo should not be stored in direct sunlight, and the Alhemo pen should be kept away from direct heat. Do not freeze or store it close to a cooling element in a refrigerator (the part that cools the refrigerator). Do not use Alhemo if it has been frozen or stored at temperatures above 86˚F (30˚C). 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).  Thromboembolic events: Inform patients of the signs and symptoms of thromboembolic events, including swelling, warmth, pain, or redness of the skin (and that these could be symptoms of a blood clot in the legs or arms); shortness of breath or severe chest pain (and that these could be symptoms of blood clots in the chest [heart and lungs]).; headache, confusion, difficulty with speech or movement, numbness of the face, eye pain or swelling, or vision problems (and that these could be symptoms of a blood clot in the brain or eyes); or sudden pain in the stomach or lumbar area (and that these could be symptoms of blood clots in the gut or kidneys). Advise patients to contact their healthcare provider for mild reactions and to seek urgent medical attention for moderate to severe reactions [see Warnings and Precautions (5.1)]. o In conditions in which tissue factor is overexpressed (e.g., advanced atherosclerotic disease, crush injury, cancer, or septicemia), there may be a risk of thromboembolic events or disseminated intravascular coagulation (DIC) with Alhemo treatment.  Hypersensitivity: Inform patients of the early signs of hypersensitivity reactions, including rash, redness, hives, and itching, facial swelling, tightness of the chest, and wheezing as well the signs of an anaphylactic reaction such as itching on large areas of skin; redness and/or swelling of lips, tongue, face, or hands; difficulty swallowing; shortness of breath; wheezing; tightness of the chest; pale and cold skin; fast heartbeat; or dizziness/low blood pressure. Advise patients to discontinue use of Alhemo immediately and contact their healthcare provider if any signs or symptoms occur [see Warnings and Precautions (5.2)]. Advise patients on the importance of adherence to daily dosing and to speak with their healthcare provider before discontinuing treatment with Alhemo as patients who are not adhering to daily dosing or stop treatment with Alhemo may no longer be protected against bleeding. Advise patients to follow the recommendations regarding proper sharps disposal provided in the FDA-approved Instructions for Use. Patent information: http://novonordisk-us.com/products/product-patents.html Alhemo® is registered trademark of Novo Nordisk Health Care AG. NovoFine®, NovoFine® Plus, and Novo Nordisk are registered trademarks of Novo Nordisk A/S. For information about Alhemo contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-844-668-6732 Manufactured by: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 U.S. License No. 1261 At: Novo Nordisk A/S Novo Allé 1 2880 Bagsværd Denmark © 2024 Novo Nordisk Reference ID: 5501236 MEDICATION GUIDE Alhemo® (al-HEE-mo) (concizumab-mtci) injection, for subcutaneous use What is the most important information I should know about Alhemo?  It is important to follow the daily dosing schedule of Alhemo to stay protected against bleeding. This is especially important during the first 4 weeks of treatment to make sure a correct maintenance dose is established. Use Alhemo exactly as prescribed by your healthcare provider. Do not stop using Alhemo without talking to your healthcare provider. If you miss doses, or stop using Alhemo, you may no longer be protected against bleeding.  Your healthcare provider may prescribe bypassing agents during treatment with Alhemo. Carefully follow your healthcare provider’s instructions regarding when to use on-demand bypassing agents, and the recommended dose and schedule for breakthrough bleeds. See “How should I use Alhemo?” for more information on how to use Alhemo. What is Alhemo? Alhemo is a prescription medicine used for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children 12 years of age and older with hemophilia A with factor VIII inhibitors or hemophilia B with factor IX inhibitors. It is not known if Alhemo is safe and effective in people using Alhemo while receiving ongoing Immune Tolerance Induction (ITI). It is not known if Alhemo is safe and effective for hemophilia A and B with and without inhibitors in children younger than 12 years of age. Do not use Alhemo if you are allergic to concizumab-mtci or any of the ingredients in Alhemo. See the end of this Medication Guide for a complete list of ingredients in Alhemo. Before using Alhemo, tell your healthcare provider about all of your medical conditions, including if you:  have a planned surgery. Your healthcare provider may stop treatment with Alhemo before your surgery. Talk to your healthcare provider about when to stop using Alhemo and when to start it again if you have a planned surgery.  are pregnant or plan to become pregnant. It is not known if Alhemo may harm your unborn baby. Females who are able to become pregnant o Your healthcare provider may do a pregnancy test before you start treatment with Alhemo. o You should use an effective birth control (contraception) during treatment with Alhemo and for 7 weeks after ending treatment. Talk to your healthcare provider about birth control methods that you can use during this time.  are breastfeeding or plan to breastfeed. It is not known if Alhemo passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with Alhemo. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use Alhemo? Read the Instructions for Use that comes with Alhemo for information about how to prepare and inject a dose of Alhemo, and how to properly throw away (dispose of) used Alhemo pens and needles.  Use Alhemo exactly as prescribed by your healthcare provider.  Your healthcare provider will provide instructions for stopping (discontinuing) your current treatment when switching to Alhemo.  Inject Alhemo 1 time a day.  Your healthcare provider should show you or your caregiver how to use Alhemo before you use it for the first time.  Alhemo is given as an injection under the skin (subcutaneous injection) by you or a caregiver.  Ask your healthcare provider if you need to use a different injection technique. For example, children and people who are lean may need to inject into a pinched fold of skin to avoid injecting too deep (into the muscle).  Change (rotate) your injection site with each injection. Do not use the same site for each injection.  You will inject a larger dose (a loading dose) of Alhemo on your first day of treatment. Then your healthcare provider will prescribe a dose to inject 1 time a day until your maintenance dose is established.  To determine the right maintenance dose for you, your healthcare provider will do a blood test to check the amount of Alhemo in your blood. Your healthcare provider may do additional blood tests during treatment with Alhemo. Reference ID: 5501236  Your healthcare provider will prescribe your dose based on your weight. If your weight changes, tell your healthcare provider.  Your healthcare provider will provide information on the treatment of breakthrough bleeding during your treatment with Alhemo.  Do not share your Alhemo pens and needles with another person, even if the needle has been changed. You may give another person an infection or get an infection from them.  If you miss a dose of Alhemo during the first 4 weeks of treatment, contact your healthcare provider right away. Your healthcare provider will tell you how much Alhemo to inject.  If you miss a dose of Alhemo after your daily maintenance dose is established: o For 1 missed dose, continue your normal daily dose. o For 2 to 6 missed doses, give 2 doses as soon as you remember. Then continue your normal daily dose the next day. o For 7 or more missed doses, contact your healthcare provider right away as you will need to receive a new loading dose before continuing your normal daily dose. o If you are unsure about how much to Alhemo to inject, contact your healthcare provider. What are the possible side effects of Alhemo? Alhemo may cause serious side effects, including:  Blood clots (thromboembolic events). Alhemo may cause blood clots to form in blood vessels, such as in your arms, legs, heart, lung, brain, eyes, kidneys, or stomach. You may be at risk for getting blood clots during treatment with Alhemo if you use high or frequent doses of factor products or bypassing agents to treat breakthrough bleeds, or if you have certain conditions. Get medical help right away if you have any signs and symptoms of blood clots, including: o swelling, warmth, pain, or redness of the skin o headache o trouble speaking or moving o eye pain or swelling o sudden pain in your stomach or lower back area o feeling short of breath or severe chest pain o confusion o numbness in your face o problems with your vision  Allergic reactions. Alhemo can cause allergic reactions, including redness of the skin, rash, hives, itching, and stomach-area (abdominal) pain. Stop using Alhemo and get emergency medical help right away if you develop any signs or symptoms of a severe allergic reaction, including: o Itching on large areas of skin o trouble swallowing o wheezing o pale and cold skin o dizziness due to low blood pressure o redness or swelling of lips, tongue, face, or hands o shortness of breath o tightness of the chest o fast heartbeat The most common side effects of Alhemo include:  bruising, redness, bleeding, or itching at the site of injection  hives These are not all the possible side effects of Alhemo. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Alhemo?  Before first use: o Store unused Alhemo pens in the refrigerator between 36°F to 46°F (2°C to 8°C).  After first use: o Store the Alhemo pen in the refrigerator between 36°F to 46°F (2° to 8°C) or at room temperature below 86°F (30°C) for up to 28 days. o Write the date of first use in the space provided on the carton. o Throw away (discard) the Alhemo pen 28 days after first opening even if some medicine is left in the pen.  Store Alhemo with the cap on and keep it in the original carton to protect from light.  Do not store Alhemo in direct sunlight and keep away from direct heat.  When stored in the refrigerator, do not store the pen directly next to the cooling element (the part that cools the refrigerator).  Do not freeze Alhemo.  Do not use Alhemo if it has been frozen or if it has been stored above 86°F (30°C). Keep Alhemo and all medicine out of the reach of children. Reference ID: 5501236 General information about the safe and effective use of Alhemo. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Alhemo for a condition for which it was not prescribed. Do not give Alhemo to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Alhemo that is written for health professionals. What are the ingredients in Alhemo? Active ingredient: concizumab-mtci Inactive ingredients: arginine hydrochloride, histidine, phenol, polysorbate 80, sodium chloride, sucrose, and water for injection. Hydrochloric acid and sodium hydroxide may be added for pH adjustment. Patent information: http://novonordisk-us.com/products/product-patents.html Alhemo is a registered trademark of Novo Nordisk Health Care AG. For information about Alhemo contact: Novo Nordisk Inc., 800 Scudders Mill Road Plainsboro, NJ 08536. Manufactured by: Novo Nordisk Inc., 800 Scudders Mill Road, Plainsboro, NJ 08536 U.S. License No. 1261 At: Novo Nordisk A/S, Novo Allé 1, 2880 Bagsværd, Denmark © 2024 Novo Nordisk For more information, go to Alhemo.com or call 1-844-668-6732. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: Dec/2024 Reference ID: 5501236 INSTRUCTIONS FOR USE Alhemo® (al-HEE-mo) (concizumab-mtci) injection, for subcutaneous use 60 mg/1.5 mL (40 mg/mL) single-patient-use prefilled pen = This Instructions for Use contains information on how to inject Alhemo. Read and understand these instructions before you use the Alhemo pen. Make sure you have received training from your healthcare provider before you inject with this pen for the first time. Gather the following supplies:  1 Alhemo pen Supplies you will need that are not included in the carton:  a new needle for each injection. The Alhemo pen is recommended to be used with NovoFine and NovoFine Plus needles with a gauge of 32 and length of 4 mm (32G x 4 mm).  sharps disposal container. See “Throwing away (disposing of) Alhemo pens, needles and needle caps.”  alcohol swab  Take your dose as prescribed by your healthcare provider.  Alhemo is supplied as a prefilled pen (called “Alhemo pen” or “pen” in these instructions). It contains 60 milligrams (mg) of Alhemo for subcutaneous injection. The pen contains multiple doses of Alhemo.  The pen can deliver a maximum of 32 mg in one injection. The interval on the dose counter is 0.4 mg. If you need more than 32 mg, you need to inject multiple times. Your healthcare provider will tell you how much Alhemo to inject. Where on my body should I inject my dose? Reference ID: 5501236  You can inject into the skin of: o your stomach-area (abdomen) at least 2 inches from your belly button (navel) or o your upper legs (thigh).  The gray areas on the picture to the right show the injection sites.  Change (rotate) your injection site with each injection every day. Do not use the same site for each injection.  Do not inject into skin that is tender, bruised, red or hard, or areas where there are moles, scars, or stretch marks. 1. Check your Alhemo pen  Wash your hands with soap and water Dry them well.  Check the pen label Check the name, strength, and colored label to make sure you have the right medicine.  Check the expiration date Check the expiration date (EXP) on the pen label to make sure it has not passed (YYYY-MM-DD). If the expiration date has passed, do not use the pen.  Inspect the medicine Pull off the pen cap and check that Alhemo in the pen window is almost clear and colorless to slightly yellow. The medicine may contain particles that you can see-through or are white. Do not use the pen if the medicine is discolored.  If your pen is cold You can inject Alhemo right from the refrigerator or let it reach room temperature before you inject. You can warm the pen in the palms of your hands. Do not use any other heating sources. Figure A 2. Attach a new needle  Take a new needle and tear off the paper tab.  Push the needle straight onto your pen. Turn the needle clockwise until it is on tight. See Figure A. Reference ID: 5501236 Needle Inner needle cap Outer needle cap Figure B  Pull off the outer needle cap. See Figure B.  Pull off the inner needle cap. See Figure B.  Throw the needle caps away in a FDA-cleared sharps disposal container. Note: Always use a new needle for each injection. 3. Prime before each dose. Dial to ‘0.4’ and test the flow before each dose  A drop of Alhemo may appear at the needle tip, but you should still test the Alhemo flow before each injection to make sure you get the correct dose of Alhemo: o Turn the dose selector one marking to select 0.4 mg. See Figure C. o Press the dose button. See Figure D. o Watch a stream of Alhemo leaving the needle tip. See Figure D.  If no stream appears, go to “Troubleshooting if no stream appears when testing the flow.” Figure C Figure D 0.4 mg selected 4. Select your dose  Turn the dose selector to select your prescribed dose.  You can adjust your dose by turning the dose selector in either direction (forwards or backwards).  If you need a larger dose than you can dial, you must inject yourself multiple times to get your full dose. For more information, see Step 6.  Each pen contains 60 mg of Alhemo.  The pen can deliver doses from 0.4 mg to 32 mg in one injection. Reference ID: 5501236 Example 9.6 mg Alhemo® Example 9.6 mg Example 12 mg 5a. Prepare the injection site Read Steps 5a and 5b before you start injecting. This is to make sure you get your full dose.  Select the injection site. See “Where on my body should I inject my dose?”  Wipe the injection site with an alcohol swab and let the area dry. Do not touch the injection site after cleaning.  Insert the needle straight into your stomach-area (abdomen) or upper legs (thigh) at a 90-degree angle, as instructed by your healthcare provider. 90° Ninety degrees 5b. Inject Alhemo  Press and hold the dose button down until the dose counter returns to “0”.  After the dose counter has returned to “0”, count slowly to 6 while the needle is still in your skin. Count slowly:  Remove the needle from your skin. Reference ID: 5501236 The pen clicks during the injection and you might also hear or feel a click when the dose counter returns to “0”. 6. Remove the needle  Carefully remove the needle from your pen by turning the needle counterclockwise. Do not touch the pen needle on either side to avoid sticking yourself with the needle.  Place the needle in an FDA-cleared sharps disposal container right away to reduce the risk of a needle stick. See “Throwing away (disposing of) Alhemo pens, needles and needle caps.”  Do not put the needle cap back on. Back end of needle Needle tip Do you need a larger dose than you can dial? Repeat Steps 1 to 6 until you have received your full dose. When you have received your full dose go to Step 7.  Use a new needle for each injection.  Test the Alhemo flow before each injection.  Make sure you know how much to inject in each injection to receive your full dose. Note: Only split your dose if you have been trained or told by your healthcare provider on how to do this. 7. Recap the pen  Put the pen cap back on your pen to protect Alhemo from light.  Now your pen is ready for storage until you need it next time. See “Storing Alhemo.” Reference ID: 5501236 Important information you need to know before injecting Alhemo  Use Alhemo exactly as prescribed by your healthcare provider.  Your Alhemo pen is for single-patient-use only. Do not share your Alhemo pen with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them.  Your healthcare provider should show you or your caregiver how to use Alhemo before you use it for the first time.  Ask your healthcare provider if you need to use a different injection technique. For example, children and people who are lean may need to inject into a pinched fold of skin to avoid injecting too deep (into the muscle).  After 28 days, you must throw away (discard) your pen in an FDA-cleared sharps disposal container even if some medicine is left in the pen.  The pen can deliver doses from 0.4 mg to 32 mg in one injection. If your dose is more than 32 mg, you need to inject multiple times. Important information about needles  Needles can be used for 1 injection only. Always use a new needle for each injection.  Do not re-use needles as this reduces the risk of contamination, infection, leakage, blocked needles, and incorrect dosing.  Never share needles with others.  Alhemo is recommended to be used with NovoFine and NovoFine Plus 32G x 4 mm injection needles.  If you use needles longer than 4 mm, talk to your healthcare provider about how to perform your injection.  Talk to your healthcare provider or pharmacist for more information about needles for your Alhemo pen.  Do not use the needle if it is bent or damaged. Troubleshooting if no stream appears when testing the flow (Step 3)  If no stream appears, repeat Step 3 up to 6 times until you see a stream.  If still no stream appears, prepare a new needle (Step 2) and test again (Step 3).  If still no stream appears after attaching a new needle, do not use the pen. Use a new pen or call Novo Nordisk at 1-844-668-6732 for help. How much Alhemo is left in your pen? The pen scale shows about how much Alhemo is left in your pen. In the example below, 24 milligrams (mg) is remaining in the pen. Example: 24 mg left If you want to see more accurately how much Alhemo is left in your pen, turn the dose selector until it stops. The dose pointer will line up with the number of mg left in the pen. If the dose counter shows 32 mg, at least 32 mg is left in the pen. If the dose counter shows less than 32 mg, the number shown in the dose counter is the number of mg left in your pen. In the example below, the dose counter shows 13.6 mg, so there is 13.6 mg of Alhemo left in the pen. Example: 13.6 mg left Reference ID: 5501236 Storing Alhemo  Before first use: o Store unused Alhemo pens in the refrigerator between 36°F to 46°F (2°C to 8°C).  After first use: o Store the Alhemo pen in the refrigerator between 36°F to 46°F (2°C to 8°C) or at room temperature no warmer than 86°F (30°C) for up to 28 days. o Write the date of first use in the space provided on the carton. o Throw away (discard) the Alhemo pen 28 days after first opening even if some medicine is left in the pen.  Store Alhemo with the cap on and keep it in the original carton to protect from light.  Do not store Alhemo in direct sunlight and keep away from direct heat.  When stored in the refrigerator, do not store the pen directly next to the cooling element (the part that cools the refrigerator).  Do not freeze Alhemo.  Do not use Alhemo if it has been frozen or if it has been stored above 86°F (30°C). Keep Alhemo and all medicine out of the reach of children. Throwing away (disposing of) Alhemo pens, needles and needle caps  Put your used pens, needles, and needle caps in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and pens in your household trash.  If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: o made of heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labelled to warn of hazardous waste inside the container.  When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should dispose of used needles and pens. For more information about safe sharps disposal, and for specific information about safe sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.  Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Scan the QR code below to access the Instructions for Use or visit: www.Alhemopen.com Patent information: http://novonordisk-us.com/products/product-patents.html Alhemo® is a registered trademark of Novo Nordisk Health Care AG. NovoFine®, NovoFine® Plus, and Novo Nordisk are registered trademarks of Novo Nordisk A/S. © 2024 Novo Nordisk Health Care AG For further information contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536, USA 1-844-668-6732 Manufactured by: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 U.S. License No. 1261 At: Novo Nordisk A/S Reference ID: 5501236 Novo Allé 1 2880 Bagsværd Denmark This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 12/2024 Reference ID: 5501236 INSTRUCTIONS FOR USE Alhemo® (al-HEE-mo) (concizumab-mtci) injection, for subcutaneous use 150 mg/1.5 mL (100 mg/mL) single-patient-use prefilled pen This Instructions for Use contains information on how to inject Alhemo. Read and understand these instructions before you use the Alhemo pen. Make sure you have received training from your healthcare provider before you inject with this pen for the first time. Gather the following supplies:  1 Alhemo pen Supplies you will need that are not included in the carton:  a new needle for each injection. The Alhemo pen is recommended to be used with NovoFine and NovoFine Plus needles with a gauge of 32 and length of 4mm (32G x 4 mm).  sharps disposal container. See “Throwing away (disposing of) Alhemo pens, needles and needle caps.”  alcohol swab.  Take your dose as prescribed by your healthcare provider.  Alhemo is supplied as a prefilled pen (called “Alhemo pen” or “pen” in these instructions). It contains 150 milligrams (mg) of Alhemo for subcutaneous injection. The pen contains multiple doses of Alhemo.  The pen can deliver a maximum of 80 mg in one injection. The interval on the dose counter is 1 mg. If you need more than 80 mg, you need to inject multiple times. Your healthcare provider will tell you how much Alhemo to inject. Where on my body should I inject my dose? Reference ID: 5501236  You can inject into the skin of: o your stomach-area (abdomen) at least 2 inches from your belly button (navel) or o your upper legs (thigh).  The gray areas on the picture to the right show the injection sites.  Change (rotate) your injection site with each injection every day. Do not use the same site for each injection.  Do not inject into skin that is tender, bruised, red or hard, or areas where there are moles, scars, or stretch marks. 1. Check your Alhemo pen  Wash your hands with soap and water Dry them well.  Check the pen label Check the name, strength, and colored label to make sure you have the right medicine.  Check the expiration date Check the expiration date (EXP) on the pen label to make sure it has not passed (YYYY-MM-DD). If the expiration date has passed, do not use the pen.  Inspect the medicine Pull off the pen cap and check that Alhemo in the pen window is almost clear and colorless to slightly yellow. The medicine may contain particles that you can see-through or are white. Do not use the pen if the medicine is discolored.  If your pen is cold You can inject Alhemo right from the refrigerator or let it reach room temperature before you inject. You can warm the pen in the palms of your hands. Do not use any other heating sources. 2. Attach a new needle  Take a new needle and tear off the paper tab.  Push the needle straight onto your pen. Turn the needle clockwise until it is on tight. See Figure A.  Pull off the outer needle cap. See Figure B.  Pull off the inner needle cap. See Figure B.  Throw the needle caps away in a FDA-cleared sharps disposal container. Note: Always use a new needle for each injection. Reference ID: 5501236 Figure A Needle Inner needle cap Outer needle cap Figure B 3. Prime before each dose. Dial to ‘1’ and test the flow before each dose  A drop of Alhemo may appear at the needle tip, but you should still test the Alhemo flow before each injection to make sure you get the correct dose of Alhemo: o Turn the dose selector one marking to select 1 mg. See Figure C. o Press the dose button. See Figure D. o Watch a stream of Alhemo leaving the needle tip. See Figure D.  If no stream appears, go to “Troubleshooting if no stream appears when testing the flow.” Figure C Figure D 1 mg selected 4. Select your dose  Turn the dose selector to select your prescribed dose. Reference ID: 5501236  You can adjust your dose by turning the dose selector in either direction (forwards or backwards).  If you need a larger dose than you can dial, you must inject yourself multiple times to get your full dose. For more information, see Step 6.  Each pen contains 150 mg of Alhemo.  The pen can deliver doses from 1 mg to 80 mg in one injection. Example 24 mg Alhemo® Example 24 mg Example 15 mg 5a. Prepare injection site Read through Steps 5a and 5b before you start injecting. This is to make sure you get your full dose.  Select the injection site. See “Where on my body should I inject my dose?”  Wipe the injection site with an alcohol swab and let the area dry. Do not touch the injection site after cleaning.  Insert the needle straight into your stomach-area (abdomen) or upper legs (thigh) at a 90-degree angle, as instructed by your healthcare provider. 90° Ninety degrees 5b. Inject Alhemo  Press and hold the dose button down until the dose counter returns to “0”. Reference ID: 5501236  After the dose counter has returned to “0”, count slowly to 6 while the needle is still in your skin. Count slowly:  Remove the needle from your skin. The pen clicks during the injection and you might also hear or feel a click when the dose counter returns to “0”. 6. Remove the needle  Carefully remove the needle from your pen by turning the needle counterclockwise. Do not touch the pen needle on either side to avoid sticking yourself with the needle.  Place the needle in an FDA-cleared sharps disposal container right away to reduce the risk of a needle stick. See “Throwing away (disposing of) Alhemo pens, needles and needle caps.”  Do not put the needle cap back on. Back end of needle Needle tip Do you need a larger dose than you can dial? Repeat Steps 1 to 6 until you have received your full dose. When you have received your full dose go to Step 7.  Use a new needle for each injection.  Test the Alhemo flow before each injection.  Make sure you know how much to inject in each injection to receive your full dose. Note: Only split your dose if you have been trained or told by your healthcare provider on how to do this. 7. Recap the pen  Put the pen cap back on your pen to protect Alhemo from light.  Now your pen is ready for storage until you need it next time. See “Storing Alhemo.” Reference ID: 5501236 Important information you need to know before injecting Alhemo  Use Alhemo exactly as prescribed by your healthcare provider.  Your Alhemo pen is for single-patient-use only. Do not share your Alhemo pen with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them.  Your healthcare provider should show you or your caregiver how to use Alhemo before you use it for the first time.  Ask your healthcare provider if you need to use a different injection technique. For example, children and people who are lean may need to inject into a pinched fold of skin to avoid injecting too deep (into the muscle).  After 28 days, you must throw away (discard) your pen in an FDA-cleared sharps disposal container even if some medicine is left in the pen.  The pen can deliver doses from 1 mg to 80 mg in one injection. If your dose is more than 80 mg, you need to inject multiple times. Important information about needles  Needles can be used for 1 injection only. Always use a new needle for each injection.  Do not re-use needles as this reduces the risk of contamination, infection, leakage, blocked needles, and incorrect dosing.  Never share needles with others.  Alhemo is recommended to be used with NovoFine and NovoFine Plus 32G x 4 mm injection needles.  If you use needles longer than 4 mm, talk to your healthcare provider about how to perform your injection.  Talk to your healthcare provider or pharmacist for more information about needles for your Alhemo pen.  Do not use the needle if it is bent or damaged. Troubleshooting if no stream appears when testing the flow (Step 3)  If no stream appears, repeat Step 3 up to 6 times until you see a stream.  If still no stream appears, prepare a new needle (Step 2) and test again (Step 3).  If still no stream appears after attaching a new needle, do not use the pen. Use a new pen or call Novo Nordisk at 1-844-668-6732 for help. How much Alhemo is left in your pen? Reference ID: 5501236 The pen scale shows about how much Alhemo is left in your pen. In the example below, 60 milligrams (mg) is remaining in the pen. Example: 60 mg left If you want to see more accurately how much Alhemo is left in your pen, turn the dose selector until it stops. The dose pointer will line up with the number of mg left in the pen. If the dose counter shows 80 mg, at least 80 mg is left in the pen. If the dose counter shows less than 80 mg, the number shown in the dose counter is the number of mg left in your pen. In the example below, the dose counter shows 34 mg, so there is 34 mg of Alhemo left in the pen. Example: 34 mg left Storing Alhemo  Before first use: o Store unused Alhemo pens in the refrigerator between 36°F to 46°F (2°C to 8°C).  After first use: o Store the Alhemo pen in the refrigerator between 36°F to 46°F (2°C to 8°C) or at room temperature no warmer than 86°F (30°C) for up to 28 days. o Write the date of first use in the space provided on the carton. o Throw away (discard) the Alhemo pen 28 days after first opening even if some medicine is left in the pen.  Store Alhemo with the cap on and keep it in the original carton to protect from light.  Do not store Alhemo in direct sunlight and keep away from direct heat.  When stored in the refrigerator, do not store the pen directly next to the cooling element (the part that cools the refrigerator).  Do not freeze Alhemo.  Do not use Alhemo if it has been frozen or if it has been stored above 86°F (30°C). Keep Alhemo and all medicine out of the reach of children. Throwing away (disposing of) Alhemo pens, needles, needle caps  Put your used pens, needles, and needle caps in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and pens in your household trash.  If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: o made of heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labelled to warn of hazardous waste inside the container.  When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should dispose of used needles and pens. For more information about safe sharps disposal, and for specific information about safe sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.  Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Reference ID: 5501236 Scan the QR code below to access the Instructions for Use or visit: www.Alhemopen.com Patent Information: http://novonordisk-us.com/products/product-patents.html Alhemo® is a registered trademark of Novo Nordisk Health Care AG. NovoFine®, NovoFine® Plus, and Novo Nordisk are registered trademarks of Novo Nordisk A/S. © 2024 Novo Nordisk Health Care AG For further information contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536, USA 1-844-668-6732 Manufactured by: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 U.S. License No. 1261 At: Novo Nordisk A/S Novo Allé 1 2880 Bagsvaerd Denmark This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 12/2024 Reference ID: 5501236 INSTRUCTIONS FOR USE Alhemo® (al-HEE-mo) (concizumab-mtci) injection, for subcutaneous use 300 mg/3 mL (100 mg/mL) single-patient-use prefilled pen Outer needle cap Inner needle cap Needle Paper tab Pen overview and needle example Pen label Dose counter Dose pointer Dose selector Dose button Pen cap Pen scale Pen window Alhemo® (concizumab-mtci) injection This Instructions for Use contains information on how to inject Alhemo. Read and understand these instructions before you use the Alhemo pen. Make sure you have received training from your healthcare provider before you inject with this pen for the first time. Gather the following supplies:  1 Alhemo pen Supplies you will need that are not included in the carton:  a new needle for each injection. The Alhemo pen is recommended to be used with NovoFine and NovoFine Plus needles with a gauge of 32 and length of 4mm (32G x 4 mm).  sharps disposal container. See “Throwing away (disposing of) Alhemo pens, needles and needle caps.”  alcohol swab  Take your dose as prescribed by your healthcare provider.  Alhemo is supplied as a prefilled pen (called “Alhemo pen” or “pen” in these instructions). It contains 300 milligrams (mg) of Alhemo for subcutaneous injection. The pen contains multiple doses of Alhemo.  The pen can deliver a maximum of 80 mg in one injection. The interval on the dose counter is 1 mg. If you need more than 80 mg, you need to inject multiple times. Your healthcare provider will tell you how much Alhemo to inject. Where on my body should I inject my dose? Reference ID: 5501236  You can inject into the skin of: o your stomach-area (abdomen) at least 2 inches from your belly button (navel) or o your upper legs (thigh).  The gray areas on the picture to the right show the injection sites.  Change (rotate) your injection site with each injection every day. Do not use the same site for each injection.  Do not inject into skin that is tender, bruised, red or hard, or areas where there are moles, scars, or stretch marks. 1. Check your Alhemo pen  Wash your hands with soap and water Dry them well.  Check the pen label Check the name, strength, and colored label to make sure you have the right medicine.  Check the expiration date Check the expiration date (EXP) on the pen label to make sure it has not passed (YYYY-MM-DD). If the expiration date has passed, do not use the pen.  Inspect the medicine Pull off the pen cap and check that Alhemo in the pen window is almost clear and colorless to slightly yellow. The medicine may contain particles that you can see-through or are white. Do not use the pen if the medicine is discolored.  If your pen is cold You can inject Alhemo right from the refrigerator or let it reach room temperature before you inject. You can warm the pen in the palms of your hands. Do not use any other heating sources. 2. Attach a new needle  Take a new needle and tear off the paper tab.  Push the needle straight onto your pen. Turn the needle clockwise until it is on tight. See Figure A.  Pull off the outer needle cap. See Figure B.  Pull off the inner needle cap. See Figure B.  Throw the needle caps away in an FDA-cleared sharps disposal container. Note: Always use a new needle for each injection. Reference ID: 5501236 Figure A Needle Inner needle cap Outer needle cap Figure B 3. Prime before each dose. Dial to ‘1’ and test the flow before each dose  A drop of Alhemo may appear at the needle tip, but you should still test the Alhemo flow before each injection to make sure you get the correct dose of Alhemo: o Turn the dose selector one marking to select 1 mg. See Figure C. o Press the dose button. See Figure D. o Watch a stream of Alhemo leaving the needle tip. See Figure D.  If no stream appears, go to “Troubleshooting if no stream appears when testing the flow.” 1 mg selected Figure D Figure C Reference ID: 5501236 4. Select your dose  Turn the dose selector to select your prescribed dose.  You can adjust your dose by turning the dose selector in either direction (forwards or backwards).  If you need a larger dose than you can dial, you must inject yourself multiple times to get your full dose. For more information, see Step 6.  Each pen contains 300 mg of Alhemo.  The pen can deliver doses from 1 mg to 80 mg in one injection. Example 24 mg Example 24 mg Example 15 mg 5a. Prepare the injection site Read through Steps 5a and 5b before you start injecting. This is to make sure you get your full dose.  Select the injection site. See “Where on my body should I inject my dose?”  Wipe the injection site with an alcohol swab and let the area dry. Do not touch the injection site after cleaning.  Insert the needle straight into your stomach-area (abdomen) or upper legs (thigh) at a 90-degree angle, as instructed by your healthcare provider. Ninety degrees 90° 5b. Inject Alhemo Reference ID: 5501236  Press and hold the dose button down until the dose counter returns to “0”.  Once the dose counter has returned to “0”, count slowly to 6 while the needle is still in your skin. Count slowly:  Remove the needle from your skin. The pen clicks during the injection and you might also hear or feel a click when the dose counter returns to “0”. 6. Remove the needle  Carefully remove the needle from your pen by turning the needle counterclockwise. Do not touch the pen needle on either side to avoid sticking yourself with the needle.  Place the needle in an FDA-cleared sharps disposal container right away to reduce the risk of a needle stick. See “Throwing away (disposing of) Alhemo pens, needles and needle caps.”  Do not put the needle cap back on. Back end of needle Needle tip Do you need a larger dose than you can dial? Repeat Steps 1 to 6 until you have received your full dose. When you have received your full dose go to Step 7.  Use a new needle for each injection.  Test the Alhemo flow before each injection.  Make sure you know how much to inject in each injection to receive your full dose. Note: Only split your dose if you have been trained or told by your healthcare provider on how to do this. 7. Recap the pen  Put the pen cap back on your pen to protect Alhemo from light.  Now your pen is ready for storage until you need it next time. See “Storing Alhemo.” Reference ID: 5501236 Important information you need to know before injecting Alhemo  Use Alhemo exactly as prescribed by your healthcare provider.  Your Alhemo pen is for single-patient-use only. Do not share your Alhemo pen with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them.  Your healthcare provider should show you or your caregiver how to use Alhemo before you use it for the first time.  Ask your healthcare provider if you need to use a different injection technique. For example, children and people who are lean may need to inject into a pinched fold of skin to avoid injecting too deep (into the muscle).  After 28 days, you must throw away (discard) your pen in an FDA-cleared sharps disposal container even if some medicine is left in the pen.  The pen can deliver doses from 1 mg to 80 mg in one injection. If your dose is more than 80 mg, you need to inject multiple times. Important information about needles  Needles can be used for 1 injection only. Always use a new needle for each injection.  Do not re-use needles as this reduces the risk of contamination, infection, leakage, blocked needles, and incorrect dosing.  Never share needles with others.  Alhemo is recommended to be used with NovoFine and NovoFine Plus 32G x 4 mm injection needles.  If you use needles longer than 4 mm, talk to your healthcare provider about how to perform your injection.  Talk to your healthcare provider or pharmacist for more information about needles for your Alhemo pen.  Do not use the needle if it is bent or damaged. Troubleshooting if no stream appears when testing the flow (Step 3)  If no stream appears, repeat Step 3 up to 6 times until you see a stream.  If still no stream appears, prepare a new needle (Step 2) and test again (Step 3).  If still no stream appears after attaching a new needle, do not use the pen. Use a new pen or call Novo Nordisk at 1-844-668-6732 for help. How much Alhemo is left in your pen? The pen scale shows about how much Alhemo is left in your pen. In the example below, 200 milligrams (mg) is remaining in the pen. Reference ID: 5501236 Example: 200 mg left If you want to see more accurately how much Alhemo is left in your pen, turn the dose selector until it stops. The dose pointer will line up with the number of mg left in the pen. If the dose counter shows 80 mg, at least 80 mg is left in the pen. If the dose counter shows less than 80 mg, the number shown in the dose counter is the number of mg left in the pen. In the example below, the dose counter shows 34 mg, so there is 34 mg of Alhemo left in the pen. Example: 34 mg left Storing Alhemo  Before first use: o Store unused Alhemo pens in the refrigerator between 36°F to 46°F (2°C to 8°C).  After first use: o Store the Alhemo pen in the refrigerator between 36°F to 46°F (2°C to 8°C) or at room temperature no warmer than 86°F (30°C) for up to 28 days. o Write the date of first use in the space provided on the carton. o Throw away (discard) the Alhemo pen 28 days after first opening even if some medicine is left in the pen.  Store Alhemo with the cap on and keep it in the original carton to protect from light.  Do not store Alhemo in direct sunlight and keep away from direct heat.  When stored in the refrigerator, do not store the pen directly next to the cooling element (the part that cools the refrigerator).  Do not freeze Alhemo.  Do not use Alhemo if it has been frozen or if it has been stored above 86°F (30°C). Keep Alhemo and all medicine out of the reach of children. Throwing away (disposing of) Alhemo pens, needles, needle caps  Put your used pens, needles, and needle caps in an FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and pens in your household trash.  If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: o made of heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labelled to warn of hazardous waste inside the container.  When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should dispose of used needles and pens. For more information about safe sharps disposal, and for specific information about safe sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.  Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Scan the QR code below to access the Instructions for Use or visit: www.Alhemopen.com Reference ID: 5501236 Patent Information: http://novonordisk-us.com/products/product-patents.html Alhemo® is a registered trademark of Novo Nordisk Health Care AG. NovoFine®, NovoFine® Plus, and Novo Nordisk are registered trademarks of Novo Nordisk A/S. © 2024 Novo Nordisk Health Care AG For further information contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536, USA 1-844-668-6732 Manufactured by: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 U.S. License No. 1261 At: Novo Nordisk A/S Novo Allé 1 2880 Bagsvaerd Denmark This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: 12/2024 Reference ID: 5501236
custom-source
2025-02-12T15:47:58.828398
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